use of a salvia miltiorrhiza-based composition for the secondary prevention of coronary heart diseas

专利摘要:
USE OF MILTIORRHIZA SALVIA COMPOSITION IN DRUG PREPARATION FOR SECONDARY CARDIOCORONARY DISEASE PREVENTION. The use of a Salvia miltiorrhiza composition in the preparation of drugs for the secondary prevention of cardio-coronary disease is provided, and particularly the use of the Salvia militiorrhiza composition in the preparation of drugs for the secondary prevention of stable angina pectoris-type disease and reduction of stable angina pectoris of serious vascular events.
公开号:BR112013002814B1
申请号:R112013002814-9
申请日:2011-08-08
公开日:2020-10-27
发明作者:Xijun Yan；Naifeng Wu；Kaijing Yan；He Sun；Zhixin Guo；Guoguang Zhu；Weiwei Liu；Libin Zhao；Ruizhi Luo
申请人:Tasly Pharmaceutical Group Co., Ltd；
IPC主号:

专利说明:

Field of the Invention
[001] The present invention is related to the use of composite drugs in the preparation of medications for the prevention of cardio-coronary disease (CHD), in particular the use of a traditional Chinese medicated compound in the preparation of a medicament for the prevention of CHD. Fundamentals of the Invention
[002] Atherosclerotic cardio-coronary disease (CAHD) refers to a type of heart disease, which is caused by vascular stenosis or vascular obstruction due to coronary arteriosclerosis, and / or by ischemic myocardial hypoxia or myocardial necrosis due to changes the functioning of the coronary arteries (for example, spasm). All of these are collectively called as cardio-coronary disease (abbreviated as CHD), also called as ischemic heart disease. CAHD is known as the most common type of organic pathology induced by atherosclerosis, which has also been a common disease that seriously harms human health.
[003] In general, CHD is caused by coronary atherosclerosis. The onset of coronary heart disease increases with increasing age. The older the patients are, the more serious the illnesses get. As confirmed by some data, since the age of 40, the possibilities of CHD are increased by 1 time with every 10 years of additional age. There is a more rapid development of coronary atherosclerosis in men after the age of 50, or in women after the age of 60. Likewise, the risk of myocardial infarction is increased with increasing age. In recent years, the age of onset of coronary heart disease has shown a tendency towards younger age. Now, the percentage of young people under 35 who suffer from coronary heart disease is on the rise, and the smallest patient was just 20 years old. Due to its high incidence and high mortality, CHD has become a disease that seriously threatens human health. That is why he is called as the “first human killer”. Because none of the symptoms are observed at all before the onset of CHD, the consequences in some patients can be extremely bad without timely emergency treatment. Therefore, in terms of CHD, prevention is more important than treatment itself.
[004] Usually, prevention of coronary heart disease includes primary prevention, secondary prevention and triple prevention. This primary prevention is aimed at the population at risk who has not yet suffered from CHD, secondary prevention is for patients who have had CHD at an early stage; and triple prevention is the prevention of the occurrence of CHD progression and its complications. In practice, prevention has become very important for both coronary patients and the high-risk population of CHD. Secondary prevention of CHD refers to the early discovery, diagnosis and treatment of patients with CHD. The goal of secondary prevention is focused on improving symptoms, preventing disease deterioration, improving prognosis and preventing CHD recurrence. Currently, there are two main measures used for the secondary prevention of CHD, one is to discover and control risk factors; and the other is reliable and continuous pharmacological therapy.
[005] Coronary heart disease prevention should be largely focused on several factors, including diet, exercise, medication, control of risk factors, etc. Especially for coronary patients, the goal of prevention is to improve the symptoms of the disease, prevent its progress, and prevent its recurrence. The prevention of coronary heart disease includes two “ABCDE” s, which occur at each stage of the disease. Only by insisting on secondary prevention, treatment is effectively directed to the etiology of effective recurrence reduction.
[006] From the first “ABODE” of secondary prevention of coronary artery disease, “A” represents aspirin, whose main effect is to prevent the formation of atherosclerosis, by resisting the aggregation of platelets and the release and improvement of ba -lance of prostaglandins and thromboxane A2. Clinically, routine administration of 100 mg coated aspirin tablets a day can prevent the recurrence of coronary heart disease. The "B" represents hypertension, which can not only accelerate the rate of progression of atherosclerosis, but also increase its extent. The higher the blood pressure, the greater the possibility of the occurrence or recurrence of CHD. Effective blood pressure reduction can prevent the recurrence of coronary heart disease. The "C" represents hyperlipidemia. On the one hand, hyperlipidemia, decreases the amount of blood supply in the brain, making blood viscous and slowing blood flow; on the other hand, it damages the vascular endothelium to the point that it is deposited on the vascular wall to form the atherosclerotic plaque. All of these act directly to cause the occurrence and development of cardiovascular and cerebrovascular diseases. The "D" stands for diabetes. More than 80% of diabetes results in abnormal lipid metabolism, which is often accompanied by cardio-vascular and cerebrovascular diseases; for example, atherosclerosis and hyperlipidemia. At the same time, the rise in blood glucose levels increases viscosity and blood clotting, making diabetics very likely to develop CHD. The “E” stands for education rehabilitation. The popularity of hypertension education, CHD and the prevention of atherosclerosis must be reinforced by the publication in the communication networks, free distribution of reading and the constant instruction in rehabilitation. Through the active intervention of risk factors, patients become willing to accept long-term preventive measures with patience, and active with drug treatment.
[007] From the second “ABODE” of secondary prevention of coronary disease (CHD), “A” represents active physical exercise. Not only does proper exercise increase fat consumption, but it also reduces cholesterol deposition in the body and improves insulin sensitivity. It is useful for the following aspects: preventing obesity, controlling body weight, increasing circulation function, regulating blood lipids, lowering blood pressure and reducing thrombosis, which are known as the active measures for prevent CHD. Strenuous exercise is not suitable for patients; for example, intense running and uphill. Aerobic exercises are recommended; for example, light running, walking, gymnastics and Tai Chi. "B" represents weight control. The IMG should be kept in the range of 18.5 ~ 24.9 kg / m2 and the waist circumference less than 90 cm. "C" stands for smoking cessation. There are reportedly more than 3000 types of harmful substances in cigarettes. If the nicotine in the smoke is inhaled into the body, it can stimulate the autonomic nervous system, cause the blood vessel to convulse, speed up the heartbeat rate, increase blood pressure and blood cholesterol levels, thereby accelerating atherosclerosis. "D" stands for reasonable diet. The diet should be varied and based on cereals. The recommended diet for patients is currently as follows: more foods rich in magnesium, for example, grains, nuts and algae; more foods rich in cellulose, for example, vegetables, bananas and potatoes, milk, beans and other products daily; an adequate amount of eggs and lean meat frequently; and give me fatty meat; pigskin, cartilage and meat dishes. Food intake and physical activity must be kept balanced, and an adequate body weight must be maintained. The diet must be poor and salt and sugar, and the amount of salt is reduced to 6 g per day. "E" stands for emotional stability. Optimistic and stable emotion, together with a comfortable and balanced state of mind are important factors not only in the prevention of cardiovascular and cerebrovascular diseases, but also the keys and secrets to a long life.
[008] Clinically, CHD is divided into five types according to its location and scope, degree of vascular occlusion and speed of development, scope and degree of myocardial ischemia. 1. Latent CHD, also known as asymptomatic coronary disease, refers to those patients whose ECG, although showing no symptoms, demonstrated changes in myocardial ischemia of ST segment depression, reduced, flattened or inverted T-wave after rest or cardiac stress. 2. CHD Angina pectoris refers to patients suffering from paroxysmal retrosternal pain caused by transient myocardial ischemia. 3. CHD myocardial infarction has severe symptoms due to ischemic myocardial necrosis caused by coronary artery occlusion. 4. CHD Heart failure and arrhythmia show symptoms of heart hypertrophy, heart failure and arhythmia caused by myocardial fibrosis and enlarged heart due to long-standing chronic myocardial ischemia. 5. Sudden death CHD always results in sudden death from primary cardiac arrest, which is mainly caused by severe arrhythmia due to electrophysiological disease generated locally in ischemic myocardium, for example, ventricular tachycardia and ventricular fibrillation.
[009] Currently, β-receptor blocker is mainly used to prevent CHD Angina pectoris. It works by preventing angina pectoris by reducing myocardial oxygen consumption under the condition of exercise and tension. Its main contraindication is bradycardia, bronchospasm and decompensated heart failure. Thus, for patients with asthma or other obstructive airway diseases, the β-receptor blocker could make their situation worse.
[0010] Recently, what has been used for the prevention of malignant vascular events is mainly focused on antiplatelet agents. They have the effect of inhibiting platelet adhesion, aggregation and secretion through a mechanism of inhibiting arachidonic acid metabolism and increasing cAMP levels in platelets. Its main side effect is bleeding. Therefore, they are not used for patients suffering from blood clotting dysfunction or ulcerative diseases.
[0011] The present invention is related to a compound of Salvia Miltiorrhiza composition, which was developed based on both traditional Chinese medicine (TMC) and modern pharmacological studies. According to the TMC theory, the pathological basis of chest congestion and cardiac pain is the failure to assist the circulation of blood in the heart caused by the stagnation of blood stasis in the cardiac vessels and poor blood circulation. After long-term pharmacological tests and clinical studies, through the selection of the formula, the inventors of the present invention developed the aforementioned Salvia Miltiorrhiza compound having blood activation effects by removing stasis, interrupting the pain upon relaxation of chest congestion and resuscitation with aromatic herbs. In this composition, Salvia Miltiorrhiza is used as the monarch drug, Panax Notoginseng as the minister drug and Borneol as the adjuvant drug. Clinically, it is mainly used for the treatment of CHD angina pectoris. Summary of the Invention
[0012] The purpose of the present invention is to provide the use of a Chinese medicine composition in the preparation of drugs for the treatment of secondary prevention of myocardial infarction. Said secondary prevention of myocardial infarction includes secondary prevention of coronary artery disease angina pectoris and reduction of the occurrence and recurrence of serious vascular events. The said composition of Chinese medicine comprises Salvia miltiorrhiza (Danshen) and Panax Notoginseng (Sanqi) and borneol extract (Bingpian) in a weight ratio of (8 ~ 15): 1, where the weight of Salvia miltiorrhiza (Danshen) and extract of Notoginseng Panax (Sanqi) is the dry weight.
[0013] According to the invention, said secondary prevention of CHD angina pectoris refers to the secondary prevention of stable CHD angina pectoris. The said composition of Chinese medicine has the effect of increasing stress tolerance and prolonging the total exercise time in patients with stable CHD angina pectoris. In addition, said Chinese medicine composition can delay ST-segment depression or prolong its interval, delay the onset of angina pectoris or prolong its interval in patients with stable CHD induced angina pectoris, reduce the frequency angina pectoris, decrease the consumption of nitroglycerin and improve the quality of life in patients with stable CHD angina pectoris. In addition, said secondary prevention of stable CHD angina pectoris includes the improvement of biochemical parameters as follows: natriuretic peptide type-B (BNP), C-reactive protein (PCR), phospholipase A2 lipoprotein (Lp-PLA2) and homocysteine ( HCY). In recent years, a number of studies have shown that BNP, PCR, Lp-PLA2 and HCY participated in the pathogenesis of coronary heart disease, and they were probably the important factors leading to the local inflammatory reaction in CHD. These biochemical parameters develop in patients with coronary heart disease. As shown in studies of the present invention, the aforementioned composition of Chinese medicine can effectively reduce the increase in said biochemical parameters, and there is no statistically significant difference between the post and pre-treatment parameters (P <0.01).
[0014] According to the present invention, said Chinese medicine composition can be used in combination with β-receptor blockers in the treatment of secondary prevention of stable CHD angina pectoris. Said β-blockers include, but are not limited to, propranolol, pindolol, timolol, metoprolol (Betaloe ®) and acebutolol, preferably Betaloe ®. In addition, the use of said composition of traditional Chinese medicine, in combination with other or emerging β-receptor blockers should be included in the context of the present invention.
[0015] In accordance with the present invention, said reduction in the occurrence and recurrence of a serious vascular event (EVG) refers especially to reducing the occurrence or re-occurrence of serious events; for example, death, myocardial infarction, ischemic shock, etc., in coronary patients. In addition, it includes reducing the need for myocardial revascularization (myocardial revascularization), transluminal percutaneous coronary angioplasty (ACPT) and angiocardiography.
[0016] According to the present invention, said Chinese medicine composition can be used in combination with antiplatelet agents to reduce the occurrence or recurrence of serious vascular events. Said antiplatelet agents include, but are not limited to, aspirin, acemetacin, troxerutin, dipyridamole, cilostazol, ticlopidine hydrochloride and sodium ozagrel, preferably aspirin. In addition, the use of said composition of traditional Chinese medicine in combination with other or emerging antiplatelet agents should be included within the scope of the present invention.
[0017] According to the present invention, said Chinese medicine composition comprises extract of Radix Salvia miltiorrhiza and Radix Notoginseng and borneol (Bingpian), preferably in a weight ratio of (9 ~ 10): 1, where the weight of Radix Salvia miltiorrhiza and Radix Notoginseng extract is the dry weight, said Radix Salvia miltiorrhiza and Radix Notoginseng extract is prepared from the extraction of Radix Salvia miltiorrhiza and Radix Notoginseng simultaneously. The weight ratio of raw drug Radix Salvia miltiorrhiza and Radix Noto-ginseng used as starting material is (3 ~ 7): 1, preferably (4 ~ 6): 1, and more preferably 5: 1 . Said extract of Radix Salvia miltiorrhiza and Radix Notoginseng can be prepared by conventional extraction methods, preferably the method of extraction with a weak aqueous alkaline solution. Preferably, said weak alkaline aqueous solution is an aqueous solution having a pH value greater than or equal to 8, more preferably the pH value of 8 to 9, more preferably the pH value of 8. the aforementioned extract of Radix Salvia miltiorrhiza and Radix Notoginseng is prepared by a method that comprises: spraying Radix Salvia miltiorrhiza and Radix Notoginseng with water or a weak aqueous alkaline solution, filtration, adequate concentration of the filtrate, carrying out the precipitation of the alcohol by adding alcohol to the concentrated solution, rest, recovery of the obtained supernatant and concentration to produce the extract.
[0018] According to the invention, said extract of Radix Salvia miltior-rhiza and Radix Notoginseng is prepared by a method comprising the following steps: a. Extract sprayed Radix Salvia miltiorrhiza and Radix Notoginseng together with water or weak aqueous alkaline solution 2 to 3 times, in an amount of 4 ~ 8 times the weight of the raw drugs Radix Salvia miltiorrhiza and Radix Notoginseng for each time, filter the extract, mix the filtrate and concentrate the filtrate appropriately; B. Addition of high concentration alcohol to the concentrated solution to produce a final alcohol concentration of 50 to 85% (v / v) and allow to stand for precipitation, filtration of the supernatant, recovery of alcohol from the supernatant and concentration to produce the extract.
[0019] Where, in step (a), said extraction temperature is preferably maintained at 60 ~ 120 ° C. Said pH value of the weak alkaline aqueous solution is greater than or equal to 8, preferably from 8 to 9, more preferably 8. The said weak aqueous alkaline solution is preferably an aqueous sodium bicarbonate solution at a concentration of 0 .3% ~ 1% (w / w), more preferably, the aqueous sodium bicarbonate solution at a concentration of 0.45% (w / w). Said filtrate is concentrated until an extract is produced in an extract volume ratio (L) for the gross admitted drug weight (Kg) of 1: (0.7 ~ 1.3).
[0020] In step (b), alcohol is used to perform the precipitation. The said final concentration of the concentrate solution is preferably 50 to 80% (v / v). The relative density of the obtained extract is 1.15 ~ 1.45.
[0021] In accordance with the present invention, said Chinese medicine composition can be prepared in any type of pharmaceutical dosage form, according to a conventional or frequently used process; for example, droplet pills, capsules, granules, tablets, suspensions, injection, syrup, tincture, powder, medicinal tea, local medicinal solution, spray, suppository, microcapsule or other pharmaceutically acceptable dosage form, preferably droplet pills. The drip pill is made up of the said composition of Chinese medicine and matrix adjuvant.
[0022] According to the present invention, said droplet pills are made up of said composition of Chinese medicine and the adjuvant of the matrix. Preferably the matrix adjuvant is selected from PEG-4000 or PEG-6000. The weight ratio of said composition of Chinese medicine to matrix adjuvant is (0.2 ~ 0.8): 1, preferably (0.29 ~ 0.7): 1, more preferably (0.5 ~ 0.6): 1 .
[0023] According to the present invention, said droplet of the Chinese medicine composition can be prepared by conventional methods known in the prior art, also a method as follows: mixing said composition of Chinese medicine well with the matrix adjuvant , melt on heat, transfer the melted solution into a drip tank, let the melted solution drip into liquid paraffin at low temperature, remove the residual paraffin and select to produce the final product. The melting temperature is maintained at 60 ~ 100 ° C, preferably 75 ~ 85 ° C, and the temperature of liquid paraffin at 0 ~ 20 ° C, preferably 5 to 15 ° C.
[0024] According to the present invention, said matrix adjuvant is natural adjuvant to the plant-derived droplet pill, which includes at least one type of matrix adjuvant and at least one type of plasticizer adjuvant.
[0025] According to the present invention, said matrix adjuvant can be selected from the group consisting of a pharmaceutically acceptable carrier of D-ribose, fructose, xylose, fucose, raffinose, maltose, agarose, sucrose ester , y-lactone D-ribonic acid, erythritol, sorbitol, xylitol, arabitol, isomaltitol, malic acid latitol, sterin, shellac, phenylethylene glycol, polyoxyethylene alkyl ether, and the compounds mentioned above, containing hydrate water.
[0026] In addition, said plasticizer adjuvant is selected from the group consisting of pregelatinized starch, carboxymethyl starch, gum arabic, dextran, Sesbania gum, carrageenan, Indian gum, furcelaran, tragacanth gum, gum of tamarind, pectin, xanthan gum, alginic acid and its salts, agar, lactose, glyceryl monostearate, polyoxyethylene monostearate, cross-linked sodium carboxymethylcellulose and silica.
[0027] According to the present invention, if the existence or appearance of matrix adjuvant and plasticizer adjuvant have similar or similar qualities to those already mentioned from natural sources and if they have safe characteristics without toxicity, they can replace those already mentioned, matrix adjuvant and plasticizer adjuvant of plant origin, as to be applied in the preparation of droplet pills.
[0028] According to the present invention, the ratio of said matrix adjuvant to plasticizer adjuvant is 1:00 ~ 1: 1.5, preferably 1: 0.1 ~ 1: 0.9, and more preferably 1: 0.1 ~ 1: 0.5.
[0029] According to the present invention, the method of using the above-mentioned matrix adjuvant and the plasticizer adjuvant as an excipient comprises the main steps: a. select one or more types of said matrix adjuvants, or add one or more low melting point matrix adjuvants with one or more types of said plasticizer adjuvants, mix well; B. transferring the obtained well-mixed matrix adjuvant or mixture into a drip tank, into which the medicinal extract is added and continued to be well mixed with the adjuvant; ç. heat the obtained mixture until it is well melted, dripping the melted solution in a cooling liquid, and after solidification, remove the formed pills by sieving; d. remove the coolant from the outer surface by cleaning or centrifuging, e. dry clean pills at low temperature to produce the product.
[0030] In the aforementioned method of preparing the droplet pills, the weight ratio of said matrix adjuvant to the plasticizer adjuvant is 1:00 ~ 1: 1.5, preferably 1: 0.1 ~ 1: 0.9, most preferably 1: 0.1 ~ 1: 0.5. The weight ratio of the matrix adjuvant to the active substances is 1: 0.1 ~ 1: 1, preferably 1: 0.1 ~ 1: 0.6, most preferably 1: 0.2 ~ 1: 0, 4.
[0031] In the said method of preparing the droplet pills, the mixing time of the active substance and matrix adjuvant is 10 ~ 30 min. The heating temperature for melting (or dripping) after the active substance is mixed well with the matrix adjuvant is maintained at 45 ~ 95 ° C, preferably 60 ~ 95 ° C. The coolant is liquid paraffin, methylated silicone oil or vegetable oil (soy oil or castor oil, for example), preferably liquid paraffin or methylated silicone oil. Coolant temperature is -20 ~ 30 ° C, preferably 0 ~ 18 ° C. The internal diameter of the dripper is 1.0 ~ 4.0 mm, preferably 1.2 ~ 2.5 mm. The smaller the difference between the internal and external diameter of the dripper, the better dripping effect can be obtained with the pills.
[0032] According to the present invention, said droplet pill can be prepared by using cooling air instead of cooling liquid. The facilities and method that are used are clearly registered in Chinese Patent Application 200710060640.1 (Title: Method for preparing dropping pill using cool air and equipment using the method, publication date: Oct.8, 2008, publi-cation No. : CN101279220A), Chinese Patent Application 200710060641.6 (Title: Equipment for preparing pill using cold wind and trap cooling gas, publication date: Jul.30, 2008, publication No .: CN101229099A), and Chinese Patent Application 200710060642.0 (Title: Equipment for preparing dropping pill with air cooled by cold trap, publication date: Oct.8, 2008, publication No .: CN101279221 A). These documents are hereby incorporated by reference.
[0033] According to the present invention, said droplet pills can be coated by applying material according to a theoretical weight increase of 3% w-6% w, preferably 4% w. In practice, the weight gain should not be less than 80% of the theoretical increase in weight.
[0034] According to the present invention, said droplet pill can be either coated or uncoated. For convenient administration, said droplet pills can be loaded into a capsule. Clinical Trial
[0035] In phase II of the clinical trial, a double-blind, placebo-controlled, randomized, multicenter, parallel-controlled clinical trial was conducted to assess the safety and efficacy of the said composition of Chinese medicine (co-named “T89- 005-0001-AU ”) of the present invention in patients with stable chronic angina pectoris. The purpose of this phase II clinical trial was to confirm the effectiveness of said composition of Chinese medicine in patients with stable angina pectoris, and to evaluate the effectiveness of said composition of Chinese medicine through increased exercise time in a tolerance test (ETT) according to the Standard Bruce Protocol. The second objective was to assess the safety and tolerance of the said composition of Chinese medicine in patients with stable chronic angina pectoris.
[0036] Preliminary testing, after approval by the Australia Drug Administration (TGA), was carried out in Australia and New Zealand. The design of this study was essentially the same as the trial in the USA (coded as “T89-005-0003- US”), except that there were only two groups in this study: placebo group, ex-experimental group (375mg of that Chinese medicine composition prepared according to Example 11, twice a day).
[0037] This survey was operated by an Australia CRO and managed by CNS. There were a total of 10 patients seen at a Center in Australia and a center in New Zealand. This trial started in May 2008 and ended in July 2009. The trial of the last patient was completed in May 2009.
[0038] This experimental research included two parts: one was a 2-week study on screening the baseline value of TTE patients in groups twice; another was a double-blind, placebo-controlled, randomized 8-week study; that is, the treadmill assay when drug absorption peaked and peaked at 4th week and 8th week.
[0039] Patients who had moderate stable angina pectoris, aged 18 ~ 80, and diagnosed with grade I and grade II angina pectoris by the Canadian Cardiovascular Society (CCS) could accept TTE, according to the Bruce Standard Protocol. Except those who had been allowed to take short-acting drugs; for example, nitroglycerin, β-blockers or calcium channel blockers during the 14-day screening stage, patients were required to suspend the drug previously used for the treatment of angina pectoris. Patients should receive a series of inspections during the screening phase: anamnesis, physical examination, resting electrocardiogram, blood pressure measurement, heart rate and analysis of items for clinical inspection. Patients eligible for inclusion must have a detailed anamnesis document regarding myocardial infarction (Ml) or severe coronary heart disease, which has been diagnosed by a non-invasive method or angiography. In addition, symptoms should support the diagnosis of chronic angina pectoris, and / or angina pectoris patients had a history of abnormal motion reaction and / or ECG changes. In addition, eligible patients must have limited ability to practice sports (maximum TED in the Bruce Standard Protocol is 3 to 7 minutes), which must be confirmed on the seventh day and on day 0. In the tolerance test, however, the difference between the two tests cannot be more than 15% of the longest test. After two visits on day 7- and day 0Q, eligible patients were divided into random groups.
[0040] In total, 10 patients were included and assigned to treatment groups 1 and 2. In the double-blind stage, patients should note the frequency of angina pectoris and short-acting nitroglycerin dosage on the daily note card. According to the Bruce Standard Protocol, ETT was performed on the 28th day (peak wave, 1 ~ 2 hours (s) after administration), 29th day (wave valley, 11-13 hours after administration), 56Q day (peak wave) and 57Q day (wave valley).
[0041] According to the original plan, at least 70 patients with chronic stable angina pectoris must be enrolled and 60 of them must complete the test with 30 individuals in each group. However, because the researchers did not foresee the difficulties in enrolling individuals in Australia and New Zealand, until the end of the trial, there were only 10 individuals who were distributed in the groups. Among these patients, only 3 individuals did not violate the agreement or abandoned the research early, but they did not have any statistical significance for the assessment of efficacy.
[0042] Safety assessment should be performed on all patients who have received treatment. No reports of serious adverse events (SAE) with respect to the drug tested were recorded in this trial, which had been recorded with respect to the document of safe use of the said composition of Chinese medicine. 1.1 .T89-005-0003-US Clinical Trial 1.1.1 Scope of the Test
[0043] Title of 89-005-0003-US is “A Phase II, Double Blind, Placebo-controlled, Randomized, Multi-Center, Parallel Group Study to Evaluate the Efficacy and Safety of T89 in Patient with Chronic Stable Angina Pectoris” . The flowchart of the trial is in Figure 1. In this research experiment, a total of 125 male and female patients aged 18-75 years were enrolled, and the trial was supervised by iCS, a US CRO company. Enrolled patients were distributed to 15 medical centers in the USA. After being approved by the Institutional Research Council (IRB), the study plan was submitted to the FDA. The first patient was enrolled in March 2008, and the final visit of the last patient on December 22, 2009.
[0044] The target population of the study was male or female patients with moderate chronic stable angina pectoris, aged 18 ~ 80, and diagnosed as having grade II and grade III angina pectoris by the Cardiovascular Society Canadian (CCS). Patients eligible for inclusion must have a detailed history document of the case of myocardial infarction (Ml) or severe coronary heart disease, diagnosed by a non-invasive method or angiography. In addition, symptoms should support the diagnosis of chronic angina pectoris, and / or angina pectoris patients had a history of abnormal motion reaction and / or ECG changes. Except those who were allowed to take drugs of short effectiveness; for example, nitroglycerin, β-receptor blockers or calcium channel blockers, for 14 days before the screening phase, patients were required to discontinue drug previously used for the treatment of angina pectoris. In addition, eligible patients must have limited capacity for sports (maximum TED in the Bruce Standard Protocol is 3 to 7 minutes), which must be confirmed on the seventh day and on day 0. In the tolerance test, however , the difference between the two tests cannot be more than 15% of the longest test. After two visits on day 7- and day 0Q, eligible patients were divided into random groups.
[0045] Participating patients were randomly divided into 3 treatment groups: placebo group, low dose group and high dose group (0.125 mg or 187.5 mg, the test drug was prepared by the method of EXAMPLE 11 , administered once for 12 hours a day at a dose of 0, 250 mg and 375 mg.). Other drugs taken simultaneously to treat angina pectoris can be stopped. If necessary, short-acting nitroglycerin and a type of β-receptor blocker or calcium channel blocker. The duration of treatment was 8 weeks.
[0046] In this double-blind phase, patients should note the frequency of angina pectoris and the short-acting nitroglycerin dosage on the daily card. According to the Bruce Standard Protocol, ETT was performed on day 28 (peak wave, 1 ~ 2 hours (s) after administration), day 29 (wave valley 11-13 hours after administration), day 56 (peak of the wave) and day 57 (valley of the wave). 1.1.2 Study Control
[0047] The complete phase II clinical trial strictly followed the requirements of the GCP. Before the drugs were distributed to study center (s), the training program was completed for researchers, and the GCP training program and visits to the study center were started. In the survey, all reports of serious adverse events (SAE) must be analyzed and approved by the Institutional Research Council (IRB). Because no SAE was mentioned with respect to drugs and the research plan, there were no pertinent suggestions proposed by the IRB throughout the trial. All advertising materials, for example, brochures, television scripts and articles, were not compiled until they were approved by the IRB. All patients who voluntarily participated in the tests were asked to sign a consent form and did so. The CRO clinical inspector monitored all research centers. In addition, the applicant and the CRO completed the research and visitation process and the training program with respect to related individuals. 1.1.3 Determining the Sample Size
[0048] Based on the assumption of normal distribution of the TTE data and individual SD within 90s, 30 eligible patients in each group were required and a success rate of 80% in order to detect the difference in TED within 30s between 187.5 mg of the Chinese medicine composition group and the placebo group at the primary turning point. Taking into account a dropout rate of 20%, it was estimated that 36 patients were required to enter the groups. I. 1.4 Data Analysis
[0049] All data were entered twice in the CRF21 software (DMsys 5.0). Under the control of the data manager, at least two independent data insertions were required before the data was closed, all work must be completed, including the CRF search, DCF query, error checking and data cleaning. Before closing the data closure record, the data evaluation committee can double-check the decisions and reasons why patients were excluded from the ITT or PPT analytical set. The process of opening the blind person was divided into two stages: the first stage was, after closing the data, opening the grouping code in order to perform the data analysis; the second step was to make it clear which treatment method the three groups A, B and C represented, respectively. ITT Analytical Suite
[0050] The ITT analytical set included patients who received ETT at least once. Two excluded patients were present in Table 1.Table 1 - Individuals Excluded from the ITT analysis set

[0051] PPT dataset: The PPT analysis set included patients who received treatment with the drug for 8 weeks, did not violate the research plan, did not take any drugs not allowed and did not have chronic obstructive pulmonary disease (COPD). Patients who had their data lost were allowed to remain in the pool. The list of patients excluded from the PPT is shown in Table 2 and Table 3.Table 2 - Individuals excluded from the set of PPT analyzes due to deviation from baseline data

Table 3 - Individuals excluded for taking prohibited accompanying drugs


[0052] Safety data set: Safety data included patients who had taken the test drug at least once.
[0053] Dealing with values outside or lost values: for patients who lost data on the 57th day, the last data observed before was used to replace the lost value except in the baseline observation. The population of the ITT group, 15 patients (12.2%) completed the trial in the absence of the exercise test on day 57, 6 patients in group A (43 cases), three patients in group B (37 cases), and six patients group C (43 cases). The final observation time for 2 patients was on day 28, 4 patients on day 56 and 2 patients on day 29. There were 7 patients who lost data in the main terminal moment on day 57, and were marked with N / A because they had only the baseline of ETT. 1.1.5 Population characteristics
[0054] About 70% of the individuals were white, the average age was 60 years. No evident difference in baseline and population characteristics between treatment groups. Demographic statistics and initial characteristics are shown in Fig.2, Fig.3 and Table 4. Table 4 - Statistical characteristics of the population in each treatment group (ITT analytical set)

I.1.6 Effectiveness Responses
[0055] The set of ITT and PPT analyzes was evaluated together. Without the interim analysis of the effectiveness assessment in this study, the P value does not need data adjustment.
[0056] According to the Bruce Standard Protocol, the main indices for therapeutic effects were to compare the change in TED when the drug content reached the peak level and is valid in patients between the treatment group and the placebo group in 4- week and 8th week. The arithmetic mean of the mixed data collected from various centers and the standard deviation (SD) was used to evaluate the therapeutic parameters. Considering the impact of comprehensive factors, for example, sex, age and / or body weight, diet, the method of calculating data on the difference in treatment was the arithmetic mean (SD) or the least squares method analysis (LSM), the significance was 0.05. (A) Unadjusted Main Therapeutic Analysis Data
[0057] Tables 5 and 6 show a summary of the main variables of the effectiveness of the ITT and PPT analyzes using the mathematical mean method. Table 5 - Summary of TED Changes in the ETT, X ± SD (set of ITT analyzes)


[0058] * In the first stage, the average value of the change in TED compared to baseline was calculated by calculating the change in TED between each individual and the baseline; in the second stage, the mean value and SD of that day in the group were calculated.
[0059] ** The improvement data in relation to the placebo group was calculated by subtracting the mean value of the placebo group from the corresponding index of the treatment group on the same day. *** P <0.05, statistical significance
[0060] In the ITT analysis set, there were 4 subjects who finished the trial without performing the stress test at the 8th week valley concentration, 12 subjects (27.9%) in the high dose group (187.5 mg, bid ), 9 individuals (20.9%) in the low dose group (125 mg, bid) and 4 individuals (10.8%) in the placebo group. Table 6 - Summary of Alteration of TED compared to X ± SD (set of PPT analyzes)

[0061] * In the first stage, the average value of the change in TED compared to baseline was calculated by calculating the change in TED between each individual and the baseline; in the second stage, the mean value and SD of that day in the group were calculated.
[0062] ** The improvement data in relation to the placebo group were calculated by subtracting the mean value of the placebo group from the corresponding index of the treatment group on the same day.
[0063] *** P <0.05, statistical significance.
[0064] As shown in Table 5, and Fig.4 Fig.5, for the population eligible for the ITT analysis set, the change in the mean TED value was greater than that in the placebo group in patients who took the medicine composition Chinese (187.5 mg or 125 mg, three times a day). The result in improving patients in the highest dose group (187.5 mg, twice daily), taking the composition of Chinese medicine was much higher than in the low dose group (125 mg, bid) in the concentration of peak and valley, in support of the dose-effect relationship. Similar results occurred in the analytical set of PPT, see Table 6, Fig.6 and Fig.7. The effect of the composition of Chinese medicine against antiangina pectoris has been illustrated. B) Analysis of the main effective data, adjusted according to age
[0065] The change in the TED has no positive correlation with the baseline condition, body weight and sex (Fig.δa and fig. 8b). It was observed that changes in TED had a positive correlation with age in all visits to TTE in the ITT analysis set (Figure 9).
[0066] Considering the correlation between age and improvement in TED, and the influence of age, the mixed linear model (MLM) was used to calculate the statistically significant difference between the treatment group and the placebo group through LSM . (Table 7, 8 and Fig.10a-b show the LSM analysis in improving the TED relative to baseline in the population of the ITT analysis set in the valley concentration; Figure 10b shows the LSM analysis in improving the TED relative to baseline in the population of the ITT analysis set at peak concentration). TED B change (high dose) (n = 40) A (low dose) (n = 40) C (Placebo) (n = 35) Table 7 - Analysis of LSM in the improvement of TED in ETT, X ± SD (set of ITT analyzes)

P <0.05, statistically significant difference Table 8 - LSM analysis in the improvement of TED in ETT, X ± SD (set of ITT analyzes)



[0067] As shown above, there was an evident dose-effect relationship in improving TED. In other words, as the dose increased, the efficacy became more significant. For example, on day 29, compared to the placebo group, the high dose group and the low dose group increased by 19s and 45s, respectively.
[0068] On day 28Q and 29Q, there was a statistically significant difference between the high dose group and the placebo group. C) Secondary analysis of actual data
[0069] Effective secondary data included weekly angina frequency (WFA), weekly nitroglycerin consumption (WNC), time for ST depression (TSTD), time for chest pain (TCP) and quality of life (QoL). The ECG and biochemical indices were monitored as exploratory parameters.
[0070] As shown in Fig.12a and Fig.12b, compared to the placebo group and the low dose group (125 mg, bid), there was clinical significance in the mean decrease in the frequency of angina pectoris in the discharge group dose (187.5 mg, bid). Compared to the placebo group. Fig.13a and Fig. 13b show that two treatment groups (187.5 mg and 125 mg) have had significant efficacy in clinically reducing the dose. The mean baseline WFA was 2.74 times per week, and the mean baseline WNC was 0.53 mg per week.
[0071] In the PPT set, compared to the placebo group, the frequency of angina pectoris and nitroglycerin consumption decreased significantly in patients who took the Chinese medicine composition. In the IIT set, there were 20 patients who took the banned drug, and it was likely to reduce the clinical effects of the composition of Chinese medicine. Figs 11a-b show the LSM analysis in improving TED over baseline in the population of the set of PPT analyzes separately at peak and valley concentration. Fig.11 a showed the LSM analysis in improving the TED relative to baseline in the population of the set of PPT analyzes in the valley concentration; Figure 11 b showed the LSM analysis in improving the TED relative to baseline in the population of the set of PPT analyzes at peak concentration.
[0072] As shown in Table 9 and Figure 14, compared to the placebo group, the TCP (peak value and valley value) was significantly increased relative to baseline in both treatment groups with the composition of Chinese medicine. It was shown that the composition of Chinese medicine had an anti-anginal effect.Table 9 - Change in time of attack of angina pectoris in TTE, X ± SD

[0073] As shown in table 10 and Fig. 15, there was comparability in the alteration of the TSTD between the high dose group (valley wave) and the low dose group. In comparison with the placebo group, there was a statistically significant difference in both treatment groups. The composition of Chinese medicine has been shown to have an anti-myocardial effect. Although the analysis of the ST-segment pressure under a relatively low n-value can reduce the reliability of the result, this trend was consistent with the results of the main turning point. Table 10 - time of the ST-segment depression 0.1 mvnaETT (s), X ± SD (ITT analysis set)
D) Analysis of biochemical indices and quality of life questionnaire
[0074] The Seattle Angina Questionnaire (SAQ) was used to investigate the improvement in quality of life. No statistically significant difference was found between the treatment and placebo groups (Fig. 16).
[0075] In this study, biochemical markers were analyzed only to explore biochemical indices useful for clinical trial or clinical monitoring in the future. The statistical difference between treatment groups has not been evaluated. An exploratory model analysis was performed with respect to biochemical indices, the primary turning point index and the secondary turning point index. In addition, in changing the indices between different times, different and different dosage groups were monitored.
[0076] The average of the biochemical indices already mentioned was present as follows, which provided us with some significant clarification.
[0077] As shown in Figure 17, compared to the placebo group, the BNP of both treatment groups has obviously been reduced since the first visit. On the 14th day, compared to the placebo group, the LP-PLA2 value of both treatment groups was reduced slightly. Later, on day 28Q, the LP-PLA2 value of patients taking the Chinese medicine composition in both treatment groups was significantly reduced. (Fig. 18)
[0078] However, the biochemical indices mentioned above were not only related to each other, but also to the baseline TED value and to the change in TED on the 29th and 57th days. It was not possible to establish a relevance or predictive model. Thus, the evaluation of efficacy by biochemical indexes has yet to be confirmed. Figure 19 showed a correlation between biochemical indices and TTE. 1.1.7 Group Essay
[0079] In order to assess whether the effectiveness of Chinese medicine has been maintained consistent with a wide range of population with chronic angina pectoris, an exploratory analysis has been done in different groups. Age (<64.5 years or> 64.5 years) and baseline TED (<300 s or 300 s) were considered as inclusion criteria for each group respectively.
[0080] Compared to the group (less than 64.5 years old), TED was apparently improved in older patients who were treated with different doses of the composition of Chinese medicine. It is noteworthy that the placebo produced much more effect in the age group <64.5 years (Fig. 20a) than in the age group> 64.5 years (Fig.20b). Figures 20a-b described the change in TED from baseline in populations of different ages. Figure 20a described the change in the TED ratio from baseline in populations (<64.5 years). Fig. 20b showed the change in the TED ratio from baseline in populations (> 64.5 years). Patients in the age group> 64.5 years, however, were treated with placebo, with little or no effect, or even lower effect than baseline. This phenomenon could explain why the older population was in worse health than the younger population. Thus, your health could not be improved by placebo alone. These results suggest that, in this study, the elderly population may be more sensitive to the effectiveness of the composition of Chinese medicine at the primary turning point.
[0081] Likewise, placebo produced a clearer effect in the relatively better health group (according to baseline TED, baseline 300s) than in the <300s group. These results were the same with the conclusion drawn from the age group (Fig.21 a). The poorer the patients had their baseline health, the less effective the improvement that was produced by the placebo (Fig. 21b). 1.1.8 Assessment of Treatment Adherence
[0082] As shown in the assessment of adherence to the drug, the number of patients who failed to take at least one capsule was evenly distributed among the three treatment groups (Fig. 22). Figure 22 illustrates the number of patients who stopped taking the capsule in the treatment groups of the different doses in the ITT analysis set. Adherence was poorer was that of the placebo group. There were 48%, 45% and 63% of patients who did not take at least one capsule respectively in the high dose treatment group, low dose treatment group and placebo group.
[0083] As suggested in these results, patients in the placebo group had no incentive to continue the drug when they found no improvement after being treated with the drug. In contrast, patients in the high-dose group may have been more motivated to take the study more seriously in part because they had more satisfactory efficacy. When patients in the placebo group saw no effect after 4 weeks of the “trial”, they stopped taking most drugs at the end of the secondary treatment period. However, patients in the high-dose group missed fewer doses, because they got more benefits from the treatment. In addition, this corroborated our conclusion. 1.1.9 - Summary of Effectiveness
[0084] As shown in the phase II clinical trial (T89-005-003-US), drug administration (bid) can therapeutically improve the main turning point indexes (total ETT time in the valley content at the end week 4 and week 8). Compared with the placebo group, the improvement in TTE due to the composition of Chinese medicine (187.5 mg) was of statistical and clinical significance on day 29Q and day 57Q (voucher value).
[0085] Tolerance time in TTE showed a clear relationship of dose-effect. After 4 weeks of treatment, compared to the baseline value (300s), the tolerance time for both low and high dose groups increased respectively from 17s and 44s (valley value). With the improved effect of the trial after 8 weeks of treatment in the placebo group, the change in both high-dose and low-dose groups was 28s, compared with the placebo group. The absolute value of TED started to rise continuously from the 28th day and 29th day.
[0086] The change in the TED of the level is valid in each dose group was more than that of the peak level in the 4th week and 8th week, which illustrated a time lapse between the maximum effect of the composition of Chinese medicine and its concentration. Due to having a different mechanism with nitroglycerin in the anti-anginal effect, this time lag with the composition of Chinese medicine was incomprehensible. There are no data to support the possibility of the training effect (the ETT voucher was made on the second day after the ETT peak). Both the peak and valley of TED were the same in the placebo.
[0087] The results analyzed above, not only by the ITT set, but also the PPT set, were consistent. Most importantly, other secondary efficacy rates consistently pointed to a unified trend; for example, improved quality of life, delayed attack of angina pectoris in TTE, delayed ST-segment depression, low weekly frequency of angina pectoris, reduced weekly consumption of nitroglycerin and biochemical indices. They almost followed the same dose-effect relationship and were of the same clinical and statistical significance. In any case, since the results of the analysis were of statistical significance, the sample size was proven to be reasonable. Therefore, although the aforementioned results were obtained based on the sample size of about 30 patients in each treatment group, any random possibility of efficacy that we had observed in clinical studies was excluded by the strong combination of evidence and statistical significance.
[0088] The results mentioned were consistent with the analysis of the ITT set and PPT set. The difference between the treatment group and the placebo group was generally greater either at the primary turning point or at the secondary turning point, either at week 4 or week 8. 1.1.10 Security Results
[0089] The “Safety Data Set” (SD) method was used for the safety analysis, including all patients who received treatment with the drug at least once. The 123 patients were included in the DS. The information regarding the patients and the drugs they used are listed in Table 11. The number of adverse drug reactions (ADR) and their occurrence in the different stages were investigated. Patients who stopped taking drugs in advance due to serious adverse effects (SAE) and / or adverse events (AE) were listed in the Table below. Table 11 - Drug Administration in Different Groups (SD)

a) Summary of Safety Data
[0090] By the analyzes, in the total of 123 patients, there were 51% of individuals with ADR (21/41) in the low dose group, 61% in the high dose group (27/44), and 66% in the placebo group (25/38). Most of the ADR was mild in the clinical trial, and had nothing to do with the tested drug. All adverse reactions were listed in table 12. Among them, CHD symptoms (eg, tachypnea, chest tightness and chest pain), pain symptoms (eg, neck, shoulders, back were muscular, leg, arm, hand and toothache) and flu symptoms (fever, for example, mucus, nasal congestion and cough) should not be considered as ADR, but can be used as a reference. In addition, there were some ADRs that occurred before drug treatment. If these ADRs were eliminated from Table AE, the number of AE patients could be significantly reduced.
[0091] Compared with the placebo group, none of the obvious evidence was present to support the prolonged QTc (corrected value of the QT interval) on the 14th day, 4 weeks and 8 weeks. 5 SAEs were not related to the study or drugs. Other adverse events were few and relatively small, which occurred before the clinical trial. Perhaps they were unrelated to the drugs (for example, toothache, flu or chest pain). By cross-comparison, there was the same incidence rate in the placebo group. Table 12 - Adverse drug reaction rate in each group (SD)




[0092] * Refers to the incidence rate of ADRs in each group. There were a total of 41 patients in the lowest dose group, 44 patients in the highest dose group, and 38 patients in the placebo group.
[0093] Except for three serious ADRs, the majority of ADRs occurring in the three groups were considered to be of mild or moderate degree. There was one patient with diabetic foot ulcers (uncorrelated) in the low dose group, one with headache (uncorrelated) in the high dose group, and one with intense chest pain (uncorrelated) in the placebo group.
[0094] The patients included in this study had a history of complicated disease, progressive disease and combined medication. According to the trial, treatment-related AE included: • low dose group (5 cases): 1 case of mild dizziness, 1 case of mild diarrhea, 1 case of mild indigestion; 1 case of mild watery stools and 1 case of mild abdominal distention. • high dose group (3 cases): 1 case of intermittent mild flushing, feeling of distension in the head and mild headache and palpitations; 1 case of mild abdominal distension and 1 case of mild watery stools. • Placebo group (4 cases): 1 case of mild dizziness and headache, 1 case of mild constipation; 1 case of mild indigestion and 1 case of mild drowsiness. In the placebo group, the low dose group and the high dose group, patients with symptoms of coronary heart disease (including wheezing, chest pain or discomfort, angina pectoris) are 23.7%, 12.2% and 9.1%, respectively, which demonstrate that the Dantonic® group has a significant difference from the placebo group, and has a slight difference between low and high dose groups. b) Death, another serious adverse effect (SAE) and another important adverse effect (AE)
[0095] None of the cases of death were found in the composition of Chinese medicine in the phase II clinical trial in the USA. As shown in Table 13, said SAE in the trial was present as follows: 1 case of cardiovascular symptoms of chest pain, atrial fibrillation and acute myocardial infarction (AMI), 1 case of foot ulcer and 1 case of hyperglycemia. Said SAE in the treatment groups (high and low dose) of the composition of Chinese medicine included a case of chest pain, a case of atrial fibrillation, a case of AMI, a case of foot ulcer and 1 case of hyperglycemia. In addition, there were 2 SAEs in the placebo group, who had chest pain.
[0096] After being analyzed, according to their disease histories, none of the cases of SAE was correlated with drug treatment. Eventually, the SAE results were good (1 case improved and 6 cases resolved completely). In the high dose group, chest pain in 1 patient and ulcer etching on the foot of another patient were considered to be more serious than the other mild and moderate AEs. In addition, there were 3 patients who were removed / eliminated early from the trial; they included 1 case of severe chest pain in the high dose group, 1 case of mild foot ulcer in the low dose group and 1 case of chest pain in the placebo group.
[0097] In summary, the aforementioned symptoms of the study belonged mainly to mild and moderate AE, which was related to the patients' disease history, not related to the drug treatment of the Chinese medicine composition. Table 13 Summary of the serious adverse effect (SAE) reported

Security Summary
[0098] Most adverse drug reactions (ADRs) occurring in the phase II clinical trial were mild and not correlated with drug treatment. In comparison with the placebo group, adverse events (AEs) occurring in the Dantonic® group had only a mild irritating effect on the digestive system; for example, the feeling of abdominal distension. The appearance of mild flushing was an indication of the effect of improving blood circulation. It was confirmed in the study, that the composition of Chinese medicine proved to be a safe drug for clinical use.
[0099] During the 18-month clinical trial, all 5 cases of SAE reported were unrelated to the drug tested. Other AEs listed in the disease category had a rare occurrence, or had previously existed, for example, cold, toothache and chest pain. By cross-comparison, the drug tested in the composition of Chinese medicine had the same relation of incidence of AE with that of the placebo group. Therefore, it was determined that the AE had nothing to do with drug treatment. 1.1.11 - Cardiac Safety
[00100] The QT interval showed an evident correlation with heart rate (HR). QTc was determined by the Frederica method and, consequently, QTc was independent with HR (Fig.23a and 23b). The mean QTc variation at week 2, week 4 and week 8 was determined by two values above baseline (Table 14). None of the QTc intervals were found in the 2 treatment groups during the drug treatment period. Data set Change in QTc according to time Table 14 - Change in QTc according to time in all treatment groups (ITT population and PPT)

Cartoon Illustration
[00101] Figure 1 was the flow chart of the T89-005-0003-US trial.
[00102] Figure 2 shows population statistics and baseline characteristics in the ITT analysis set.
[00103] Figure 3 shows population statistics and baseline characteristics in the set of PPT analyzes.
[00104] Figure 4 represents the change in the TED value of the population of the ITT analysis set at the ETT voucher level.
[00105] Figure 5 represents the change in the TED value of the population of the ITT analysis set at the peak ETT level.
[00106] Figure 6 represents the change in the TED value of the population of the set of PPT analyzes in relation to the baseline in the ETT valley level.
[00107] Figure 7 represents the change in the TED value of the population of the set of PPT analyzes relative to the baseline at the peak level of the ETT.
[00108] Figures 8a-b represent the change in the TED value of the population in the ITT analysis set in relation to the different baseline TED over a different period of time; Figure 8a describes the change in the TED value of the population in the ITT analysis set in relation to the different TED baseline on the 29th day; and Figure 8b describes the change in the TED value of the population in the ITT analysis set in relation to the different baseline TED at 572 days.
[00109] Figure 9 shows the correlation between the population change in the ITT analysis set and age.
[00110] Figures 10a-b show the LSM analysis in improving the TED value compared to baseline in the population of the ITT analysis set, separately in peak and valley concentration; Figure 10a shows the LSM analysis in improving the TED relative to baseline in the population of the ITT analysis set in the valley concentration; Figure 10b shows the LSM analysis in improving the TED over baseline in the population of the ITT analysis set at peak concentration.
[00111] Figures 11 a-b show the LSM analysis in improving the TED value compared to baseline in the population of the set of PPT analyzes separately at peak and valley concentration; Figure 11 shows the LSM analysis in relation to the improvement of the TED relative to the baseline in the population of the set of PPT analyzes in the valley concentration; Figure 11b shows the LSM analysis on improving TED relative to baseline in the population of the set of PPT analyzes at a peak concentration.
[00112] Figures 12a-b describe the average variation in the weekly frequency of angina relative to baseline in the population of the ITT and PPT analysis set; Figure 12a describes the average variation in the weekly frequency of angina relative to baseline in the population of the ITT analysis set; Figure 12b describes the half change in the weekly frequency of angina relative to baseline in the population of the set of PPT analyzes.
[00113] Figures 13a-b describe the average variation of weekly nitroglycerin consumption relative to baseline in the population of the ITT and PPT analysis set; Figure 13a describes the average variation of weekly nitroglycerin consumption compared to baseline in the population of the ITT analysis set; Figure 13b shows the average variation of weekly nitroglycerin consumption compared to baseline in the population of the set of PPT analyzes.
[00114] Figure 14 describes the improvement in TCP of the population of the ITT analysis set at the ETT voucher level.
[00115] Figure 15 describes the improvement of ST-segment depression in different dose groups at the ETT valley level.
[00116] Figure 16 describes the variations in quality of life over time in the population of the ITT analysis set.
[00117] Figure 17 represents the percentage of BNP change from baseline in the population of the ITT analysis set.
[00118] Figure 18 describes the percentage of Lp-PLA2 change from baseline in the population of the ITT analysis set.
[00119] biochemical indices.
[00120] Figures Fig. 20a-b show the change in the TED value from baseline for populations of different ages; Figure 20a describes the change in the TED value from baseline in the population (<64.5 years); Figure 20b shows the change in the TED value from baseline in the population (> 64.5 years).
[00121] Figures 21 a-b describe the change in the TED value from baseline in populations from different baseline; Figure 21a describes the change in the TED value from baseline in the population (baseline <300s); Figure 21 b describes the change in the TED value from baseline in the population (baseline> 300s).
[00122] Figure 22 shows the number of the population in the ITT analysis set that stopped taking the capsule.
[00123] Figures 23a-b analyzed the correlation between QTc and heart rate respectively in the population of the ITT and PPT analysis set; Figure 23a shows the correlation between QTc and heart rate in the population of the ITT analysis set; Figure 23b shows the correlation between QTc and heart rate in the population of the set of PPT analyzes. Modalities
[00124] The present invention will be described further with reference to the examples presented below, which are only used to illustrate the present invention, without limitation. Preparative Example 1 (1) Formulation (2) Radix Salvia miltiorrhiza - 45.0 g (3) Radix Notoginseng - 47.0 g (4) Borneol - 0.1 g (5) PEG-6000 adjuvant - 18 g (6 ) A thousand droplet pills were prepared. (2) Extraction of Radix Salvia miltiorrhiza and Radix Notoginseng:
[00125] Radix Salvia miltiorrhiza (45.0g) and Radix Notoginseng (47.0g) coarsely crushed were placed in an extraction tank, into which water with 5 times the weight of the drugs Radix Salvia miltiorrhiza and Radix Notoginseng raw was poured to cook for 2 hours for the first time, after filtration, 4 times of water was added to the drug residues to cook for one hour for the second time. After filtration, the residues were discarded. After combining the cooking result, the solution was filtered and concentrated to obtain an extract in a ratio of extract volume (L) to weight (Kg) of the raw drugs Radix Salvia miltiorrhiza and Radix Notoginseng as 1: 0.9 ~ 1.1 . