WO2010028596A1 - 含阿魏酸与苦参碱类化合物的药物组合物及其制备和用途 - Google Patents

含阿魏酸与苦参碱类化合物的药物组合物及其制备和用途 Download PDF

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WO2010028596A1
WO2010028596A1 PCT/CN2009/073837 CN2009073837W WO2010028596A1 WO 2010028596 A1 WO2010028596 A1 WO 2010028596A1 CN 2009073837 W CN2009073837 W CN 2009073837W WO 2010028596 A1 WO2010028596 A1 WO 2010028596A1
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Prior art keywords
ferulic acid
pharmaceutical composition
matrine
compound
preparation
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PCT/CN2009/073837
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English (en)
French (fr)
Inventor
孙小杰
马维富
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青岛启元生物技术有限公司
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Priority claimed from CN200810304457A external-priority patent/CN101669945A/zh
Priority claimed from CN200810304458A external-priority patent/CN101669946A/zh
Priority claimed from CN200810304902A external-priority patent/CN101723944A/zh
Priority claimed from CN200810305381A external-priority patent/CN101732299A/zh
Application filed by 青岛启元生物技术有限公司 filed Critical 青岛启元生物技术有限公司
Priority to EP09812662A priority Critical patent/EP2343065A4/en
Priority to JP2011520315A priority patent/JP5538386B2/ja
Priority to CA2734309A priority patent/CA2734309C/en
Priority to US13/058,738 priority patent/US8785471B2/en
Publication of WO2010028596A1 publication Critical patent/WO2010028596A1/zh

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    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Definitions

  • composition containing ferulic acid and matrine compound and preparation and use thereof
  • the present invention relates to a pharmaceutical composition comprising ferulic acid and a matrine compound, a process for the preparation of the same, and use thereof.
  • ferulic acid is 4-hydroxy-3-indolyl cinnamic acid, which is a phenolic acid commonly found in the plant kingdom. It is one of the active constituents of traditional Chinese medicines such as Angelica, Chuanxiong and Awei. It is widely present in many kinds. In plants. It can be obtained by extraction or synthesis, which has a wide range of pharmacological effects such as anti-inflammatory, antibacterial, anti-oxidation, immune enhancement, anti-tumor, anti-cardiovascular disease, anti-fibrosis, anti-age dementia and the like. Sophora flavescens is one of the commonly used traditional Chinese medicines.
  • the drugs developed by it include oxymatrine, matrine, and sophoridine, which are mainly used for the treatment of chronic liver diseases, antiviral, antitumor treatment, and cardiovascular disease treatment. They have antiviral and anti-fibrosis. , immune regulation and anti-inflammatory, anti-allergic effects.
  • the pharmaceutical composition containing ferulic acid and matrine can significantly increase the effect of matrine or ferulic acid, and the two have obvious synergistic effects in vivo, which can reduce matrine.
  • the toxicity of the compound increases the water solubility and fat solubility of both.
  • the pharmaceutical composition of the present invention is a pharmaceutical composition containing ferulic acid and a matrine compound.
  • the ferulic acid comprises one or more of the following: ferulic acid, isoferulic acid, isomer of isferic acid, isomer of isoferulic acid Or their inorganic salt compounds; wherein the basic structure of ferulic acid is: The basic structure of isoferulic acid is:
  • the compound mainly includes one or more of the following substances: matrine, oxymatrine, saponin, saponin, sterol, leucovorin, sophoridine, isosporine, or The isomers of these compounds, or their inorganic salts.
  • the matrine compound is one or more of matrine, oxymatrine or saponin, and the molar ratio of ferulic acid to the matrine compound is 1:0. 1 ⁇ 10.
  • the matrine compound is one or two of oxymatrine or matrine, and the molar ratio of ferulic acid to the matrine compound is 1:0. .
  • a second object of the present invention is to provide a pharmaceutical preparation method comprising ferulic acid and a matrine compound, wherein the medicament is a pharmaceutical composition containing ferulic acid and a matrine compound, and the molar is taken.
  • the ferulic acid and the matrine compound having a ratio of 1:0 to 1 are added to a pharmaceutical preparation, and a preparation of a certain dosage form is prepared by a pharmaceutical method.
  • the pharmaceutical excipient may be administered with water for injection, and the water for injection is added to the pharmaceutical composition, and stirred until dissolved to prepare an injection.
  • the pharmaceutical excipient may be used with starch, 10% starch slurry, dry starch and magnesium stearate; the pharmaceutical composition is first mixed with starch, and added with 10% starch slurry. The soft material, after drying, is added with dry starch and magnesium stearate to form an oral tablet.
  • the pharmaceutical excipient can be used with carbomer, propylene glycol, Parabens and purified water; carbomer is dispersed in purified water, parabens are dissolved in propylene glycol, added to the dispersed carbomer, and swollen with purified water; the pharmaceutical composition is dissolved in purified water And added to the above carbomer solution to mix, add purified water and mix and hook, to prepare a skin and mucous membrane preparation.
  • the pharmaceutical composition containing ferulic acid and matrine compound can be applied to anti-fibrosis, change blood rheology, anti-virus, anti-inflammatory, inhibit cholinesterase, analgesic and antipruritic, anti-age dementia Anti-thrombotic, anti-bacterial, anti-tumor, anti-oxidant hypolipidemic, anti-arteriosclerosis, anti-rheumatic, immune-enhancing, anti-hypertensive, increased sperm motility and exercise in the preparation of drugs.
  • the composition containing ferulic acid and matrine compound of the invention has obvious synergistic effect, can not only increase the pharmaceutical effect of ferulic acid, but also The pharmaceutical effect of the matrine compound is increased, and the water solubility and fat solubility of the ferulic acid and the matrine alkaloid are significantly increased.
  • the pharmaceutical composition is prepared into an oral preparation, an injection or a preparation for skin and mucous by pharmacy, and can prevent and treat tumor, arteriosclerosis, heart, cerebrovascular disease, bone and joint disease, cold, dementia, Inflammation of the skin, eczema, acne, maculopapular rash, urticaria, psoriasis, gastrointestinal motility, inflammation of the organs such as hepatitis, nephritis, and organ fibrosis, as well as the effects of acute and chronic inflammation of the whole body or organs.
  • the pharmaceutical composition proposed by the present invention is a pharmaceutical composition containing ferulic acid and a matrine compound.
  • the molar ratio of the ferulic acid to the matrine compound is 1:0.1 to 10, preferably the molar ratio is 1:1 to 5.
  • the ferulic acid may be a positive ferulic acid, isoferulic acid, an isomer of ferulic acid, an isomer of isoferulic acid, or an inorganic salt thereof.
  • the compound or the like may also be a combination of any two or more of the above.
  • the basic structure of ferulic acid is:
  • the basic structure of isoferulic acid is: and the basic structural feature of the matrine compound is a tetracyclic quinolizinidine having the formula:
  • Such compounds mainly include matrine, oxymatrine, saponin, saponin, sterol, leucorrhizine, sophoridine, isosporine, etc., or isomers of the above compounds Or, they may be inorganic salts, and may of course be a combination of any two or more of the above.
  • the matrine compound is preferably one or more of matrine, oxymatrine or saponin, and the molar of ferulic acid and the matrine compound.
  • the ratio is 1:1.0, preferably the molar ratio is 1:1 ⁇ 3.
  • the matrine compound is preferably one or two of oxymatrine or matrine, and the molecular molar ratio of ferulic acid to the matrine compound is 1 : 0. 1-10 , preferably the molar ratio is 1: 1 ⁇ 2.
  • compositions of the above may be formulated with appropriate pharmaceutical excipients, and conventional pharmaceutical preparations may be used to prepare preparations of different dosage forms, such as injections, oral preparations, preparations for skin and mucous membranes, and the like.
  • the present embodiment provides a preparation method of a sodium ferulate sodium oxymatrine compound freeze-dried powder needle. First, sodium ferulate 30. 87g, oxymatrine 69.13g, and 1000ml water for injection were selected.
  • the preparation method is as follows: in a sterile operation room, a sodium ferulate 30. 87 g, oxymatrine 69. 1 g (a molar ratio of sodium ferulate to oxymatrine is 1: 2), placed in a sterile container
  • the 0.02% activated carbon is added to the sterilized water for injection. Stir for 5-10 minutes, filter with 2 layers of sterile filter paper with sterile suction funnel, and then finely filter with sterilized G6 leaching glass funnel. After passing the filtrate, it is packed in 2ml ampoules and frozen at low temperature. After drying for about 24-26 hours, it can be aseptically sealed, each containing 100 mg of the drug.
  • Embodiment 2 provides a method for preparing a fermented alkaloid tablet.
  • ferulic acid which may include 60% of ferulic acid and 40% of isoferulic acid
  • saponin the molar ratio of ferulic acid to saponin is 10:1
  • starch 40 g 10% starch slurry 24 g, dry starch 23 g, magnesium stearate 3 g.
  • the preparation method comprises the following steps: fertilizing ferulic acid and ruthenium through 80 mesh sieve, mixing with starch, adding 10% starch slurry to make soft material, granulating with 14 mesh sieve, and drying at 70-80 ° C. 12 mesh sieved whole granules, mixed with dry starch and magnesium stearate, and then compressed into 1000 tablets, each tablet containing 200 mg of drug.
  • Embodiment 3 This embodiment provides a preparation method of a sodium ferulate oxymatrine gel.
  • the preparation method comprises the following steps: dispersing carbomer with 20 ml of water, dissolving parabens with propylene glycol, adding to the dispersed carbomer, and adding about 500 ml of purified water to swell for 12 to 24 hours; sodium ferulate and sophora flavescens It is dissolved in about 100ml of purified water, added to the above carbomer solution, mixed with purified water to 1000ml, mixed evenly, adjusted to pH 6.5-7.5 with ammonia water, and packed in 20g aluminum plastic tube, quality inspection It will be obtained after passing the test.
  • Embodiment 4 This embodiment provides a preparation method of ferulic acid ginseng total alkali capsule.
  • ferulic acid and 450 g of Sophora flavescens extract are selected (the total alkali content is 60-80%, which contains 10-30% of oxymatrine, 30-60% of matrine, 10-20% of sophorine, and others.
  • Matrine alkaloids are about 1-3%), starch 40g, 10% starch slurry 24g, magnesium stearate 3g.
  • the ferulic acid and Sophora flavescens extracts were passed through an 80 mesh sieve, mixed with starch, and added with 10% starch slurry to make soft materials.
  • the pellets were sieved into 14 mesh sieves, and dried at 70-80 ° C for 12 mesh.
  • the granules, after adding dry starch and magnesium stearate, are mixed with the hard shell of No. 3, and the rubber cap is placed, and 1000 capsules are prepared, each containing 50 mg of ferulic acid and 450 mg of total base of Sophora flavescens.
  • the present embodiment compares the effects of several pharmaceutical compositions on oxymatrine and ferulic acid in analgesic, anti-inflammatory, anti-cholinesterase and the like through a plurality of experimental data.
  • Table 1 is a formulation table of five pharmaceutical compositions.
  • Composition code ferulic acid (molar number) matrine (molar number) oxymatrine (molar number) sophorine (molar number) I 1 1 0 0
  • mice Healthy mice were selected, 10 in each group. After intragastric administration of 20 mg/kg for 3 consecutive days, 30 minutes after the last administration, 0.5% acetic acid 10 ml / kg was intraperitoneally injected. The number of writhing reactions in the mice was recorded within 15 minutes, and the percentage of drug analgesia was calculated.
  • Percentage of drug analgesia (number of writhing in the control group - number of writhing in the treatment group) / number of writhing in the control group X 100%
  • Table 2 is a comparison of the analgesic effects of oxymatrine, ferulic acid and five pharmaceutical compositions on mouse acetic acid writhing.
  • the dosage and pharmaceutical composition were prepared as shown in Table 1. Healthy mice were selected, and 10 mice in each group were weighed. The right ear of the mouse was contacted with a diphenyl phenyl cotton ball for 5 seconds, and the left ear was used as the left ear. Control, after 10 minutes of inflammation, respectively, on the inflammation-induced ear shell, the drug concentration was 1% of the test drug, the blank control group was given normal saline, and after 30 minutes, the mouse neck was dislocated and the diameter was 6 mm. The puncher is weighed by the left (self-control) and the right ear (diphenylbenzene treatment), and the ear swelling rate is calculated:
  • Ear swelling rate (%) right ear weight - left ear weight / left ear weight X 100%.
  • Group swelling rate (%) right ear weight - left ear weight / left ear weight X 100%.
  • hepatic stellate cell proliferation and secretory I collagen Materials and reagents: Rat type I collagen ELISA kit, trypsin, fetal bovine serum, etc.
  • METHODS Rat hepatic stellate cells (HSC) were resuscitated, inoculated in a 100 mL plastic flask, and cultured in a C02 incubator with 5% CO 2 and 95% humidity.
  • the culture flask After the cells in the culture flask grow into a single layer, discard the culture solution, add 0.25% trypsin digestion solution, collect the digestive juice, centrifuge at 2200 rPmin for 7 minutes, discard the supernatant, and then centrifuge once with DMEM medium to wash the cell mass.
  • the block was suspended and counted in a DMEM containing 20% fetal bovine serum.
  • the cell suspension was diluted with DMEM-containing medium and inoculated into a 96-well culture plate at 100 ⁇ l per well for 48 hours, then the culture solution was aspirated and then contained 10%.
  • the DMEM medium of calf serum synchronizes the cells to synchronize the cells in the stationary phase.
  • the experimental group (physiological saline) was added with the drug so that the concentration of the drug in each group was 50 ⁇ /L, and the culture was repeated 3 times in each well. After 48 hours, the culture was terminated, and 5 mg/L thiazole was added to each well. Blue ( ⁇ ) 20 ⁇ , further cultured for 4 h, shaken for 10 minutes after adding DMS0, and the absorbance of HSC was measured with a microplate reader (wavelength 570). After the drug is taken, the cells are cultured as described above, and the supernatant is aspirated, and the type I collagen content is determined according to the kit instructions. The results are shown in Table 5.
  • the drug was diluted with physiological saline to a solution to be tested at 0 5 10 20 40 80 160 320 640 mg/L.
  • the activity of whole blood acetylcholinesterase was measured according to the acetylcholinesterase kit instructions, and the half inhibitory concentration (IC50) was calculated.
  • IC50 half inhibitory concentration
  • Drugs and reagents Kushensu injection, Shandong Xinhua Pharmaceutical Co., Ltd. (batch number: 0306003); ⁇ , Shandong Tianfu Pharmaceutical Factory (batch number: 0404131); Atropine sulfate injection, produced by Shandong Tianfu Pharmaceutical Factory (batch number: 0409271); morphine sulfate controlled release tablets, produced by Beijing Mengti Pharmaceutical Co., Ltd. (batch number: 04082312).
  • mice were intragastrically administered with the corresponding drugs or physiological saline for 3 consecutive days. After the last administration, the rats were fasted for 16 hours. After 30 minutes of administration, each mouse was intragastrically administered with 5% activated carbon suspension. 2 ml, 20 minutes later, the mice were sacrificed by dislocation, the mesenteric membrane was opened by abdominal cavity, the intestine of the pylorus to the ileocecal area was cut, placed on a tray, the small intestine was gently drawn into a straight line, and the length of the intestine was measured as the total length of the small intestine. The distance to the leading edge of the charcoal is used as the propulsion distance of the charcoal in the intestine. Calculate the carbon propulsion rate using the following formula:
  • Charcoal propulsion rate (%) propellant distance in the intestine / total length of the small intestine X 100%
  • Table 7 shows the effects of several compounds on the intestinal propulsion rate in normal mice (: SD). Compared with the control group: * P ⁇ 0.05. ** p ⁇ 0.01. Where p is a statistically significant value; * P ⁇ 0.05, indicating a statistically significant difference; ** P ⁇ 0.01, indicating a statistically significant difference.
  • mice Take mice, 10 rats in each group, once intragastric administration, observe 72 hours, record death Compound dose (mg/kg) N Number of dead animals
  • Test method 140 males were randomly divided into 7 groups, normal control group, model group, positive control group (lovastatin 10 mg/kg), ferulic acid oral control group (40 mg/kg) and pharmaceutical composition. High, medium and low dose groups (10, 20, 40 mg/kg, respectively). In addition to the normal control group fed the basic feed, the remaining 6 groups were established according to the literature method to establish a high-fat diet arteriosclerosis model.
  • Each drug group was intragastrically administered once a day for 4 weeks. At the end of the fourth week after administration, 10 animals in each group were tested for serum lipids. Pathological examination of surviving sputum was performed at the end of the experiment.
  • Serum lipid content determination In the 4th week after the drug administration, 2 mL of blood was taken from the jugular vein after 12 hours of fasting, serum was separated, and serum cholesterol (TC) and triglyceride (TG) levels were determined by enzymatic method.
  • TC serum cholesterol
  • TG triglyceride
  • RESULTS The avermectin composition of ferulic acid significantly reduced the levels of serum TC and TG in the arteriosclerosis model, and its effect was significantly enhanced compared with ferulic acid, as shown in Table 9. Most of the aorta in the model group had obvious lesions. Most of the atherosclerosis As lesions were above grade 2, and the aortic atherosclerosis of the avermectin composition was aortic. The degree of lesions is lighter, mostly below 1 ⁇ 2, see Table 10. Microscopically, most of the arterial intima are intact, some have mild lipid infiltration, and the inner part is scattered in foam cells.
  • Table 10 Effect of oxymatrine with ferulic acid on aortic atherosclerotic lesions in hyperlipidemia The following is the effect of ferulic acid matrine gel on acute rheumatoid arthritis.
  • Preparation of the drug After ferulic acid and matrine are mixed at a molar ratio of 1:1, a cream is prepared according to a pharmacy method.
  • Case selection Age 18-25 years old, bilateral rash on the body, gender is not limited, 10 cases of each drug experiment. Partially applied 1% drug on the rash, self-single blind control, drug on the left limb, normal saline in the right limb, and evaluation of the result 10 minutes after application.
  • Oxymatrine, matrine and sophoridine are produced by Ningxia Boer Taili Pharmaceutical Co., Ltd., and Huperzine tablets are produced by Shanghai Hongqi Pharmaceutical Factory.
  • D-galactose was produced by Shanghai Reagent No. 2 Plant, and amanita valine (IB0) was purchased from Sigma Company, all of which were of analytical grade.
  • the (TchE) test kit was provided by the Nanjing Institute of Bioengineering.
