WO2006017994A1 - Préparation pharmaceutique analgésique - Google Patents

Préparation pharmaceutique analgésique Download PDF

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Publication number
WO2006017994A1
WO2006017994A1 PCT/CN2005/001295 CN2005001295W WO2006017994A1 WO 2006017994 A1 WO2006017994 A1 WO 2006017994A1 CN 2005001295 W CN2005001295 W CN 2005001295W WO 2006017994 A1 WO2006017994 A1 WO 2006017994A1
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Prior art keywords
aconitine
benzoyl
group
test
dose
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PCT/CN2005/001295
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English (en)
Chinese (zh)
Inventor
Jiansheng Wang
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Jiansheng Wang
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Priority to CN2005800199141A priority Critical patent/CN1968694B/zh
Publication of WO2006017994A1 publication Critical patent/WO2006017994A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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]

Definitions

  • the present invention relates to an analgesic pharmaceutical composition, in particular to an analgesic drug prepared by the aconitine component extracted from the aconite plant as an effective drug.
  • Aconite is the genus Aconite (Aeonitam earm gae Debi).
  • the lateral root of Aeonitam earm gae Debi is a traditional Chinese medicine. It is a commonly used anti-retroviral drug in ancient warming agents because it has obvious toxicity and dosage. and nearly toxic dose, poisoning and death frequently reported clinical phenomenon s therefore has a large number of its students about drug prescription coverage for cooking up chemistry, pharmacology and toxicology, and clinical trials and other work ..
  • analgesic pharmaceutical composition comprising an aconitine component isolated and extracted from an aconite plant as an effective pharmaceutical ingredient, which can achieve an effective analgesic effect of high efficiency and low toxicity.
  • the invention provides an analgesic pharmaceutical composition, which is prepared by using aconitine compound benzoyl aconitine, aconitine, and aconitine as active ingredients.
  • the dosage of the medicament is as follows: 0-600 parts of aconitine in benzoyl, 0-6 parts of hypoaconitine, 0-3 parts of metoconium, and at least two ratios of distribution ratio Can't be zero.
  • the three alkaloids of Hypaconi «ne , Mesaconitine and Benzoylmesaconine are active ingredients in the pharmaceutical compositions of the present invention.
  • the structure of the lower aconitine is as shown in the formula ( ⁇ ), and the structure of the aconitine is as shown in the formula (ffl), and the structure of the aconitine in the benzoyl group is as shown in the formula (W).
  • the pharmaceutical composition is prepared by using a lower weight ratio of aconitine compound as an active ingredient: benzoyl aconitine 100-300 parts of aconitine 1-3 parts preferably: benzene Acetyl aconitine i is divided into 1 part of aconitine
  • an agent prepared by the following weight-matching aconitine compound as an active ingredient 2-6 parts of hypoaconitine, 1-3 parts of mesaconitine: 2 parts of hypoaconitine, Zhongwu Reduce the head by 3 copies.
  • an agent prepared by the following weight-matching aconitine compound as an active ingredient 200-600 parts of aconitine in benzoyl and 1-3 parts of aconitine in benzoyl: benzoyl Stereophylline 200 parts of aconitine 3 parts.
  • an agent prepared by the following a weight-matched aconitine compound as an active ingredient 100-600 parts of aconitine in benzoyl, 1-6 parts of aconitine, and aconitine 1- 3 parts of preference: 100 parts of benzoyl aconitine, 1 part of aconitine and 1 part of aconitine
  • the agent is: an oral preparation, an external preparation, and an injection.
  • the oral preparations are tablets, capsules, pills, granules.
  • the external preparation is a lotion, an ointment, a suppository, or a medicinal dressing.
  • the injection is an injection solution or a powder for injection.
  • the toxicity test results of the above effective pharmaceutical ingredients showed that the LD S0 of the aconitine was 6.41 m g / k g , and the LD 5 ( ) of the aconitine was 12.8 mg / kg.
  • the toxicity of the base was relatively low, and the LD 5 () value was not measured, and the maximum tolerated amount was 1000 mg/kg body weight.
  • the amount of the three aconitine compounds in the present invention is within the above safe range, and the synergistic effect of the synergistic effect of the three compounds in combination or the simultaneous use of the three compounds can be achieved.
  • the drug composition after compatibility does not have a simple dose-effect linear relationship, that is, the more the dosage, the better the drug effect, but the drug is best at a specific ratio. Tests have shown that the best combination of pharmaceutical compositions in the best ratio can achieve the best efficacy and significantly reduced toxicity.
  • the pharmaceutical composition of the present invention achieves the purpose of reducing efficacy and low toxicity, and provides a new choice for clinical use.
  • aconitine alkaloids are used as effective pharmaceutical ingredients, mixed with other auxiliary and/or additional ingredients which are allowed and acceptable in the medicine, and processed according to the corresponding pharmaceutical method, so that they can be prepared for use.
  • a corresponding analgesic formulation pharmaceutical composition For example, it can be prepared into a tablet by mixing with a commonly used auxiliary component such as a disintegrator, an excipient, a lubricant, a binder, a filler, and the like which are acceptable in an oral preparation, and according to a corresponding conventional process.
  • Oral drugs in the form of solid preparations such as pills, capsules, granules and corresponding sustained release agents, controlled release agents.
  • the corresponding injectable drug can be prepared after the appropriate solvent and additive which are allowed to be used in the injectable pharmaceutical preparation and the corresponding process operation. Mixing with the corresponding external drug dispersing agent, curing agent, stabilizer, etc., can be prepared into a corresponding externally used drug including ointment, suppository, lotion and medicinal dressing.
  • Examples 1 to 7 Oral Capsule Drugs The composition of each drug in parts by weight is shown in Table 1.
  • Preparation method The effective pharmaceutical ingredient is pulverized and sieved according to the conventional preparation method of the capsule medicine, and then starch is added and mixed with an appropriate amount of medical ethanol to be granulated on a swing granulator, and after drying the whole granule, it is mixed with a proper amount of lubricant such as stearin and magnesium. The required dose of the drug is filled in the capsule.
  • composition of each drug is the same as in Examples 1-7.
