Application of monoethyl succinate substituted berberine derivative in preparation of drugs for treating hypertension

Abstract

The invention discloses application of a monoethyl succinate substituted berberine derivative in preparation of a medicine for treating hypertension, and belongs to the technical field of biological medicines. The monoethyl succinate substituted berberine derivative has a structure as shown in a formula (B2). In the research, the inventor finds that the monoethyl succinate substituted berberine derivative shows the activity for treating hypertension, the antihypertensive effect is consistent with that of a positive control medicine nifedipine, and the medicine is good in safety, simple and reasonable in preparation route, low in cost and suitable for large-scale industrial production. The invention provides a new technical means for treatment of hypertension, has huge economic benefits in the future, can generate wide social benefits, and has wide application prospects. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the use of monoethyl succinate-substituted berberine derivatives in the preparation of antihypertensive drugs. The present invention belongs to the field of biomedical technology. Background Art

[0002] Hypertension is a globally prevalent disease with a high prevalence rate, high disability and fatality rates, and is known as the "silent killer". In China, the hypertensive population is as high as 330 million, with an incidence rate of up to 33.5%, meaning that one in every three people has hypertension. However, the control rate of hypertension is less than 20%, indicating that the prevention and treatment of hypertension in China still has a long way to go. Nevertheless, for such a serious global health problem, the new drugs launched in the past decade have not performed satisfactorily in the market. The vast majority of hypertensive patients treated with single therapies have failed to achieve the goal of reducing blood pressure. Existing drugs have drawbacks such as drug side effects, poor bioavailability, and insufficient applicability, which also become important factors restricting the therapeutic effect.

[0003] Currently, there are five major categories of commonly used antihypertensive drugs in clinical practice, including: angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, calcium antagonists, diuretics, and β-blockers. Among them, angiotensin-converting enzyme inhibitors are commonly used antihypertensive drugs in clinical practice. This drug has relatively good compliance, but the incidence of cough caused by it is as high as 43%. In addition to cough, the common side effects of this type of drug also include rash and palpitations. Clinically, calcium antagonists have a strong antihypertensive effect and are suitable for elderly hypertensive patients and hypertensive patients with atherosclerosis, but they still have common side effects such as edema, headache, skin flushing, and tachycardia. Diuretics are generally used for early hypertensive patients and elderly hypertensive patients, and are often taken in combination with other antihypertensive drugs to treat essential hypertension, but they are often accompanied by side effects such as hypokalemia. Long-term hypokalemia can damage kidney function. β-blockers are also one of the common antihypertensive drugs, but side effects such as abnormal cardiac function will occur during the medication period, such as: slowed heart rate, conduction block, decreased blood pressure, aggravated heart failure, and cold extremities caused by peripheral vasospasm.

[0004] Nifedipine belongs to the dihydropyridine class of calcium channel blockers and blocks the calcium channels of vascular smooth muscle to prevent extracellular Ca 2+It enters the cells, reduces the excitation-contraction coupling of vascular smooth muscle, thereby dilating the peripheral arterial vessels, reducing the peripheral vascular resistance, and ultimately playing a role in lowering blood pressure. Based on this, nifedipine can rapidly exert its blood pressure-lowering effect, but its rapid vasodilation effect may also cause reflex tachycardia and increase cardiac output, increasing the risk of cardiovascular adverse events. Therefore, nifedipine immediate-release tablets are only used for temporarily lowering blood pressure and are not used as long-term antihypertensive drugs in clinical practice. At the same time, since nifedipine only functions through smooth muscle and has no regulatory effect on vascular endothelium, when hypertension leads to vascular remodeling or vascular dysfunction, some patients may not be suitable or may have poor effects. Therefore, it is still urgent to actively explore ideal antihypertensive drugs.