  • Animal grouping, modeling and administration 57 female Wi s tar rats of 15 months old age, weighing 300-450 g, were provided by the Animal Center of Qingdao Drug Inspection Institute. Regular caged feeding, natural lighting, free access to water and feeding. Randomly divided into 6 groups, of which the normal control group (referred to as the normal group), intraperitoneal injection of normal saline for 6 weeks and intracerebral Meyner t nuclear injection of normal saline, AD model group (referred to as model group), intraperitoneal injection of D-galactose (48 mg / kg) /d) 6 weeks and bilateral bilateral Meyner t nuclear injection of IBO, Huperzine ⁇ control group (Jane The test group was found to be the same model group as the test group.
  • the Huperzine sputum group was intragastrically administered with huperzine ⁇ 50ug/kg, and the pharmaceutical compositions II, III and V were administered with 50mg/kg.
  • the normal group and the model group were given the same volume of physiological saline.
  • the medium was made into a 10% (W/V) cerebral cortex tissue homogenate. Brain tissue and whole blood acetylcholinesterase activity were measured according to the kit instructions.
  • Detection index Animal memory behavior test: Passive avoidance platform test, the rats were placed in the reaction chamber to adapt to the environment for 3 minutes, and then passed through 50V AC. After the electric shock was struck by the rat, the escape response was to jump on the platform to avoid noxious stimulation. Record the number of shocks (number of errors) within 5 minutes as a result of academic performance to reflect learning ability. The rats were placed directly on the platform after 24 hours. The incubation period of the first jump was recorded to reflect the memory capacity and the number of errors within 5 minutes. The incubation period was more than 5 minutes in 5 minutes.
  • Table 12 Effects of pharmaceutical compositions II, III, and V on TChE levels in whole blood and brain tissue of rats Compared with the model group: *p ⁇ 0. 05; ** p ⁇ 0.01. Where p represents a statistically significant value; * P ⁇ 0. indicates a statistically significant difference; ** P ⁇ 0.01 indicates a statistically significant difference.
  • Double benefit control 4 ⁇ 2. 3* 135 ⁇ 55* 2 ⁇ 1. 6*

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Description

含阿魏酸与苦参碱类化合物的药物组合物及其制备和用途 技术领域
本发明涉及含有阿魏酸与苦参碱类化合物的药物组合物、 以及该药物组合 物的制备方法及其用途。 背景技术
