Lotus plumule extract sublingual tablet and preparation method thereof

Abstract

The invention relates to a lotus plumule extract sublingual tablet and a preparation method thereof, the lotus plumule extract sublingual tablet takes lotus plumule as a raw material, and the preparation method comprises the following steps: taking a lotus plumule extract, crushing, carrying out beta-cyclodextrin inclusion, drying, crushing, adding a pore-foaming agent mannitol, xylitol or sorbitol, a disintegrating agent sodium carboxymethyl starch, cross-linked povidone or low-substituted hydroxy propyl cellulose, and uniformly mixing to obtain the lotus plumule extract sublingual tablet. The preparation method comprises the following steps: granulating the raw materials into granules according to a conventional dry method, straightening the granules, and tabletting to prepare the sublingual tablet.

Description

Technical Field

[0001] The invention relates to the field of medicines, and in particular to a lotus seed core extract sublingual tablet and a preparation method thereof. Background Art

[0002] Arrhythmia refers to a type of disease caused by abnormal cardiac autonomic function or disturbance of excitation conduction, such as tachycardia, bradycardia, irregular heartbeat or ectopic heartbeat. Its clinical manifestations include sudden palpitations, chest pain, dizziness, discomfort in the precordial area, stuffiness, shortness of breath, cold hands and feet, syncope, and even unconsciousness. A small number of patients with arrhythmia may be asymptomatic, with only electrocardiogram changes. Its morbidity and mortality rates are both high, accounting for about 11% of the number of natural deaths. According to statistics, about 600,000 people die of sudden cardiac death in my country each year, of which 90% are caused by malignant arrhythmias. Therefore, the treatment of arrhythmias has become the focus of medical workers.

[0003] Clinically, Western medicine treatment for arrhythmias has the characteristics of rapid action and definite efficacy, but it has large side effects, and the several types of antiarrhythmic drugs currently used in clinical practice have shortcomings. For example, when treating arrhythmias, they often induce arrhythmias again, with an incidence rate of more than 10%; at the same time, they are also prone to induce conduction block and drug-induced heart failure, and are ineffective for some refractory arrhythmias.

[0004] TCM's understanding of arrhythmia was recorded as early as in the Yellow Emperor's Internal Classic. For example, in the Plain Questions, it is said that "when a person exhales, his pulse beats once, and when he inhales, his pulse beats once, which means he has insufficient energy. ... When a person exhales, his pulse beats more than four times, which means he is dead." In addition, the Pulse Classic states that the pulse is "sometimes large, sometimes small, sometimes sparse, sometimes rapid," and "like a bean hitting the hand," which vividly describe the pulse of arrhythmia. Through clinical practice, later doctors described the pulse as knotted, intermittent, rapid, slow, etc.

[0005] Traditional Chinese medicine believes that if you suffer from chest pain, heart pain, abdominal distension, cough and asthma, heart paralysis and other diseases for a long time, it can cause deficiency of Yang Qi, loss of warming and circulation of the heart meridian, deficiency of Yin Blood, loss of collateral nourishment of the heart meridian and cause disease, thus leading to the appearance of delayed, rapid, rapid, knotted, intermittent, or even more serious pulses such as absent pulses. These pulses can reflect arrhythmia. The treatment principle of TCM based on syndrome differentiation is to replenish Qi and blood, nourish the heart and calm the mind.

[0006] In recent years, studies have found that phenolic alkaloids extracted from the traditional Chinese medicine lotus seed core, such as liensinine, methyl liensinine, and isoliensinine, have significant anti-arrhythmic effects. Therefore, in order to improve the bioavailability and stability of the drug, combined with the compliance of arrhythmia patients with treatment, and convenient for patients to take, lotus seed core is prepared into a solid rapid-release sublingual tablet. Summary of the invention

[0007] The purpose of the present invention is to provide a lotus seed core extract sublingual tablet;

[0008] Another object of the present invention is to provide a method for preparing a lotus seed core extract sublingual tablet.

[0009] The object of the present invention is achieved through the following technical solutions:

[0010] The lotus seed extract sublingual tablet of the present invention is prepared from the following raw materials in parts by weight:

[0011] 1-10 parts of lotus seed core extract, 2-20 parts of beta-cyclodextrin, 0.1-5 parts of mannitol, xylitol or sorbitol, 0.1-3 parts of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, 0.01-1 parts of colloidal silicon dioxide and 0.01-1 parts of flavoring agent.

[0012] Preferably, it is prepared from the following raw materials in parts by weight:

[0013] 1-5 parts of lotus seed core extract, 2-15 parts of beta-cyclodextrin, 0.5-5 parts of mannitol, xylitol or sorbitol, 0.1-2 parts of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, 0.02-1 parts of colloidal silicon dioxide and 0.02-1 parts of flavoring agent.

