A traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, a preparation method and application thereof

Abstract

The application provides a traditional Chinese medicine compound preparation for treating paroxysmal atrial fibrillation, a preparation method and application thereof, and belongs to the technical field of traditional Chinese medicines. The application has the characteristics of simple prescription, controllable quality and convenient taking; can reduce the frequency and duration of atrial fibrillation attacks, prolong the effective refractory period (ERP) of the atrium, and inhibit atrial electrical remodeling.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, and in particular to a traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, its preparation method and application. Background Technology

[0002] Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice, with a global prevalence of 1-2%, and the incidence increases exponentially with age. In my country, the standardized prevalence in people aged 35 and above is 0.77%, with an estimated number of patients >10 million. Among them, paroxysmal atrial fibrillation (PAF) accounts for more than 30%, which can progress to persistent atrial fibrillation and significantly increase the risk of stroke, heart failure, and death.

[0003] Both traditional Chinese medicine (TCM) and Western medicine have drugs for atrial fibrillation. For example, Western medicine class Ic / III antiarrhythmic drugs (amiodarone, propafenone, etc.) have an efficacy rate of 40-60%, but have side effects such as arrhythmia, pulmonary-thyroid-hepatic toxicity, and QT prolongation; catheter ablation is expensive and has a recurrence rate of 30-50%; TCM preparations such as Wenxin Granules and Shengsong Yangxin Capsules have some effect on patients with "qi and yin deficiency" or "blood stasis," but there are no specific preparations for atrial fibrillation caused by "internal retention of dampness and disordered qi circulation." Inventor Rong Rucheng, drawing on over thirty years of clinical experience in treating atrial fibrillation, proposed a treatment principle of "tonifying qi and nourishing the stomach, promoting diuresis and resolving dampness, and warming yang and calming palpitations," based on the pathological mechanism of water retention in the stomach and disordered water and qi transport. He invented an oral preparation with strong pathogenesis targeting, definite efficacy, few side effects, and industrial production capability. Summary of the Invention

[0004] In view of this, the purpose of this invention is to provide a traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, which has the characteristics of simple formulation, controllable quality, and convenient administration; it can reduce the frequency and duration of atrial fibrillation attacks, improve symptoms such as palpitations, chest tightness, fatigue, and poor appetite, prolong the effective refractory period (ERP) of the atria, and inhibit atrial electrical remodeling.

[0005] The traditional Chinese medicine compound for treating paroxysmal atrial fibrillation according to the present invention comprises the following ingredients: Cinnamon twig 10-40 parts, prepared licorice root 5-20 parts, Poria cocos 10-40 parts, ginseng root 5-20 parts, dried tangerine peel 10-40 parts, immature bitter orange 10-30 parts, Atractylodes macrocephala 5-20 parts, fresh ginger 10-40 parts, jujube 10-40 parts.

[0006] Preferably, the traditional Chinese medicine compound for treating paroxysmal atrial fibrillation includes the following ingredients: 20 parts cinnamon twig, 10 parts prepared licorice root, 20 parts poria cocos, 10 parts ginseng root, 20 parts dried tangerine peel, 15 parts immature bitter orange, 10 parts atractylodes macrocephala, 20 parts fresh ginger, and 20 parts jujube.

[0007] In this invention, cinnamon twig warms and invigorates the heart yang, calms the rebellious qi, and relieves adverse qi flow; prepared licorice root and ginseng rootlets replenish qi, restore pulse, and generate fluids, serving as assistant herbs; poria and atractylodes macrocephala strengthen the spleen and eliminate dampness; tangerine peel and immature bitter orange regulate qi, resolve dampness, and harmonize the stomach; and ginger and jujube harmonize the ying and wei, acting as guiding herbs. The entire formula works to "replenish qi and nourish the stomach, promote diuresis and resolve dampness, warm yang, and calm palpitations."