  • Preparation method According to the methods of Examples 1 to 7, granulation and drying, sieving and adding an appropriate amount of talc enamel compression tablets, and then using a conventional coating method with a combination of HPMC propylene glycol, titanium dioxide, medical ethanol and Tween-g0 Coating the coated tablets with the liquid
  • Example 1S ⁇ 21 Oral granule analgesic
  • composition of each drug in parts by weight is shown in Table 2.
  • Example 15 Example 16 Case 17 Case 1 ⁇ Example W
  • Example 20 Case 21 Aconitine 8.9 8.9 8.9 ⁇ Aconitine 7.8 7.8 A 7.8 7.8 Monobenzoyl aconitine 41.1 A 41.1 41.1 A 41.1 Starch (X 1000) 800 800 800 800 800 Sugar powder (1 00) 200 200 200 200 200 200 200 200 200 200 200 200 200 200 200 200 200
  • composition of each drug in parts by weight is shown in Table 3.
  • Preparation method Add the effective pharmaceutical ingredients to the appropriate amount of water for injection, Tween-80, EDTA and CMC-Na in the conventional range, stir well and mix with ultrasonic wave, fully dissolve, dilute with water for injection, filter, and use appropriate amount of hydrochloric acid when needed. Adjust pH 4-9 and fill with ampoule.
  • Example 29 ⁇ 35 topical analgesics
  • Preparation method The effective pharmaceutical ingredients are dissolved by heating with medical ethanol, filtered, and then mixed with 1IMK X 10 parts (both weights) of cetostearyl alcohol and 150 (X 10 parts) of hard fat 3 ⁇ 4, and heated and stirred. After uniform heating, it is a spare oil phase material. Separately, 10 s 000 parts of sodium laurylsulfate stone block 150 parts Teng Dou stirred uniformly mixed with the high-speed standby oil phase of the composition sufficient to Canadian ethyl paraben 1000 (X 1000) parts of purified water was heated After mixing and mixing, cool the package.
  • analgesic patch (adhesive plaster): According to the conventional preparation method of adhesive plaster, 4 leak (X leak) rubber matrix is pressed and dipped, and effective pharmaceutical ingredients and 100 (X 1000) parts of Vase #, 50 ( X 1000) parts of lanolin 000 ( X 1000) parts of rosin 30 ( X 1000 ) parts of fillers such as zinc oxide and dispersing agent, mixed with paste and filtered, and coated with paste on the carrier The recovered solvent is cut to size and packaged.
  • composition of each drug in parts by weight is shown in Table 4.
  • the effective drug composition of each case is the same as the above-mentioned analgesic aerosol.
  • Preparation method adding effective pharmaceutical ingredients to medical ethanol (300 (X 1000) parts for lotion; 100 (X 1000) parts for lotion), mixing and filtering, and adjusting to a total amount of 1000 (X 1000) parts with medical water , that is, the available analgesic/lust-fixing drugs respectively; after mixing and filtering, adding or not adding medical water as needed, quantitatively loading the pressure-resistant container and charging according to the prescribed standard, then becoming an analgesic aerosol Drugs.
  • the effective drug composition of each case is the same as the above-mentioned analgesic aerosol.
  • Preparation method After fully pulverizing the effective pharmaceutical ingredients, they are uniformly mixed with 100 (X 1000) parts of glycerin and about 5,000 parts of Tween-80, and then mixed with the solution prepared from polyvinyl alcohol (PVA). After defoaming, it is fully mixed with liquid paraffin to form a film, which can be dried.
  • PVA polyvinyl alcohol
  • Example 57 ⁇ 63 Analgesic wet dressing
  • composition of each drug in parts by weight is shown in Table 5.
  • the medicinal aconitine white crystal granules provided by the Chengdu Zhizhi Pharmaceutical Co., Ltd., the aconitine 20 mg, and the distilled water to 20 ml, diluted 1:0 to form a ratio of 0. 8C 0. 64, 0. 51, 0. 41 mg / ml - a series of concentrations of the drug solution.
  • Kunming mice male and female, 18 ⁇ 22 g, provided by the Experimental Animal Center of Sichuan University, a 3 -grade animal, certificate number: Chuan Shidong No. 67; Feed provider with animals, free Qin water breeding room The temperature is 21 ⁇ 2 V and the relative humidity is: 50 ⁇ 60% 0
  • mice 10 minutes to 4 hours after gavage most of them showed signs of fatigue, hypotonia, and vertical hair, and with increasing dose, there appeared an increasing degree of hiccup reaction and some or all animal death.
  • the behavior, activity, diet, fur luster and weight gain of the undead mice returned to normal after one day.
  • the dead mice were dissected, and no obvious abnormal changes were observed by visual observation of the major organs. After 7 days, the mice were sacrificed and dissected. No obvious abnormal changes were observed by the naked eyes.
  • the death of mice in each dose group is shown in Table 6.
  • LD 5 was calculated according to the Bliss method in the NDST software package. For a 12. 8 mg/kg, the 95% confidence limit is 10.93 ⁇ ; 14. 99 mg/kg.
  • the drug aconitine has certain toxicity, Kunming mice are administered intragastrically, LD 5 .
  • Kunming mice are administered intragastrically, LD 5 .
  • the 95% confidence limit is 10.93 ⁇ : 14. 99 mg/kgo
  • aconitine, white crystalline granules provided by Chengdu Zhizhi Pharmaceutical Co., Ltd. to take 15 mg of aconitine, add distilled water to 23. 4 ml (0. 64 rag/ml), take out 16 ml, ammonium 1: 0. 8 equal dilution was formulated into 0. 51 0. 41 , 0. 33 0. 26, 0. 21 mg / ml - a series of concentrations of the drug solution, spare.
  • Kunming mice are male and female, 18 ⁇ 22 g, and the first-level animal certificate number is provided by the Experimental Animal Center of Sichuan University: Chuan Shidong Pipe Quality No. 67; Feeding provider is the same animal, free drinking water breeding room temperature is 21 Soil 2 V, relative humidity: 50 ⁇ 60%
  • mice were fasted and not for 14 hours, and were randomly divided into 6 groups. 2 ml / The volume of the aconitine administered to the mice in each group was 0. 2 ml / each of the two groups of mice was given a dose of 0. 2 ml / Immediately after the administration of 10 g D , the response of the animals was observed. The toxic reaction and death of the mice were recorded on the 7th day.
