WO2016180347A1 - 一种中药组合物在制备钾离子通道调节剂药物中的应用 - Google Patents

一种中药组合物在制备钾离子通道调节剂药物中的应用 Download PDF

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WO2016180347A1
WO2016180347A1 PCT/CN2016/081796 CN2016081796W WO2016180347A1 WO 2016180347 A1 WO2016180347 A1 WO 2016180347A1 CN 2016081796 W CN2016081796 W CN 2016081796W WO 2016180347 A1 WO2016180347 A1 WO 2016180347A1
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traditional chinese
chinese medicine
medicine composition
parts
ion channel
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PCT/CN2016/081796
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English (en)
French (fr)
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王保安
毛鹏
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陕西摩美得制药有限公司
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Priority to JP2018511318A priority Critical patent/JP2018515609A/ja
Priority to EP16792197.2A priority patent/EP3295948A4/en
Priority to KR1020177034662A priority patent/KR20180030469A/ko
Priority to US15/573,583 priority patent/US11160841B2/en
Publication of WO2016180347A1 publication Critical patent/WO2016180347A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/718—Coptis (goldthread)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8968—Ophiopogon (Lilyturf)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/282—Artemisia, e.g. wormwood or sagebrush
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/489—Sophora, e.g. necklacepod or mamani
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/62—Nymphaeaceae (Water-lily family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
    • A61K36/8888—Pinellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to a traditional Chinese medicine, in particular to a traditional Chinese medicine composition, in particular to a traditional Chinese medicine composition for preparing a potassium ion channel modulator medicine.
  • Potassium channel is the most sub-type and most complex channel found. It is generally divided into delayed rectifier potassium channel, transient outward potassium channel, and introversion. There are five major categories of rectifier potassium channels, adenosine triphosphate-sensitive potassium channels, and acetylcholine-sensitive potassium channels, all of which are closely related to the occurrence and development of arrhythmias.
  • Delayed rectifier potassium channels are classified into three categories, namely, fast-acting delayed rectifier potassium current (Ikr), slow activation of delayed rectifier potassium current (Iks), and overspeed activation of delayed rectifier potassium current (Ikur). Rapid activation of delayed rectifier potassium current and slow activation of delayed rectifier potassium current are important for regulating the termination of phase 2 plateau and repolarization of phase 3 of cardiomyocyte action potential. Abnormal or up-regulation of Ikr and Iks channels can lead to arrhythmia, so Ikr and Iks channels are important targets for arrhythmia and antiarrhythmic drugs.
  • the inward rectifier potassium channel (Kir) consists of a tetramer of two transmembrane subunits that can be blocked by intracellular Mg2 and polyamines at a positive potential.
  • the transient outward potassium channel is the main membrane current involved in the repolarization of cardiac action potential.
  • the channel opening is characterized by instantaneous net outward current, which is turned off, forming a phase of action potential, which has a great influence on the action potential duration and morphology.
  • KATP channel myocardial KATP is inhibited by intracellular physiological level of ATP, which couples cellular metabolism to membrane potential.
  • the inward rectification mechanism involves the inhibition of open channels by intracellular Mg and Na.
  • Acetylcholine-activated K-potassium channels are present in pacemaker cells of the sinoatrial node and Atrial myocytes, regulate heart rate.
  • the density of atrial IKAch is about 6 times that of the ventricle. IKAch activation causes hyperpolarization of membrane potential, reduces the spontaneousity of sinus node and atrioventricular node pacemaker cells, and delays the conduction of atrioventricular node.
  • Arrhythmia is caused by dysfunction or activation of sinus node sinus outside the sinus node, stimuli conduction slow, block or conduction through abnormal channels, ie the origin of cardiac activity and/or the conduction disorder causes the frequency of heart beats and (or The rhythm is abnormal.
  • Arrhythmia is an important group of diseases in cardiovascular disease. It can be associated with cardiovascular disease alone or in combination with cardiovascular disease. Sudden onset and sudden death, can also continue to affect the heart and fail.
  • Arrhythmia can be seen in a variety of organic heart disease, including coronary atherosclerotic heart disease (referred to as coronary heart disease), cardiomyopathy, myocarditis and rheumatic heart disease (referred to as rheumatic heart disease) is more common, especially in the occurrence of heart Arrhythmias that occur in patients with basic health or autonomic dysfunction are also uncommon in patients with depletion or acute myocardial infarction.
  • the main causes of arrhythmia are: impulsive abnormalities (increased ectopic rhythm self-discipline, post-depolarization and triggering activities), or impulsive conduction anomalies (reentry), or both. Therefore, the treatment of arrhythmia should reduce self-discipline, reduce post-depolarization, and eliminate reentry.
  • Class I sodium channel blockers
  • Class II ⁇ adrenergic receptor antagonists
  • Class III extended Action potential time course drug (potassium channel blocker)
  • class IV calcium channel blocker.
  • the main drugs for treating arrhythmia include quinidine, lidocaine, spirulina, amiodarone, verapamil, etc., which have certain curative effects, but at the same time, they show obvious adverse reactions and side effects.
  • some Chinese medicines have also been invented.
  • 200310122205.9 discloses a heart-speed capsule for treating heart palpitations, which is a traditional Chinese medicine for treating ventricular premature beats (heart palpitations) and a preparation method thereof, but the application range is very limited, and the potassium ion channel of the pharmaceutical composition is not disclosed.
  • the adjustment function (prolonging the action potential time course), the patent of the present invention is further studied on the basis of the original patent technology, and the adjustment effect of the composition on the potassium ion channel (prolonging the action potential time course) can be used for Treating arrhythmias in ventricular, atrial, and supraventricular, as well as reducing blood sugar, The application of drugs that lower blood pressure.