[0014] The following are the main effects and pharmacological actions of the lotus seed core of the present invention:

[0015] Lotus seed heart is the green radicle in the middle of the mature seed of the lotus plant Nelumbo nucifera Gaertn. of the Nymphaeaceae family. It is bitter and cold in nature and enters the heart and kidney meridians. Lotus seed heart has the effects of clearing the heart and calming the mind, connecting the heart and kidney, and stopping bleeding. It is used for heat entering the pericardium, coma and delirium, heart and kidney disharmony, insomnia and spermatorrhea, and vomiting blood due to blood heat. According to the "New Materia Medica", lotus seed heart "clears heart fire, calms liver fire, drains spleen fire, reduces lung fire, relieves heat and restlessness, promotes fluid and quenches thirst, and treats red and swollen eyes." Lotus seed heart is included in the 2015 edition of the "Chinese Pharmacopoeia" and is mainly produced in Hunan, Hubei, Fujian, Jiangsu, Zhejiang and other places.

[0016] Lotus seeds contain a variety of alkaloids: liensinine, isoliensinine, neferine, lotusine, methye-corypalline, nuciferine, pronuciferine, demethylcoclaurine, lotusine, and amorphous alkaloid Nn-9 was obtained from the mother liquor of liensinine. It also contains flavonoids such as galuteolin, hyperin, and rutin. In addition, lotus seeds also contain water-soluble polysaccharides and trace elements such as zinc, copper, iron, calcium, magnesium, sodium, potassium, nickel, manganese, and cadmium.

[0017] Modern phytochemical studies have shown that the phenolic alkaloids in lotus seed mainly contain liesinine, methyl liesinine and isoliensinine. Modern pharmacological studies have shown that both the total alkaloids and monomers of lotus seed have a wide range of anti-arrhythmic, anti-myocardial ischemic and hypotensive effects, and are mainly suitable for the treatment of arrhythmias and myocardial ischemia. Its anti-arrhythmic effect is better than that of the traditional drug quinine, and its anti-myocardial ischemic effect is equivalent to that of diltiazem. In addition, it also has hypotensive and antioxidant effects and is used for the prevention and treatment of diabetic syndrome.

[0018] The pharmacological effects and mechanisms of the main components of lotus seed alkaloids, including liesinine, isoliensinine, methyl liansinine, and quaternary ammonium alkaloids are as follows:

[0019] 1. Lien has a good antiarrhythmic effect, and its mechanism of action may be related to blocking the transmembrane transport of Na+, Ca2+, and K+.

[0020] 2. Neferine (Nef) can inhibit the autonomy of slow-response cells in the sinoatrial node and delay atrioventricular conduction, and has a central antiarrhythmic effect. It is a Class Ia antiarrhythmic drug, and its antiarrhythmic mechanism is similar to that of quinidine or procainamide.

[0021] 3. Lotus quaternary ammonium base (lotus, Lotucine) is a water-soluble alkaloid in lotus seed. Lot increases the contractility of isolated myocardium in a dose-dependent manner and has a stronger effect than amrinone (Am) and papaverine (Pa). However, it does not have an antiarrhythmic effect. The characteristics of Lot's effect on hemodynamics are similar to those of phosphodiesterase III inhibitors.

[0022] 4. Iso has a relatively obvious blocking effect on α receptors and can inhibit the release of calcium and influx of calcium caused by the receptors. It also has a blocking effect on voltage-dependent calcium channels. The transient mild hypotensive and anti-arrhythmic effects of Iso may be related to these.

[0023] The present invention also provides a method for preparing the lotus seed core extract, which is prepared by ultrasonic water extraction or low-grade alcohol extraction, microfiltration, ultrafiltration, and purification of the extract by macroporous adsorption resin, and β-cyclodextrin inclusion. The specific preparation method is as follows:

[0024] Scheme 1: Take lotus seed core, crush it, add water and perform ultrasonic extraction 2-3 times, the amount of water added each time is equivalent to 5-12 times the total weight of the medicinal materials, the extraction time each time is 0.5-3 hours, combine the extracts, filter, and the filtrate is clarified and impurities removed by a 50nm ceramic membrane system, the dialysate is collected and enters a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the ultrafiltration dialysate is collected, and is fully adsorbed by AB-8 macroporous resin, eluted with water, the eluate is discarded, and then eluted with 60% ethanol, the eluate is collected, and reduced pressure is concentrated at 60°C to a thick paste with a relative density of 1.20-1.40, the thick paste is taken and fully homogenized with a saturated aqueous solution of β-cyclodextrin, and vacuum dried at 50°C to obtain the lotus core extract.

[0025] Solution 2: Take lotus seed core, crush it, add water and ultrasonically extract it 2-3 times, the amount of water added each time is equivalent to 5-12 times the total weight of the medicinal materials, and the extraction time each time is 0.5-3 hours. Combine the extracts, filter, and take the supernatant after standing. The filtrate is pressurized and concentrated to a clear paste with a relative density of 1.05-1.20 at 25°C. Ethanol is added to make the alcohol content 40%-70%, stand for 6-24 hours, filter, and the filtrate is clarified and impurities are removed through a 50nm ceramic membrane system. The dialysate is collected and enters a 50,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the ultrafiltration dialysate is collected, and is fully adsorbed by a D101 macroporous resin, eluted with water, the eluate is discarded, and then eluted with 60% ethanol, the eluate is collected, and concentrated under reduced pressure at 60° C. to a thick paste with a relative density of 1.20-1.40, the thick paste is taken and fully homogenized with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50° C. to obtain the lotus core extract.