[0008] Another object of the present invention is to provide a method for preparing a traditional Chinese medicine preparation for treating paroxysmal atrial fibrillation, comprising the following steps: (1) Water decoction extraction: Weigh the Chinese herbal raw materials according to the proportion, soak them in water and decoct them, repeat twice to obtain the decoction; collect the distillate during the first decoction, add β-cyclodextrin to the distillate, stir, refrigerate, filter out the precipitate, and dry the precipitate to obtain the volatile oil inclusion complex. (2) Filtration and concentration: The decoction is filtered, the two filtrates are combined, and concentrated to obtain the compound extract of traditional Chinese medicine; (3) Drying and granulation: The compound extract of traditional Chinese medicine is spray-dried to obtain extract powder; (4) Add additives and the volatile oil inclusion complex from step (1) to the extract powder, mix evenly, and obtain the traditional Chinese medicine compound preparation.

[0009] Preferably, the water decoction extraction method in step (1) is as follows: weigh the Chinese herbal raw materials according to the proportion, add 8-12 times the amount of water to soak for 15-30 min, decoct twice, each time for 1-1.5 h, to obtain the decoction; wherein, during the first decoction, collect 0.2 times the amount of distillate, add 4-8% β-cyclodextrin to the distillate, stir at 30-45℃ for 15-30 minutes, refrigerate at 2-8℃ and stand for 12-24 hours, filter out the precipitate, dry the precipitate at 50-70℃, pulverize, and obtain the volatile oil inclusion complex.

[0010] Preferably, the filtration pore size in step (2) is 100-200 mesh, and the concentration temperature is 50-65℃; the relative density of the traditional Chinese medicine compound extract at 60℃ is 1.05-1.15.

[0011] Preferably, the drying conditions in step (3) are an inlet air temperature of 160-190℃ and an outlet air temperature of 80-100℃.

[0012] Preferably, the traditional Chinese medicine compound preparation in step (4) is granules or mixture; the additive is a mixture of dextrin and lactose, or a mixture of potassium sorbate and citric acid solution.

[0013] Furthermore, when the traditional Chinese medicine compound preparation is in the form of granules, the additive is a mixture of dextrin and lactose, and the mass ratio of the extract powder, dextrin, and lactose is 1-1.2:0.1-0.3:0.15-0.2; when the traditional Chinese medicine compound preparation is in the form of a mixture, the additive is a mixture of potassium sorbate and citric acid, and the amount of potassium sorbate added is 0.1% of the mass of the extract powder, the concentration of the citric acid solution is 5%, and the pH of the mixture is adjusted to 5.0–6.0.

[0014] The present invention also provides an application of a traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, wherein the traditional Chinese medicine compound is used to prepare a drug for treating paroxysmal atrial fibrillation.

[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, its preparation method, and its application. The key pathogenesis is "deficiency of the middle jiao and dampness retention, and suppression of heart yang". The treatment principle is "tonifying qi and nourishing the stomach, promoting diuresis and resolving dampness, and warming and unblocking heart yang". It has the characteristics of simple formulation, controllable quality, and convenient administration. It can reduce the frequency and duration of atrial fibrillation attacks, improve symptoms such as palpitations, chest tightness, fatigue, and poor appetite, prolong the effective refractory period (ERP) of the atria, and inhibit atrial electrical remodeling. Detailed Implementation

[0016] The present invention will be further described below with reference to the embodiments.

[0017] Example 1 A traditional Chinese medicine compound preparation for treating paroxysmal atrial fibrillation, with the following ingredients: Cinnamon twig 6000 g, prepared licorice root 3000 g, Poria cocos 6000 g, ginseng root 3000 g, dried tangerine peel 6000 g, immature bitter orange 4500 g, Atractylodes macrocephala 3000 g, fresh ginger 6000 g, jujube 6000 g.