[0005] In the research, the inventor found that the succinic acid monoethyl ester-substituted berberine derivative (shown in formula B2) can act on both vascular endothelium and vascular smooth muscle at the same time, has relatively stable blood pressure control, and the antihypertensive effect is consistent with that of the positive control drug nifedipine. Moreover, this drug has good safety, low cost, and is easy to prepare. The "Opinions on Comprehensively Deepening the Reform of Drug and Medical Device Supervision and Promoting the High-quality Development of the Pharmaceutical Industry" clearly states that it is necessary to increase support for the R & D and innovation of traditional Chinese medicines. Berberine, also known as berberine hydrochloride, is a quaternary ammonium alkaloid isolated from the traditional Chinese medicine Coptis chinensis. As a derivative of berberine modification, the succinic acid monoethyl ester-substituted berberine derivative has significantly better antihypertensive effect than berberine. It conforms to the national policies and regulations supporting the R & D of traditional Chinese medicines and provides effective assistance for the research and development of traditional Chinese medicines. Summary of the Invention

[0006] To solve the above problems, the purpose of the present invention is to provide a succinic acid monoethyl ester-substituted berberine derivative shown in formula (B2) and its use in the treatment of hypertension.

[0007] To achieve the above purpose, the present invention adopts the following technical means:

[0008] The present invention provides the use of a succinic acid monoethyl ester-substituted berberine derivative in the preparation of a drug for the treatment of hypertension, and the succinic acid monoethyl ester-substituted berberine derivative has the structure shown in formula (B2):

[0009]

[0010] Among them, preferably, the drug also contains a pharmaceutically acceptable carrier, diluent or excipient.

[0011] Among them, preferably, the drug contains 0.01 to 99 wt% of the monoethyl succinate-substituted berberine derivative. More preferably, the drug contains 0.01% to 50 wt% of the monoethyl succinate-substituted berberine derivative. More preferably, the drug contains 20% to 50 wt%, and most preferably contains 30% to 50 wt% of the monoethyl succinate-substituted berberine derivative.

[0012] Among them, preferably, the drug further comprises other drugs helpful for reducing blood pressure.

[0013] Among them, preferably, the hypertension includes spontaneous hypertension and hypertension induced by high-salt diet.

[0014] The specific carriers, diluents or excipients used in the present invention will depend on the manner and purpose of application of the compounds of the present invention. Suitable carriers, diluents or excipients include: carbohydrates, water-soluble or swellable polymers, hydrophilic or hydrophobic materials, waxes, gelatin, oils, solvents, water, etc. As the above carriers, diluents or excipients, specifically, it may include, for example: water, starch, lactose, dextrose, fructose, sucrose, polyethylene glycol, propylene glycol, sorbitol, mannitol, polyvinyl alcohol, rubber, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, sugar water, methyl cellulose, polyvinylpyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerol, sesame oil, olive oil, soybean oil, etc.

[0015] The drug of the present invention may further comprise one or more binders, disintegrants, suspending agents, stabilizers, isotonic agents, surfactants, wetting agents, lubricants, buffers, solubilizers, emulsifiers, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, colorants, sweeteners, flavoring agents, aromatic agents and other known additives.

[0016] The drug of the present invention can be prepared by combining the monoethyl succinate-substituted berberine derivative of formula (B2) of the present invention with a suitable carrier, diluent or excipient, and can be formulated into capsules, tablets, powders, granules, sustained-release agents, injections or other preparations.

[0017] In a preferred embodiment, the drug of the present invention is a drug modified by a carrier. Preferably, the carrier is one or more of advanced dosage forms such as microspheres, liposomes, microemulsions, polymeric surfactants, nanoparticles, implants, etc. When the active ingredient is modified by a carrier, it is beneficial to absorption and to improve oral bioavailability.

[0018] In the present invention, the dosage of the active ingredient can vary within a wide range. For example, it can be 1 - 1000 mg for adults, preferably 10 - 500 mg, more preferably 20 - 100 mg. Generally, an effective amount of the drug is provided at a dosage level of about 0.1 - 50 mg / kg body weight, preferably 0.5 - 20 mg / kg, more preferably 0.8 - 5 mg / kg body weight. The ideal dosage to be administered can be easily determined by those skilled in the art and will vary depending on the specific compound used, the mode of administration, the specification of the formulation, the mode of administration, and the progression of the disease condition. Additionally, factors related to the specific patient being treated can lead to the need for dosage adjustment, including the patient's age, weight, diet, and administration time. The pharmaceutical composition can be administered as a single daily dose.

