WO2013170711A1 - 一种用于镇痛的药物组合产品 - Google Patents

一种用于镇痛的药物组合产品 Download PDF

Info

Publication number
WO2013170711A1
WO2013170711A1 PCT/CN2013/075205 CN2013075205W WO2013170711A1 WO 2013170711 A1 WO2013170711 A1 WO 2013170711A1 CN 2013075205 W CN2013075205 W CN 2013075205W WO 2013170711 A1 WO2013170711 A1 WO 2013170711A1
Authority
WO
WIPO (PCT)
Prior art keywords
sinomenine
pain
analgesic
dose
paracetamol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2013/075205
Other languages
English (en)
French (fr)
Inventor
高同强
徐晓军
郝景霞
高天乐
维森非尔德-哈林•苏珊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to EP13790165.8A priority Critical patent/EP2851074B1/en
Publication of WO2013170711A1 publication Critical patent/WO2013170711A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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]

Definitions

  • the present invention relates to a novel analgesic drug combination product based on the traditional Chinese medicine active ingredient Sinomenine, and a novel analgesic method using the same.
  • the present invention relates to the administration of a combination of sinomenine and another analgesic, and the time difference of drug administration by a clinically acceptable sustained-release, controlled-release technique, thereby enhancing the analgesic effect, thereby More widely used in a variety of clinical acute and chronic stubborn pain. Background technique
  • Chronic pain such as neurogenic pain caused by peripheral or central nervous system injury or chronic infectious pain caused by chronic infectious diseases such as rheumatoid arthritis, is an important clinical problem because of the complexity of such pain, Long-term and resistance to treatment.
  • neuropathic pain animal models e.g., spinal cord injury pain models, and peripheral nerve injury models
  • disease-induced peripheral neuropathic pain models e.g., cancer pain models.
  • Sinomenine (synthesis of its structure is shown in Chemical Formula 1) is an alkaline substance extracted from the roots of the genus O Vwomem' m ⁇ 3 ⁇ 4c m) in wet diseases such as rheumatoid arthritis.
  • sinomenine In the mouse collagen-induced arthritis (CIA) model, treatment with sinomenine reduces the frequency of arthritis. Rate and severity (Huang W o/., 2007). Compared with non-steroidal gingivitis drugs (NSAIDS), sinomenine is more effective in improving early arthritis stiffness, joint pain, and erythrocyte sedimentation rate (Xu et ⁇ , 2008). Sinomenine is also used as an immunosuppressant, which inhibits lymphocyte proliferation and antibody synthesis in sputum cells (He et ⁇ , 2005). Its anti-inflammatory and neuroprotective effects are mainly through inhibition of NADPH oxidase in microglia. The superoxide ions produced are completed (Qian e o/., 2007). In addition, sinomenine inhibits the synthesis of prostaglandin E2 (PGE2) by inhibiting exosomal cyclooxygenase (COX-2) (Liu et al., 1994)
  • PGE2 prostaglandin E2
  • CN1790014 discloses a traditional Chinese medicine composition for treating cancer pain, which is prepared from a medicinal herb of Cyclobalanopsis chinensis, celandine and Hantao, for treating cancer pain, especially for treating lung cancer pain or liver cancer pain.
  • CN1214245 discloses a new use of sinomenine, i.e., the application of sinomenine in the preparation of analgesic drugs, especially for the treatment of postoperative pain, with good curative effect.
  • CN101347408 discloses an injection containing sinomenine which can treat chronic pain.
  • CN101411707 discloses a pharmaceutical composition containing sinomenine which can treat rheumatoid arthritis and the pain it causes.
  • sinomenine as an anti-arthritis drug
  • the adult dose of sinomenine is 200 to 240 mg / day (Xu et al., 2008).
  • sinomenine is an anti-arthritis drug
  • the effect of sinomenine on neuropathic pain has not been reported.
  • GABA drugs are important inhibitory neurotransmitters in the mammalian central nervous system. They play an important role in the human cerebral cortex, hippocampus, thalamus, basal ganglia and cerebellum, and regulate various functions of the body. When the body lacks GABA, it will produce anxiety, anxiety, fatigue, anxiety and other emotions. Generally, people who are in high-stress group for a long time, such as people in the competitive environment, athletes, office workers, etc., are prone to lack of GABA and need to be replenished in time to soothe. mood. Taking gabapentin as an example, the current clinical analgesic dose for adults is 300 to 600 mg/time, 900 to 3600 mg/day.
  • Paracetamol is the most commonly used non-anti-inflammatory antipyretic analgesic, especially suitable for patients who cannot use carboxylic drugs for colds, toothaches and other symptoms.
  • the analgesic dose for adults is 500 ⁇ 1000 mg/time, 1000 ⁇ 4000 mg/day.
  • the present invention relates to sinomenine and other analgesic drugs for treating chronic pain, especially neuropathic pain Combination.
  • the present inventors have found for the first time that although sinomenine has no significant analgesic effect when used alone, it can exert a remarkable synergistic effect in analgesia when used in combination with other analgesic drugs.
  • rat ischemic spinal cord injury model Xu W ⁇ /., 1992
  • a rat and mouse peripheral nerve injury model eg, a partial sciatic ischemic injury model
  • sinomenine and GABA drugs eg, gabapentin
  • the combination of sinomenine and GABA drugs has a significant synergistic effect on analgesia; acute and chronic inflammation in large mice
  • the combination of sinomenine and paracetamol analgesics for example, paracetamol
  • these animal models are generally accepted internationally as representative models of neurogenic pain.
  • the present invention provides a pharmaceutical combination product for analgesia comprising the following (i) and (ii) or consisting of the following (i) and (ii):
  • the invention further relates to the use of a combination of sinomenine or a pharmaceutically acceptable salt thereof and a GABA-like or acetaminophen analgesic in the manufacture of a pharmaceutical combination for analgesia.
  • the present invention also relates to an analgesic method comprising administering to a patient suffering from pain an analgesic effective amount of (i) sinomenine and/or a pharmaceutically acceptable salt thereof, and (ii) a GABA-like drug or paracetamol Analgesics.
  • This method is particularly useful for relieving neuropathic pain or acute and chronic inflammatory pain.
  • the invention combines GABA drugs or paracetamol analgesics with sinomenine, so that the single dose of GABA drugs and paracetamol analgesics is only one quarter to one tenth of the current prior art dosage. Or lower, not only enhances the analgesic effect of the existing drug, but also reduces side effects by reducing the dose administered, thereby preventing and delaying the occurrence of drug tolerance.
  • Figures 1A-1C show the synergistic analgesic effect of sinomenine and gabapentin in a mouse peripheral nerve injury model.
  • the pain index is the contraction threshold (unit: g) of the hind paw of the mouse under mechanical stimulation.
  • Figure 1A shows that sinomenine and gabapentin have no analgesic effect when administered alone;
  • Figure 1B shows that gabapentin has no analgesic effect prior to administration of sinomenine;
  • Figure 1C shows sinomenine in gabapentin for 30 minutes to 1 Administration before the hour, a combination of low-dose drugs can produce significant analgesic effects.
  • Figures 2A-2D show the synergy of sinomenine and gabapentin in a chronic pain model of spinal cord injury in rats Analgesic effect, the pain index is the squeal threshold (g) of the rat's body under mechanical stimulation and the response score under cold stimulation.