阿魏酸的化学名称为 4-羟基 -3-曱氧基肉桂酸， 是植物界普遍存在的一种 酚酸,是当归、 川芎、 阿魏等中药的有效成分之一， 广泛存在于多种植物中。 可 以通过提取或合成的方法获得， 其具有广泛的药理作用， 例如抗炎、 抗菌、 抗 氧化、 增强免疫、 抗肿瘤、 抗心血管疾病、 抗纤维化、 抗老年痴呆等。 苦参是 常用的中药之一， 其含有多种生物碱， 以苦参碱（ma tr ine)、 氧化苦参碱 (oxyma-tr ine) 为主 , 其次含有槐果减 (1-sophocarpine) 、 槐定减 (sophor id ine) , N-氧化槐果碱（N- oxysophocarpine)、 和异苦参碱等。 其开发 的药物有苦参素、 苦参碱、 槐果碱等在临床上主要用于慢性肝病的治疗、 抗病 毒、 抗肿瘤的治疗以及心血管病的治疗， 具有抗病毒、 抗肝纤维化、 免疫调节 作用及抗炎、 抗变态反应作用等。 经我们研究发现， 含有阿魏酸与苦参碱类化 合物的药物组合物可明显增加苦参碱类化合物或阿魏酸的作用， 二者在体内具 有明显的协同作用， 可降低苦参碱类化合物的毒性， 增加二者的水溶性和脂溶 性。 发明内容
本发明的目的在于提供一种含有阿魏酸与苦参碱类化合物的药物组合物， 以明显增加阿魏酸或苦参碱类化合物的药学效应。
为解决上述技术问题， 本发明釆用以下技术方案予以实现：
本发明的药物组合物是一种含有阿魏酸与苦参碱类化合物的药物组合物。 进一步的， 所述阿魏酸包括以下物质中的一种或者多种： 正阿魏酸、 异阿 魏酸、 正阿魏酸的同分异构体、 异阿魏酸的同分异构体、 或它们的无机盐类化 合物； 其中， 正阿魏酸的基本结构是：
Figure imgf000003_0001
, 异阿魏酸的基本结构是:
Figure imgf000003_0002
又进一步的， 所述苦参碱类化合物的基本结构特征是具有如下式所示的四 环喹 11秦啶：
Figure imgf000003_0003
该类化合物主要包括以下物质中的一种或者多种： 苦参碱、 苦参素、 槐果碱、 氧化槐果碱、 槐醇、 白金雀花碱、 槐定碱、 异苦参碱、 或上述这些化合物的同 分异构体、 或它们的无机盐类。
优选的，所述苦参碱类化合物是苦参碱、苦参素或槐果碱中的一种或几种， 并且阿魏酸与所述苦参碱类化合物的摩尔比为 1: 0. 1~10。
再进一步的， 所述苦参碱类化合物是苦参素或苦参碱中的一种或两种， 并 且阿魏酸与所述苦参碱类化合物的摩尔比为 1: 0. 1~10。
本发明的目的之二在于提供一种含有阿魏酸与苦参碱类化合物的药物制备 方法， 其中， 所述药物是一种含有阿魏酸与苦参碱类化合物的药物组合物， 取 摩尔比为 1: 0. 1~10 的阿魏酸和苦参碱类化合物， 加入药用辅料， 釆用药剂学 的方法制备成一定剂型的制剂。
如果制备注射剂， 则所述的药用辅料可以釆用注射用水， 在所述药物组合 物中加入所述的注射用水， 并搅拌至溶解后， 即制成注射剂。
如果制备口服制剂， 则所述的药用辅料可以釆用淀粉、 10%淀粉浆、干淀粉 和硬脂酸镁； 将所述药物组合物首先与淀粉混合均勾， 加入 10%淀粉浆制成软 材， 干燥后加入干淀粉及硬脂酸镁混合， 即可制成口服片剂。
如果制备皮肤粘膜用制剂， 则所述的药用辅料可以釆用卡波姆、 丙二醇、 尼泊金曱酯和纯化水； 将卡波姆用纯化水分散， 尼泊金曱酯用丙二醇溶解后加 入分散的卡波姆中， 加入纯化水溶胀； 将所述药物组合物用纯化水溶解， 并加 入到上述的卡波姆溶液中混合， 加入纯化水混合均勾， 即可制成皮肤粘膜用制 剂。
所述的含有阿魏酸与苦参碱类化合物的药物组合物可以应用于抗纤维化、 改变血流变学、 抗病毒、 抗炎、 抑制胆碱酯酶、 止痛和止痒、 抗老年痴呆、 抗 血栓、 抗菌、 抗肿瘤、 抗氧化降血脂、 抗动脉硬化、 抗风湿、 增强免疫、 抗高 血压、 增加精子活力和运动的药物制备中。
与现有技术相比， 本发明的优点和积极效果是： 本发明的含有阿魏酸与苦 参碱类化合物的组合物具有明显的协同效应， 既能增加阿魏酸的药学效应， 又 能增加苦参碱类化合物的药学效应， 并且可明显增加阿魏酸和苦参碱类生物碱 的水溶性和脂溶性。 将所述药物组合物釆用药剂学的方法制备成口服制剂、 注 射剂或者皮肤粘膜用制剂， 可以起到预防和治疗肿瘤、 动脉硬化、 心、 脑血管 病、 骨关节疾病、 感冒、 老年痴呆、 皮肤的炎症、 湿疹、 痤疮、 斑丘疹、 荨麻 疹、 牛皮癣、 胃肠道动力低下， 肝炎、 肾炎等脏器的炎症和脏器纤维化、 以及 全身或脏器发生的急性和慢性炎症的作用。 具体实施方式
下面结合附图对本发明的具体实施方式进行详细地描述。
本发明所提出的药物组合物是一种含有阿魏酸与苦参碱类化合物的药物组 合物。 其中， 所述阿魏酸与苦参碱类化合物的摩尔比为 1: 0. 1~10, 优选其摩尔 比为 1: 1~5。
在本发明中， 所述的阿魏酸可以是正阿魏酸、 异阿魏酸、 正阿魏酸的同分 异构体、 异阿魏酸的同分异构体、 或者它们的无机盐类化合物等， 也可以是上 述任意两种或者多种物质的组合形式。 其中， 正阿魏酸的基本结构是：
Figure imgf000005_0001
, 异阿魏酸的基本结构是： 而所述的苦参碱类化合物 的基本结构特征是具有如下式所示的四环喹嗪啶:
Figure imgf000005_0002
该类化合物主要包括苦参碱、 苦参素、 槐果碱、 氧化槐果碱、 槐醇、 白金雀花 碱、 槐定碱、 异苦参碱等、 或者上述这些化合物的同分异构体、 或者是它们的 无机盐类， 当然也可以是上述任意两种或者多种物质的组合形式。
作为一种优选方案， 所述的苦参碱类化合物优选釆用苦参碱、 苦参素或槐 果碱中的一种或几种， 并且阿魏酸与所述苦参碱类化合物的摩尔比在 1 : 0. 1-10 , 优选其摩尔比为 1 : 1~3。
作为另外一种优选方案， 所述的苦参碱类化合物优选釆用苦参素或苦参碱 中的一种或两种， 并且阿魏酸与所述苦参碱类化合物的分子摩尔比在 1 : 0. 1-10 , 优选其摩尔比为 1 : 1~2。
釆用上述的药物组合物配以适当的药用辅料， 并使用常规的药剂学方法即 可制备出不同剂型的制剂， 比如注射剂、 口服制剂、 皮肤粘膜用制剂等等。 下 实施例一，本实施例提供了一种阿魏酸钠苦参素复方冻干粉针的制备方法。 首先， 选取阿魏酸钠 30. 87g、 苦参素 69. 1 3g、 注射用水 1000ml。