[0019] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0020] 1. In a spontaneous hypertensive rat (SHR) model, when the berberine derivative substituted with monoethyl succinate of the present invention was administered at doses of 5, 10, and 20 mg / kg, a blood pressure lowering effect was observed in all cases, and it showed a dose-dependence; a significant blood pressure lowering effect could be exerted 1 hour after administration, with a fast onset; after 4 weeks of administration, the blood pressure lowering effect of the 20 mg / kg administration group was basically the same as that of nifedipine.

[0021] 2. In a hypertensive rat model induced by a high-salt diet, when the berberine derivative substituted with monoethyl succinate of the present invention was administered at a dose of 20 mg / kg, a blood pressure lowering effect consistent with that of the positive drug nifedipine was observed in the 1st, 2nd, 3rd, and 4th weeks.

[0022] 3. In vitro experiments showed that the berberine derivative substituted with monoethyl succinate of the present invention had an obvious anti-contraction effect on mesenteric blood vessels. This effect was mainly related to the release of nitric oxide (NO) when the endothelium was intact, and it could also affect the influx of extracellular calcium into smooth muscle.

[0023] 4. The berberine derivative substituted with monoethyl succinate of the present invention exerts a blood pressure lowering effect through multiple mechanisms, has the characteristics of a fast onset, good effect, and low toxicity and side effects, and has the prospect of clinical development. Description of the Drawings

[0024] Figure 1 Measurement results of the blood pressure of different groups of SHRs using an animal non-invasive blood pressure measuring instrument;

[0025] Figure 2 Measurement results of the blood pressure of different groups of hypertensive rats induced by a high-salt diet using an animal non-invasive blood pressure measuring instrument;

[0026] Figure 3 For vascular tension detection experiments and NO fluorescence probe experiments;

[0027] Among them, Figure 3 (A) is to detect the vasodilatory effect of berberine derivatives substituted with monoethyl succinate at different concentrations after PE stimulation under the condition of intact endothelium; Figure 3 (B) is to detect the fluorescence intensity of berberine derivatives substituted with monoethyl succinate (2.5 μM) incubated for different times using a NO fluorescence probe;

[0028] Figure 4 It is a vascular tension detection experiment.

[0029] Among them, Figure 4 (A) is to detect the vasodilatory effect of berberine derivatives substituted with monoethyl succinate at different concentrations after PE stimulation under the condition of endothelium denudation; Figure 4 (B) is to detect the calcium fluorescence change after administration of 5 μM berberine derivatives substituted with monoethyl succinate using a dynamic calcium fluorescence detector; Figure 4 (C) is to detect the vasodilatory effect of berberine derivatives substituted with monoethyl succinate at different concentrations after CaCl2 stimulation under the condition of endothelium denudation. Specific embodiments

[0030] In this article, the terms "treatment" and other similar synonyms include alleviating, reducing or improving the symptoms of a disease or disorder, preventing other symptoms, improving or preventing the underlying metabolic causes leading to the symptoms, inhibiting a disease or disorder, such as preventing the development of a disease or disorder, alleviating a disease or disorder, making a disease or disorder better, alleviating the symptoms caused by a disease or disorder, or aborting the symptoms of a disease or disorder. In addition, this term includes the purpose of prevention. This term also includes obtaining a therapeutic effect and / or a preventive effect. The therapeutic effect refers to curing or improving the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms related to the underlying disease is also a therapeutic effect. For example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed. In terms of the preventive effect, the composition can be administered to a patient at risk of developing a specific disease, or to a patient presenting one or more physiological symptoms of the disease even though a disease diagnosis has not been made.

[0031] In this article, the term "effective amount" refers to the amount of at least one agent or compound that, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or disorder being treated. The result can be the reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, the "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant alleviation of the disorder clinically. Techniques such as dose escalation trials can be used to determine the effective amount suitable for any individual case.