  • Figures 2A and 2B show that sinomenine and gabapentin have no analgesic effect on mechanical stimulation and cold stimulation when administered alone;
  • Figures 2C and 2D show that sinomenine is administered from gabapentin 30 minutes to one hour before administration, low dose Drug combinations produce significant analgesic effects on mechanical and cold stimuli.
  • Figures 3A and 3B show the synergistic analgesic effect of sinomenine and gabapentin in a chronic pain model of rat spinal cord injury.
  • the pain index is the squeak threshold (g) of the rat's body under mechanical stimulation and the response under cold stimulation. Minute.
  • Simultaneous administration of 10 mg/kg sinomenine and 4 mg/kg gabapentin produced significant analgesic effects.
  • Figures 4A and 4B show the synergistic analgesic effect of sinomenine and gabapentin in a rat model of chronic pain in spinal cord injury.
  • the pain index is the barking threshold of the rat's body under mechanical stimulation (g).
  • the sustained analgesic effect and background pain relief of the low-dose combination administration over seven days and fourteen days did not show an observable drug tolerance effect.
  • Figures 5A-5C show the synergistic analgesic effect of sinomenine and acetaminophen in combination with inflammatory pain caused by carrageenan in mice.
  • the pain index is the contraction threshold (g) of the hind limbs under mechanical stimulation.
  • Figure 5A shows that sinomenine and acetaminophen have no analgesic effect on mechanical stimulation when administered alone;
  • Figure 5B shows that sinomenine is administered 30 minutes to one hour before gabapentin, and a small dose of drug combination can produce a significant pair Analgesic effect of mechanical stimulation;
  • Figure 5C shows that significant synergy can also be observed when sinomenine and paracetamol are administered simultaneously.
  • the present invention provides a pharmaceutical combination product for analgesia comprising the following (i) and (ii) or consisting of (i) and (ii) below:
  • the isolated forms are: (i) and (ii) separately packaged in separate single dose formulations.
  • the forms are isolated from one another such that (i) and (ii) can first release (i) sinomenine and/or its pharmaceutically acceptable salt, re-release (ii) GABA in the same single dose formulation.
  • the GABA class of the single-dose preparation is 50 mg to 200 mg
  • the paracetamol analgesic in the single-dose preparation is 50 mg to 400 mg
  • the sinomenine in the single-dose preparation is 50 mg to 200 mg.
  • the mass ratio of (i) and (ii) in the form of a single-dose preparation is 3:1 to 1:1 (for sinomenine: gabapentin, for example 2.5 to 1.3:1), or 1:1 to 1:2 (Applicable to sinomenine: paracetamol, eg 1:1.5), and the proportion of the drug can be adjusted according to the clinical effect.
  • the pharmaceutical combination product in which (i) and (ii) are in an intermixed form, is a pharmaceutical composition containing the (i), (ii) and a pharmaceutically acceptable auxiliary.
  • Agents eg, pharmaceutically acceptable excipients, diluents, and/or carriers.
  • the mass ratio of the (i) and (ii) is preferably from 3:1 to 1:1 (for sinomenine: gabapentin, for example 2.5 to 1.3:1), or 1:1. To 1:2 (for sinomenine: paracetamol, eg 1:1.5), and the proportion of the drug can be adjusted according to the clinical effect.
  • the pain targeted by the pharmaceutical combination products and pharmaceutical compositions of the present invention includes: (a) acute pain, such as post-operative pain and severe visceral pain; (b) chronic pain, such as cancer pain, arthritic pain, and low back pain; (c) Neuropathic pain, such as pain from nerve and spinal cord injury, pain after stroke, neuropathic pain caused by diabetes, pain caused by herpes virus, trigeminal nerve and other facial neuralgia.
  • the sinomenine-based pharmaceutical combination of the present invention achieves (1) enhancing the analgesic effect of existing drugs, (2) reducing side effects by reducing the dose administered, and (3) preventing and delaying the occurrence of drug tolerance. , with broadly application foreground. Accordingly, the present invention also relates to the use of sinomenine or a pharmaceutically acceptable salt thereof in combination with a GABA-like drug or a paracetamol analgesic in the preparation of a pharmaceutical combination for analgesia according to the present invention.
  • the invention relates to a pharmaceutical combination product and method for treating, ameliorating and ameliorating nerve damage pain in a subject, the pharmaceutical combination comprising sinomenine and gabapentin in a separate dosage form from each other.
  • sinomenine is administered first, and gabapentin is administered after 30 minutes to 1 hour, wherein the sinomenine is preferably administered at a dose of 10 mg/kg of mouse body weight to 20 mg/kg of mouse body weight (mouse dose).
  • rat body weight or 5 mg/kg rat body weight ⁇ 20 mg / kg rat body weight (rat dose) or equivalent human dose
  • gabapentin is preferably administered at a dose of 7.5 mg / kg Rat body weight ⁇ 15 mg / kg mouse body weight (mouse dose) or equivalent human dose, or 2 mg / kg rat body weight ⁇ 7.5 mg / kg rat body weight (rat dose) or equivalent Human dose
  • the human dose can be calculated based on the human body weight and the mouse dose disclosed in the present invention and according to known methods (for example, body weight method or body surface area method) and refer to known clinical doses. Get it.
  • the method comprises administering the pharmaceutical combination product to a subject (e.g., mouse, rat, human) experiencing neuropathic pain in the above-described administration sequence and therapeutically effective dose.
  • the invention relates to a pharmaceutical composition and method for treating, ameliorating and ameliorating neuropathic pain in a subject, the pharmaceutical composition comprising sinomenine and gabapentin.
  • a pharmaceutical composition of gabapentin containing 10 mg/kg rat body weight (or equivalent human dose) and 4 mg/kg rat body weight (or equivalent human dose) was administered.
  • the method comprises administering the pharmaceutical composition to a subject (e.g., mouse, rat, human) experiencing neuropathic pain at a therapeutically effective dose.
  • the pharmaceutical combination product comprises sinomenine and gabapentin in a separate dosage form from each other.
  • each administration is 10 mg / kg rat body weight (or equivalent human dose) of sinomenine for 30 minutes ⁇ 1 hour after administration of 4 mg /kg rat body weight (or equivalent human dose) of gabapentin, continued for 7 to 14 days.
  • the method comprises administering the pharmaceutical combination product to a subject (e.g., a mouse, a rat, a human) suffering from nerve injury pain in the order of administration, the frequency of administration, the time of administration, and the therapeutically effective dose.
  • the present invention relates to a pharmaceutical combination product and method for treating, ameliorating and ameliorating inflammatory pain in a subject, the pharmaceutical combination comprising sinomenine and acetaminophen in a separate dosage form from each other.
  • sinomenine is administered first, and paracetamol is administered after 30 minutes to 1 hour, wherein the dose of sinomenine is preferably 20 mg/kg of mouse body weight (mouse dose) or equivalent human dose.
  • the dosage of paracetamol is preferably 30 mg/kg of mouse body weight (mouse dose) or a human dose equivalent thereto.