[0018] The preparation method of the traditional Chinese medicine compound for treating paroxysmal atrial fibrillation includes the following steps: (1) Water decoction extraction: Weigh the Chinese herbal raw materials according to the proportion, add 10 times the amount of water to soak for 30 min, decoct twice to obtain decoction; collect 0.2 times the amount of distillate (volatile oil solution) during the first decoction, add 6% β-cyclodextrin to the distillate, stir at 40℃ for 15 min, refrigerate at 5℃, stand for 12 hours, filter out the precipitate, dry the precipitate at 65℃, and pulverize to obtain volatile oil inclusion complex; (2) Filtration and concentration: The two decoctions from step (1) were filtered through a 100-mesh sieve, and the two filtered decoctions were combined and concentrated under reduced pressure at 60 °C to a relative density of 1.08 (60 °C) to obtain a compound extract of traditional Chinese medicine. (3) Drying and granulation: The compound extract of traditional Chinese medicine was spray-dried (inlet air temperature 180℃, outlet air temperature 90℃) to obtain extract powder; (4) Mix the extract powder, dextrin and lactose in a mass ratio of 1:0.1:0.15, add the volatile oil inclusion complex, mix evenly, and then press, granulate and size the mixture using a dry granulator to obtain granules, denoted as FFZY.

[0019] The granules are packaged into 10g bags (equivalent to 48g of raw medicinal materials).

[0020] Comparative Example 1 A traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, with the raw materials and preparation method as described in Example 1, except that Comparative Example 1 does not add cinnamon twig and poria cocos, but adds dextrin and lactose (in a mass ratio of 10:15) to make 10g of granules equivalent to 48g of raw herbs.

[0021] Comparative Example 2 A traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, with the raw materials and preparation method as described in Example 1, differs in that Comparative Example 2 does not add roasted licorice root, ginseng root, or jujube, but adds dextrin and lactose (in a mass ratio of 10:15) to supplement 10g of granules, which is equivalent to 48g of raw herbs.

[0022] Comparative Example 3 A traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, with the raw materials and preparation method as described in Example 1, differs in that Comparative Example 3 does not add tangerine peel, immature bitter orange, atractylodes macrocephala, or ginger, but adds dextrin and lactose (in a mass ratio of 10:15) to supplement 10g of granules, which is equivalent to 48g of raw herbs.

[0023] Comparative Example 4 A traditional Chinese medicine compound for treating paroxysmal atrial fibrillation, the raw materials and preparation method are the same as in Example 1, except that Comparative Example 4 does not use 6% β-cyclodextrin for inclusion, and the distillate is instead adsorbed with 6% starch. The same method is used for refrigeration, standing, filtration and drying.

[0024] Example 2 A traditional Chinese medicine compound preparation for treating paroxysmal atrial fibrillation, with the same raw material composition as in Example 1, and the preparation method of the traditional Chinese medicine compound preparation is as follows: Steps (1)-(3) are the same as in Example 1; Step (4) Add the volatile oil inclusion complex to the extract powder, then add 0.1% potassium sorbate, adjust the pH to 5.0–6.0 with 5% citric acid solution, add water to adjust the volume to make the daily dosage 200ml, stir, filter, boil at 100 ℃ for 30 min, dispense into 100 mL / bag, sterilize, and obtain the traditional Chinese medicine compound preparation.

[0025] Pharmacological trials 1. Acetylcholine-calcium chloride (ACh-CaCl2) inducing atrial fibrillation in mice (1) Experimental animals: Male SPF-grade ICR mice, 7-8 weeks old, weighing 22-25g. The mice were housed in an environment with a 12h / 12h light / dark cycle, a temperature of 22-24℃, and a relative humidity of 45-65%, with free access to food and water. The mice were acclimatized for 7 days before the experiment and those with normal baseline electrocardiograms were included.

[0026] (2) Number of animals and grouping: The mice were randomly divided into 9 groups of 12 mice each, specifically as follows: Blank group (normal control) Model group (ACh-CaCl2 model group) Amio group (Amiodarone 50 mg·kg) -1 (positive control group) The WXKL group (Wenxin Granules, 8 g / kg, positive control group) received twice the human dose. FFZYL group (Example 1: Compound Chinese Medicine Granules 2.5g / kg, equivalent to 12g raw drug·kg) -1 ) FFZYM group (Example 1: Compound Chinese Medicine Granules 5g / kg, equivalent to 24g crude drug·kg) -1 ) Group FFZYH (Example 1: Compound Chinese Medicine Granules 10 / kg, equivalent to 24g crude drug·kg) -1 ) Control group 1 (granules of Comparative Example 1 in Practice 1, 5 g / kg, equivalent to 24 g crude drug·kg) -1 ) Control group 2 (granules of Comparative Example 2 in Experiment 1, 5 g / kg, equivalent to 24 g crude drug·kg) -1 ) Control group 3 (granules of Comparative Example 3 in Experiment 1, 5 g / kg, equivalent to 24 g crude drug·kg) -1 ) (3) Dosing regimen The Amio group, WXKL group, FFZYL group, FFZYM group, FFZYH group and control group 1-3 were administered 0.1 mL / 10 g via gavage for 7 consecutive days. The Model group was given the same volume of physiological saline.