  • the technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, and to study the design of the potassium ion channel regulation (prolonging the action potential time course), and can be used for treating traditional Chinese medicine compositions such as ventricular, atrial, and supraventricular. .
  • the invention provides an application of a traditional Chinese medicine composition in preparing a potassium ion channel modulator drug.
  • the traditional Chinese medicine composition of the present invention comprises a traditional Chinese medicine and a medicinal auxiliary material as active ingredients.
  • the traditional Chinese medicine composition of the present invention is prepared from the raw materials of various traditional Chinese medicines according to the following weight ratios:
  • the traditional Chinese medicine composition of the present invention is prepared from the raw materials of the traditional Chinese medicine according to the following weight ratios:
  • the mechanism of action of the traditional Chinese medicine composition of the present invention is to prolong the action potential time course and adjust the potassium separation Subchannels suppress various potassium currents.
  • the traditional Chinese medicine composition prolongs the action potential interval of myocardial cells, thereby prolonging the refractory period of myocardial electrical activity, and the action mechanism has the effect of inhibiting arrhythmia induced by excitatory reentry, but has no toxic side effects.
  • the traditional Chinese medicine composition of the present invention performs myocardial cell electrophysiological test, and the test results show that the traditional Chinese medicine composition of the present invention significantly prolongs the action potential interval of myocardial cells and has the function of regulating potassium ion channels.
  • the test results show that the drug of the invention significantly prolongs the action potential interval of cardiomyocytes, has the effect of regulating potassium channel, and the drug effect has a correlation with the drug dose concentration.
  • the drug concentration is 1 mg/ml
  • the drug of the invention regulates potassium ion.
  • the effect of the drug on the channel and delayed action of the myocardial cell action potential was not obvious.
  • the test and the control were repeated 4 times, and there was no statistical significance compared with the control group.
  • the drug of the present invention has a significant effect on the action of delaying the action potential interval of the cardiomyocytes by adjusting the potassium ion channel, and the test and the control are repeated 7 times, and there is a significant difference compared with the control group (P ⁇ 0.05). ).
  • the drug concentration is 4 mg/ml
  • the drug of the present invention has a significant effect on the action of delaying the action potential interval of the cardiomyocytes by regulating the potassium ion channel, and the test and the control are repeated 7 times, and there is a significant difference compared with the control group.
  • the traditional Chinese medicine composition of the present invention can be used for preparing a potassium ion channel modulator drug.
  • Another object of the present invention is to provide a process for the preparation of the traditional Chinese medicine composition.
  • the method includes the following steps:
  • Step (4) Dregs and Ophiopogon japonicus, Artemisia annua, licorice combined, add water to cook 2 times, add 10 times for the first time, add 8 times for the second time, each time for 1 hour, combined with decoction
  • the filtrate was concentrated to a clear paste having a relative density of 1.05 to 1.06 (measured at 80 ° C), and 95% ethanol was added to make the alcohol content 70%, stirred, and allowed to stand for 24 hours, and the supernatant was taken and filtered. Collect the filtrate for use;
  • Step (5) filtrate and step (6)
  • the filtrate is combined, and the ethanol is recovered under reduced pressure (0.04 KPa, 70 ° C), and further concentrated to a thick paste having a relative density of 1.38 (measured at 60 ° C), and dried at 80 ° C to form a dry paste. spare;
  • the step (4) is combined with the dry paste of the step (7), pulverized into a fine powder of 100 mesh, added with an appropriate amount of dextrin, mixed, filled into capsules, or prepared into a preparation with a medicinal auxiliary.
  • the traditional Chinese medicine composition of the present invention is prepared according to a conventional method of medicine, and comprises an oral preparation such as a tablet, a capsule, a granule, an oral liquid, a pill, etc., and an auxiliary material used in the pharmacy, such as a filler, a binder, and a collapse, is added during the preparation process.
  • an oral preparation such as a tablet, a capsule, a granule, an oral liquid, a pill, etc.
  • an auxiliary material used in the pharmacy such as a filler, a binder, and a collapse, is added during the preparation process.
  • the invention provides a traditional Chinese medicine composition for use in preparing a potassium ion channel modulator; the application is in the preparation of an anti-arrhythmia drug.
  • the invention provides a traditional Chinese medicine composition for the preparation of a potassium ion channel modulator drug; the application is for the preparation of a medicament for treating a ventricular, atrial or supraventricular arrhythmia.
  • the invention provides a traditional Chinese medicine composition for use in preparing a potassium ion channel modulator drug; the application is in the preparation of a prolonged action potential time course, adjusting a potassium ion channel, and inhibiting various potassium current drugs.
  • the traditional Chinese medicine composition prolongs the action potential interval of myocardial cells, thereby prolonging the refractory period of myocardial electrical activity, and the action mechanism has the effect of inhibiting arrhythmia induced by excitatory reentry, but has no toxic side effects.
  • the invention provides a new potassium ion channel regulating agent traditional Chinese medicine, and provides a new medicine for treating diseases such as ventricular, atrial or supraventricular arrhythmia, and has a good application prospect, and the method of the invention is simple and convenient to operate. Suitable for large-scale production.
  • the abscissa indicates the administration time (unit: minute), and the ordinate indicates the action potential decay time (unit: millisecond). 1 indicates that the drug of the present invention has a administration period of 2 mg/ml from 0.65 minutes to -10.16 minutes.
  • Figure 2 Chinese medicine composition 2mg/ml, 4mg/ml action potential map
  • the abscissa indicates the time of administration (unit: millisecond), and the ordinate indicates the action potential (unit: millivolt).