  • mice 10 minutes to 4 hours after gavage In the mice 10 minutes to 4 hours after gavage, most of them showed fatigue and less movement, vertical hair, and increased dose-like hiccups with increasing doses and some or all animals died. Fur gloss and weight gain returned to normal. The dead mice were dissected, and no obvious abnormal changes were observed by visual observation of the major organs. Seven days later, the mice were sacrificed and the major organs were visually observed without obvious abnormal changes. The death of mice in each dose group is shown in Table 7.
  • Aconitine has certain toxicity in the drug, Kunming mice are administered once a day, LD 5 .
  • the preservative limit of 95% is 5.19 ⁇ 7. 74 mg/kg
  • the drug benzoyl aconitine, light yellow crystalline granules, has garlic odor, by Chengdu Zhizhi Pharmaceutical Co., Ltd. Offer
  • Kunming mice are 18 ⁇ 22 g male and female, and the first-level animals are provided by the Experimental Animal Center of Sichuan University. Certificate No.: ⁇ Chuan Shi Dong Guan No. 67; Feeding Providers with Animals, Free Qin Water Breeding Room Temperature For 21 ⁇ 2 3 ⁇ 4 pairs of humidity: ⁇ ⁇
  • the drug benzoyl aconitine base granules were sonicated with a very small amount of ethanol, and then distilled water was added to prepare a concentration of 0.5 g/ml solution for 20 Kunming mice that were fasted for 14 hours.
  • the stomach was given a solution of aconitine in the benzopyrene mill. 0. 2ml/10g, and the animal reaction was immediately observed.
  • the behavioral activity of the mouse was recorded for 7 days and the skin weight and death of the skin were recorded.
  • mice 15 minutes to 4 hours after the gavage most of the tired and less moving vertical hair, 4 hours after the behavioral active diet gradually returned to normal. During the observation period, no animals died. The animal's eating behavior was normal, and the normal hair color was normal, and the body weight was normal. (The body weight of the mice before the experiment was 19. 5 ⁇ l. lg, and the weight was observed after 7 days. The weight was 25. 2 ⁇ 1. 8g). In the future, the mice were sacrificed, and no obvious abnormalities were observed by naked eyes. Therefore, the maximum tolerated dose of benzoyl aconitine in a single gavage is 1 g/kg e
  • aconitine referred to as "component of Formula ( ⁇ )"
  • aconitine referred to as "Formula (III) component
  • benzoyl aconitine referred to as "formula (IV) component
  • the components of formula (II) are separately prepared into distilled liquids with a gradient content of 0.2, 0.1, 0.05 and 0.025 mg / ml
  • the formula ( ⁇ ) is formulated with distilled water to a gradient of 0.1, 0.05, 0.025 and 0.0125 mg, respectively.
  • /ml solution The compound of formula (IV) is formulated with distilled water to prepare a solution having a gradient content of 20, 10, 5 and 2.5 m g /ml.
  • the control drug A was a drug solution in which the content of pethidine hydrochloride injection (Qinghai Pharmaceutical Factory, batch number 20010510) was diluted with physiological saline to a content of 2 m g /ml.
  • the control drug B was obtained by dissolving aspirated aspirin tablets (Nanjing Baijingyu Pharmaceutical Factory, batch number 031016) and dissolving in distilled water to obtain a drug solution of 10 mg/ml.
  • mice were randomly divided into groups of 10, one of which was a blank control group, which was given distilled water at a dose of 0.2 ml/10 g body weight; the positive control group A was 40 mg/kg body weight (equivalent to 20 times the clinical dose).
  • the dose was administered intraperitoneally to the control drug A; the positive drug group B was administered with the control drug B at a dose of 200 m g / kg body weight (equivalent to 20 times the clinical dose); the rest was administered by different dose gradients.
  • the present invention corresponds to a test group of test drugs.
  • the administration volume of each of the administration groups was 0.2 ml/10 g body weight.
  • the dose gradients, the doses and the administration methods of the test drugs were the same as those of the above-mentioned writhing test, and the control drug group only used pethidine hydrochloride as a control drug.
  • the temperature of the constant temperature water bath was controlled to 55 ⁇ 0.5°C, and the mice were placed in a constant temperature aluminum drum, and the time from the placement to the hindfoot (pain threshold) was recorded, and the measurement was repeated twice, and the measurement interval was 5 times. Minutes, the average value is the pain threshold before the mice.
  • Mice with a pain threshold of 5 to 30 seconds were grouped into groups of 10 per group.
  • the pain thresholds of the mice were measured twice at 15, 30, 60, 90 and 120 minutes after administration, and the average pain threshold and pain threshold increase rate at each time point were calculated. Statistical analysis was performed on the test data, and the pain threshold increase rate and standard deviation of each group were calculated.
  • mice developed painful reactions such as lameness, kicking hind legs and jumping under thermal stimulation. Only the hind paws were selected as the pain response index.
  • the test results are shown in Table 9.
  • the active ingredients of the present invention have obvious analgesic effects and have a linear effect in a single dose.
  • the pain threshold of the high dose group of the aconitine component of formula (II) was significantly increased at each time point measured, and the analgesic effect of the control drug meperidine hydrochloride was maintained for a long time, within 2 hours.
  • Test Example 3 Analgesic effect test of different ratios of aconitine in benzoyl and aconitine
  • the test showed that the drug benzoyl aconitine 100 mg / kg and the lower aconitine lmg / kg dose have an obvious analgesic effect, the pain inhibition rate was 33.7% and 46.9%.
  • the 300:1, 100:1, 100:3 ratio of benzoyl aconitine and aconitine also significantly inhibited the writhing reaction in mice induced by acetic acid, and the pain inhibition rate was 57. 1%, 61.7% and 40.0%, of which 300: 1, 100: 1 ratio of the dose group is higher than 100mg/kg of benzoyl aconitine and 1mg/k g of aconitine .