[0027] (4) Preparation of atrial fibrillation model Mice in the Model group, Amio group, WXKL group, FFZYL group, FFZYM group, FFZYH group, and control groups 1-3 were treated with isoflurane inhalation anesthesia. After anesthesia, subcutaneous needle electrodes were connected to an RM-6240 multi-channel physiological instrument in the limbs. ACh-CaCl2 mixture (acetylcholine ACh 60 μg·kg⁻¹) was rapidly injected via the tail vein. -1+CaCl2 12 mg·kg -1 0.1 mL was injected within 5 seconds; ECG was simultaneously recorded continuously in lead II of the limb for 20 minutes. Criteria for successful induction: disappearance of the P wave, irregular RR interval lasting ≥1 second.

[0028] (5) Observation and measurement Record the induction rate, number of attacks (total number of AF attacks within 20 minutes), duration (average number of seconds per AF attack), heart rate (HR), peak heart rate (PR), and QT interval corrected value (QTc, measured 5 minutes during induction). (6) Statistical processing Quantitative data are expressed as mean ± SD, and one-way ANOVA with LSD method is used for comparisons among multiple groups; categorical data are expressed as χ². 2 Test. Significance level α = 0.05.

[0029] Changes in the electrocardiogram of mice were recorded at 24-hour intervals for 7 consecutive days. The duration of atrial fibrillation in mice was observed after each administration.

[0030] Experimental results The susceptibility indicators for atrial fibrillation in each group (Mean±SD, n=12) are shown in Table 1. Table 1

[0031] In Table 1, P < 0.001 vs Model; P < 0.01 vs Model; P<0.05vs Model; #P<0.05vsFFZYM; &&P<0.01vs WXKL; &P<0.05vs WXKL.

[0032] Acute electrophysiological remodeling, ECG parameters (Mean±SD, n=12) 5 min after induction are shown in Table 2. Table 2

[0033] In Table 2, △△△P<0.001 vs Blank; P<0.001 vs Model; P<0.01 vs Model; P<0.05 vs Model; #P<0.05 vs FFZYM; &&&P<0.001 vs WXKL; &P<0.05 vs WXKL.

[0034] As can be seen from Tables 1 and 2, FFZY 12-48 g·kg -1 It dose-dependently reduced the induction rate, frequency, and duration of atrial fibrillation in ACh-CaCl2 mice; medium-dose FFZYM showed significant efficacy, and high-dose FFZYH was superior to the positive controls amiodarone and Wenxin granules; the drugs synchronously reversed model tachycardia, shortened PR interval, and prolonged QTc. Among them, the granule group of the split formula was significantly different from the medium dose (same dosage) of the whole formula (P<0.05 or <0.01), indicating that the formula was reasonable and necessary.

[0035] In summary, FFZY compound granules demonstrated a dose-dependent effect, definite efficacy, and controllable safety in the classic ACh-CaCl2 atrial fibrillation model. The medium dose of FFZYM can be used as a recommended dose for subsequent pharmacodynamic and toxicological studies and has the potential to enter preclinical evaluation.

[0036] Stability test Chromatographic conditions and system suitability tests were performed using octadecylsilane-bonded silica gel as the stationary phase; acetonitrile as mobile phase A and 0.1% TFA aqueous solution as mobile phase B, with gradient elution as specified in the table below; the detection wavelength was 290 nm. The mobile phase gradient elution table is shown in Table 3. Table 3

[0037] Preparation of reference solution: Take an appropriate amount of cinnamaldehyde reference standard and add methanol to prepare a reference solution containing 50 ug / mL of cinnamaldehyde.