  • the method comprises administering the pharmaceutical combination product to a subject (e.g., mouse, rat, human) experiencing neuropathic pain in the above-described administration sequence and therapeutically effective dose.
  • the invention in another embodiment, relates to a pharmaceutical composition and method for treating, ameliorating and ameliorating inflammatory pain in a subject, the pharmaceutical composition comprising sinomenine and acetaminophen.
  • a pharmaceutical composition of acetaminophen containing 20 mg/kg of mouse body weight (or equivalent human dose) and 30 mg/kg of mouse body weight (or an equivalent human dose) was administered.
  • the method comprises administering the pharmaceutical composition to a subject (e.g., mouse, rat, human) experiencing inflammatory pain at a therapeutically effective dose.
  • the single analgesic dose of gabapentin in synergy with sinomenine is 7.5 to 15 mg/kg of mouse body weight or 2 to 7.5 mg/kg of rat body weight, corresponding to about 20 mg to about
  • the human dose of 75 mg (calculated by body surface area method, the adult body weight is about 60 kg, the same below), far lower than the general adult dose of gabapentin as an analgesic drug alone (single 300 mg ⁇ 600 mg);
  • the chronic analgesic dose of sinomenine synergistically with gabapentin was: 4 mg/kg rat body weight/time, 8 mg/kg rat body weight/day, A human dose equivalent to approximately 80 mg/day is much lower than the usual adult dose of gabapentin as an analgesic when administered orally (900 mg to 3600 mg daily).
  • the single analgesic dose of paracetamol in synergy with sinomenine is preferably 30 mg/kg of mouse body weight, which corresponds to a human dose of about 150 mg, which is much lower than the general adult dose of paracetamol as an analgesic alone. (single 500 mg ⁇ 1000 mg). Accordingly, the pharmaceutical compositions, pharmaceutical compositions, and methods of the present invention for treating, ameliorating, and alleviating pain in a subject can achieve an analgesic effect using a conventional analgesic that is significantly lower than the daily dose.
  • the human equivalent dose of sinomenine is about 200 mg/day (chronic analgesia), 50 to 200 mg/time (single administration), and does not exceed the reported adult dose. Since gabapentin and acetaminophen are themselves analgesic drugs, the actual dose of gabapentin and acetaminophen may be higher than the above-mentioned equivalent human dose when administering the pharmaceutical combination or pharmaceutical composition of the present invention, as long as it does not exceed the adult dosage when administered separately.
  • the actual human dose will vary depending on the patient's weight, physical condition, and other clinical trial results and known clinical doses; therefore, the actual administered dose can be up and down, for example, for adult patients, gabapentin
  • the single dose can be 50 ⁇ 200 mg, and the single dose of paracetamol can be 50 ⁇ 400 mg o
  • analgesics in combination with sinomenine in the present invention are not limited to those enumerated above, and analgesics similar to the analgesic drugs are also within the scope of the present invention.
  • the GABA class of drugs may be gabapentin and pregabalin, and the paracetamol analgesics may be acetaminophen, aspirin, and ibuprofen.
  • the difference in administration time in the embodiment of the present invention can be achieved by sequential administration, but for those skilled in the art, the time difference can also be achieved by a clinically acceptable drug controlled release technique.
  • gabapentin can be added to a specific sustained-release capsule by the same administration, or sinomenine and gabapentin can be encapsulated in different capsules, thereby utilizing different release characteristics to achieve the practical effect of successive release.
  • the unit "mg/kg” means the dose (mg) of the drug weight per kg of the subject unless otherwise specified.
  • Example 1 Synergistic analgesic effect of sinomenine and gabapentin in a mouse peripheral neuropathic pain model
  • a mechanical allodynia can be observed, which is manifested by a decrease in the response threshold to mechanical stimuli.
  • 20 mg/kg of mouse body weight of sinomenine was administered orally and the contraction threshold (g) of the mice was observed within 0.5 to 4 hours after administration (every 30 minutes to 60 minutes), and the results showed no analgesic effect.
  • sinomenine and gabapentin are administered in combination in small doses
  • sinomenine is administered first
  • gabapentin is administered after 30 minutes to 1 hour, and within 0.5 to 4 hours (observed every 30 minutes to 60 minutes) after administration of gabapentin.
  • a significant analgesic effect was observed with the reduced leg threshold, and the analgesic effect increased with increasing doses of sinomenine and gabapentin (see Figure 1C).
  • the doses of the three groups of "sinomenine + gabapentin" in Figure 1C are "10 mg/kg + 7.5 mg/kg", "20 mg/kg + 7.5 mg/kg” and "wheat" 20 mg/kg + 15 mg/kg.
  • the above analgesic combination had no observable side effects in the mice.
  • the threshold of the leg in the results was the average of 6 mice.
  • the above analgesic combination has no observable side effects in rats.
  • the squeaking threshold and the response score in the results were both average values of 6 to 11 rats.
  • the combination of sinomenine at 10 mg/kg rat body weight and gabapentin at 4 mg/kg rat body weight was selected to study the effect of chronic administration.
  • each administration was administered 10 mg / kg sinomenine for 30 minutes ⁇ 1 hour after the application of 4 mg / kg gabapentin, and in the first time
  • the baseline squeak threshold i.e., pain threshold
  • the snoring threshold was recorded 2 hours after the second dose, with two dosing intervals of 6 hours.
  • the combined administration produced significant analgesic effects in 7 days (Fig. 4A) or 14 days (Fig. 4B), and no toleration occurred. More importantly, during the chronic administration, the pain threshold before administration also increased significantly, indicating that the drug produced a sustained analgesic effect; and about 2 days after the end of the administration, the pain threshold of the rat decreased. .
  • the above analgesic combination did not produce observable side effects during chronic administration in rats.
  • the threshold for squeaking in the results was the average of 6 rats.
  • One of the important applications of the present invention is to achieve an effective analgesic effect by combining small doses of the drug, reducing the occurrence of side effects and drug tolerance. It has been proven that small doses of these drugs are used when large doses of analgesics, such as gabapentin, sinomenine and acetaminophen, do not achieve effective analgesic effects. Specific combinations, in the optimal dosing sequence, produce an effective analgesic effect with no side effects.
  • the present invention covers both sinomenine and two types of analgesics for clinical use. Gabapentin and its derivatives include, but are not limited to, pregabalin, and the combination of pyrexis and similar analgesics.
  • the present invention facilitates the marketing of one or more combinations of drugs comprising different ingredients and strengths which provide effective treatment for pain patients worldwide, reducing side effects and drug tolerance, including but not limited to Inflammation, arthritis, cancer, diabetes, pityriasis, nerve damage, AIDS, chemotherapy complications, stroke and spinal cord injury. references