其制备方法是： 在无菌操作室内秤取阿魏酸钠 30. 87g , 苦参素 69. 1 3g (阿 魏酸钠与苦参素的摩尔比为 1 : 2 ), 置于无菌容器中， 加入无菌注射用水约 100ml , 搅拌溶解， 用氢氧化钠调 PH值在 6. 5~7. 5范围内， 补加无菌注射用水 至 1000ml , 搅拌均匀， 然后加入 0. 02%活性炭， 搅拌 5-10分钟， 用无菌抽滤漏 斗铺 2层灭菌滤纸过滤，再用经灭菌的 G6垂溶玻璃漏斗精滤，滤液检查合格后， 分装在 2ml安瓿瓶中， 低温冷冻干燥约 24-26小时后， 无菌溶封即可， 每支含 药物 100mg。
实施例二， 本实施例提供了一种阿魏酸槐果碱片剂的制备方法。 首先， 选取阿魏酸 182g (其中可包括 60%的正阿魏酸和 40%的异阿魏酸）， 槐果碱 18g (阿魏酸与槐果碱的摩尔比为 10: 1 ), 淀粉 40g, 10%淀粉浆 24g, 干淀粉 23g, 硬脂酸镁 3g。
其制备方法是： 将阿魏酸和槐果碱过 80目筛， 与淀粉混合均勾， 加 10%淀 粉浆制成软材， 以 14 目筛制成颗粒， 置 70-80°C干燥后 12 目筛整粒， 加入干 淀粉及硬脂酸镁混合后， 压片， 制成 1000片， 每片含药物 200mg。
实施例三， 本实施例提供了一种阿魏酸钠苦参素凝胶剂的制备方法。
首先， 选取阿魏酸钠 6.17g, 苦参素 13.83g (阿魏酸钠与苦参素的摩尔比 为 1: 2 ), 卡波姆 10g, 丙二醇 167ml, 尼泊金曱酯 0.15g, 纯化水 1000ml。
其制备方法是：将卡波姆用 20ml水分散，尼泊金曱酯用丙二醇溶解后加入 分散的卡波姆中， 加入约 500ml纯化水溶胀 12至 24小时； 将阿魏酸钠和苦参 素用约 100ml 的纯化水溶解， 加入到上述卡波姆溶液中混合， 加入纯化水至 1000ml, 混合均匀， 用氨水调 PH值至 6.5-7.5, 分装在 20g的铝塑管中， 质量 检查合格后即得。
实施例四， 本实施例提供了一种阿魏酸苦参总碱胶嚢的制备方法。
首先， 选取阿魏酸 50g, 苦参提取物 450g (总碱含量为 60-80%, 其中含 苦参素 10- 30% ,苦参碱 30-60% ,槐果碱 10-20% ,其他苦参碱类生物碱约 1 -3% ) , 淀粉 40g, 10%淀粉浆 24g, 硬脂酸镁 3g。
将阿魏酸和苦参提取物过 80目筛， 与淀粉混合均勾， 加 10%淀粉浆制成软 材， 以 14 目筛制成颗粒， 置 70-80°C干燥后 12 目筛整粒， 加入干淀粉及硬脂 酸镁混合后， 选择 3号硬胶嚢壳填充， 套合胶嚢帽， 制成 1000粒， 每粒含阿魏 酸 50mg, 苦参总碱 450mg。
实施例五，本实施例通过多组实验数据来对几种药物组合物在镇痛、抗炎、 抗胆碱酯酶等方面与苦参素和阿魏酸的作用进行比较。
表 1是五种药物组合物的配制表。
组合物代号 阿魏酸（摩尔数） 苦参碱（摩尔数） 苦参素 （摩尔数） 槐果碱（摩尔数） I 1 1 0 0
II 1 2 0 0
III 1 1 1 0
IV 1 0 1 0
V 1 0 0 2
表 1
选取健康小鼠， 每组 10只。 灌胃给药 20mg/kg , 连续 3天， 末次给药 30 分钟后， 腹腔注射 0. 6%醋酸 10ml /kg , 记录 15分钟内小鼠出现扭体反应次数， 计算药物镇痛百分率。
药物镇痛百分率（％) = (对照组扭体次数 -治疗组扭体次数） /对照组扭体次 数 X 100%
表 2是苦参素、阿魏酸和五种药物组合物对小鼠醋酸扭体的镇痛作用比较。
Figure imgf000007_0001
表 2
下面是几种化合物的抗炎作用及其与苦参素和阿魏酸的作用比较。
剂量和药物组合物的配制如表 1所示， 选取健康小鼠， 小鼠每组 10只， 称 重标记后， 将小鼠的右耳用二曱苯棉球接触 5秒钟， 左耳作为对照， 于致炎 1 0 分钟后， 分别在致炎耳壳上， 涂覆给予药物浓度为 1%受试药物， 空白对照组给 生理盐水， 30分钟后将小鼠颈脱臼处死， 用直径 6mm打孔器取等积左（自身对 照）、 右耳（二曱苯处理）称重， 计算耳肿胀率：
耳肿胀率（％) =右耳重量-左耳重量 /左耳重量 X 100%。 组别 肿胀率 (%)
空白对照组 173.72
苦参碱 133.4
阿魏酸 164.6
I 74.9
II 98.9
III 36.4
IV 111.2
V 96.7
表 4、 药物组合物对小鼠耳肿胀的作用
下面是几种化合物对肝脏肝星状细胞增值和分泌型 I胶原蛋白的作用。 材料与试剂： 大鼠 I型胶原蛋白 ELISA试剂盒， 胰蛋白酶， 胎牛血清等。 方法： 大鼠肝脏肝星状细胞（hepatic stellate cell, HSC )复苏后接种在 lOOmL塑料培养瓶中，于 5% C02、 95%湿度的 C02培养箱里培养。 待培养瓶中细 胞长成单层后，弃去培养液， 加入 0.25%胰蛋白酶的消化液， 收集消化液， 2200rPmin离心 7分钟， 弃上清液， 再用 DMEM培养液离心洗涤一次， 细胞团块 用含 20%胎牛血清 DMEM培养液悬浮并计数， 用含 DMEM培养液稀释细胞悬液， 接种于 96孔培养板,每孔 100 μ 1, 48小时后吸去培养液再用含 10%小牛血清的 DMEM培养液同步化细胞，使细胞同步化于静止期。 实验分组（生理盐水）， 加入 药物使得各组培养液中药物浓度分别是 50 μηιοΙ/L, 每组 6孔重复培养 3次， 作用 48小时后， 终止培养， 分别在每孔加入 5mg/L噻唑蓝（ΜΤΤ)20μί, 再培养 4h, 加入 DMS0后振荡 10分钟， 用酶标仪（波长 570讓）测定 HSC吸光度。 领 取药物作用后的细胞， 按照上述方法培养后， 吸取上清液， 按照试剂盒说明书 测定 I型胶原蛋白含量。 其结果见表 5。
组别 平均吸光度 I型胶原蛋白含量 g/L)
空白对照组 73· 55± 13.28
苦参碱 0.39± 0.17 63·42± 9.76
阿魏酸 I 0.35 ± 0.09 34.57 ± 8.29
II 46.92 ± 11.56
III 0.32 ± 0.06 36.48 ± 10.07
IV 11.29± 8.55
V
表 5、 化合 if勿对大鼠肝脏肝星状细胞增值和 I型胶原蛋白含量 以下是几种化合物抗胆碱酯酶的作用比较。
从健康大鼠取血 5ml, 放入加有抗凝剂的试管中， 用生理盐水稀释 10倍， 待用。