[0038] Preparation of test solution: Take particles from Example 1 and Comparative Example 4 respectively. The granules are ground into a fine powder. 0.5 g is accurately weighed and placed in a stoppered conical flask. 25 mL of methanol is accurately added, and the weight is measured. The mixture is sonicated for 30 minutes, cooled, and weighed again. The weight loss is replenished with methanol, the mixture is shaken well, centrifuged, and the supernatant is collected.

[0039] Detection method: Accurately pipette 10 μl each of the reference solution and the test solution and inject them into the liquid chromatograph for determination. The results of cinnamaldehyde content and stability tests for particles processed by different methods are shown in Table 4.

[0040] Table 4

[0041] Therefore, without inclusion with 6% β-cyclodextrin, the resulting granules have low and unstable cinnamaldehyde content, decreasing by more than 50% after 12 months. However, using the inclusion process, the cinnamaldehyde content is 2.5 times higher, and the decrease after 12 months is less than 10%, remaining essentially stable.

[0042] clinical trials Subject selection criteria Inclusion criteria The participants were aged 50-75 years, with no gender restriction, and 50 participants in each gender group. They met the diagnostic criteria for paroxysmal atrial fibrillation: atrial fibrillation confirmed by electrocardiogram, lasting ≥30 seconds; frequency of attacks ≥2 times / month in the past 3 months; ≥1 atrial fibrillation episode recorded at baseline (screening period of 2 weeks); and were diagnosed by traditional Chinese medicine as having internal retention of dampness and disharmony of the stomach, with a white and greasy tongue coating and a soft and slow or slippery pulse; symptoms included cold extremities, aversion to drinking water, poor appetite, epigastric fullness, and loose stools.

[0043] Those who are willing to wear an electrocardiogram (ECG) watch and record the ECG during an atrial fibrillation episode, and fill out an atrial fibrillation diary card.

[0044] Exclusion criteria Persistent, long-term persistent, or permanent atrial fibrillation; need for long-term use of antiarrhythmic chemotherapy; atrial fibrillation radiofrequency ablation within the past six months; severe liver or kidney dysfunction; history of drug allergy.

[0045] Those who are unwilling to wear an ECG watch and record the ECG during an atrial fibrillation episode, or who are unwilling to fill out an atrial fibrillation diary card.

[0046] test drug Name: FFZY Mixture (Example 1) or Wenxin Granules (Shandong Buchang Pharmaceutical Co., Ltd.) Usage: FFZY compound: 3 times a day, 1 sachet each time, 2 weeks of treatment, 2 weeks of rest after stopping the medication. If atrial fibrillation improves, stop the medication. If the frequency of atrial fibrillation does not decrease significantly, continue the medication for another 2 weeks. A maximum of two courses of treatment can be taken.

[0047] Wenxin Granules: Take 1 sachet 3 times a day for 2 weeks, stop for 2 weeks, and then take it for a total of 2 courses of treatment.

[0048] Starting on the second day of medication, atrial fibrillation episodes were recorded, including the number of episodes and their duration. An electrocardiogram (ECG) watch was used to record heart rate, QT, and HRV during each atrial fibrillation episode. The recording period was 12 weeks.

[0049] During an attack, depending on the intensity, you can take a commonly used medication such as metoprolol 0.5-1 tablet.

[0050] therapeutic indicators Baseline values: The average number of atrial fibrillation episodes during the screening period was used as the baseline. Changes in the frequency and duration of atrial fibrillation episodes over 12 weeks were statistically analyzed. Heart rate, QT, HRV, etc., during atrial fibrillation episodes over 12 weeks were also statistically analyzed based on electrocardiogram records.

[0051] The primary endpoints were calculated as follows: the rate of change in seizure frequency was calculated as shown in equation (1), and the rate of change in seizure duration was calculated as shown in equation (2). (1) (2) Secondary endpoints are calculated as follows, with the rate of change of HRV as shown in equation (3): (3) The clinical trial results for atrial fibrillation caused by "internal retention of dampness and disharmony of the stomach" are shown in Table 5.