[0032] The preferred examples of the invention will be described in detail below. The examples are provided to better illustrate the invention, but the invention is not limited to the examples. Non-essential improvements and adjustments to the embodiments based on the invention still fall within the scope of the invention.

[0033] Experimental animals

[0034] Spontaneously hypertensive rats and high-salt diet-induced hypertensive rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0035] Experimental drugs

[0036] The succinic acid monoethyl ester-substituted berberine derivative (shown in formula (B2), molecular weight 485.9136 g / mol) was prepared according to the method described in the patent application with the publication number CN116731009A and the invention name "Succinic Acid Monoethyl Ester-Substituted Berberine Derivative and Its Preparation Method and Application in the Preparation of Drugs for Treating Osteosarcoma".

[0037]

[0038] Example 1: Test for the median lethal dose (LD50) of the succinic acid monoethyl ester-substituted berberine derivative

[0039] SPF-grade Kunming mice weighing 18 - 22 g were randomly divided into 6 groups and were respectively given the succinic acid monoethyl ester-substituted berberine derivative at doses of 1000 mg / kg, 1261.82 mg / kg, 1592.16 mg / kg, 2008.99 mg / kg, 2534.94 mg / kg, and 3200 mg / kg.

[0040] Observation was carried out for 14 days. Using the Karber method, the LD50 value of the succinic acid monoethyl ester-substituted berberine derivative was obtained as 2930 g / kg, and the 95% confidence interval was 2470 - 2480 g / kg. In the LD50 test, the mortality rates of the animals in each group during the test are shown in Table 1.

[0041] Table 1 Detection of the median lethal dose of the succinic acid monoethyl ester-substituted berberine derivative by the Karber method

[0042]

[0043] Example 2: Test for the effect of the succinic acid monoethyl ester-substituted berberine derivative on reducing the arterial blood pressure of spontaneously hypertensive rats (SHR)

[0044] Spontaneously hypertensive rats (SHR) were randomly divided into groups and given 5 mg / kg, 10 mg / kg, and 20 mg / kg of the berberine derivative substituted with monoethyl succinate, respectively. The positive control group was given nifedipine at 0.2 mg / kg. The rats in each treatment group were administered by gavage. The model group was composed of spontaneously hypertensive rats without any drug treatment, and the control group was composed of normal rats. The tail artery blood pressure of the rats was measured on the 7th, 14th, 21st, and 28th days after drug administration.

[0045] The results are as Figure 1 shown in Table 2. The results showed that the treatment groups of 5 mg / kg, 10 mg / kg, and 20 mg / kg of the berberine derivative substituted with monoethyl succinate could all reduce blood pressure, and there was a dose-dependence. Among them, the antihypertensive effect of the 20 mg / kg treatment group was consistent with that of the positive drug nifedipine ( # P < 0.05, ## P < 0.01, ### P < 0.001).

[0046] Table 2 Effects of the berberine derivative substituted with monoethyl succinate of the present invention on the arterial blood pressure of spontaneously hypertensive rats

[0047]

[0048]

[0049] # P < 0.05, ## P < 0.01, ### P < 0.001 vs the model group; *P < 0.05, **P < 0.01, ***P < 0.001 vs the control group.

[0050] Example 3: Test on the reduction of arterial blood pressure in hypertensive rats induced by high-salt diet by the berberine derivative substituted with monoethyl succinate

[0051] Hypertensive rats induced by high-salt diet for 6 weeks were randomly divided into groups, including a treatment group of the berberine derivative substituted with monoethyl succinate (20 mg / kg) and a positive control group (0.2 mg / kg, with the positive control drug being nifedipine). The treatment group was administered by gavage (i.g.). The model group was composed of hypertensive rats induced by high-salt diet for 6 weeks without any drug treatment, and the control group was composed of normal rats. The tail artery blood pressure of the rats was measured on the 7th, 14th, 21st, and 28th days after drug administration.