[0026] Scheme 3: Take lotus seed core, crush it, add alcohol to extract 2-3 times, the amount of alcohol added each time is equivalent to 5-12 times the total weight of the medicinal materials, the extraction time each time is 1-3 hours, the extracts are combined, filtered, the filtrate is clarified and impurities are removed by a 50nm ceramic membrane system, the dialysate is collected, and it is concentrated at a reduced pressure of 50°C and low temperature, and the alcohol is recovered until there is no alcohol taste, diluted with water, and clarified again by a 50nm ceramic membrane system, the dialysate is collected, and enters a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the ultrafiltration dialysate is collected, and it is fully adsorbed by LSA-10 macroporous resin, eluted with water, the eluate is discarded, and then eluted with 60% ethanol, the eluate is collected, and it is concentrated at a reduced pressure of 60°C to a thick paste with a relative density of 1.20-1.40, and the thick paste is taken and fully homogenized with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50°C to obtain the lotus core extract.

[0027] Scheme 4: Take lotus seed core, crush it, add alcohol to extract 2-3 times, the amount of alcohol added each time is equivalent to 5-12 times the total weight of the medicinal materials, the extraction time each time is 1-3 hours, the extracts are combined, filtered, the filtrate is concentrated at 50°C under reduced pressure and low temperature to a clear paste with a relative density of 1.05-1.20, water is added to make the water content 40%-70%, and it is allowed to stand for 6-24 hours, filtered, and the filtrate is clarified and impurities are removed by a 50nm ceramic membrane system, the dialysate is collected, and it enters a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the ultrafiltration dialysate is collected, and it is fully adsorbed by XDA-8 macroporous resin, eluted with water, the eluate is discarded, and then eluted with 60% ethanol, the eluate is collected, and it is concentrated at 60°C under reduced pressure to a thick paste with a relative density of 1.20-1.40, the thick paste is taken and fully homogenized and ground with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50°C to obtain the lotus core extract.

[0028] The low-grade alcohol extract is one of methanol, ethanol, n-propanol, isopropanol, allyl alcohol, n-butanol, isobutanol, secondary butanol and tertiary butanol, or a mixture of two or more thereof.

[0029] The flavoring agents include but are not limited to the following:

[0030] Flavoring agents: sucrose, simple syrup, aromatic syrup, stevioside, glycerin, sorbitol, mannitol, saccharin sodium, aspartame, menthol, natural borneol.

[0031] The present invention also provides a method for preparing a lotus seed extract sublingual tablet:

[0032] Method 1: Take the lotus seed extract obtained above, dry it, grind it through a 100-mesh sieve, add pore-forming agent mannitol, disintegrant sodium carboxymethyl starch, lubricant colloidal silicon dioxide, and flavoring agent according to weight parts, granulate it into granules according to conventional dry granulation method, and compress it into sublingual tablets after granulation.

[0033] Method 2: Take the lotus seed extract obtained above, dry it, grind it through an 80-mesh sieve, add pore-forming agent xylitol, disintegrant low-substituted hydroxypropyl cellulose, lubricant colloidal silicon dioxide, and flavoring agent according to weight parts, granulate it according to conventional wet granulation method, and press it into sublingual tablets after granulation.

[0034] The lotus seed extract sublingual tablet of the present invention is a Chinese medicine effective part preparation, the main effective ingredients have clear physical and chemical properties, clear mechanism of action, small dosage, high content of active ingredients, wide safety range, and meet the basic conditions for preparing new and efficient dosage forms. The lotus seed extract sublingual tablet has rapid drug release, and the drug is absorbed by the sublingual mucosa and directly enters the systemic circulation, which reduces the damage of the gastrointestinal tract to the drug and reduces the first-pass effect of the liver. Therefore, compared with ordinary tablets, it not only has a fast onset, but also has a significantly improved bioavailability, which meets the clinical medication requirements of emergency arrhythmias in traditional Chinese medicine. Compared with injections, this dosage form has the advantages of small size, good stability, fast drug absorption, and convenient taking and carrying.

[0035] The present invention aims at the current status of clinical treatment of arrhythmia, overcomes the shortcomings of existing arrhythmia treatment drug preparations, actively uses modern Chinese medicine pharmaceutical technology under the guidance of traditional Chinese medicine theory, and further designs and develops a fast-acting and efficient pure Chinese medicine preparation that not only meets the characteristics of clinical treatment of traditional Chinese medicine, but also has the characteristics of modern preparations on the basis of existing research. The present invention has an important and positive impact on the treatment of arrhythmia and the preparation technology of sublingual tablets, and will also produce huge social and economic benefits.