[0052] Table 5

[0053] In Table 5, P<0.01 vs. stable-core granules; P<0.05 vs. stable-core granules; The results showed that, compared with Wenxin granules, the change rate of attack frequency and the change rate of attack duration were significantly different after 1-2 courses of treatment. This indicates that it has a good effect on reducing the attack frequency and duration of atrial fibrillation caused by "internal retention of dampness and stomach disharmony", and can also increase the HRV time during the attack.

[0054] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine compound preparation for treating paroxysmal atrial fibrillation, characterized in that, Including the following parts by weight of raw materials: Cinnamon twig 10-40 parts, prepared licorice root 5-20 parts, Poria cocos 10-40 parts, ginseng root 5-20 parts, dried tangerine peel 10-40 parts, immature bitter orange 10-30 parts, Atractylodes macrocephala 5-20 parts, fresh ginger 10-40 parts, jujube 10-40 parts.

2. The traditional Chinese medicine compound preparation for treating paroxysmal atrial fibrillation according to claim 1, characterized in that, Including the following raw materials: 20 parts cinnamon twig, 10 parts prepared licorice root, 20 parts poria cocos, 10 parts ginseng root, 20 parts dried tangerine peel, 15 parts immature bitter orange, 10 parts atractylodes macrocephala, 20 parts fresh ginger, and 20 parts jujube.

3. The method for preparing the traditional Chinese medicine compound preparation for treating paroxysmal atrial fibrillation according to claim 1, characterized in that, Includes the following steps: (1) Water decoction extraction: Weigh the Chinese herbal raw materials according to the proportion, soak them in water and decoct them, repeat twice to obtain the decoction; collect the distillate during the first decoction, add β-cyclodextrin to the distillate, stir, refrigerate, filter out the precipitate, and dry the precipitate to obtain the volatile oil inclusion complex. (2) Filtration and concentration: The decoction is filtered, the two filtrates are combined, and concentrated to obtain the compound extract of traditional Chinese medicine; (3) Drying and granulation: The compound extract of traditional Chinese medicine is spray-dried to obtain extract powder; (4) Add additives and the volatile oil inclusion complex from step (1) to the extract powder, mix evenly, and obtain the traditional Chinese medicine compound preparation.

4. The method for preparing the traditional Chinese medicine preparation for treating paroxysmal atrial fibrillation according to claim 3, characterized in that, The water decoction extraction method described in step (1) is as follows: Weigh the Chinese herbal raw materials according to the proportion, add 8-12 times the amount of water and soak for 15-30 min, decoct twice, each time for 1-1.5 h, to obtain the decoction; during the first decoction, collect 0.2 times the amount of distillate, add 4-8% β-cyclodextrin to the distillate, stir at 30-45℃ for 15-30 min, refrigerate at 2-8℃ and stand for 12-24 hours, filter out the precipitate, dry the precipitate at 50-70℃, pulverize, and obtain the volatile oil inclusion complex.

5. The method for preparing the traditional Chinese medicine preparation for treating paroxysmal atrial fibrillation according to claim 3, characterized in that, The filter pore size in step (2) is 100-200 mesh, and the concentration temperature is 50-65℃; the relative density of the traditional Chinese medicine compound extract at 60℃ is 1.05-1.

15.

6. The method for preparing the traditional Chinese medicine preparation for treating paroxysmal atrial fibrillation according to claim 3, characterized in that, The drying conditions described in step (3) are an inlet air temperature of 160-190℃ and an outlet air temperature of 80-100℃.

7. The method for preparing the traditional Chinese medicine compound preparation for treating paroxysmal atrial fibrillation according to claim 3, characterized in that, The traditional Chinese medicine compound preparation in step (4) is granules or mixture; the additive is a mixture of dextrin and lactose, or a mixture of potassium sorbate and citric acid solution.

8. The application of the traditional Chinese medicine preparation for treating paroxysmal atrial fibrillation according to claim 1, characterized in that, The traditional Chinese medicine compound was used to prepare a drug for treating paroxysmal atrial fibrillation.

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