[0052] The results are as Figure 2 shown in Table 3. The 20 mg / kg treatment group of the berberine derivative substituted with monoethyl succinate (i.e., Figure 2Both groups (group B2) were able to reduce blood pressure. The antihypertensive effect of the 20 mg / kg treatment group was similar to that of the positive drug nifedipine ( # P<0.05, ## P<0.01, ### P<0.001). # P<0.05, ## P<0.01, ### P<0.001 vs model group; **P<0.01 vs control group.

[0053] Table 3 Effects of berberine derivatives substituted with monoethyl succinate on blood pressure in hypertensive rats induced by high-salt diet

[0054]

[0055] # P<0.05, ## P<0.01, ### P<0.001 vs model group; *P<0.05, **P<0.01, ***P<0.001 vs control group.

[0056] Example 4: The berberine derivatives substituted with monoethyl succinate of the present invention affect the endothelium-dependent vasodilation function of the mesenteric artery

[0057] 1. Method

[0058] 1.1 Preparation of rat mesenteric artery samples

[0059] (1) Adult SD rats weighing between 250 and 350 g were anesthetized with sodium pentobarbital, and the entire mesentery was quickly dissected under a microscope and transferred to a cold physiological saline solution (4 °C) saturated with oxygen (95% O2 + 5% CO2).

[0060] ) (2) The adipose tissue surrounding the mesenteric artery was removed under a microscope to allow the remaining blood in the blood vessel to flow out, and the mesenteric artery that was separated cleanly and had no residual blood was cut into blood vessel rings of 2 - 3 mm for standby.

[0061] (3) If endothelium-denuded mesenteric blood vessel rings are needed in the experiment, after taking the blood vessel rings and hanging them in the bath of the DMT 620M microvascular tension detector, the endothelial cells are scraped off with a rat whisker of appropriate diameter with appropriate force while keeping the remaining blood vessel tissue intact.

[0062] 1.2 Detection of mesenteric artery tension

[0063] (1) The mesenteric artery rings were connected to the bath (containing 5 mL of PSS solution) of the DMT 620M microvascular tension detector with two metal wires, and oxygen was continuously bubbled (95% O2 + 5% CO2) into the bath solution.

[0064] (2) The contractile tension of the mesenteric blood vessels was recorded using a microvascular tension detector, and the optimal equilibrium tension of the blood vessels was calculated by software. After stabilization, the mesenteric blood vessels were equilibrated in PSS solution for 60 minutes, and then subsequent experiments were carried out to verify the vascular activity.

[0065] (3) KPSS and PE were used to stimulate and activate the blood vessels to test whether the vascular activity and functionality were intact. The isolated mesenteric arteries were randomly grouped and treated with different concentrations of the berberine derivative substituted by monoethyl succinate.

[0066] (4) After the vascular activity test was completed, the vessels were washed three times with PSS solution to remove residual PE and KPSS. After stabilization for 10 minutes, the vessels were stimulated again with PE to keep the tension stable. Five minutes later, Ach was added to test the integrity of the endothelial function. If the degree of vasodilation exceeded 80%, it was determined that the endothelium was intact; if the degree of vasodilation was less than 5%, it was determined that the endothelium was completely removed.

[0067] (5) ddH2O, solvent, or the berberine derivative substituted by monoethyl succinate was added to the bath of the blood vessels maintaining their function, and the tension of the vascular ring under PE stimulation was recorded. The final statistical result was the vasodilation ratio of the drug administration group minus the control group (ddH2O / DMSO).

[0068] 1.3 Detection of NO fluorescence probe

[0069] DAF-FM DA was diluted with the DAF-FM DA dilution solution provided by the Beyotime DAF-FM DA (NO fluorescence probe) kit at a ratio of 1:1000 to make the final concentration 5 micromoles per liter. The cell culture medium was removed, and an appropriate volume of the diluted DAF-FM DA was added. The added volume should be sufficient to cover the cells. Usually, for one well of a six-well plate, the volume of the diluted DAF-FM DA added was 1 milliliter. Incubate in a 37 °C cell culture incubator for 20 minutes. Wash the cells three times with PBS (pH 7.4) to fully remove the DAF-FM DA that did not enter the cells.