将药物用生理盐水分别稀释为 0 5 10 20 40 80 160 320 640 mg/L 的待测溶液。取 0.05ml不同的待测溶液中加入 0.5ml稀释了的全血中，充分混 匀后， 置 37°C环境预孵 1小时。 然后， 按照乙酰胆碱酯酶试剂盒说明书测定全 血乙酰胆碱酯酶的活性， 计算半数抑制浓度（ IC50)。 其结果如表 6所示， 有表 6可见： 药物组合物 I -V都具有抑制全血乙酰胆碱酯的作用， 其中， 药物组合 物 III的抑制作用最强。
Figure imgf000009_0001
表 6 几种化合物对胆碱酯酶抑制作用的 IC50 下面是几种化合物对小鼠肠动力的作用比较。
药品和试剂： 苦参素注射液， 山东新华制药股份有限公司生产 （批号: 0306003 ); 曱石克酸新斯的明注射液， 山东天福制药厂生产 （批号： 0404131 ); 硫酸阿托品注射液， 山东天福制药厂生产（批号： 0409271 ); 硫酸吗啡控释片， 北京萌蒂制药有限公司生产 （批号： 04082312 )。
动物及饲养环境： 健康昆明小鼠， SPF级， 雌雄各半， 体重 18-22g , 由山 东绿叶制药股份有限公司动物实验中心提供。 合格证号： SYXK (鲁） 20030020 动物每笼 10只放置。饲料由山东省实验动物中心提供。屏障系统饲养， 过滤送 风， 室内温度 18_22 °C ; 湿度 50-60%; 光照 12小时。
实验方法： 小鼠灌胃给相应药物或生理盐水， 连续 3天， 末次给药前禁食 不禁水 16小时，于给药 30分钟后，每只小鼠灌胃给予 5%活性炭混悬液 0. 2 ml , 20分钟后脱臼处死小鼠， 打开腹腔分离肠系膜， 剪取幽门至回盲部的肠管， 置 于托盘上， 轻轻将小肠拉成直线， 测量肠管长度作为小肠总长度， 从幽门至炭 末前沿的距离作为炭末在肠内推进距离。 用以下公式计算炭末推进率：
炭末推进率（％) =炭末在肠内推进距离 /小肠总长度 X 100%
表 7 表示了几种化合物对正常小鼠小肠炭末推进率的影响 （: 士 SD )。 与 对照组比较： * P<0. 05 ; ** p<0. 01。 其中， p 表示统计学差异值； * P<0. 05 表示具有明显的统计学差异； ** P<0. 01表示具有极显著的统计学差异。
Figure imgf000010_0001
表 7
以下是几种药物组合物在急性毒性方面的实验数据。
实验方法： 取小鼠， 每组 10只， 1次灌胃给药， 观察 72小时， 记录死亡 化合物 给药剂量 (mg/kg) N 死亡动物数
苦参碱 500 10 10
阿魏酸 1000 10 0
槐果碱 500 10 10
I 800 10 0
II 800 10 0
III 800 10 0
IV 800 10 0
V 800 10 0
表 8、 几种化合物 ^卜小鼠毒性的观察 (： +SD) 下面是阿魏酸苦参素组合物在抗动脉硬化方面的观察。
药物制备： 将阿魏酸与苦参素以 1: 1的分子摩尔比混合后配成溶液。 按照文献方法进行 [刘占涛， 刘赛， 王守兰， 张健， 仲伟珍。 海洋贝类综合 提取物对实验性动脉粥样硬化的治疗作用。 中国动脉硬化杂志 2005年第 13卷 第 3期； 305-308]。
试验方法： 取雄性鹌鹑 140只， 随机分为 7组， 正常对照组、 模型组、 阳 性对照组（罗伐它丁 10mg/kg) , 阿魏酸口服对照组（40mg/kg )和药物组合物高、 中、 低剂量组（分别给药 10、 20、 40mg/kg)。 除正常对照组喂基础饲料外， 其 余 6组按照文献方法建立高脂食饵性动脉硬化模型。
各用药组灌胃给药， 每日一次， 连续用药 4周。 分别于用药后第 4周末， 每组取 10 只动物测定其血清脂质。 于实验结束时对存活的鹌鹑进行病理学检 测。
血清脂质含量测定：各组于用药后第 4周末，禁食 12小时后经颈静脉取血 2 mL, 分离血清， 釆用酶法测定血清胆固醇（TC)、 甘油三酯（TG)水平。
结果：阿魏酸苦参素组合物可明显降低动脉硬化模型鹌鹑血清 TC、TG水平， 其作用比阿魏酸明显增强， 参见表 9所示。 模型组多数主动脉有明显的病变， 多数动脉粥样硬化 As病变在 2级以上，阿魏酸苦参素组合物的主动脉粥样硬化 病变程度较轻， 多在 1 ~ 2级以下， 参见表 10所示。 镜下可见多数动脉内膜完 整， 部分有轻度脂质浸润，内含散在泡沫细胞。
Figure imgf000012_0001
表 9、 阿魏酸苦参素对高血脂模型鹌鹑血脂的影响
Figure imgf000012_0002
表 10、 阿魏酸苦参素对高血脂模型鹌鹑主动脉动脉硬化病变的影响 下面是阿魏酸苦参碱凝胶对急性风湿性关节炎的影响。
药物制备： 将阿魏酸和苦参碱以 1 : 1分子摩尔比混合后，按照药剂学方法 制成乳膏剂。
风湿性关节炎病人 30对， 其中 30例为对照组， 30例为试验组。 对照组单 独口服奈普生 200g , 治疗组患处涂抹阿魏酸苦参碱乳膏， 每天 1次， 连续用药 5天。
疗效观察： 肿胀和疼痛基本消失， 为显效； 轻度肿胀， 疼痛基本消失为有 效； 肿胀和疼痛均未好转， 为无效。 结果： 试验组显效 21例， 有效 8例， 总有效率为 96. 7%。 对照组显效 12 例， 有效 11例， 总有效率为 76. 7 %。
以下是几种化合物对皮疹的治疗作用。
病例选择： 年龄在 18-25岁， 身体双侧皮疹， 性别不限， 每种药物实验 10 例。 在皮疹上局部涂抹 1% 药物， 自身单盲对照， 左侧肢体涂抹药物， 右侧肢 体生理盐水， 涂抹后 10分钟进行结果评价。
结果评价： 对消肿止痒作用进行评价。 显效： 皮疹明显消退， 止痒作用明 显。 有效： 有一定的止痒作用， 丘疹有一定程度的消退。 无效： 未见明显作用。 结果见表 11。
Figure imgf000013_0001
表 11、 几种化合物对皮疹的治疗作用疗效评价 下面是药物组合物 II、 III、 V对大鼠老年痴呆的治疗作用。
1. 药品与试剂： 苦参素、 苦参碱和槐果碱由宁夏博尔泰力药业股份有限公 司生产， 石杉碱曱片由上海红旗制药厂生产。 D-半乳糖为上海试剂二厂出产， 鹅膏蕈氨酸（IB0)购自 S igma 公司， 均为分析纯。 全血和脑组织总胆碱酯酶
( TchE )检测试剂盒由南京建成生物工程研究所提供。
2. 动物分组、 造模与给药： 15月龄初老年雌性 Wi s tar大鼠 57只， 体重 300 ~ 450 g , 均由青岛市药检所动物中心提供。 常规分笼饲养， 自然照明，随意 饮水和取食。 随机分成 6组， 其中正常对照组（简称正常组）， 腹腔注射生理盐 水 6周及脑内 Meyner t核注射生理盐水， AD模型组（简称模型组）， 腹腔注射 D -半乳糖（48mg/kg/d) 6周和脑内双侧 Meyner t核注射 IB0 ,石杉碱曱对照组（简 称石杉碱曱组）和受试物观察组造模均同模型组。造模结束后，石杉碱曱组灌胃 给予石杉碱曱 50ug/kg , 药物组合物 II、 III、 V组分别灌胃药物 50mg/kg。 正常 组、 模型组给予同体积的生理盐水。 连续给药 7天， 在末次给药 1小时后， 进 行学习能力检测， 然后大鼠用戊巴比妥麻醉， 在水台上腹主动脉釆血 5ml , 解 剖迅速取出大脑皮层以生理盐水作为勾浆介质，制成 10% (W/V)大脑皮层组织匀 浆。 按照试剂盒说明进行脑组织和全血乙酰胆碱酯酶活性的测定。
3.检测指标： 动物记忆行为测试： 被动回避跳台试验， 将大鼠置反应箱内 适应环境 3分钟， 然后通以 50V交流电。 大鼠受到电击后， 逃避反应为跳上平 台以躱避伤害性刺激。 记录 5分钟内受到电击次数 (错误次数)作为学习成绩以 反应学习能力。 24小时后直接将大鼠置于平台上。 记录第 1次跳下的潜伏期以 反应记忆能力和 5分钟内错误次数， 潜伏期超过 5分钟者以 5分钟计。
数据处理釆用组间比较 t检验， 以 p<0. 05作为统计显著性指标。
4. 结果： 3种药物组合物均能够降低全血和脑组织胆碱酯酶水平， 提高大 鼠学习记忆成绩， 参见表 12、 13。
Figure imgf000014_0001
表 12、 药物组合物 II、 III、 V对大鼠全血及脑组织内 TChE水平的影响 与模型组比较： *p<0. 05； ** p<0. 01。其中， p表示统计学差异值； * P<0. 表示具有明显的统计学差异； ** P<0. 01表示具有极显著的统计学差异。
组别 5m i n内错误次数 潜伏期（S) 24h后 5mi n内错误次数 正常对照 0. 9 ± 0. 7 237 士 86 0. 3 ± 0. 2 模型对照 16 ± 7. 6 78 ± 27 9 ± 4. 2
双益平对照 4 ± 2. 3* 135 ± 55* 2 ± 1. 6*
II 5 ± 1. 9* 187 ± 43* 4 ± 2. 1 *
III 3 ± 2. 2* 222 ± 78* 3 ± 1. 0*
V 4 ± 2. 7* 112 ± 41 * 2 ± 1. 5*
表 13、 药 组合物 II、 III、 V对大鼠跳台试验学习和记忆能力的影响 与模型组比较： *p<0. 05 , 表示具有明显的统计学差异。
当然， 以上所述仅是本发明的一种优选实施方式， 应当指出的是， 对于本 技术领域的普通技术人员来说， 在不脱离本发明原理的前提下， 还可以做出若 干改进和润饰， 这些改进和润饰也应视为本发明的保护范围。

Claims

权 利 要 求 书
1、一种含阿魏酸与苦参碱类化合物的药物组合物， 其特征在于： 所述药物 组合物是一种含有阿魏酸与苦参碱类化合物的药物组合物。
2、根据权利要求 1所述的药物组合物， 其特征在于： 所述阿魏酸包括以下 物质中的一种或者多种： 正阿魏酸、 异阿魏酸、 正阿魏酸的同分异构体、 异阿 魏酸的同分异构体、 或它们的无机盐类化合物； 其中， 正阿魏酸的基本结构是：
Figure imgf000016_0001
异阿魏酸的基本结构是： 。
3、根据权利要求 1所述的药物组合物， 其特征在于： 所述苦参碱类化合物 的基本结构特征是具有如下式所示的四环喹嗪啶：
Figure imgf000016_0002
该类化合物主要包括以下物质中的一种或者多种： 苦参碱、 苦参素、 槐果碱、 氧化槐果碱、 槐醇、 白金雀花碱、 槐定碱、 异苦参碱、 或上述这些化合物的同 分异构体、 或它们的无机盐类。
4、根据权利要求 1或 2或 3所述的药物组合物， 其特征在于： 所述苦参碱 类化合物是苦参碱、 苦参素或槐果碱中的一种或几种， 并且阿魏酸与所述苦参 碱类化合物的摩尔比为 1 : 0. 1~1 0。
5、根据权利要求 1或 2或 3所述的药物组合物， 其特征在于： 所述苦参碱 类化合物是苦参素或苦参碱中的一种或两种， 并且阿魏酸与所述苦参碱类化合 物的摩尔比为 1 : 0. 1~10。
6、 一种含阿魏酸与苦参碱类化合物的药物制备方法， 其特征在于： 所述药 物是一种含有阿魏酸与苦参碱类化合物的药物组合物， 取摩尔比为 1 : 0. 1~10 的阿魏酸和苦参碱类化合物， 加入药用辅料， 釆用药剂学的方法制备成一定剂 型的制剂。
7、根据权利要求 6所述的制备方法， 其特征在于： 所述药用辅料为注射用 水， 在所述药物组合物中加入所述的注射用水， 并搅拌至溶解后， 制成注射剂。
8、 根据权利要求 6所述的制备方法， 其特征在于： 所述药用辅料为淀粉、 10%淀粉浆、干淀粉和硬脂酸镁； 将所述药物组合物首先与淀粉混合均勾， 加入 10%淀粉浆制成软材， 干燥后加入干淀粉及硬脂酸镁混合， 制成口服制剂。
9、根据权利要求 6所述的制备方法，其特征在于：所述药用辅料为卡波姆、 丙二醇、 尼泊金曱酯和纯化水； 将卡波姆用纯化水分散， 尼泊金曱酯用丙二醇 溶解后加入分散的卡波姆中， 加入纯化水溶胀； 将所述药物组合物用纯化水溶 解， 并加入到上述的卡波姆溶液中混合， 加入纯化水混合均勾， 制成皮肤粘膜 用制剂。
10、 一种如权利要求 1至 3中任一项所述的含阿魏酸与苦参碱类化合物的 药物组合物的用途， 其特征在于： 所述含有阿魏酸与苦参碱类化合物的药物组 合物适用于制备治疗抗纤维化、 改变血流变学、 抗病毒、 抗炎、 抑制胆碱酯酶、 止痛和止痒、 抗老年痴呆、 抗血栓、 抗菌、 抗肿瘤、 抗氧化降血脂、 抗动脉硬 化、 抗风湿、 增强免疫、 抗高血压、 增加精子活力和运动的药物中。
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