  • Benzoyl aconitine light yellow powder; Hypaconitine, white crystalline granules, supplied by Chengdu Zhizhi Pharmaceutical Co., Ltd.
  • Weigh 250 mg of aconitine in benzoyl add 2.5 ml of absolute ethanol, heat in a water bath at 42 ° C and solubilize with ultrasound, add distilled water to 25 ml, and prepare benzoyl aconite.
  • a solution of 10 mg/ml of the base weigh 2. 5 mg of aconitine, add 2.5 ml of absolute ethanol, and after heating in a water bath at 42 ° C and ultrasonic solubilization, add distilled water to 25 ml to prepare a mixture.
  • a solution of aconitine 0.1 mg/ml According to Table 10, different volumes of benzoyl aconitine base V under aconitine solution were prepared and formulated into different proportions of benzoyl aconitine and aconitine solution.
  • Aspirin enteric-coated tablets white, 25 mg/tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd., batch number: 20050312. Take 4 tablets of aspirin enteric-coated tablets, grind them, and use distilled water to 10 ml to prepare a liquid containing aspirin 10 mg/ml. Take 1ml of absolute ethanol, add distilled water to 10 ml of 103 ⁇ 4 ethanol
  • Glacial acetic acid Analytically pure, Chengdu Chemical Reagent Factory Batch No.: 2005042
  • mice were randomly divided into 7 groups, 10 rats, male and female weighing 18 ⁇ 22g e
  • Group 1 was the negative control group was given 10% ethanol 0.2 ml / 10g body weight;
  • Group 2 positive The control group was given 200 mg/kg of escitalin (equivalent to 20 times of clinical dose);
  • Groups 3, 4, 5, and 6. were the aconitine and aconitine in the drug benzamidine and its Three different proportions of the dose group were given benzoyl aconitine, aconitine and three different ratios, respectively.
  • the dosages of each group were 0.2 ml/lOg, and 30 doses were administered.
  • Injection of acetic acid can cause longer-lasting painful stimulation in mice.
  • the mice repeatedly have abdomen and hind leg extension, and the hips are high (twisted).
  • the number of writhing in mice induced by glacial acetic acid was significantly decreased (P ⁇ 0.001), and the analgesic effect was very obvious.
  • the pain inhibition rate was 82.9%.
  • Test Example 4 Analgesic effect test of different ratios of aconitine and mesaconine
  • Aconitine white crystalline granules; aconitine, near white powder, supplied by Chengdu Zhizhi Pharmaceutical Co., Ltd. Weigh 2.5 mg of aconitine, add 2.5 ml of absolute ethanol, heat in 42 ⁇ water bath and sonicate, add distilled water to 25 ml, and prepare a solution containing 0.1 mg/ml of aconitine; Head base 1.25 mg, add 2.5 ml of absolute ethanol, heated in 42 ° water bath and sonicated, add distilled water to 25 ml, and prepare a solution containing aconitine 0.05 mg / ml.
  • Table 12 different volumes of hypoxazone and aconitine solution were prepared into different ratios of hypoxazone and aconitine solution, and spare D
  • Aspirin enteric-coated tablets white, 25nig/tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd. Batch number: 20050312. Take 4 tablets of aspirin enteric-coated tablets, grind them, and use distilled water to 10 ml to prepare a liquid containing aspirin 10 mg/ml.
  • Kunming mice male and female, 18 ⁇ 22 g, provided by Experimental Animal Center of Sichuan University, primary animal, certificate number: No. 10; vocabulary provider with animals, free drinking water, observation room temperature is 21 ⁇ 2 ° C, relative humidity: 50 ⁇ 60%.
  • Glacial acetic acid Analytically pure, Chengdu Chemical Reagent Factory, batch number: 20050423.
  • mice Seventy Kunming mice were randomly divided into 7 groups, 10 males and a half each, weighing 18-22 g.
  • Group 1 was given a negative control group with 10% ethanol 0.2ml/10g ⁇ weight;
  • Group 2 was a positive control group, and aspirin was given 200 mg/kg by gavage (equivalent to 20 times the clinical dose); 3 ⁇ 4 5, 6.
  • Group 7 was given aconitine, aconitine and its three different ratios in the treatment of aconitine and its three different ratios.
  • the dosage volume of the group was 0.2 ml/lOg, and 0.2 ml/0.6 ml of glacial acetic acid solution was intraperitoneally injected 30 minutes after the administration, and the writhing reaction of each mouse within 10 minutes after the injection of the acetic acid solution for 5 minutes was observed. (The number of abdomen hind legs stretched up the hips). Statistical analysis was performed on the test data to calculate the mean, standard deviation and pain inhibition rate of the writhing body in each dose group. The difference between the groups of the drug-administered group and the negative control group was compared by t test.
  • the drugs had a significant analgesic effect on the aconitine lmg/kg and the aconitine 0.5 mg/kg dose, and the pain inhibition rates were 46.9% and 73.1%, respectively.
  • the 6:1, 2:1, and 2:3 ratio drugs of hypocotyl and aconitine also significantly inhibited the writhing reaction induced by acetic acid in mice, and the pain inhibition rates were 74.3%, 66.9%, and 78.3%. It can be seen from the pain inhibition rate that the following analgesic effect is the strongest when the ratio of aconitine and meconium is 2:3. It can be considered that the best ratio of the analgesic effect of the lower aconitine and the aconitine is 2:3.
  • Test Example 5 Analgesic effect test of different ratios of aconitine and aconitine in benzoyl
  • the experiment showed that the drug benzoyl aconitine 100rag/kg and mesaconitine 0.5mg/kg dose had obvious analgesic effect, and the pain inhibition rates were 33.7% and 73.1%, respectively.
  • the 600:1, 200:1, and 200:3 ratio of benzoyl aconitine and aconitine also significantly inhibited the writhing reaction in mice induced by acetic acid, and the pain inhibition rate was 51.4. %, 75.4% and 84.6%, of which the ratio of 200:1, 200:3 was higher than 100 mg/kg of benzoyl aconitine and 0.5 mg/kg of aconitine.