  • Line 1 indicates the relationship between the action potential and time of the control group
  • line 2 indicates the relationship between the action potential and time of the drug administration group (2 mg/ml) of the present invention
  • line 3 indicates the relationship between the action potential and time after the recovery of the washed cells.
  • Fig. 3 is a graph showing the relationship between the action potential attenuation of the traditional Chinese medicine composition of the present invention at different concentrations (1 mg/ml, 2 mg/ml, 4 mg/ml), the abscissa indicating the concentration groups of different concentrations, and the ordinate indicating the attenuation of the action potential, and the histogram 1 is In the control group, the action potential attenuation amount was set to 1 in the control group, and the column 2 is the action potential attenuation amount of the drug 1 mg/ml of the present invention.
  • the column chart 3 is the action potential attenuation of the drug 2 mg/ml of the present invention.
  • the amount, the bar graph 4 is the action potential attenuation amount of the drug of 1 mg/ml of the present invention.
  • the pharmaceutical composition of the present invention is prepared into a lyophilized powder or extract according to a prescription ratio.
  • Group B ginseng, wolfberry, Pinellia medicinal materials washed twice with tap water 13kg, then rinsed twice with purified water 6.5kg, then extracted with 70% ethanol reflux 2 times, the first addition of 5.3L, the second addition 4L, each time 2h, combine the extract, filter, the filtrate and the dregs are reserved;
  • group C Ophiopogon japonicus Artemisia annua L., licorice roots washed twice with tap water 13kg, then rinsed twice with purified water 6.5kg, then combined with the above group B spare dregs, add boiling water for cooking twice, first Add 6.7L of water for 1 hour, add 5.3L of water for the first time for 1 hour, combine the second filtrate, discard the drug residue, concentrate the filtrate to a thick paste with a relative density of 1.05 ⁇ 1.06 (80 °C), add 95% ethanol to contain The amount of alcohol is 70%, stir well, and allowed to stand for 24 hours.
  • the supernatant is filtered and combined with the above-mentioned Group B spare filtrate to recover ethanol (0.04Kpa, 70 ° C) to no alcohol flavor, thick paste plus 6 times 4L water for injection. , heating to a temperature of 50 ° C ⁇ 60 ° C, stirring to fully dissolve, hot filtered, the filtrate was allowed to stand overnight, the supernatant was filtered, and set aside;
  • Artemisia annua L., Sophora flavescens, licorice, alfalfa, berberine, medlar, Changshan, ginseng, and pinellia are separated from foreign matter, non-medicinal parts, etc., washed (or sprayed) with running water, or slightly Run), cut into pieces or segments. After the wheat is moisturized, it is flat. Dry at 70-80 ° C for use.
  • Group B ginseng, wolfberry, Pinellia medicinal materials washed twice with tap water 13kg, then rinsed twice with purified water 6.5kg, then extracted with 70% ethanol reflux 2 times, the first addition of 5.3L, the second addition 4L, each time 2h, combine the extract, filter, the filtrate and the dregs are reserved;
  • group C Ophiopogon japonicus Artemisia annua L., licorice roots washed twice with tap water 13kg, then rinsed twice with purified water 6.5kg, then combined with the above group B spare dregs, add boiling water for cooking twice, first Add 6.7L of water for 1 hour, add 5.3L of water for the first time for 1 hour, combine the second filtrate, discard the drug residue, concentrate the filtrate to a thick paste with a relative density of 1.05 ⁇ 1.06 (80 °C), add 95% ethanol to contain The amount of alcohol is 70%, stir well, and allowed to stand for 24 hours.
  • the supernatant is filtered and combined with the above-mentioned Group B spare filtrate to recover ethanol (0.04Kpa, 70 ° C) to no alcohol flavor, thick paste plus 6 times 4L water for injection. , heating to a temperature of 50 ° C ⁇ 60 ° C, stirring to fully dissolve, hot filtered, the filtrate was allowed to stand overnight, the supernatant was filtered, and set aside;
  • Artemisia annua L., Sophora flavescens, licorice, alfalfa, berberine, medlar, Changshan, ginseng, and pinellia are separated from foreign matter, non-medicinal parts, etc., washed (or sprayed) with running water, or slightly Run), cut into pieces or segments. After the wheat is moisturized, it is flat. Dry at 70-80 ° C for use.
  • Group B ginseng, wolfberry, Pinellia medicinal materials washed twice with tap water 13kg, then rinsed twice with purified water 6.5kg, then extracted with 70% ethanol reflux 2 times, the first addition of 5.3L, the second addition 4L, each time 2h, combine the extract, filter, the filtrate and the dregs are reserved;
  • group C Ophiopogon japonicus, Artemisia annua L., licorice roots washed twice with tap water 13kg, then rinsed twice with purified water 6.5kg, then combined with the above group B spare dregs, add boiling water for cooking twice, first Add 6.7L of water for 1 hour, add 5.3L of water for the first time for 1 hour, combine the second filtrate, discard the drug residue, concentrate the filtrate to a thick paste with a relative density of 1.05 ⁇ 1.06 (80 °C), add 95% ethanol to contain The amount of alcohol was 70%, stirred and allowed to stand for 24 hours.
  • the supernatant was collected by filtration and combined with the above-mentioned Group B spare filtrate to recover ethanol (0.04 Kpa, 70 ° C) to an alcohol-free taste. Thick paste plus 6 times the amount of 4L water for injection, heating to a temperature of 50 ° C ⁇ 60 ° C, stirring to fully dissolve, hot filtered, the filtrate was allowed to stand overnight, the supernatant was filtered, and set aside;
  • the Chinese medicine composition of the present invention (freeze-dried powder prepared in Example 1) was subjected to cardiomyocyte electrophysiological test.
  • test powder of the present invention (made in Example 1).
  • test powder of the present invention was accurately weighed and dissolved in the extracellular fluid to a final concentration of 1 mg/ml and 2 mg/ml, respectively, at 4 mg/ml.
  • the reagents were purchased from Sigma.
  • Electrode solution (mmol/L): KCl 140; MgCl2 1; EGTA 5.0; Hepes 10.0; Na2ATP 2.0 (pH 7.2)
  • protease 4U / ml protease was added to the perfusate to replace the calcium-free perfusate (Sigma type XXIV). Perfusion for 2 minutes, 2 minutes after perfusion The fluid was switched again to collagenase (Worthington 2, 0.3 mg/ml) and hyaluronidase (Sigma, 0.6 mg/ml). After the perfusion lasted 5–10 min, the heart was removed from the cannula. The atrial discarding chamber was chopped and placed in a high potassium solution.
  • the composition was: (KOH 5; potassium chloride 30; KH2PO4 30; MgSO 4 3; glutamic acid 50; taurine 20; EGTA 0.5; HEPES 10, glucose 10 (pH 7.4), the tissue should be filtered through four layers of gauze, centrifuged at 1500 rpm, and centrifuged for 2 minutes. Clock. Cell pellet, supernatant is discarded, high potassium solution is added, and then centrifuged once. The cells are placed in a high potassium solution and kept at 4 °C.
  • the separated cells were placed in a cell bath and continuously perfused (22-24 ° C).
  • the cell membrane potential was recorded by whole-cell voltage clamp technique using an axon 200B patch clamp electrode amplifier, borosilicate glass electrode, and conductive in the electrode.
  • the resistance after liquid is between 1.5 and 3 ⁇ .
  • the current was recorded by the ninth generation PCLAMPEX software (Axon, USA).
  • the data analysis was analyzed by PCLAMPFIt software (Axon, USA), and the original software (USA, OriginLab) was used to map the drug in the perfusate. After 3 minutes of perfusion The administration was started, and the data expression was averaged and standard deviation. The effect of the drug was the difference between the two groups of data after the control and the administration, and the t test was used for the statistics.
  • the drug of the invention has no obvious effect on the action of delaying the action potential interval of myocardial cells by regulating the potassium ion channel, and the test and the control are repeated 4 times, and there is no statistical significance compared with the control group.
  • the drug concentration is 2 mg/ml
  • the drug of the present invention has a significant effect on the action of delaying the action potential interval of the cardiomyocytes by adjusting the potassium ion channel, and the test and the control are repeated 7 times, and there is a significant difference compared with the control group (P ⁇ 0.05). ).
  • the drug of the present invention has a significant effect on the action of delaying the action potential interval of myocardial cells by adjusting the potassium ion channel, and the test and the control are repeated 7 times, and there is a significant difference compared with the control group (P ⁇ 0.05). ).
  • the results are shown in Figures 2 and 3.

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Abstract

一种中药组合物在制备钾离子通道调节剂药物中的应用，所述的中药组合物由各中药原料按下列重量份配比制成：黄连250-450，半夏150-350，茯苓150-450，枳实65-265，常山150-350，莲子心10-70，苦参150-350，青蒿150-350，人参65-265，麦冬150-350，甘草65-265，该中药组合物可延长心肌细胞动作电位间期，从而延长心肌电活动的不应期，具有抑制兴奋折返而诱发的心律失常作用，为临床提供了新的治疗室性、房性或室上性心率失常等疾病的药物，有较好的应用前景，无毒副作用，操作简便，宜于规模化生产。

Description

一种中药组合物在制备钾离子通道调节剂药物中的应用 技术领域
本发明涉及中药，具体涉及中药组合物，尤其涉及一种中药组合物在制备钾离子通道调节剂药物中的应用。
背景技术
有关心脏疾病的研究探讨中，对于钾离子通道的研究已日益增多，钾离子通道是发现的亚型最多、作用最复杂的一类通道，一般分为延迟整流钾通道、瞬时外向钾通道、内向整流钾通道、三磷酸腺苷敏感钾通道和乙酰胆碱敏感性钾通道5大类，且这些都与心律失常的发生、发展密切相关。
延迟整流钾通道分为3类，即快速激活延迟整流钾电流(Ikr)，缓慢激活延迟整流钾电流(Iks)，超速激活延迟整流钾电流(Ikur)。快速激活延迟整流钾电流，缓慢激活延迟整流钾电流，对调节心肌细胞动作电位2期平台期的终止及3期复极化具有重要意义。Ikr、Iks通道异常或数目上调、下调均可导致心律失常的发生，故Ikr、Iks通道是心律失常发生及抗心律失常药物作用的重要靶点。
内向整流钾通道(Kir)，主要功能是维持细胞膜静息电位，同时也是复极三期的主要电流。内向整流钾通道(Kir)由两次跨膜亚单位的四聚物组成，在正电位时可被胞内Mg2和多胺阻断。瞬时外向钾通道是参与心脏动作电位复极化的主要膜电流，通道开放表现为瞬时净外向电流，随之关闭，形成动作电位的1期，对动作电位时程和形态有较大影响。KATP通道心肌KATP被胞内生理学水平的ATP抑制，将细胞代谢与膜电位耦联。内向整流机制包含了胞内Mg和Na对开放通道的阻止。
乙酰胆碱激活K钾通道(IKAch)存在于窦房结的起搏细胞和 心房肌细胞，调节心率。心房IKAch的密度大约是心室的6倍，IKAch激活引起膜电位的超极化，降低窦房结和房室结起搏细胞的自发性，延缓房室结的传导性。
心律失常是由于窦房结激动异常或激动产生于窦房结以外，激动的传导缓慢、阻滞或经异常通道传导，即心脏活动的起源和(或)传导障碍导致心脏搏动的频率和(或)节律异常。心律失常是心血管疾病中重要的一组疾病。它可单独发病亦可与心血管病伴发。可突然发作而致猝死，亦可持续累及心脏而衰竭。心律失常可见于各种器质性心脏病，其中以冠状动脉粥样硬化性心脏病(简称冠心病)，心肌病，心肌炎和风湿性心脏病(简称风心病)为多见，尤其在发生心力衰竭或急性心肌梗塞时，发生在基本健康者或植物神经功能失调患者中的心律失常也不少见。而心律失常发生的主要原因为：冲动形成异常(异位节律点自律性提高、后除极和触发活动)，或冲动传导异常(折返)，或二者兼有。因此对心律失常的治疗应降低自律性、减少后除极、消除折返。
目前，根据药物的主要作用通道和电生理特点，将众多化学结构不同的药物归纳成四大类：Ⅰ类：钠通道阻滞药；Ⅱ类：β肾上腺素受体拮抗药；Ⅲ类：延长动作电位时程药(钾离子通道阻滞药)；Ⅳ类：钙通道阻滞药。临床上主要治疗心率失常的药物有奎尼丁，利多卡因、西律、胺碘酮，维拉帕米等，有一定的疗效，但同时表现出明显的不良反应和毒副作用。除了化学药之外，还发明了一些中药。专利号200310122205.9公开了一种治疗心悸的心速宁胶囊，其为用于治疗室性早搏(心悸)的中药及其制备方法，但是，应用范围非常有限，未公开该药物组合物对钾离子通道的调节作用(延长动作电位时程)，本发明专利在原有专利技术基础上，进一步进行了深入研究，证实了该组合物对钾离子通道的调节作用(延长动作电位时程)，能用于治疗室性、房性、室上性等方面的心率失常，以及用于降低血糖， 降低血压的药物中的应用。
发明内容
本发明所要解决的技术问题在于克服上述不足之处，研究设计对钾离子通道的调节作用(延长动作电位时程)，能用于治疗室性、房性、室上性等方面的中药组合物。
本发明提供了一种中药组合物在制备钾离子通道调节剂药物中的应用。
本发明所述中药组合物由作为活性成分的中药与药用辅料组成。
本发明所述中药组合物由各中药原料按下列重量份配比制成：
Figure PCTCN2016081796-appb-000001
优选的，本发明所述中药组合物由各中药原料按下列重量份配比制成：
Figure PCTCN2016081796-appb-000002