[0070] Loading the probe after collecting cells: Dilute DAF-FM DA with the DAF-FM DA dilution solution provided in the kit at a ratio of 1:1000 to make the final concentration 5 μmol / L. After collecting the cells, resuspend the cells with the diluted DAF-FM DA at a cell concentration of one million to twenty million cells / mL and incubate in a 37 °C cell culture incubator for 20 minutes. The above operations can be carried out in a centrifuge tube. Invert and mix well every 3 - 5 minutes to ensure full contact between the probe and the cells. Wash the cells three times with PBS (pH 7.4) to fully remove the DAF-FM DA that has not entered the cells. Stimulate the cells directly with monoethyl succinate-substituted berberine derivatives or divide the cells into several equal parts and then stimulate the cells. Observe and record using a fluorescence microscope.

[0071] 1.4 Experiments on rat aortic smooth muscle cells

[0072] (1) Culture rat aortic vascular smooth muscle cells (A10) using DMEM medium containing 15% FBS and 1% penicillin / streptomycin solution at 37 °C with constant temperature, saturated humidity, and 5% CO2. The experiment is divided into three groups: control group (without any treatment), CaCl2 group (treated with 2 mM CaCl2), and CaCl2 + B2 group (treated with 2 mM CaCl2 and 5 μM monoethyl succinate-substituted berberine derivatives). Discard the culture medium, wash three times with high-glucose DMEM complete medium, and then add 1 mL of complete medium.

[0073] (2) Incubate with 5 μmol / L Fluo-3 / AM and Hoechst (1 μg / mL) for 15 minutes respectively, then gently rinse the cells 3 - 4 times with pre-warmed PBS at 37 °C, and then add 1 mL of pre-warmed PBS and wait for detection.

[0074] (3) Detect using a Zeiss LSM 700 confocal microscope under the conditions of an excitation wavelength of 488 nm and an emission wavelength of 518 nm, and judge the intracellular calcium concentration ([Ca 2+ i ) level of A10 through the fluorescence level.

[0075] 4. Results

[0076] 4.1 Mesenteric vascular tension experiment with intact endothelium

[0077] ​In the experiment of the vascular tension of the endothelium-intact mesentery of SD rats, compared with the control group, the berberine derivative substituted by monoethyl succinate had an obvious effect on resisting the vasoconstriction caused by PE in the endothelium-intact mesentery vessels, and showed a concentration-dependent manner. When the concentration reached 1 μM, the anti-constriction effect could reach more than 90%, as Figure 3 shown in A.

[0078] 4.2 Detection with NO fluorescence probe

[0079] It was found by detection with NO fluorescence probe that after human umbilical vein endothelial cells (HUVECs) were given the berberine derivative substituted by monoethyl succinate (2.5 μM) for 30 minutes, 60 minutes, and 90 minutes, the release of NO increased significantly, as Figure 3 shown in B.

[0080] 4.3 Experiment on the vascular tension of the denuded mesentery

[0081] In the experiment of the vascular tension of the denuded mesentery of SD rats, compared with the control group, the berberine derivative substituted by monoethyl succinate had an obvious effect on resisting the vasoconstriction caused by PE in the denuded mesentery vessels, and showed a concentration-dependent manner. When the concentration reached 2 μM, the anti-constriction effect could reach more than 90%, as Figure 4 (A) shown.

[0082] In cultured rat aortic smooth muscle cells, the change in fluorescence intensity after the release of a high-concentration Ca 2+ solution in the CaCl2 + B2 group also proved the inhibitory effect of the berberine derivative substituted by monoethyl succinate on calcium efflux, as Figure 4 (B) shown.