[0036] The lotus seed core extract sublingual tablet provided by the present invention has the following advantages:

[0037] 1. The lotus seed extract sublingual tablet provided by the present invention does not need to be taken with water, and is placed in the oral cavity to disintegrate or melt. It is particularly suitable for patients with poor swallowing function and difficulty in taking water.

[0038] 2. The lotus seed extract sublingual tablet provided by the present invention has a rapid onset of action and can reduce the "first-pass effect" of the drug.

[0039] 3. Sublingual tablets of Chinese herbal medicine extracts are a new type of oral solid preparation of Chinese herbal medicine that has appeared in the pharmaceutical consumer market in recent years. They are increasingly favored by patients due to their unique advantages. The lotus seed extract sublingual tablets provided by the present invention have broad market prospects. DETAILED DESCRIPTION

[0040] The present invention will be further described below by way of examples. It should be understood that the embodiments of the present invention are intended to illustrate the present invention rather than to limit the present invention. Simple modifications to the present invention according to the essence of the present invention all fall within the scope of protection claimed in the present invention. Unless otherwise indicated, the percentage of the amount of ethanol in the present invention is by volume, and v / v represents the volume ratio of the solution.

[0041] Example 1

[0042] 50g lotus seed extract, 300g beta-cyclodextrin, 50g mannitol, 12g sodium carboxymethyl starch, 0.8g colloidal silicon dioxide, and 0.4g flavoring agent.

[0043] Take 1000g of lotus seed core, dry it and grind it into coarse powder, add water for ultrasonic extraction 3 times, the ultrasonic power is 500W, the frequency is 40kHz, the amount of water added for three times is equivalent to 12 times, 8 times and 5 times the total weight of the medicinal materials, respectively, the extraction time for each time is 1.5 hours, 1 hour and 0.5 hours, the extracts are combined and filtered, the filtrate is clarified and impurities are removed by a 50nm ceramic membrane system, the operating pressure of the ceramic membrane system is controlled at 2-3bar, the temperature is controlled below 45°C, the dialysate is collected and entered into a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the operating pressure of the ultrafiltration membrane system is controlled at 2bar, the temperature is controlled below 45°C, the ultrafiltration dialysate is collected, fully adsorbed by AB-8 macroporous resin, eluted with 10BV water, the eluate is discarded, and then eluted with 3BV The mixture was eluted with 60% ethanol, the eluate was collected, and concentrated under reduced pressure at 60° C. to a thick paste with a relative density of 1.20-1.40. The thick paste was fully homogenized and ground with a saturated aqueous solution of β-cyclodextrin, and vacuum dried at 50° C. to obtain the lotus seed extract.

[0044] Take lotus seed core extract, grind it through a 100-mesh sieve, add mannitol, sodium carboxymethyl starch, colloidal silicon dioxide and flavoring agent, dry granulate it, and compress it into sublingual tablets after granulation.

[0045] Example 2

[0046] 5g lotus seed extract, 30g hydroxypropyl β-cyclodextrin, 100g xylitol, 2.7g sodium carboxymethyl starch, 1.3g colloidal silicon dioxide, 1.4g flavoring agent.

[0047] 100 g of lotus seed core is taken, dried and crushed into coarse powder, and water is added for ultrasonic extraction 3 times (power 500 W, frequency 40 kHz), the amount of water added each time is respectively equivalent to 10 times and 6 times the total weight of the medicinal material, and the extraction time is 1 hour each time. The extracts are combined, filtered, and the supernatant is taken after standing. The filtrate is concentrated to a clear paste with a relative density of 1.05 at 25° C., ethanol is added to make the alcohol content 70%, and the mixture is stood for 24 hours and filtered; the filtrate is clarified and impurities are removed by a 50 nm ceramic membrane system, the operating pressure of the ceramic membrane system is controlled at 2-3 bar, and the temperature is controlled at below 45° C. The dialyzate is collected and enters a 50,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the operating pressure of the ultrafiltration membrane system is controlled at 2 bar, and the temperature is controlled at below 45° C. The ultrafiltration dialyzate is collected, fully adsorbed by a D101 macroporous resin, eluted with 8 BV water, the eluate is discarded, and then eluted with 4 BV The mixture was eluted with 60% ethanol, the eluate was collected, and concentrated under reduced pressure at 60° C. to a thick paste with a relative density of 1.20-1.40. The thick paste was fully homogenized and ground with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50° C. to obtain the lotus seed extract.

[0048] The lotus seed extract obtained above is taken, dried, crushed and passed through an 80-mesh sieve, and pore-forming agent xylitol, disintegrant sodium carboxymethyl starch, lubricant colloidal silicon dioxide and flavoring agent are added according to weight portions, and granules are prepared by conventional wet granulation method. After the granules are granulated, they are compressed into sublingual tablets.