  • Benzoyl aconitine light yellow powder; Aconitine near white powder is supplied by Chengdu Zhizhi Pharmaceutical Co., Ltd. Weigh benzoyl aconitine 250 mg, add 2.5 ml of anhydrous acetamidine, After heating in 42 °C water bath and ultrasonic assisted solution, add steamed water to 25 ml to prepare a solution containing 10 mg/ml of benzoyl aconitine; weigh aconitine.
  • Aspirin enteric-coated tablets white 25mg/tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd., batch number: 20050312 0
  • Kunming mice male and female, 18 22 g, provided first-class animals by the Experimental Animal Center of Sichuan University, certificate number: No. 10; vocabulary provider with animals, free drinking water, observation room temperature is 21 ⁇ 2 ⁇ , relative humidity: 50 60%
  • Glacial acetic acid Analytically pure, Chengdu Chemical Reagent Factory, batch number:
  • mice Seventy Kunming mice were randomly divided into 7 groups, 10 in each group, half male and half female, weighing 18 22g.
  • Group 1 was a negative control group, and 10% ethanol was administered orally with 0.2 ml/10 g body weight;
  • Group 2 was a positive control group, and aspirin was given 200 mg/kg by gavage (equivalent to 20 times the clinical dose);
  • 5 6 7 groups were the drug benzoyl aconitine, mesaconitine and its three different ratios.
  • the benzoyl aconitine 3 ⁇ 43 ⁇ 4, aconitine and 3 of them were administered by gavage.
  • each group of the drug volume was .2 ml / lOg, intraperitoneal injection of 0.6% glacial acetic acid solution 0.2 ml / only 30 minutes after administration, observed within 10 minutes after the injection of acetic acid solution for 5 minutes
  • the number of times the writhing reaction of the mouse (the abdomen hind legs stretched and the buttocks rose).
  • Statistical analysis was performed on the test data, and the mean, standard deviation and pain inhibition rate of the writhing body in each dose group were calculated, and the difference between the groups of the drug-administered group and the negative control group was compared by t test.
  • Injection of acetic acid can cause longer-lasting painful stimulation in mice.
  • the mice have repeated abdominal and hind leg extension, and the buttocks rise (the writhing reaction.
  • Aspirin-positive control group the number of writhing in mice caused by glacial acetic acid decreased significantly (P ⁇ 0.001), the analgesic effect is very obvious, the pain inhibition rate is 82.9%.
  • the drug benzoyl aconitine lOOmg/kg and mesaconitine 0.5mg/kg dose have significantly reduced mice induced by acetic acid Twisting reaction, its pain Pain inhibition rates were 33.7% and 73.13 ⁇ 4 "in aconine benzoyl aconitine 600: 1,200: 1,200: 3 ratio of drugs have varying degrees of inhibition of writhing in mice caused by acetic acid s
  • the number of writhings was significantly different from that of the negative control group, showing a significant 12345 difference, showing a significant analgesic effect; the pain inhibition rates were 51.43 ⁇ 4, 75.43 ⁇ 4 and 84.6%, respectively, of which 200:1, 200:3 ratio
  • the aconitine and the aconitine of 0.5 mg/kg were higher than 100 m g /kg.
  • the drug benzoyl aconitine 100mg/kg and mesaconitine 0.5m g / kg dose have obvious analgesic effect, the pain inhibition rate is 33.7% and 73.1%.
  • the 600:1, 200:1, 200:3 ratio of benzoyl aconitine and aconitine also significantly inhibited the writhing reaction in mice induced by acetic acid, and the pain inhibition rate was 51.4. %, 75.4% and 84.6%, of which the ratio of 200:1, 200:3 in the dose group was higher than 100 mg/kg of benzoyl aconitine and 0.5 mg/kg of aconitine.
  • Test Example 6 Analgesic effect test of benzoyl aconitine, aconitine and mesaconine in different proportions.
  • Benzoyl aconitine light yellow powder; aconitine, near white powder; hypocotyl, white crystalline granules, supplied by Chengdu Zhizhi Pharmaceutical Co., Ltd.
  • Weigh 250 mg of acetoyl aconitine add 2.5 ml of anhydrous alcohol, heat in 42 °C water bath and sonicate, add distilled water to 25 ml, and prepare benzoyl aconitine 10 m g /ml solution; weigh 1.25 m g of aconitine, add 2.5 ml of absolute ethanol, after heating in 42 ° C water bath and ultrasonic solubilization, add distilled water to 25 ml, and prepare aconitine a solution of 0.05 mg/ml; weigh 2.5 mg of aconitine, add 2.5 ml of absolute ethanol, heat it in a water bath at 42 ° C and solubilize with ultrasound, add distilled water to 25 ml, and formulate acon
  • benzoyl group the proportion of the mixture, aconitine, aconitine, aconite, lower aconite, 3 ⁇ 4
  • Glacial acetic acid Analytical purity Chengdu Chemical Reagent Factory, batch number: 20050423
  • Kunming mice were randomly divided into 6 groups, 10 per group, male and female weighing 18 ⁇ 22g Q
  • Group 1 was the negative control group, 10% of intragastric administration of ethanol 0.2ml / 10g body weight;
  • Group 2 For the positive control group, aspirin was given 200 mg/kg by gavage (equivalent to 20 times of the clinical dose);
  • the third group was the drug of benzoyl aconitine, aconitine and hypoaconitine.
  • Four different proportions of the dose group were administered with 4 different ratios of benzoyl aconitine and aconitine and aconitine. The dosages of each group were 0.2ml/10g.
  • Injection of acetic acid can cause longer-lasting painful stimulation in mice.
  • the mice repeatedly have abdomen and hind leg extension, and the hips are high (twisted).
  • the number of writhing in mice induced by glacial acetic acid was significantly decreased (P ⁇ 0.001), and the analgesic effect was very obvious.
  • the pain inhibition rate was 88.0%.
  • the compound benzoyl aconitine, aconitine and hypoaconitine have a ratio of 200:1:2, 400:1:2, 100:1:1 and 200:1:4.
  • the writhing response of mice induced by acetic acid was reduced to some extent.
  • mice The number of writhing reactions in mice was significantly different from that of the negative control group, showing obvious analgesic effect.