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

说明书
种用于镇痛的药物组合产 技术领域
本发明涉及一种基于中药有效成分青藤碱 (Sinomenine)的新型镇痛药物组 合产品， 以及使用该药物组合的新的镇痛方法。具体而言， 本发明涉及施用青藤 碱与另一种镇痛药的组合， 并通过临床可接受的缓释、控释技术实现药物给药的 时间差，从而实现镇痛作用的加强，使其更广泛应用于各种临床急慢性顽固疼痛。 背景技术
慢性疼痛， 如外周或中枢神经系统损伤后造成的神经源性疼痛或慢性感染 性疾病如风湿性关节炎造成的慢性感染性疼痛， 是重要的临床问题， 这是因为此 类疼痛具有复杂性、 长期性和对治疗的抵抗性。
对慢性疼痛的治疗目前以药物治疗为主， 但相当一部分病人的疼痛得不到 有效的控制， 现有药物如阿片类镇痛药产生很多副作用， 且药物耐受性 (长期给 药过程中， 药效逐渐减弱的现象)也是治疗慢性疼痛中的难题， 所以对慢性疼痛 治疗的当务之急是： （1)增强现有药物的镇痛效果； （2)通过减少给药剂量而减少 副作用； （3)预防和推迟药物耐受性的发生。
对于药物和 /或治疗方法的镇痛效果的研究可以借助于多种成熟的动物疼 痛模型来进行。 这些模型包括但不限于神经病理性疼痛动物模型 (例如， 脊髓损 伤疼痛模型， 和外周神经损伤模型)、 疾病所致的周围神经病变疼痛模型和癌性 疼痛模型。
青藤碱 (Sinomenine, 其结构见化学式 1)是从青风藤 O Vwomem' m <¾c m)根 部提取的一种碱性物质， 在 湿病如类风湿性关节炎。
Figure imgf000002_0001
化学式 1 在小鼠胶原性关节炎 (CIA)模型中，应用青藤碱治疗可降低关节炎的发病频 率和严重程度 (Huang W o/., 2007)。 与非类固醇类炕炎药物 (NSAIDS)相比， 青藤 碱对清晨关节炎僵硬、 关节痛、 以及红细胞沉降率的改善更加明显 (Xu et αί , 2008)。 青藤碱也被用作免疫抑制剂， 它可以抑制淋巴细胞增殖和 Β细胞的抗体 合成 (He et αί , 2005) , 其抗炎和神经保护作用主要是通过抑制小胶质细胞中 NADPH氧化酶产生的超氧离子来完成的 (Qian e o/.,2007)。 此外， 青藤碱还可以 通过抑制离体环氧化酶 (COX-2)从而抑制前列腺素 E2 (PGE2)的合成 (Liu et al., 1994)
CN1790014公开一种治疗癌性疼痛的中药组合物，该药物组合物由青风藤、 白屈菜和汉桃叶三味药制成，用于治疗癌性疼痛， 尤其是治疗肺癌疼痛或肝癌疼 痛。
CN1214245公开了青藤碱的药物新用途， 即青藤碱在制备止痛药物中的应 用， 尤其是用于治疗术后疼痛， 疗效较好。
CN101347408公开了一种含有青藤碱的注射剂可以治疗慢性疼痛。
CN101411707公开了一种含有青藤碱的药物组合物可以治疗风湿关节炎及 其引起的疼痛。
青藤碱 (作为抗关节炎药)的成人剂量为 200〜240毫克 /日 (Xu et al., 2008)。 但青藤碱对神经源性疼痛的作用目前未见报道。
GABA类药物是哺乳动物中枢神经系统中重要的抑制性神经传达物质， 在 人体大脑皮质、 海马、 丘脑、 基底神经节和小脑中起重要作用， 并对机体的多种 功能具有调节作用。 当人体内 GABA缺乏时， 会产生焦虑、 不安、 疲倦、 忧虑 等情绪，一般长久处于高压力族群如身处竞争环境中的人群、运动员、上班族等， 都很容易缺乏 GABA需要及时补充以便舒缓情绪。 以加巴喷丁为例， 目前临床 的用于成人的镇痛剂量为 300〜600 mg/次， 900〜3600 mg/日。
扑热息痛是最常用的非抗炎解热镇痛药， 特别适合于不能应用羧酸类药物 的病人，用于感冒、牙痛等症。用于成人的镇痛剂量为 500〜1000 mg/次， 1000〜 4000 mg/日。
另外， 目前对青藤碱与其他药物联用时的镇痛协同作用尚未见报道。 发明内容
本发明涉及治疗慢性疼痛特别是神经源性疼痛的青藤碱与其他镇痛药物的 组合。本发明人首次发现， 虽然青藤碱在单独使用时无显著镇痛效果， 但与其他 镇痛药物组合使用时可以在镇痛方面发挥出显著的协同效果。
具体而言， 在大鼠缺血性脊髓损伤模型 (Xu W β/.， 1992)或大鼠和小鼠外周 神经损伤模型 (例如， 部分坐骨神经缺血性损伤模型） (Kupers et al. , 1998; Hao et al. , 2000)的神经源性疼痛中，青藤碱和 GABA类药物 (例如，加巴喷丁 (gabapentin)) 的联合在镇痛方面有显著的协同增强作用； 在大小鼠急慢性炎症 (例如， 鹿角菜 胶引起的小鼠炎症痛）中， 青藤碱和扑热息痛类镇痛药（例如， 扑热息痛 (paracetamol))的联合在镇痛方面有显著的协同增强作用。这些动物模型均被国际 上普遍接受为有代表性的神经源性疼痛模型。
因此， 本发明提供一种用于镇痛的药物组合产品， 所述药物组合产品包含 下述 (i)和 (ii)或由下述 (i)和 (ii)组成：
(i)青藤碱和 /或其药物可接受的盐， 和
(ii) GABA类药物或扑热息痛类镇痛药。
本发明还涉及青藤碱或其药物可接受的盐与 GABA类药物或扑热息痛类镇 痛药的组合在制备用于镇痛的药物组合产品中的应用。
本发明还涉及一种镇痛方法， 该方法包括给患有疼痛的患者服用镇痛有效 量的 (i)青藤碱和 /或其药物可接受的盐， 和 (ii) GABA 类药物或扑热息痛类镇痛 药。 该方法特别用于缓解神经源性疼痛或急慢性炎症疼痛。
本发明通过将 GABA 类药物或扑热息痛类镇痛药与青藤碱配合， 使得 GABA类药物和扑热息痛类镇痛药物的单次用量仅为目前已有技术用量的四分 之一到十分之一或更低， 不仅增强了现有药物的镇痛效果， 还由于减少了给药剂 量而减少副作用， 从而预防和推迟了药物耐受性的发生。 附图说明
图 1A-1C显示了青藤碱和加巴喷丁在小鼠外周神经损伤模型中的协同镇痛 作用， 疼痛指标是小鼠后足在机械刺激下的縮腿阈值 (单位： g)。 图 1A显示了青 藤碱和加巴喷丁在单独给药时无镇痛作用； 图 1B显示了加巴喷丁先于青藤碱给 药时无镇痛作用； 图 1C显示了青藤碱于加巴喷丁 30分钟到 1小时前给药， 小 剂量药物联合可产生显著的镇痛作用。
图 2A-2D显示了青藤碱和加巴喷丁在大鼠脊髓损伤慢性疼痛模型中的协同 镇痛作用， 疼痛指标是大鼠身体在机械刺激下的嘶叫阈值 (g)和冷刺激下的反应 给分。 图 2A和 2B显示了青藤碱和加巴喷丁在单独给药时对机械性刺激和冷刺 激无镇痛作用； 图 2C和 2D显示了青藤碱于加巴喷丁 30分钟到 1小时前给药， 小剂量药物联合可产生显著的对机械性刺激和冷刺激的镇痛作用。
图 3A和 3B显示了青藤碱和加巴喷丁在大鼠脊髓损伤慢性疼痛模型中的协 同镇痛作用， 疼痛指标是大鼠身体在机械刺激下的嘶叫阈值 (g)和冷刺激下的反 应给分。 同时施用 10 mg/kg青藤碱和 4 mg/kg加巴喷丁可产生显著的镇痛作用。
图 4A和 4B显示了青藤碱和加巴喷丁在大鼠脊髓损伤慢性疼痛模型中的协 同镇痛作用， 疼痛指标是大鼠身体在机械刺激下的嘶叫阈值 (g)。 小剂量联合给 药在七天和十四天的持续镇痛作用和背景疼痛的减轻，并且没有出现可观察到的 药物耐受效应。
图 5A-5C显示了青藤碱和扑热息痛联合给药在小鼠鹿角菜胶引起的炎症痛 中的协同镇痛作用， 疼痛指标是大鼠后肢在机械刺激下的縮腿阈值 (g)。 图 5A显 示了青藤碱和扑热息痛在单独给药时对机械性刺激无镇痛作用； 图 5B显示了青 藤碱于加巴喷丁 30分钟到 1小时前给药， 小剂量药物联合可产生显著的对机械 性刺激的镇痛作用； 图 5C显示了在同时施用青藤碱和扑热息痛时也可以观察到 显著的协同作用。 具体实施方式
本发明提供一种用于镇痛的药物组合产品， 所述药物组合产品包含下述 (i) 和 (ii)或由下述 (i)和 (ii)组成：
(i)青藤碱和 /或其药物可接受的盐， 和
(ii) GABA类药物或扑热息痛类镇痛药。
其中， 所述 (i)和 (ii)可以以彼此隔离的形式存在， 或者以相互混合的药物组 合物的形式存在。