[0049] Example 3

[0050] Lotus seed extract 15g, β-cyclodextrin 150g, sorbitol 150g, cross-linked polyvinylpyrrolidone 3.2g, colloidal silicon dioxide 1.6g, flavoring agent 0.6g.

[0051] Take 300g of lotus seed core, dry it and crush it into coarse powder, add 60% ethanol for ultrasonic extraction 3 times, the ultrasonic power is 500W, the frequency is 40kHz, the amount of water added each time is equivalent to 12 times, 8 times, and 6 times the total weight of the medicinal material, and the extraction time each time is 1.5 hours, 1 hour, and 0.5 hours, respectively. Combine the extracts, filter, and take the supernatant after standing. The filtrate is clarified and impurities are removed by a 50nm ceramic membrane system. The operating pressure of the ceramic membrane system is controlled at 2-3bar, and the temperature is controlled below 45°C. The dialysate is collected , concentrate at 50℃ under reduced pressure and low temperature, recover alcohol until there is no alcohol taste, dilute with water, clarify again through a 50nm ceramic membrane system, control the operating pressure of the ceramic membrane system at 2-3bar, and the temperature at below 45℃, collect the dialysate, enter the 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, control the operating pressure of the ultrafiltration membrane system at 2bar, and the temperature at below 45℃, collect the ultrafiltration dialysate, fully adsorb through LSA-10 macroporous resin, elute with 6BV water, discard the eluate, and then elute with 8BV 60% ethanol, collect the eluate, and concentrate under reduced pressure at 60℃ to a thick paste with a relative density of 1.20-1.40, take the thick paste and a saturated aqueous solution of β-cyclodextrin and fully grind them homogeneously, and dry them in a vacuum at 50℃ to obtain the lotus heart extract.

[0052] The lotus seed extract obtained above is taken, dried, crushed and passed through a 100-mesh sieve, pore-forming agent sorbitol, disintegrant cross-linked polyvinylpyrrolidone, lubricant colloidal silicon dioxide and flavoring agent are added according to weight portions, granulated by conventional dry granulation method, and then compressed into sublingual tablets after granulation.

[0053] Example 4

[0054] Lotus seed extract 20g, hydroxypropyl β-cyclodextrin 80g, mannitol 40g, low-substituted hydroxypropyl cellulose 14g, colloidal silicon dioxide 0.8g, flavoring agent 1.5g.

[0055] Take 400g of lotus seed core, crush it, add 70% ethanol to ultrasonically extract 2-3 times, the ultrasonic power is 500W, the frequency is 40kHz, the amount of alcohol added each time is equivalent to 12 times, 10 times, and 6 times the total weight of the medicinal materials, and the extraction time is 1 hour, 1 hour, and 0.5 hour each time. The extracts are combined and filtered. The filtrate is concentrated at 60°C under reduced pressure and low temperature to a clear paste with a relative density of 1.05-1.20, water is added to make the water content 40%-70%, and it is allowed to stand for 6-24 hours. Filter, the filtrate is clarified and impurities are removed by a 50nm ceramic membrane system, the operating pressure of the ceramic membrane system is controlled at 2-3bar, and the temperature is controlled below 45°C, the dialysate is collected, and it enters a 50,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the operating pressure of the ultrafiltration membrane system is controlled at 2-3bar, and the temperature is controlled below 45°C, the ultrafiltration dialysate is collected, and it is fully adsorbed by an XDA-8 macroporous resin, eluted with 6BV water, the eluate is discarded, and then 4BV The mixture was eluted with 70% ethanol, and the eluate was collected and concentrated under reduced pressure at 60° C. to a thick paste with a relative density of 1.20-1.40. The thick paste was fully homogenized and ground with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50° C. to obtain the lotus seed extract.

[0056] The lotus seed extract obtained above is taken, dried, crushed and passed through a 100-mesh sieve, pore-forming agent mannitol, low-substituted hydroxypropyl cellulose, lubricant colloidal silicon dioxide and flavoring agent are added according to weight parts, granulated by conventional dry granulation method, and then compressed into sublingual tablets.

[0057] Example 5

[0058] Lotus seed extract 40g, hydroxypropyl β-cyclodextrin 640g, mannitol 200g, sodium carboxymethyl starch 54g, colloidal silicon dioxide 10g, flavoring agent 10g.