[0083] In the experiment of the vascular tension of the denuded mesentery of SD rats, compared with the control group, the berberine derivative substituted by monoethyl succinate had an obvious effect on inhibiting the influx of extracellular calcium and simultaneously inhibiting the release of intracellular calcium in the endothelium-intact mesentery vessels, and showed a concentration-dependent manner. When the concentration reached 5 μM, the anti-constriction effect could reach more than 90%, as Figure 4 (C) shown. *P < 0.05, **P < 0.01 vs control group.

[0084] Example 5: Preparation of the drug with the effective ingredient of the berberine derivative substituted by monoethyl succinate of the present invention

[0085] Taking the berberine derivative substituted by monoethyl succinate as the effective ingredient, adding appropriate excipients, and preparing an oral preparation by tabletting with a suitable process. The total weight of each tablet is about 0.2 g, each tablet contains 0.1 g of the effective ingredient, and it is taken orally once a day. Other items should meet the relevant requirements of the tablet items in the Chinese Pharmacopoeia 2000 edition.

[0086] Step (1): Pretreatment of raw materials

[0087] API Processing: Sieve berberine succinate monoethyl ester derivative (API) through a 100-mesh sieve to avoid caking.

[0088] Excipient Processing: Sieve microcrystalline cellulose (MCC), lactose, and sodium carboxymethyl starch (CMS-Na) through an 80-mesh sieve respectively for standby.

[0089] Step (2): Wet Granulation

[0090] Mixing: Mix API, MCC, lactose, and CMS-Na in a mixer for 15 minutes until uniform.

[0091] Granulation: Slowly add 5% PVP K30 ethanol solution (ethanol: water = 7:3) as a binder, stir to make soft material. Pass the soft material through an 18-mesh sieve for granulation.

[0092] Drying: Dry the wet granules in a fluidized bed dryer at 40–45 °C until the moisture content ≤ 3% (monitored by a moisture analyzer).

[0093] Screening: Pass the dried granules through a 20-mesh sieve for screening, add magnesium stearate and colloidal silicon dioxide, and mix for 5 minutes.

[0094] Step (3): Tabletting

[0095] Tabletting Machine: Rotary tabletting machine.

[0096] Die Size: Select according to the tablet weight (such as diameter 8 mm, shallow concave die).

[0097] Tablet Weight Control: The target tablet weight is about 0.206 g (0.1 g API + excipients).

[0098] Hardness Range: 4–6 kp (tested by a hardness tester) to ensure that the tablets are not easily broken and have qualified disintegration.

[0099] Step (4): Coating (optional)

[0100] Coating Solution Preparation: Dissolve hypromellose (HPMC) coating premix (such as ) in water to a solid content of 10%.

[0101] Coating Process: Spray in a coating pan, inlet air temperature 50 °C, tablet bed temperature 40 °C, weight gain 3–5%.

[0102] Thus, the effective ingredient drug of berberine derivative substituted by succinic acid monoethyl ester can be prepared into ordinary tablets or sustained-release tablets, and the single-dose specification of the drug is about 0.2 g / tablet.

[0103] The administration method of the effective ingredient drug of berberine derivative substituted by succinic acid monoethyl ester can be oral administration, once in the morning and once in the evening.

Claims

1. Use of a berberine derivative substituted with monoethyl succinate in the preparation of a medicament for treating hypertension, wherein the berberine derivative substituted with monoethyl succinate has the structure shown in formula (B2):

2. The use according to claim 1, wherein The medicament further comprises a pharmaceutically acceptable carrier, diluent or excipient.

3. The use according to claim 1, characterized in that, The medicament contains 0.01 to 99 wt% of the berberine derivative substituted with monoethyl succinate.

4. The use according to claim 3, characterized in that, The medicament contains 0.01% to 50 wt% of the berberine derivative substituted with monoethyl succinate.

5. The use according to claim 1, characterized in that The medicament further comprises other medicaments helpful for reducing blood pressure.

6. The use according to claim 1, wherein The hypertension includes spontaneous hypertension and hypertension induced by a high-salt diet.

7. Use according to any one of claims 1 - 5, characterized in that, The medicament is a capsule, tablet, powder, granule, sustained-release preparation or injection.

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