在 (i)和 (ii)为彼此隔离形式的本发明的药物组合产品中， 所述彼此隔离的形 式为： （i)和 (ii)分别以各自的单剂量制剂分开包装。 特别而言， 所述彼此隔离的 形式为使得 (i)和 (ii)在同一单剂量制剂中能先释放 (i)青藤碱和 /或其药物可接受的 盐、 再释放 (ii) GABA类药物或扑热息痛类镇痛药的药剂形式； 或者为使得所述 (i)和 (ii)在同一单剂量制剂中能同时释放 (i)和 (ii)的药剂形式。 在此情况下， 优选 的是， 单剂量制剂中的 GABA类药物为 50 mg〜200 mg， 单剂量制剂中的扑热 息痛类镇痛药为 50 mg〜400 mg， 单剂量制剂中的青藤碱为 50 mg至 200 mg。 且单剂量制剂形式的 (i)和 (ii)的质量比为 3:1到 1:1 (适用于青藤碱:加巴喷丁， 例 如 2.5至 1.3:1)， 或者为 1:1到 1:2 (适用于青藤碱:扑热息痛， 例如 1:1.5)， 并可 以根据临床效果对药物比例进行调整。
在 (i)和 (ii)为相互混合形式的本发明的药物组合产品中， 所述的药物组合产 品为药物组合物， 该药物组合物含有所述 (i)、 （ii)和药用辅剂 (例如药用赋形剂、 稀释剂和 /或载剂)。在该药物组合物中，所述 (i)和 (ii)的质量比优选为 3:1到 1:1 (适 用于青藤碱:加巴喷丁， 例如 2.5至 1.3:1)， 或者为 1:1到 1:2 (适用于青藤碱：扑热 息痛， 例如 1:1.5)， 并可以根据临床效果对药物比例进行调整。 在该药物组合物 的单剂量制剂中， 优选含有 50 mg〜200mg的 GABA类药物或 50 mg〜400 mg 的扑热息痛类镇痛药， 以及 50〜200 mg的青藤碱。
本发明的药物组合产品和药物组合物所针对的疼痛包括： （a)急性疼痛， 例 如手术后疼痛及严重内脏疼痛； （b)慢性疼痛， 例如癌症痛、 关节炎痛和腰背痛； 和 (c)神经源性疼痛， 例如神经和脊髓损伤痛、 脑卒中后痛、 糖尿病致神经病变 痛、 疱疹病毒致痛、 三叉神经及其他面部神经痛。
本发明的基于青藤碱的药物组合实现了 (1)增强现有药物的镇痛效果、 （2) 通过减少给药剂量而减少副作用和 (3)预防和推迟药物耐受性的发生等效果， 具 有广阔的应用前景。 因此， 本发明还涉及青藤碱或其药物可接受的盐与 GABA 类药物或扑热息痛类镇痛药的组合在制备本发明的用于镇痛的药物组合产品中 的应用。
在一个实施方式中， 本发明涉及用于治疗、 改善和缓解受试对象的神经损 伤性疼痛的药物组合产品和方法，所述药物组合包含彼此为隔离剂型的青藤碱和 加巴喷丁。 在镇痛时， 先施用青藤碱， 30分钟〜 1小时后施用加巴喷丁， 其中， 青藤碱的施用剂量优选为 10 mg/kg小鼠体重〜 20 mg/kg小鼠体重 (小鼠剂量)或 与之等效的人剂量， 或 5 mg/kg大鼠体重〜 20 mg/kg大鼠体重 (大鼠剂量)或与之 等效的人剂量； 加巴喷丁的施用剂量优选为 7.5 mg/kg小鼠体重〜 15 mg/kg小鼠 体重 (小鼠剂量)或与之等效的人剂量， 或 2 mg/kg大鼠体重〜 7.5 mg/kg大鼠体重 (大鼠剂量)或与之等效的人剂量； 所述人剂量可以基于人的体重和本发明公开的 鼠剂量并根据公知方法 (例如， 体重法或体表面积法)推算并参考已知的临床剂量 得到。所述方法包括按上述施用顺序和治疗有效剂量向经受神经损伤性疼痛的受 试对象 (例如， 小鼠、 大鼠、 人） 施用所述药物组合产品。
在另一个实施方式中， 本发明涉及用于治疗、 改善和缓解受试对象的神经 损伤性疼痛的药物组合物和方法，所述药物组合物包含青藤碱和加巴喷丁。在镇 痛时， 施用含有 10 mg/kg大鼠体重 (或等效人剂量)的青藤碱和 4 mg/kg大鼠体重 (或等效人剂量)的加巴喷丁的药物组合物。 所述方法包括按治疗有效剂量向经受 神经损伤性疼痛的受试对象 (例如， 小鼠、 大鼠、 人)施用所述药物组合物。
在另一个实施方式中， 所述药物组合产品包含彼此为隔离剂型的青藤碱和 加巴喷丁。在镇痛时，每天两次 (腹腔注射)联合给药，每次给药都是施用 10 mg/kg 大鼠体重 (或等效人剂量)的青藤碱 30分钟〜 1小时后施用 4 mg/kg大鼠体重 (或等 效人剂量)的加巴喷丁， 持续给药 7〜14天。 所述方法包括按上述给药顺序、 给 药频率、 给药时间和治疗有效剂量向经受神经损伤性疼痛的受试对象 (例如， 小 鼠、 大鼠、 人)施用所述药物组合产品。
在又一个实施方式中， 本发明涉及用于治疗、 改善和缓解受试对象的炎症 性疼痛的药物组合产品和方法，所述药物组合产品包含彼此为隔离剂型的青藤碱 和扑热息痛。在镇痛时，先施用青藤碱， 30分钟〜 1小时后施用扑热息痛，其中， 青藤碱的施用剂量优选为 20 mg/kg小鼠体重 (小鼠剂量)或与之等效的人剂量；扑 热息痛的施用剂量优选为 30 mg/kg小鼠体重 (小鼠剂量)或与之等效的人剂量。所 述方法包括按上述施用顺序和治疗有效剂量向经受神经损伤性疼痛的受试对象 (例如， 小鼠、 大鼠、 人)施用所述药物组合产品。
在另一个实施方式中， 本发明涉及用于治疗、 改善和缓解受试对象的炎症 性疼痛的药物组合物和方法，所述药物组合物包含青藤碱和扑热息痛。在镇痛时， 施用含有 20 mg/kg小鼠体重 (或等效人剂量)的青藤碱和 30 mg/kg小鼠体重 (或等 效人剂量)的扑热息痛的药物组合物。 所述方法包括按治疗有效剂量向经受炎症 性疼痛的受试对象 (例如， 小鼠、 大鼠、 人)施用所述药物组合物。
在本发明的实施方式中， 与青藤碱协同作用的加巴喷丁的单次镇痛剂量为 7.5〜15 mg/kg小鼠体重或 2〜7.5 mg/kg大鼠体重， 相当于约 20 mg〜约 75 mg 的人剂量 (按体表面积法估算， 成人体重按约 60 kg算， 下同)， 远低于加巴喷丁 作为镇痛药物单独口服时的一般成人剂量 (单次 300 mg〜600 mg);与青藤碱协同 作用的加巴喷丁的慢性镇痛剂量为： 4 mg/kg大鼠体重 /次， 8 mg/kg大鼠体重 /日， 相当于约 80 mg/日的人剂量，远低于加巴喷丁作为镇痛药单独口服时的一般成人 剂量 (每日 900 mg〜3600 mg)。 此外， 与青藤碱协同作用的扑热息痛的单次镇痛 剂量优选为 30 mg/kg小鼠体重， 相当于约 150 mg的人剂量， 远低于扑热息痛作 为镇痛药单独口服时的一般成人剂量 (单次 500 mg〜1000 mg)。 因此， 本发明的 用于治疗、改善和缓解受试对象的疼痛的药物组合物、药物组合产品及方法能够 使用明显低于日常剂量的常规镇痛药来实现镇痛效果。
此外， 在本发明的实施方式中， 青藤碱的人等效剂量约为 200 mg/日 (慢性 镇痛)、 50〜200 mg/次 (单次施用)， 未超过已报导的成人剂量。 由于加巴喷丁和 扑热息痛本身为镇痛药物，在施用本发明的药物组合产品或药物组合物时， 加巴 喷丁和扑热息痛的实际剂量可以高于上述等效人剂量，只要不超过其各自单独施 用时的成人剂量即可； 另外， 实际施用的人剂量还将根据患者体重、 身体状况和 其他临床试验结果和已知临床剂量而有所变化； 所以， 实际的施用剂量可以上下 浮动， 例如， 对于成人患者， 加巴喷丁的单剂量可以为 50〜200 mg, 扑热息痛 的单剂量可以为 50〜400 mg o
应理解的是， 对于本领域的技术人员而言， 本发明中与青藤碱组合的镇痛 药不限于上述列举的那些， 与所述镇痛药物同类的镇痛药也在本发明的范围内， 例如， GABA类药物可以是加巴喷丁和普加巴林 (pregabalin), 扑热息痛类镇痛药 可以是扑热西痛、 阿司匹林和布洛芬 (ibuprofen)。
本发明实施方式中的给药时间差可以通过先后施用来实现， 但对于本领域 的技术人员而言，该时间差还能够通过临床可接受的药物控释技术来实现。例如， 可以通过同一次给药时将加巴喷丁加入特定的缓释胶囊中，或者将青藤碱和加巴 喷丁包入不同的胶囊中， 从而利用不同的释放特性来达到先后释放的实际效果。
本文中涉及药物剂量时， 如无特别说明， 其单位 "mg/kg"是指每 kg受试 对象的体重所对应的药物剂量 (mg)。
下面将通过实施例来进一步阐明本发明的实施方式和效果， 但本发明的实 施方式并不限于以下实施例。在每个实施例中， 若无特别说明， 所有药物的施用 途径都相同。 实施例
[实施例 1] 青藤碱和加巴喷丁在小鼠外周神经源性疼痛模型中的协同镇痛作用 在小鼠部分坐骨神经损伤模型中， 可以观察到机械性痛敏现象， 表现为对 机械性刺激的反应阈值下降。 单独口服施用 20 mg/kg小鼠体重的青藤碱并在施 用后 0.5到 4小时内 (每 30分钟到 60分钟观察一次)观察小鼠的縮腿阈值 (g)， 结 果表明无镇痛效果 (见图 1A); 单独口服施用 30 mg/kg小鼠体重的加巴喷丁并在 施用后 0.5到 4小时内 (每 30分钟到 60分钟观察一次)观察小鼠的縮腿阈值，结 果表明无镇痛效果 (见图 1A)。 当青藤碱和加巴喷丁在以小剂量联合给药时， 先 施用 7.5 mg/kg的加巴喷丁， 30分钟〜 1小时后施用 10 mg/kg的青藤碱， 在施用 后 0.5到 4小时内 (每 30分钟到 60分钟观察一次)观察縮腿阈值，亦无镇痛效果 (见 图 1B)。 当青藤碱和加巴喷丁在以小剂量联合给药时， 先施用青藤碱， 30分钟〜 1小时后施用加巴喷丁，在施用加巴喷丁后 0.5到 4小时内 (每 30分钟到 60分钟 观察一次)观察縮腿阈值， 可以观察到显著的镇痛作用， 而且镇痛效果随着青藤 碱和加巴喷丁的剂量增加而增加 (见图 1C)。 图 1C中三组 "青藤碱 +加巴喷丁" 的剂量分别为 " 10 mg/kg+7.5 mg/kg " "20 mg/kg+7.5 mg/kg"禾卩 "20 mg/kg+15 mg/kg 上述镇痛组合在小鼠中没有可观察到的副作用。结果中的縮腿阈值均为 6只小鼠的平均值。