[0059] Take 800g of lotus seed core, dry it and crush it into coarse powder, add 50% ethanol for ultrasonic extraction 3 times, the ultrasonic power is 500W, the frequency is 40kHz, the amount of water added each time is equivalent to 12 times, 8 times, and 6 times the total weight of the medicinal material, and the extraction time each time is 1.5 hours, 1 hour, and 0.5 hours, respectively. Combine the extracts, filter, and take the supernatant after standing. The filtrate is clarified and impurities are removed by a 50nm ceramic membrane system. The operating pressure of the ceramic membrane system is controlled at 2-3bar, and the temperature is controlled below 45°C. The dialysate is collected , concentrate at 50℃ under reduced pressure and low temperature, recover alcohol until there is no alcohol taste, dilute with water, clarify again through a 50nm ceramic membrane system, control the operating pressure of the ceramic membrane system at 2-3bar, and the temperature at below 45℃, collect the dialysate, enter a 50,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, control the operating pressure of the ultrafiltration membrane system at 2bar, and the temperature at below 45℃, collect the ultrafiltration dialysate, fully adsorb through LSA-10 macroporous resin, elute with 6BV water, discard the eluate, and then elute with 5BV 70% ethanol, collect the eluate, and concentrate under reduced pressure at 60℃ to a thick paste with a relative density of 1.20-1.40, take the thick paste and a saturated aqueous solution of hydroxypropyl β-cyclodextrin and fully grind them homogeneously, and dry them in a vacuum at 50℃ to obtain the lotus heart extract.

[0060] The lotus seed extract obtained above is taken, dried, crushed and passed through an 80-mesh sieve, mannitol, sodium carboxymethyl starch, colloidal silicon dioxide and flavoring agents are added according to weight, granulated into granules by conventional dry granulation method, and then tableted into sublingual tablets.

[0061] Example 6

[0062] Lotus seed extract 10g, β-cyclodextrin 120g, xylitol 20g, sodium carboxymethyl starch 6g, colloidal silicon dioxide 0.45g, flavoring agent 0.9g.

[0063] Take 200g of lotus seed core, dry it and crush it into coarse powder, add 70% ethanol for ultrasonic extraction twice, the ultrasonic power is 500W, the frequency is 40kHz, the amount of water added each time is equivalent to 12 times and 8 times the total weight of the medicinal materials, the extraction time is 1 hour and 1 hour respectively, the extracts are combined, filtered, and the supernatant is taken after standing. The filtrate is clarified and impurities are removed by a 50nm ceramic membrane system, the operating pressure of the ceramic membrane system is controlled at 2-3bar, the temperature is controlled below 45°C, the dialysate is collected, and it is concentrated at 50°C under reduced pressure and low temperature to recover alcohol until there is no alcohol taste, diluted with water, clarified by a 50nm ceramic membrane system again, the operating pressure of the ceramic membrane system is controlled at 2-3bar, the temperature is controlled below 45°C, the dialysate is collected, and enters a 50,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the operating pressure of the ultrafiltration membrane system is controlled at 2bar, the temperature is controlled below 45°C, the ultrafiltration dialysate is collected, fully adsorbed by AB-8 macroporous resin, eluted with 10BV water, the eluate is discarded, and then eluted with 5BV The mixture was eluted with 70% ethanol, and the eluate was collected and concentrated under reduced pressure at 60° C. to a thick paste with a relative density of 1.20-1.40. The thick paste was fully homogenized and ground with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50° C. to obtain the lotus seed extract.

[0064] The lotus seed extract obtained above is taken, dried, crushed and passed through a 100-mesh sieve, xylitol, sodium carboxymethyl starch, colloidal silicon dioxide and flavoring agents are added according to weight, granulated into granules by conventional dry granulation method, and then compressed into sublingual tablets.

[0065] Example 7

[0066] Lotus seed extract 20g, hydroxypropyl β-cyclodextrin 300g, sorbitol 80g, cross-linked polyvinylpyrrolidone 8g, colloidal silicon dioxide 4g, flavoring agent 20g.

[0067] Take 400g of lotus seed core, dry it and grind it into coarse powder, add water for ultrasonic extraction three times with an ultrasonic power of 500W and a frequency of 40kHz. The amount of water added for the three times is equivalent to 12 times, 10 times and 8 times the total weight of the medicinal materials, respectively. The extraction time for each time is 1.5 hours, 1 hour and 1 hour, respectively. Combine the extracts, filter, and pass the filtrate through a 50nm ceramic membrane system for clarification and impurity removal. The operating pressure of the ceramic membrane system is controlled at 2-3bar, and the temperature is controlled below 45°C. The dialysate is collected and enters a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization. The operating pressure of the ultrafiltration membrane system is controlled at 2bar, and the temperature is controlled below 45°C. The ultrafiltration dialysate is collected and fully adsorbed by XDA-8 macroporous resin, eluted with 6BV water, the eluate is discarded, and then eluted with 3BV The mixture was eluted with 80% ethanol, and the eluate was collected and concentrated under reduced pressure at 60° C. to a thick paste with a relative density of 1.20-1.40. The thick paste was fully homogenized and ground with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50° C. to obtain the lotus seed extract.

[0068] Take lotus seed extract, grind it through a 100-mesh sieve, add sorbitol, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide and flavoring agent, dry granulate it, and compress it into sublingual tablets after granulation.

[0069] Example 8 Pharmacodynamics Experiment

[0070] 1 Experimental study on the anti-arrhythmic effect of lotus seed extract

[0071] 1.1 Experimental animals

[0072] SD rats, aged 8 to 10 weeks and weighing 260±10 g, were provided by Guangdong Medical Experimental Animal Center. Male and female rats were separated by cages and randomly divided into 6 groups: negative control group, mexiletine group, and low, medium, and high dose groups of lotus seed extract.