  • the pain inhibition rate was 85.0%. 65.3%, 90.1%, and 86.1%.
  • the results are shown in Table 17. From the perspective of pain inhibition rate, the ratio of aconitine, aconitine and hypoaconitine in benzoyl is not dose-dependent; the ratio is 100:1:1, the dosage is small.
  • the analgesic effect is the strongest, achieving the goal of high efficiency and low toxicity.
  • the compound benzoyl aconitine, aconitine and lower aconitine have different analgesic effects.
  • the aconitine and wuwu in the benzoyl aconitine The ratio of head to base ratio is 200:1:2, 5 400:1:2, 100:1:1 and 200:1:4, the analgesic effect is the strongest at a ratio of 100:1:1, so benzoyl
  • the best analgesic effect of aconitine and aconitine in Zhongwutou base is 100:1:1.
  • Test Example 7 Analgesic effect test of intramuscular injection of aconitine in benzoyl
  • Benzoyl aconitine light yellow powder was supplied by Chengdu Zhizhi Pharmaceutical Co., Ltd. Weighed 125 mg of benzoyl aconitine, added 1.25 ml of absolute ethanol, heated by 42 ⁇ water bath and ultrasonically assisted. Serve to 25 ml., prepare a solution containing 5 mg/ml of aconitine in benzoyl, take 2.5 ml, add normal saline to 10 ml,
  • Kunming mice male and female, 18 ⁇ 22 g, provided by Experimental Animal Center of Sichuan University, first-class animals, certificate number: ⁇ 10; vocabulary provider with animals, free drinking water, observation room temperature is 21 ⁇ 2 ° C, relative humidity: 50 ⁇ 60%.
  • Glacial acetic acid Analytically pure, Chengdu Chemical Reagent Factory, Lot No.: 20050423
  • Fifty Kunming mice were randomly divided into 5 groups, 10 in each group, half male and half female, weighing 18 ⁇ 22g.
  • Group 1 was a negative control group, and 5% ethanol was given to the leg muscles by 0.2 ml/10 g body weight; the second group was a positive pair.
  • intragastric administration of aspirin 200 mg / kg (equivalent to 20 times the clinical dose); group 3 by intragastric administration of 5mg / ml
  • ⁇ 0 is different from the group of each administration group and the negative control group.
  • Injection of acetic acid can cause longer-lasting painful stimulation in mice, and the mice repeatedly have abdomen hind legs stretched and hips twitched (twisted body).
  • the number of writhing in mice induced by glacial acetic acid decreased significantly ( ⁇ 0.001), and the analgesic effect was very obvious.
  • the pain inhibition rate was 81.6%.
  • the drug benzoyl aconitine tendon 5 meat injection and intragastric administration of 100m g / kg can significantly reduce the writhing response induced by acetic acid in mice, the pain inhibition rate was 98.6% and ' 37.2%.
  • the analgesic effect of intramuscular injection was significantly stronger than that of intragastric administration.
  • mice injected intramuscularly with 100 mg/k g of benzoyl aconitine showed atrophy and decreased movement. The toxicity of the drug is more obvious. In practice, the dosage of benzoyl aconitine in intramuscular injection should be much lower than that of intragastric administration to avoid the occurrence of toxicity.
  • the muscle-stimulating drugs benzoyl aconitine 100 and 25 mg/kg had significant analgesic effects, and the analgesic effect was significantly stronger than that of 100 mg/kg.
  • the pain inhibition rate was 98.63 ⁇ 4. And 93.5%, and the pain inhibition rate of lOOmg/kg by intragastric administration is 37.2% jointlybut the same dose of toxic reaction is also more important than intragastric administration, indicating that in practical application, benzoyl Intramuscular injection of aconitine should be administered at a much lower dose than intragastric administration in order to avoid the occurrence of toxic reactions.
  • Tests have shown that benzoyl aconitine is compatible with mesaconitine or hypoaconitine. The analgesic effect can obviously achieve high efficiency and low toxicity. It is a new drug route test. ⁇ Analgesic effect test of benzoyl aconitine skin administration
  • Vaseline In the Vaseline, mix well, and evaporate the ether in a 37 °C oven overnight to prepare a Vaseline cream containing about 16 mg/g of benzoyl aconitine.
  • Aspirin enteric-coated tablets white, 25 mg/tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd., batch number: 20050312» Take 4 tablets of aspirin enteric-coated tablets, grind, use distilled water to 10 ml, and mix with aspirin 10 mg/ml Liquid, spare.
  • Kunming mice male and female, 18 ⁇ 22 g, provided by Experimental Animal Center of Sichuan University, primary animal, certificate number: No. 10; vocabulary provider with animals, free drinking water, observation room temperature is 21 ⁇ 2 ° C, relative humidity: 50 ⁇ 60%.
  • Glacial acetic acid Analytically pure, Chengdu Chemical Reagent Factory, batch number: 20050423.
  • mice Forty Kunming mice were randomly divided into 4 groups, 10 in each group, half male and half female, weighing 18 ⁇ 22 g. The day before the administration, the back of the mouse was roughly cut with a pair of scissors, and the hair was removed with an 8% sodium sulfide solution, and the area was 1. 5 cmX 1. 5 cm. The first group was a negative control group, and the skin of the back was uniformly coated with a negative control of the Vaseline cream 0. Ig/ Only ⁇ then gently covered with a layer of gauze (l. 5emX 1.
  • the second group was given aspirin 200 mg/kg (equivalent to 20 times the clinical dose) for the positive control group;
  • Group 4 coated with 16 mg / g benzoyl aconitine ointment 0. 05 8 / only prison two coated ointment group is also covered with a layer of gauze (1. 5cmX 1. 5cm) after application.
  • the rest was given an intraperitoneal injection of 0. 63 ⁇ 4 glacial acetic acid solution 0.
  • the drug benzoyl aconitine can significantly reduce the writhing reaction induced by acetic acid when the skin is applied at a dose of about 800 mg/kg.
  • the pain inhibition rate is 33.6%; the analgesic effect is not obvious in the 400 mg/kg dose group. .