[实施例 2]
青藤碱和加巴喷丁在大鼠脊髓损伤模型中的协同镇痛作用
在大鼠脊髓损伤疼痛模型中， 亦可观察到强烈的对机械刺激和冷刺激的痛 敏现象。 单独施用 (腹腔注射) 20 mg/kg大鼠体重的青藤碱或单独施用 30 mg/kg 大鼠体重的加巴喷丁，在施用后 0.5到 24小时内观察在机械刺激下的嘶叫阈值 (g) 和冷刺激下的反应给分 (大鼠对氯乙烷喷雾剂 (RSnnings Europa AB, Sweden)在其 身上痛敏部位造成的冷刺激的反应给分标准为： 0 = 没有可观察到的反应； 1 = 局部反映 （皮肤抽搐和肌肉收縮)， 无嘶叫； 2 = 暂短的嘶叫和逃避行为； 3 =持 续的嘶叫和逃避行为)， 结果表明在此模型中单独施用这两种药剂无镇痛作用 (见 图 2A和 2B)。 而在组合施用很小剂量的青藤碱和加巴喷丁时， 在施用青藤碱 30 分钟〜 1小时后施用加巴喷丁，在施用加巴喷丁后 0.5到 24小时内可以观察到强 烈的镇痛作用 (见图 2C 和 2D)， 此处三组"青藤碱 +加巴喷丁"的剂量分别为 "5 mg/kg+2 mg/kg" "10 mg/kg+4 mg/kg，，禾口'' 20 mg/kg+7.5 mg/kg，，。
此外， 在同时施用 10 mg/kg青藤碱和 4 mg/kg加巴喷丁时， 也可以观察到 显著的协同作用 (见图 3A和 3B)。
上述镇痛组合在大鼠中没有可观察到的副作用。 结果中的嘶叫阈值和反应 给分均为 6到 11只大鼠的平均值。
[实施例 3]
青藤碱和加巴喷丁联合给药的慢性协同镇痛作用
在大鼠脊髓损伤疼痛模型中，选择了 10 mg/kg大鼠体重的青藤碱和 4 mg/kg 大鼠体重的加巴喷丁的组合研究了慢性给药的作用。在两轮实验中， 每天两次联 合给药 (腹腔注射)，每次给药都是施用 10 mg/kg青藤碱 30分钟〜 1小时后施用 4 mg/kg加巴喷丁， 并在其中第一次给药前记录基准嘶叫阈值 (即痛阈值)， 在第二 次给药后 2小时后记录嘶叫阈值， 两次给药间隔 6小时。 结果如图 4A和 4B所 示， 联合给药在 7天 (图 4A)或 14天 (图 4B)中均产生明显的镇痛作用， 且无耐受 现象的发生。更重要的是，在慢性给药的过程中，给药前的痛阈值也有显著上升， 这表示药物产生了持续的镇痛作用；而在给药结束后约 2天，大鼠的痛阈值下降。 上述镇痛组合在大鼠中慢性给药过程中没有产生可观察到的副作用。结果中的嘶 叫阈值均为 6只大鼠的平均值。
[实施例 4]
青藤碱和扑热息痛联合给药在小鼠鹿角菜胶引起的炎症痛中的协同作用 在小鼠鹿角菜胶 (Carragenan)引起的炎症痛中， 可观察到对机械刺激的痛敏 现象。 单独口服施用 40 mg/kg小鼠体重的青藤碱或单独口服施用 100 mg/kg小 鼠体重的扑热息痛， 在施用后 0.5到 4小时内 (每 30分钟到 60分钟观察一次)观 察小鼠的縮腿阈值， 结果表明在此模型中单独施用这两种药剂无显著镇痛作用 (见图 5A)。 而在组合施用很小剂量的青藤碱和扑热息痛时， 在施用 20 mg/kg青 藤碱 30分钟〜 1小时后施用 30 mg/kg的扑热息痛， 在施用后 0.5到 4小时内 (每 30 分钟到 60 分钟观察一次)观察嘶叫阈值， 可以观察到强烈的镇痛作用 (见图 5B)。 此外， 在同时施用 20 mg/kg青藤碱和 30 mg/kg扑热息痛时， 也可以观察 到显著的协同作用 (见图 5C)。上述镇痛组合在炎性疼痛的小鼠中没有产生可观察 到的副作用。 结果中的縮腿阈值均为 5到 6只小鼠的平均值。
本发明的重要应用之一是通过联合使用小剂量的药物达到有效的镇痛效 果， 减少副作用和药物耐受的发生。 事实证明， 在单独使用大剂量的镇痛药物， 如加巴喷丁，青藤碱和扑热息痛达不到有效的镇痛效果时， 上述药物的小剂量的 特定组合， 在最佳用药次序下， 可产生有效的镇痛作用， 且无副作用的发生。 本发明覆盖了青藤碱和临床应用的两类镇痛药， 加巴喷丁及其衍生物包括 但不限于普加巴林， 和普热西痛及类似镇痛药的联和应用。
本发明会促使一种或数种包含不同成分及强度的药物组合上市， 这些药品 可使全世界的疼痛患者得到有效的治疗，减少副作用和药物耐受， 所影响的病患 范围包括但不限于炎症， 关节炎， 肿瘤， 糖尿病， 庖疹， 神经损伤， 艾滋病， 化 疗并发症， 脑中风和脊髓损伤等。 参考文献
Hao J-X, Blakeman KH, Yu W, Hultenby K, Xu X-J, Wiesenfeld-Hallin Z. Development of a mouse model of neuropathic pain following photochemically induced ischemia in the sciatic nerve. Exp Neurol 2000; 163:231-8.
He XB, Wang JL, XH Guo, Liu QY, Chen TY， Cao XT, et al.. Requirement for ERK activation in sinomenine-induced apoptosis of macrophages. Immunology Letters 2005; 98: 91-96.
Huang F, Yamaki K, Takano H, Inoue K, Yanagisawa R, Yoshino S. Effect of sinomenine on collagen-induced arthritis in mice. Autoimmunity 2007; 40(7): 532-539.
Kupers R, Yu W, Persson JKE, Xu XJ, Wiesenfeld-Hallin Z. Photochemically-induced ischemia of the rat sciatic nerve produces a dose-dependent and highly reproducible mechanical, heat and cold allodynia, and signs of spontaneous pain. Pain 1998; 76:45-59.
Liu L, Riese J, Resch K, Kaever V. Impairment of macrophage eivosanoid and nitric oxide production by an alkaloid from Sinomenum acutum. Arzneimittelforschung 1994; 44: 1123-6.
Qian L, Xu ZL, Zhang W, Wilson B, Hong JS and Flood MP. Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. Journal of Neuroinflammation 2007; 4(23). Xu M, Liu L, Qi C, Deng B, Cai X. Sinomenine Versus NSAIDs for the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta- Analysis. Bibliography 2008; 74: 1423-9.
Xu X.-J" Hao J.-X., Aldskogius H., Seiger A., Wiesenfeld-Hallin Z.. Chronic pain-related syndrome in rats after ischemic spinal cord lesion: a possible animal model for pain in patients with spinal cord injury. Pain 1992; 48: 279-90.