[0073] 1.2 Drugs and Dosages

[0074] (1) Test drug: The lotus seed extract described in Example 5 of the present invention was prepared with drinking water to the required concentration before use. The low, medium and high doses were 0.3 g / kg, 0.6 g / kg and 1.2 g / kg respectively.

[0075] (2) Positive drug: Mexiletine, the dosage is 50 mg / kg.

[0076] (3) Negative drug: The matrix is ​​prepared with the auxiliary materials of the components of the present invention except lotus seed core.

[0077] Administration method: Oral administration, twice a day, once a day, for 5 consecutive days.

[0078] 1.3 Statistical analysis

[0079] Data results The significance of the difference was tested by ANOVA analysis of variance using SPSS 17.0 statistical software.

[0080] 1.4 Experimental methods and results

[0081] 1.4.1 Experimental animal modeling and drug administration

[0082] A rat arrhythmia experiment was conducted using aconitine. The negative control group was given an equal volume of blank matrix 0.6 g / kg by gavage (ig), and the low, medium, and high dose groups of lotus seed extract sublingual tablets were given ig 0.3, 0.6, and 1.2 g / kg, respectively, and mexiletine 50 mg / kg, and the administration was given for 5 days. 30 minutes after the last administration, urethane 1.2 g / kg was injected intraperitoneally (ip) for anesthesia, and the rats were fixed in the supine position, continuously monitored by a six-lead physiological signal recording and analysis system, and the electrocardiogram (ECG) lead II ECG was recorded. After the electrocardiogram stabilized, aconitine 200 μg / kg (0.01%, 0.2 ml / 100 g, completed within 3 seconds) was rapidly injected into the lingual vein (iv). Ventricular premature beats (VP) and ventricular tachycardia (VT) appeared successively, and developed into stable biphasic arrhythmias until ventricular fibrillation (VF) and cardiac arrest (CA) occurred. The heart rate was recorded for 60 minutes: the time of arrhythmia occurrence, arrhythmia duration, recovery time and normal duration (the starting time was from the injection, and the combined sum of each period was calculated).

[0083] 1.4.2 Effect of lotus seed extract on arrhythmia induced by aconitine in SD rats

[0084] Table 1 Experimental results of arrhythmia induced by aconitine in SD rats of each group

[0085]

[0086] Compared with the negative control group, * P<0.05.

[0087] 1.5 Conclusion

[0088] Studies have shown that arrhythmias induced by aconitine may be due to direct myocardial excitation, opening up myocardial Na + channels, allowing myocardial cells to + Increased influx promotes cell membrane depolarization, enhances the self-regulation of rate-determining cells, induces increased myocardial cell autonomy, shortens the refractory period of myocardial cells, triggers single or multiple ectopic rhythms, and thus causes arrhythmias such as ventricular and supraventricular ectopic rhythms and ventricular tachycardia. The results of this experiment show that lotus seed extract can prolong the time of arrhythmia occurrence, shorten the duration of arrhythmia, and prolong the normal duration. Lotus seed extract has a certain anti-experimental arrhythmia effect.

Claims

1. A lotus seed extract sublingual tablet, characterized in that It is prepared from the following raw materials in parts by weight: 1-10 parts of lotus seed core extract, 2-20 parts of beta-cyclodextrin, 0.1-5 parts of mannitol, xylitol or sorbitol, 0.1-3 parts of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, 0.01-1 parts of colloidal silicon dioxide, and 0.01-1 parts of flavoring agent.

2. The lotus seed extract sublingual tablet according to claim 1, characterized in that It is prepared from the following raw materials in parts by weight: 1-5 parts of lotus seed core extract, 2-15 parts of beta-cyclodextrin, 0.5-5 parts of mannitol, xylitol or sorbitol, 0.1-2 parts of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, 0.02-1 parts of colloidal silicon dioxide, and 0.02-1 parts of flavoring agent.

3. The lotus seed extract sublingual tablet according to claim 1 or 2, characterized in that The lotus seed core extract is prepared by low-temperature ultrasonic water extraction or low-grade alcohol extraction, and the extract is purified by microfiltration, ultrafiltration, macroporous adsorption resin, and β-cyclodextrin inclusion.

4. The lotus seed extract sublingual tablet according to claim 3, characterized in that The lotus core extract is prepared by the following method: taking lotus core, crushing it, adding water for ultrasonic extraction 2-3 times, the amount of water added each time is equivalent to 5-12 times the total weight of the medicinal materials, the extraction time each time is 0.5-3 hours, combining the extracts, filtering, the filtrate is clarified and impurity-removed by a 50nm ceramic membrane system, the dialyzate is collected and enters a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the ultrafiltration dialyzate is collected, fully adsorbed by AB-8 macroporous resin, eluted with water, the eluate is discarded, and then eluted with 60% ethanol, the eluate is collected, and reduced pressure is concentrated at 60°C to a thick paste with a relative density of 1.20-1.40, the thick paste is taken and fully homogenized and ground with a saturated aqueous solution of beta-cyclodextrin, and vacuum dried at 50°C to obtain the lotus core extract.

5. The lotus seed extract sublingual tablet according to claim 3, characterized in that The lotus seed extract is prepared by the following method: taking lotus seed core, crushing it, adding water to ultrasonically extract 2-3 times, the amount of water added each time is equivalent to 5-12 times the total weight of the medicinal material, each extraction time is 0.5-3 hours, combining the extracts, filtering, taking the supernatant after standing, pressurizing and concentrating the filtrate to a clear paste with a relative density of 1.05-1.20 at 25°C, adding ethanol to make the alcohol content 40%-70%, standing for 6-24 hours, filtering, and passing the filtrate through a 50nm ceramic membrane system The mixture was clarified and impurities removed, the dialysate was collected and entered into a 50,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the ultrafiltration dialysate was collected, and fully adsorbed by D101 macroporous resin, eluted with water, the eluate was discarded, and then eluted with 60% ethanol, the eluate was collected, and concentrated under reduced pressure at 60°C to a thick paste with a relative density of 1.20-1.40, the thick paste was taken and fully homogenized with a saturated aqueous solution of hydroxypropyl β-cyclodextrin, and vacuum dried at 50°C to obtain the lotus core extract.

6. The lotus seed extract sublingual tablet according to claim 3, characterized in that The lotus core extract is prepared by the following method: taking lotus core, crushing it, adding alcohol to extract 2-3 times, the amount of alcohol added each time is equivalent to 5-12 times the total weight of the medicinal material, the extraction time each time is 1-3 hours, combining the extracts, filtering, the filtrate is clarified and impurities removed by a 50nm ceramic membrane system, dialyzate is collected, and it is concentrated at a reduced pressure and low temperature at 50°C, alcohol is recovered until there is no alcohol taste, diluted with water, clarified by a 50nm ceramic membrane system again, dialyzate is collected, and enters a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, ultrafiltration dialyzate is collected, fully adsorbed by LSA-10 macroporous resin, eluted with water, the eluate is discarded, and then eluted with 60% ethanol, the eluate is collected, and it is concentrated at a reduced pressure at 60°C to a thick paste with a relative density of 1.20-1.40, the thick paste is taken and fully homogenized and ground with a saturated aqueous solution of hydroxypropyl beta-cyclodextrin, and vacuum dried at 50°C to obtain the lotus core extract.

7. The lotus seed extract sublingual tablet according to claim 3, characterized in that The lotus core extract is prepared by the following method: taking lotus core, crushing it, adding alcohol to extract 2-3 times, the amount of alcohol added each time is equivalent to 5-12 times the total weight of the medicinal material, the extraction time each time is 1-3 hours, combining the extracts, filtering, concentrating the filtrate at 50°C under reduced pressure and low temperature to a clear paste with a relative density of 1.05-1.20, adding water to make the water content of 40%-70%, standing for 6-24 hours, filtering, the filtrate is clarified and impurities are removed by a 50nm ceramic membrane system, dialyzate is collected, and enters a 20,000 molecular weight ultrafiltration membrane system for further impurity removal and decolorization, the ultrafiltration dialyzate is collected, fully adsorbed by XDA-8 macroporous resin, eluted with water, the eluate is discarded, and then eluted with 60% ethanol, the eluate is collected, and concentrated at 60°C under reduced pressure to a thick paste with a relative density of 1.20-1.40, the thick paste and a saturated aqueous solution of hydroxypropyl beta-cyclodextrin are fully homogenized and ground, and vacuum dried at 50°C to obtain the lotus core extract.

8. The lotus seed extract sublingual tablet according to claim 3, characterized in that: The low-grade alcohol extract is one of methanol, ethanol, n-propanol, isopropanol, allyl alcohol, n-butanol, isobutanol, secondary butanol and tertiary butanol, or a mixture of two or more thereof.

9. A method for preparing a lotus seed extract sublingual tablet, characterized in that: Take the lotus seed extract according to claim 3, dry it, crush it through a 100-mesh sieve, add β-cyclodextrin inclusion by weight, dry it, crush it, add pore-forming agent mannitol, disintegrant sodium carboxymethyl starch, lubricant colloidal silicon dioxide, and flavoring agent, granulate it according to the conventional dry granulation method, and compress it into sublingual tablets after granulation.

10. A method for preparing a lotus seed extract sublingual tablet, characterized in that: Take the lotus seed extract according to claim 3, dry it, grind it through an 80-mesh sieve, add pore-forming agent xylitol, disintegrant low-substituted hydroxypropyl cellulose, lubricant colloidal silicon dioxide, and flavoring agent according to weight parts, granulate it according to conventional wet granulation method, and press it into sublingual tablets after granulation.

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