本发明中药组合物的作用机理在于延长动作电位时程，调节钾离 子通道，抑制各种钾电流。本发明中药组合物延长心肌细胞动作电位间期，从而可延长心肌电活动的不应期，该作用机制具有抑制兴奋折返而诱发的心律失常的作用，但无毒副作用。
本发明的中药组合物进行了心肌细胞电生理试验，试验结果显示：本发明中药组合物明显延长心肌细胞动作电位间期，具有调节钾离子通道作用。试验结果显示：本发明该药品明显延长心肌细胞动作电位间期，具有调节钾离子通道作用，药物效果与药物剂量浓度具有相关性，当药物浓度为1mg/ml时,本发明药物通过调节钾离子通道,延迟心肌细胞动作电位间期的药物作用效果不明显,试验与对照重复4次，与对照组比较无统计学意义。当药物浓度为2mg/ml时,本发明药物通过调节钾离子通道,延迟心肌细胞动作电位间期的药物作用效果明显,试验与对照重复7次，与对照组比较具有显著性差异(P<0.05)。当药物浓度为4mg/ml时,本发明药物通过调节钾离子通道,延迟心肌细胞动作电位间期的药物作用效果明显,试验与对照重复7次，与对照组比较具有显著性差异。
因此，本发明中药组合物可用于制备钾离子通道调节剂药物。
本发明的另一目的是提供了所述中药组合物的制备方法。
该方法包括下列步骤：
(1)青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏、麦冬、莲子心药材分别拣出异物、非药用部位等杂质后备用；
(2)青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏分别拣出异物、非药用部位等杂质，用流动饮用水洗净切制成片或 段；麦冬用流动饮用水润透后砸扁备用；
(3)步骤(1)和(2)的药材在70-80℃,烘干备用；
(4)取黄连、枳实、常山、莲子心、苦参加60％乙醇回流提取2次，第一次加8倍量，第二次加6倍量，每次各1.5小时，合并提取液，滤过，滤液减压(0.04Kpa，70℃)回收乙醇，继续浓缩至相对密度为1.38(60℃测)的稠膏，80℃干燥成干膏备用；
(5)取人参、茯苓、半夏加70％乙醇回流提取2次，第一次加8倍量，第二次加6倍量，每次各2小时，合并提取液，滤过，滤液另器收集备用；
(6)步骤(4)药渣和麦冬、青蒿、甘草合并，加水煎煮2次，第一次加10倍量，第二次加8倍量，每次各1小时，合并煎液，滤过，滤液浓缩至相对密度为1.05～1.06(80℃测)的清膏，加95％乙醇使含醇量为70％，搅匀，静置24小时，取上清液，滤过，收集滤液备用；
(7)步骤(5)滤液和步骤(6)滤液合并，减压(0.04KPa，70℃)回收乙醇，继续浓缩至相对密度为1.38(60℃测)的稠膏，80℃干燥成干膏备用；
(8)步骤(4)与步骤(7)的干膏合并，粉碎成细粉100目，加入适量糊精，混匀，装入胶囊，或与药用辅料制成制剂即得。
本发明中药组合物按药物常规方法制成，包括片剂，胶囊，颗粒剂，口服液，丸剂等口服制剂，制备过程中加入药剂学中使用的辅料，如：填充剂，粘合剂，崩解剂，润滑剂，矫味剂等。
本发明提供的中药组合物在制备钾离子通道调节剂药物中的应用；所述应用为在制备抗心率失常药物中的应用。
本发明提供的中药组合物在制备钾离子通道调节剂药物中的应用；所述应用为在制备治疗室性、房性或室上性心率失常药物中的应用。
本发明提供的中药组合物在制备钾离子通道调节剂药物中的应用；所述应用为在制备延长动作电位时程，调节钾离子通道，抑制各种钾电流药物中的应用。
本发明中药组合物延长心肌细胞动作电位间期，从而可延长心肌电活动的不应期，该作用机制具有抑制兴奋折返而诱发的心律失常的作用，但无毒副作用。本发明提供了新的钾离子通道调节剂中药，为临床提供了新的治疗治疗室性、房性或室上性心率失常等疾病的药物，有较好的应用前景，本发明方法操作简便，宜于规模化生产。
附图说明
图1本发明药物2mg/ml动作电位延长效果与时间图
横坐标表示用药时间(单位：分钟)，纵坐标表示动作电位衰减时间(单位：毫秒)。1表示本发明药物2mg/ml给药时间段从0.65分钟---10.16分钟
图2本发明中药组合物2mg/ml,4mg/ml动作电位图
横坐标表示用药时间(单位：毫妙)，纵坐标表示动作电位(单位：毫伏)。线条1表示对照组动作电位与时间的关系，线条2表示本发明药物给药组(2mg/ml)动作电位与时间的关系，线条3表示洗出细胞恢复后动作电位与时间的关系
图3本发明中药组合物在不同浓度(1mg/ml,2mg/ml,4mg/ml)动作电位衰减关系图，横坐标表示不同浓度用药组，纵坐标表示动作电位衰减量，柱形图1为对照组动作电位衰减量，以对照组动作电位衰减量设为1，柱形图2为本发明药物1mg/ml的动作电位衰减量，柱形图3为本发明药物2mg/ml的动作电位衰减量，柱形图4为本发明药物1mg/ml的动作电位衰减量。
具体实施方式
为了便于将本发明药物组合物应用于心肌细胞电生理实验研究，本发明药物组合物按照处方比例制备成冻干药粉或浸膏。
实施例所用中药原料市售得到。
实施例1
【配方】
Figure PCTCN2016081796-appb-000003
1)以上十一味生药材，青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏、麦冬、莲子心药材分别拣出异物、非药用部位等杂质。
青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏分别拣出异物、非药用部位等杂质，用流动饮用水洗净(或喷淋)、润透 (或稍润)，分别切制成片或段。麦冬润透后砸扁。在70-80℃烘干。
2)、黄连、枳实、常山、莲子心、苦参药材用自来水20kg冲洗两次，再用纯化水10kg冲洗两次，然后用60％乙醇回流提取2次，第一次加8.4L，第二次加6.3L，每次各1.5h，合并提取液，滤过，滤液回收乙醇(0.04Kpa，70℃)至无醇味，稠膏加6.3L注射用水，加热使温度达到50℃～60℃，搅拌使充分溶解，趁热滤过，滤液静置过夜，滤取上清液，备用；
3)、B组人参、茯苓、半夏药材用自来水13kg冲洗两次，再用纯化水6.5kg冲洗两次，然后用70％乙醇回流提取2次，第一次加5.3L，第二次加4L，每次各2h，合并提取液，滤过，滤液和药渣分别备用；