Claims

权利要求书
1. 一种用于镇痛的药物组合产品， 所述药物组合产品包含下述 (i)和 (ii)或 由下述 (i)和 (ii)组成：
(i)青藤碱和 /或其药物可接受的盐， 和
(ii) GABA类药物或扑热息痛类镇痛药。
2. 如权利要求 1所述的药物组合产品，其中所述 (i)和 (ii)以彼此隔离的形式 存在， 或者以相互混合的药物组合物的形式存在。
3. 如权利要求 2所述的药物组合产品， 其中， 所述彼此隔离的形式为： 所 述 (i)和 (ii)分别以各自的单剂量制剂分开包装。
4. 如权利要求 2所述的药物组合产品， 其中， 所述彼此隔离的形式为使得 所述 (i)和 (ii)在同一单剂量制剂中能先释放 (i)青藤碱和 /或其药物可接受的盐、 再 释放 (ii) GABA类药物或扑热息痛类镇痛药的药剂形式； 或者为使得所述 (i)和 (ii) 在同一单剂量制剂中能同时释放的药剂形式。
5.如权利要求 3或 4所述的药物组合产品， 其中， 单剂量制剂中的 GABA 类药物为 50 mg〜200 mg，单剂量制剂中的扑热息痛类镇痛药为 50 mg〜400 mg， 单剂量制剂中的青藤碱为 50 mg〜200 mg。
6. 如权利要求 3或 4所述的药物组合产品， 其中， 单剂量制剂中的 (i)青藤 碱和 /或其药物可接受的盐与单剂量制剂中的 (ii)GABA类药物的质量比为 3:1到 1:1 ; 单剂量制剂中的 (i)青藤碱和 /或其药物可接受的盐与单剂量制剂中的 (ii)扑热 息痛类镇痛药的质量比为 1:1到 1:2。
7. 如权利要求 2所述的药物组合产品， 其中， 所述药物组合产品为所述 (i) 和 (ii)相互混合的药物组合物， 该药物组合物含有所述 (i)、 （ii)和药用辅剂， 并且， (i)青藤碱和 /或其药物可接受的盐与 (ii)GABA类药物的质量比为 3:1 到 1:1 ; (i) 青藤碱和 /或其药物可接受的盐与 (ii)扑热息痛类镇痛药的质量比为 1:1到 1:2。
8. 如权利要求 7所述的药物组合产品， 其中， 在所述药物组合物的单剂量 制剂中含有 GABA类药物 50 mg〜200 mg或扑热息痛类镇痛药 50 mg〜400 mg， 青藤碱的单剂量为 50 mg〜200 mg。
9. 如权利要求 1〜8任一项所述的药物组合产品， 其中， 所述 GABA类药 物为加巴喷丁或普加巴林，所述扑热息痛类镇痛药为扑热息痛、阿司匹林或布洛 芬。
10. 青藤碱或其药物可接受的盐与 GABA类药物或扑热息痛类镇痛药的组 合在制备权利要求 1〜9任一项所述的用于镇痛的药物组合产品中的应用。
11. 如权利要求 10所述的应用， 其中， 所述药物组合产品所针对的疼痛为 神经病理性疼痛、 疾病所致的周围神经病变疼痛和 /或癌性疼痛。
12. 如权利要求 10所述的应用， 其中， 所述药物组合产品所针对的疼痛为 神经源性疼痛或急慢性炎症疼痛， 例如脊髓损伤、 外周神经损伤和 /或炎症所致 的疼痛。
13. 一种镇痛方法， 该方法包括给患有疼痛的患者服用权利要求 1〜9任一 项所述的用于镇痛的药物组合产品。
14. 如权利要求 13所述的镇痛方法， 其中所述疼痛为神经源性疼痛或急慢 性炎症疼痛。
PCT/CN2013/075205 2012-05-17 2013-05-06 一种用于镇痛的药物组合产品 Ceased WO2013170711A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP13790165.8A EP2851074B1 (en) 2012-05-17 2013-05-06 Analgesic pharmaceutical composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210154087.9A CN102813924B (zh) 2012-05-17 2012-05-17 一种基于青藤碱的用于镇痛的药物组合产品
CN201210154087.9 2012-05-17

Publications (1)

Publication Number Publication Date
WO2013170711A1 true WO2013170711A1 (zh) 2013-11-21

Family

ID=47298605

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2013/075205 Ceased WO2013170711A1 (zh) 2012-05-17 2013-05-06 一种用于镇痛的药物组合产品

Country Status (3)

Country Link
EP (1) EP2851074B1 (zh)
CN (1) CN102813924B (zh)
WO (1) WO2013170711A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102813924B (zh) * 2012-05-17 2014-06-18 高同强 一种基于青藤碱的用于镇痛的药物组合产品
CN110179829A (zh) * 2019-06-25 2019-08-30 湖南正清制药集团股份有限公司 加巴喷丁、神经妥乐平和盐酸青藤碱的组合在制备用于治疗phn的药物中的应用
CN115894371B (zh) * 2022-12-30 2024-07-16 浙江震元制药有限公司 青藤碱酰胺类衍生物及其制备方法和应用、镇痛药物