  • the results showed that acetoyl aconitine played an analgesic effect on the skin for external use, and the dose used was higher. It is indicated that in this experiment, the skin absorption efficiency of aconitine in benzoyl is not high, and if the addition of excipients can be improved in the future, the skin absorption of aconitine in benzoyl can be promoted, which will help to reduce the dose. , cut costs. Tests have shown that benzoyl aconitine can be synergistically synergistic when used in combination with mesaconine or hypoaconitine, achieving high efficiency and low toxicity, and is a new route of administration.
  • Test Example 9 Analgesic effect test of intramuscular injection of aconitine
  • Aspirin enteric-coated tablets white, 25 mg/tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd., batch number: 20050312. Take 4 tablets of aspirin enteric-coated tablets, grind with distilled water to lO niL to prepare a liquid containing aspirin and weigh 10 mg/ml.
  • Glacial acetic acid Analytically pure, Chengdu Chemical Reagent Factory, batch number: 20050423.
  • Kunming mice 50 ml of Kunming mice were randomly divided into 5 groups, each group of 10 males and females, body weight 18 ⁇ 22 gffl, group 1 was negative control group, 5 leg muscles were injected intramuscularly with 52 ⁇ 4 ethanol 0. 2 ml/lOg body weight; 2 groups were positive control group, aspirin 200 mg/kg was administered by gavage (corresponding to 20 times of clinical dose); group 3 was given 0. 05 mg/ml of hypotocaline solution, and group 4 was given intramuscular injection of 0. 5 ⁇ /10g, intraperitoneal injection 30 minutes after administration, the lower aconitine solution of the 05 mg / ml group, the intramuscular injection of 0. 0125mg / ml of the lower aconitine solution is 0.
  • Injection of acetic acid can cause longer-lasting painful stimulation in mice, and the mice repeatedly have abdomen hind legs and hips high (twisted body) response.
  • the number of writhing in the mice induced by glacial acetic acid was significantly decreased (P ⁇ 0.001), and the analgesic effect was very obvious.
  • the pain inhibition rate was 81.6%.
  • Both intramuscular injection of aconitine and intragastric administration of lmg/kg significantly reduced the writhing response induced by acetic acid in mice, and the pain inhibition rates were 47.7% and 100%, respectively.
  • the analgesic effect of intramuscular injection was significantly stronger than that of intragastric administration.
  • mice with intramuscular injection of 0.25 mg/kg showed atrophy, less movement, and hiccup-like toxicity. It is indicated that, in practical application, when intramuscular injection of hypoxazone is administered, the dose should be It is much lower than the intragastric administration to avoid the occurrence of toxic reactions.
  • the doses of aconitine 100 and 25 mg/kg in the filth-injected drugs have very obvious analgesic effects, and the pain inhibition rate is 100%.
  • the analgesic effect of intramuscular injection of the same dose was significantly stronger than that of intragastric administration, but the toxicity was also heavier than that of intragastric administration. It indicated that in practical application, the dose of aconite should be administered intramuscularly.
  • the medicine is much lower, which not only maintains the efficacy but also avoids the occurrence of toxic reactions. Tests have shown that when aconitine is used in combination with mesaconitine or benzoyl aconitine, it can synergistically increase efficiency and achieve high efficiency and low toxicity. It is a new route of administration.
  • Test Example 10 Analgesic effect test of subcutaneous aconitine skin administration
  • Aspirin enteric-coated tablets white, 25 mg/tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd. Batch number: 20050312 Take 4 pieces of aspirin enteric-coated tablets, use distilled water to 10 ml, and prepare a medicine containing aspirin # 10 mg/nil Liquid spare.
  • Glacial acetic acid Analytical purity Chengdu Chemical Reagent Factory, batch number: 20050423.
  • mice 40 Kunming mice were randomly divided into 4 groups, 10 in each group, half male and half female, weighing 18 ⁇ 22 g. One day before the administration, the back hair of the mice was roughly cut with scissors, and the hair was removed with 8% sodium sulfide solution. The area was 1. 5 cmX 1. 5cm 0
  • the first group was a negative control group, and the skin of the back was depilated with a negative control of Vaseline cream 0. lg / only, then a layer of gauze ( 1. 5cmX 1 5cm) lightly covered; the second group was a positive control group, and the aspirin was given 200 mg/kg by gavage (equivalent to 20 times the clinical dose); the third group was coated with a skin at the back of the hair removal treatment.
  • the medicinal ointment containing 1. 6mg / g of aconitine 0. 05g / only.
  • the two-coated ointment group was also lightly covered with a layer of gauze (1.5 cm X 1. 5 cm) after application.
  • the 5% glacial acetic acid solution 0. 2 ml/only, observed, after the administration of 0.5% glacial acetic acid solution.
  • the number of writhing responses (abdominal hind leg extension, buttocks height) of each mouse within 10 minutes after injection of the acetic acid solution for 5 minutes was recorded.
  • Statistical analysis was performed on the test data, and the mean, standard deviation and pain inhibition rate of the writhing body in each dose group were calculated. The difference between the groups of the drug-administered group and the negative control group was compared by t test.
  • Table 21 The results showed that the lower aconitine exerted an analgesic effect on the external use of the skin, and the dosage used was higher.
  • the drug used in the treatment of aconitine skin at a dose of about 8mg / kg can significantly reduce the mouse torsion reaction caused by ester acid. 5. Pain inhibition rate is 37.2%; 4mg / kg dose group despite the pain inhibition rate of 31 8%, but the number of writhing reactions in mice was not significantly different from that in the negative control group, indicating that the analgesic effect was not obvious. The results showed that the higher dose of aconitine for external analgesia was indicated in this experiment. The skin absorption efficiency of middle and lower aconitine is not high. If the addition of excipients can be improved in the future, promoting the skin absorption of lower aconitine will help to reduce the dose reduction. Tests have shown that the combination of aconitine and mesaconine or benzoyl aconitine can synergistically increase the efficacy of 0 to achieve high efficiency and low toxicity is a new route of administration.
  • Test Example 11 Analgesic effect test of intramuscular injection of aconitine
  • Aspirin enteric-coated tablets white, 25 mg / tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd., batch number: 20050312. Take 4 tablets of aspirin enteric-coated tablets, grind them, use distilled water to 10 ml, and prepare a liquid containing aspirin 10 mg/ml.