4)、C组麦冬、青蒿、甘草药材用自来水13kg冲洗两次，再用纯化水6.5kg冲洗两次，然后与上述B组备用药渣合并，加注射用水煎煮二次，第一次加水6.7L煎煮1h，第二次加水5.3L煎煮1h，二次滤液合并，药渣弃去，滤液浓缩至相对密度1.05～1.06(80℃)的稠膏，加95％乙醇使含醇量为70％，搅匀，静置24小时，滤取上清液与上述B组备用滤液合并，回收乙醇(0.04Kpa，70℃)至无醇味，稠膏加6倍量4L注射用水，加热使温度达到50℃～60℃，搅拌使充分溶解，趁热滤过，滤液静置过夜，滤取上清液，备用；
5)、取上述A组和C组备用的上清液，合并，用旋转薄膜蒸发器60℃减压浓缩至相对密度为1.10(60℃)的稠膏，备用；
6)、取上述相对密度为1.10(60℃)的备用稠膏，置固定托盘 中，冷冻干燥，冻干条件为冷冻温度-40℃以下，真空度15pa以下，加热温度-20℃～80℃冷冻干燥20小时，取出，收集冻干固形物，粉碎，混匀，即得冻干粉590g。
实施例2
【配方】
Figure PCTCN2016081796-appb-000004
1)以上十一味生药材，青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏、麦冬、莲子心药材分别拣出异物、非药用部位等杂质备用。
青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏分别拣出异物、非药用部位等杂质，用流动饮用水洗净(或喷淋)、润透(或稍润)，分别切制成片或段。麦冬润透后砸扁。在70-80℃烘干备用。
2)、黄连、枳实、常山、莲子心、苦参药材用自来水20kg冲洗两次，再用纯化水10kg冲洗两次，然后用60％乙醇回流提取2次，第一次加8.4L，第二次加6.3L，每次各1.5h，合并提取液，滤过，滤液回收乙醇(0.04Kpa，70℃)至无醇味，稠膏加6.3L注射用水，加热使温度达到50℃～60℃，搅拌使充分溶解，趁热滤过，滤液静置过夜，滤取上清液，备用；
3)、B组人参、茯苓、半夏药材用自来水13kg冲洗两次，再用纯化水6.5kg冲洗两次，然后用70％乙醇回流提取2次，第一次加5.3L，第二次加4L，每次各2h，合并提取液，滤过，滤液和药渣分别备用；
4)、C组麦冬、青蒿、甘草药材用自来水13kg冲洗两次，再用纯化水6.5kg冲洗两次，然后与上述B组备用药渣合并，加注射用水煎煮二次，第一次加水6.7L煎煮1h，第二次加水5.3L煎煮1h，二次滤液合并，药渣弃去，滤液浓缩至相对密度1.05～1.06(80℃)的稠膏，加95％乙醇使含醇量为70％，搅匀，静置24小时，滤取上清液与上述B组备用滤液合并，回收乙醇(0.04Kpa，70℃)至无醇味，稠膏加6倍量4L注射用水，加热使温度达到50℃～60℃，搅拌使充分溶解，趁热滤过，滤液静置过夜，滤取上清液，备用；
5)、取上述A组和C组备用的上清液，合并，用旋转薄膜蒸发器60℃减压浓缩至相对密度为1.10(60℃)的稠膏，备用；
6)、取上述相对密度为1.10(60℃)的备用稠膏，置65℃水浴锅上水浴加热至无流动性稠膏，混匀，即得。
实施例3
Figure PCTCN2016081796-appb-000005
1)以上十一味生药材，青蒿、苦参、甘草、茯苓、黄连、枳实、 常山、人参、半夏、麦冬、莲子心药材分别拣出异物、非药用部位等杂质备用。
青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏分别拣出异物、非药用部位等杂质，用流动饮用水洗净(或喷淋)、润透(或稍润)，分别切制成片或段。麦冬润透后砸扁。在70-80℃烘干备用。
2)、黄连、枳实、常山、莲子心、苦参药材用自来水20kg冲洗两次，再用纯化水10kg冲洗两次，然后用60％乙醇回流提取2次，第一次加8.4L，第二次加6.3L，每次各1.5h，合并提取液，滤过，滤液回收乙醇(0.04Kpa，70℃)至无醇味，稠膏加6.3L注射用水，加热使温度达到50℃～60℃，搅拌使充分溶解，趁热滤过，滤液静置过夜，滤取上清液，备用；
3)、B组人参、茯苓、半夏药材用自来水13kg冲洗两次，再用纯化水6.5kg冲洗两次，然后用70％乙醇回流提取2次，第一次加5.3L，第二次加4L，每次各2h，合并提取液，滤过，滤液和药渣分别备用；
4)、C组麦冬、青蒿、甘草药材用自来水13kg冲洗两次，再用纯化水6.5kg冲洗两次，然后与上述B组备用药渣合并，加注射用水煎煮二次，第一次加水6.7L煎煮1h，第二次加水5.3L煎煮1h，二次滤液合并，药渣弃去，滤液浓缩至相对密度1.05～1.06(80℃)的稠膏，加95％乙醇使含醇量为70％，搅匀，静置24小时，滤取上清液与上述B组备用滤液合并，回收乙醇(0.04Kpa，70℃)至无醇味， 稠膏加6倍量4L注射用水，加热使温度达到50℃～60℃，搅拌使充分溶解，趁热滤过，滤液静置过夜，滤取上清液，备用；
5)、取上述A组和C组备用的上清液，合并，用旋转薄膜蒸发器60℃减压浓缩至相对密度为1.10(60℃)的稠膏，备用；
6)、取上述相对密度为1.10(60℃)的备用稠膏，置65℃锅上水浴加热至无流动性稠膏，80℃干燥成干膏备用；粉碎成100目药粉混匀，加入糊精200g,混匀，装胶囊，即得。
实施例4
本发明中药组合物(实施例1制得的冻干药粉)，进行心肌细胞电生理试验。
1、试验材料:
(1)试验动物：
雄性大鼠，体重250～500g，英国牛津大学实验动物中心提供。
(2).药品和试剂
本发明试验用药粉(实施例1制得)。
精密称取本发明试验用药粉溶解在细胞外液中，使其终浓度分别为1mg/ml和2mg/ml,4mg/ml。试剂购买自Sigma公司。
(2)溶液：
1)细胞外液(mmol/L)：
NaCl 112.0，KCl 10，KH2PO4 1.2，HEPES 10，MgSO4 5，NaHCO3 15，Taurine 30，Glucose 20，NaHCO3 24.0(pH 7.4)。连续通入5％的CO2和95％的O2.