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1214245A (zh) 1998-10-15 1999-04-21 湖南正清制药集团股份有限公司 青藤碱在制备止痛药物中的应用
CN1450883A (zh) * 1999-11-19 2003-10-22 美国爱科赛尔制药有限公司 乌头属生物碱经皮给药系统
CN1673212A (zh) * 2004-03-25 2005-09-28 中国人民解放军军事医学科学院毒物药物研究所 加巴喷丁与普瑞巴林的互联体前药及其医药用途
CN1790014A (zh) 2004-12-13 2006-06-21 江苏康缘药业股份有限公司 一种治疗癌性疼痛中药组合物的质量控制方法及应用
CN101066949A (zh) * 2007-05-30 2007-11-07 广东工业大学 青藤碱抗炎镇痛有机酸盐的制备方法
CN101347408A (zh) 2008-09-05 2009-01-21 李蕴麟 青藤碱静脉输液制剂
CN101352412A (zh) * 2008-09-17 2009-01-28 青岛六和药业有限公司 肠溶性非甾体解热镇痛抗炎药及其制备
CN101411707A (zh) 2008-10-10 2009-04-22 西南大学 一种治疗类风湿关节炎的药物组合物
CN101461821A (zh) * 2008-07-04 2009-06-24 青岛康地恩药业有限公司 一种用于治疗猪、牛呼吸道疾病的复方口服药物组合物
CN102813924A (zh) * 2012-05-17 2012-12-12 高同强 一种基于青藤碱的用于镇痛的药物组合产品

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060159743A1 (en) * 2001-10-25 2006-07-20 Depomed, Inc. Methods of treating non-nociceptive pain states with gastric retentive gabapentin
CN102106854A (zh) * 2009-12-25 2011-06-29 青岛康地恩药业有限公司 青藤碱在制备止痛药物中的应用

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1214245A (zh) 1998-10-15 1999-04-21 湖南正清制药集团股份有限公司 青藤碱在制备止痛药物中的应用
CN1450883A (zh) * 1999-11-19 2003-10-22 美国爱科赛尔制药有限公司 乌头属生物碱经皮给药系统
CN1673212A (zh) * 2004-03-25 2005-09-28 中国人民解放军军事医学科学院毒物药物研究所 加巴喷丁与普瑞巴林的互联体前药及其医药用途
CN1790014A (zh) 2004-12-13 2006-06-21 江苏康缘药业股份有限公司 一种治疗癌性疼痛中药组合物的质量控制方法及应用
CN101066949A (zh) * 2007-05-30 2007-11-07 广东工业大学 青藤碱抗炎镇痛有机酸盐的制备方法
CN101461821A (zh) * 2008-07-04 2009-06-24 青岛康地恩药业有限公司 一种用于治疗猪、牛呼吸道疾病的复方口服药物组合物
CN101347408A (zh) 2008-09-05 2009-01-21 李蕴麟 青藤碱静脉输液制剂
CN101352412A (zh) * 2008-09-17 2009-01-28 青岛六和药业有限公司 肠溶性非甾体解热镇痛抗炎药及其制备
CN101411707A (zh) 2008-10-10 2009-04-22 西南大学 一种治疗类风湿关节炎的药物组合物
CN102813924A (zh) * 2012-05-17 2012-12-12 高同强 一种基于青藤碱的用于镇痛的药物组合产品

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
HAO JX; BLAKEMAN KH; YU W; HULTENBY K; XU XJ; WIESENFELD-HALLIN Z: "Development of a mouse model of neuropathic pain following photochemically induced ischemia in the sciatic nerve", EXP NEUROL, vol. 163, 2000, pages 231 - 8
HE XB; WANG JL; XH GUO; LIU QY; CHEN TY; CAO XT ET AL.: "Requirement for ERK activation in sinomenine-induced apoptosis of macrophages", IMMUNOLOGY LETTERS, vol. 98, 2005, pages 91 - 96
HUANG F; YAMAKI K; TAKANO H; INOUE K; YANAGISAWA R; YOSHINO S: "Effect of sinomenine on collagen-induced arthritis in mice", AUTOIMMUNITY, vol. 40, no. 7, 2007, pages 532 - 539
KUPERS R; YU W; PERSSON JKE; XU XJ; WIESENFELD-HALLIN Z: "Photochemically-induced ischemia of the rat sciatic nerve produces a dose-dependent and highly reproducible mechanical, heat and cold allodynia, and signs of spontaneous pain", PAIN, vol. 76, 1998, pages 45 - 59
LIU L; RIESE J; RESCH K; KAEVER V: "Impairment of macrophage eivosanoid and nitric oxide production by an alkaloid from Sinomenum acutum", ARZNEIMITTELFORSCHUNG, vol. 44, 1994, pages 1123 - 6
QIAN L; XU ZL; ZHANG W; WILSON B; HONG JS; FLOOD MP: "Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase", JOURNAL OF NEUROINFLAMMATION, vol. 4, no. 23, 2007
XU X.-J; HAO J.-X.; ALDSKOGIUS H.; SEIGER A.; WIESENFELD-HALLIN Z: "Chronic pain-related syndrome in rats after ischemic spinal cord lesion:. A possible animal model for pain in patients with spinal", CORD INJURY PAIN, vol. 48, 1992, pages 279 - 90
XU. M; LIU L; QI C; DENG B; CAI X: "Sinomenine Versus NSAIDs for the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis", BIBLIOGRAPHY, vol. 74, 2008, pages 1423 - 9

Also Published As

Publication number Publication date
CN102813924B (zh) 2014-06-18
EP2851074A1 (en) 2015-03-25
EP2851074A4 (en) 2015-06-17
CN102813924A (zh) 2012-12-12
EP2851074B1 (en) 2017-08-16

Similar Documents

Publication Publication Date Title
DK167996B1 (da) Smertestillende kombinationspraeparat indeholdende en capsaicinforbindelse og en ikke-steroid anti-inflammatorisk forbindelse
JP4817495B2 (ja) 外因性カンナビノイドでの痛みの制御
US20020058656A1 (en) Triple drug therapy for the treatment and prevention of acute or chronic pain
Rastogi et al. Novel treatment modalities for painful diabetic neuropathy
JP2004508311A (ja) 頭痛、片頭痛、悪心及び嘔吐用の医薬組成物
JP2018507243A5 (zh)
KR20170068608A (ko) 관절염으로 인한 통증 치료를 위한 타펜타돌
JP2024069257A (ja) Ｌ－４－クロロキヌレニンの剤形及び治療的使用
JP2016505050A5 (zh)
WO2013170711A1 (zh) 一种用于镇痛的药物组合产品
Cerbo et al. Flunarizine-pizotifen single-dose double-blind cross-over trial in migraine prophylaxis
CN101610760A (zh) 恶病质的治疗
US9545419B1 (en) Method and compositions for treating chronic inflammatory disorders
CN106413714A (zh) (r)‑吡吲哚及其药学上可接受的盐的药学用途
CN104117065A (zh) 一种基于青藤碱的用于镇痛的药物组合产品
JP2022505184A5 (zh)
CN102631397B (zh) 一种改善脑部血液循环的中药组合物及其制备方法
KR102927058B1 (ko) 진통 가려움 완화 약학 조성물 및 그 응용 방법
JP2022504435A5 (zh)
JP2014530249A5 (zh)
CA2134783C (en) Use of remacemide for the treatment of parkinson&#39;s disease
JP7527662B2 (ja) ピモジドとメトトレキサートの医薬組成物、及びその使用
WO2019021148A1 (en) FOOD SUPPLEMENTS FOR USE IN THE PROPHYLAXIS AND TREATMENT OF MIGRAINE
CN110325214A (zh) 用于预防和治疗神经元损伤的低剂量药物组合
US3336193A (en) Analgesic composition and method employing aspirin and gelsemine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13790165

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2013790165

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2013790165

Country of ref document: EP