  • Kunming mice male and female, 18 ⁇ 22 g, provided by Experimental Animal Center of Sichuan University, primary animal, certificate number: No. 10; vocabulary provider with animals, free drinking water, observation room temperature is 21 ⁇ 2 ° C, relative humidity: 50 ⁇ 603 ⁇ 4.
  • Glacial acetic acid Analytically pure, Chengdu Chemical Reagent Factory, batch number: 20050423.
  • mice Sixty Kunming mice were randomly divided into 6 groups, 10 in each group, half male and half female, weighing 18 ⁇ 22 g.
  • the first group was a negative control group, and the intramuscular injection of 5% ethanol was 0. 2 ml/lOg body weight; the second group was positive for the 40 group, and the aspirin was given 200 mg/kg by gavage (equivalent to 20 clinical doses).
  • 00625rag/ml ⁇ The first group of intramuscular injection of 0. 025mg / ml of aconitine solution, the fourth group of intramuscular injection of 0. 025mg / ml of aconitine solution, the fifth group of intramuscular injection of 0.
  • Injection of acetic acid can cause longer-lasting painful stimulation in mice, and the mice repeatedly have abdomen hind legs stretching and hips high (twisting) response.
  • the aspirin-positive control group had a significant decrease in the number of writhing in mice induced by glacial acetic acid ( ⁇ 0. 001), and the analgesic effect was very obvious.
  • the pain inhibition rate was 81.63 ⁇ 4.
  • 10 mice due to the toxicity of intramuscular injection of 0.5 mg/kg of aconitine, 10 mice showed obvious atrophy and less dyspnea after intramuscular injection. In 30 minutes, 8 died, although The remaining two did not show a torsion reaction in the experiment. The concentration was further diluted and the dose was lowered.
  • mice injected intramuscularly with 0. 125mg/kg of aconitine also showed atrophy and less mitigation. It is indicated that in practical application, when intramuscular injection of aconitine is administered, the dose should be much lower than that of intragastric administration to avoid the occurrence of toxic reactions.
  • mice were intramuscularly injected with 0.5 mg/kg of aconitine 30 min later, and 8 died. This data is the observation result of the remaining two.
  • Intramuscular injection of 0.5 mg/kg of aconitine is too toxic.
  • the analgesic effect of the analgesic effect of the aconitine was significantly higher than that of the 0. 5 mg/kg intragastric administration, and the pain inhibition rate was 99. 6 7% ⁇ The pain inhibition rate of 56. 7%.
  • Muscle injection 0. 125 mg / kg in the aconitine group also showed atrophy, less movement, hiccup-like toxicity, only a lesser degree. It is indicated that in practical application, when intramuscular injection of aconitine is administered, the dose should be much lower than that of intragastric administration to avoid the occurrence of toxicity.
  • Test Example 12 Analgesic effect test of aconitine skin administration
  • Aspirin enteric-coated tablets white, 25 mg/tablet, Xuzhou Enhua Pharmaceutical Group Co., Ltd., batch number: 20050312. Take 4 tablets of aspirin enteric-coated tablets, grind them, and use distilled water to 10 ml to prepare a liquid containing aspirin 10 mg/ml.
  • Vaseline paste Take 2g of Vaseline, add 2. 5 ml of ether, mix well, and evaporate the ether in a 37 °C oven overnight to prepare a negative control Vaseline paste.
  • Kunming mice male and female, 18 ⁇ 22 g, provided by Experimental Animal Center of Sichuan University, first-class animal, pile number: No. 10; feeding provider with animals, free drinking water, observation room temperature is 21 ⁇ 2°C, relatively wet The degree is: 50 ⁇ 603 ⁇ 4.
  • Ice vinegar Analytically pure, Chengdu Chemical Reagent Factory Lot Number: 20050423 ⁇
  • mice 40 Kunming mice were randomly divided into 4 groups, 10 rats in each group, half male and half female, weighing 18 ⁇ 22 g ffl . The day before the administration, scissors were used to roughly cut off the back hair of the mice, and the area was removed with 8% sodium sulfide solution. 1. 5 cmX 1. 5cm. The first group was a negative control group, and the skin was evenly coated with a negative control in the back of the hair removal treatment. 0. Ig / only then with a layer of gauze (1. 5cmX 1. 5cm 8m g /g ⁇ The second group of the positive control group was given aspirin 200 mg / kg (equivalent to 20 times the clinical dose); Oral aconitine ointment O.
  • Injection of acetic acid can cause longer-lasting painful stimulation in mice, and the mice repeatedly have a high back (twisted body) reaction in the hind legs.
  • the number of writhing in mice induced by glacial acetic acid was significantly decreased (P ⁇ 0.001), and the analgesic effect was very obvious.
  • the pain inhibition rate was 81.6% D.
  • Aconitine was used as skin for external use.
  • the dose of about 4 mg/kg the writhing response of mice induced by acetic acid was significantly reduced, and the pain inhibition rate was 34.3%; the number of writhing reactions in the 2 mg/kg dose group was compared with the negative control group.
  • Aspirin 200 ig. 10 5. 1 ⁇ 6. 0*** 81. 6 aconitine about 4 external use 10 18. 2 ⁇ 7. 34. 3
  • Drug skin external aconitine about 4m g / mouse can significantly reduce the acetic acid induced writhing when k g dose, pain inhibition rate was 34.3%; the number of reaction 2mg / kg dose group and writhing Compared with the negative control group, there was no significant difference, indicating that the analgesic effect was not obvious.

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Abstract

La présente invention a pour objet une préparation pharmaceutique analgésique, constituée d'au moins deux des composants actifs suivants : benzoylmesaconine 0-600 parts, mesaconitine 0-6 parts, hypaconitine 0-3 parts. La quantité d’au moins deux desdits composants actifs est différente de zéro. Cette préparation a un effet synergique.
PCT/CN2005/001295 2004-08-19 2005-08-18 Préparation pharmaceutique analgésique WO2006017994A1 (fr)

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