2)电极液(mmol/L)：KCl 140；MgCl2 1；EGTA 5.0；Hepes 10.0；Na2ATP 2.0(pH 7.2)
2、研究方法：应用全细胞电压钳位技术记录单个心室肌细胞动作电位，通过持续灌流方法使本发明药物试验用溶液作用于细胞或洗出细胞。
1)大鼠单个心室肌细胞的分离
单个的心室肌细胞是从成年大白鼠心脏分离出来的，采用酶解法，将大白鼠撞击头部致昏，颈动脉放血后，仰卧位固定，迅速开胸取出心脏，把心脏装在兰根道夫灌流系统上，把酶液通过心脏开始灌流，置于36℃无钙液中，以无钙液连续灌流约5min，无钙液成分为：(氯化钠120，5.4；氯化钾；硫酸镁5；丙酮酸5葡萄糖20；20；牛磺酸；HEPES 10(pH 6.96)。灌流液中加入4U/ml的蛋白酶取代(Sigma type XXIV)以上无钙灌注液。灌流2分钟，2分钟后灌流液再次切换到含胶原酶后(沃辛顿2级，0.3毫克/毫升)和透明质酸酶(Sigma，0.6毫克/毫升)。灌注持续5–10min后，将心脏从套管取走后，心房丢弃心室切碎，放入高钾溶液中，成分为:(KOH 5；氯化钾30；KH2PO4 30；MgSO4 3；；谷氨酸50；牛磺酸20；EGTA 0.5；HEPES 10，葡萄糖10(pH 7.4)，组织应通过四层纱布过滤，滤液1500rpm离心，离心2分钟。细胞沉淀，上清液弃去，加入高钾溶液，再离心一次，细胞放入高钾溶液，保持在4℃备用
2)电生理技术及统计
分离好的细胞放入细胞浴槽中，连续灌流(22-24℃)，细胞膜电位是用全细胞电压钳技术记录，使用一个轴突200B膜片钳电极放大器，硼硅玻璃电极，电极中加入导电液体后电阻在1.5～3Ω之间。电流是用第九代PCLAMPEX软件(美国Axon公司)来记录完成，数据分析用PCLAMPFIt软件(美国,Axon公司)分析，用origin软件(美国,OriginLab公司)制图，把药溶解在灌流液中，至少灌流3分钟后 开始给药，数据表达采用平均值和标准差，药物的效果是用对照和给药后两组数据均数差，采用t检验进行统计。
3、研究结果：
(1)试验结果显示：本发明该药品明显延长心肌细胞动作电位间期，具有调节钾离子通道作用：对照为45.4ms±4.9，本发明药物组合物(2mg/ml)为52.2ms±4.5(P<0.01,n＝7).药物洗脱细胞后动作电位恢复到给药前的状态。结果见图1所示：试验结果显示：本发明该药品明显延长心肌细胞动作电位间期，具有调节钾离子通道作用，药物效果与药物剂量浓度具有相关性，当药物浓度为1mg/ml时,本发明药物通过调节钾离子通道,延迟心肌细胞动作电位间期的药物作用效果不明显,试验与对照重复4次，与对照组比较无统计学意义。当药物浓度为2mg/ml时,本发明药物通过调节钾离子通道,延迟心肌细胞动作电位间期的药物作用效果明显,试验与对照重复7次，与对照组比较具有显著性差异(P<0.05)。当药物浓度为4mg/ml时,本发明药物通过调节钾离子通道,延迟心肌细胞动作电位间期的药物作用效果明显,试验与对照重复7次，与对照组比较具有显著性差异(P<0.05)。结果见图2、图3。

Claims (7)

  1. 一种中药组合物在制备钾离子通道调节剂药物中的应用；其特征在于，
    所述中药组合物由各中药原料按下列重量份配比制成：
    Figure PCTCN2016081796-appb-100001
  2. 一种中药组合物在制备钾离子通道调节剂药物中的应用；其特征在于，所述中药组合物由各中药原料按下列重量份配比制成：
    Figure PCTCN2016081796-appb-100002
  3. 根据权利要求1所述的一种中药组合物在制备钾离子通道调节剂药物中的应用，其特征在于，所述中药组合物通过下列方法制得，该方法包括下列步骤：
    (1)青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏、麦冬、莲子心药材分别拣出异物、非药用部位杂质后备用；
    (2)青蒿、苦参、甘草、茯苓、黄连、枳实、常山、人参、半夏分别拣出异物、非药用部位杂质，用流动饮用水洗净切制成片或段； 麦冬用流动饮用水润透后砸扁备用；
    (3)步骤(1)和(2)的药材在70-80℃烘干备用；
    (4)取黄连、枳实、常山、莲子心、苦参加60％乙醇回流提取2次，第一次加8倍量，第二次加6倍量，每次各1.5小时，合并提取液，滤过，滤液减压0.04Kpa，70℃回收乙醇，继续浓缩至相对密度为1.38 60℃测的稠膏，80℃干燥成干膏备用；
    (5)取人参、茯苓、半夏加70％乙醇回流提取2次，第一次加8倍量，第二次加6倍量，每次各2小时，合并提取液，滤过，滤液另器收集备用；
    (6)步骤(4)药渣和麦冬、青蒿、甘草合并，加水煎煮2次，第一次加10倍量，第二次加8倍量，每次各1小时，合并煎液，滤过，滤液浓缩至相对密度为1.05～1.06(80℃测)的清膏，加95％乙醇使含醇量为70％，搅匀，静置24小时，取上清液，滤过，收集滤液备用；
    (7)步骤(5)滤液和步骤(6)滤液合并，减压0.04KPa，70℃回收乙醇，继续浓缩至相对密度为1.38 60℃测的稠膏，80℃干燥成干膏备用；
    (8)步骤(4)与步骤(7)的干膏合并，粉碎成细粉100目，加入适量糊精，混匀，装入胶囊，或与药用辅料制成制剂即得。
  4. 根据权利要求1所述中药组合物在制备钾离子通道调节剂药物中的应用，其特征在于，所述应用为在制备抗心率失常药物中的应用。
  5. 根据权利要求1所述中药组合物在制备钾离子通道调节剂药物中的应用，其特征在于，所述应用为在制备治疗室性、房性或室上性心率失常药物中的应用。
  6. 根据权利要求1所述中药组合物在制备钾离子通道调节剂药物中的应用，其特征在于，所述应用为在制备延长动作电位时程，调节钾离子通道，抑制各种钾电流药物中的应用。
  7. 根据权利要求1所述中药组合物在制备钾离子通道调节剂药物中的应用，其特征在于，所述中药组合物为片剂、胶囊、颗粒剂、口服液或丸剂。
PCT/CN2016/081796 2015-05-13 2016-05-12 一种中药组合物在制备钾离子通道调节剂药物中的应用 WO2016180347A1 (zh)

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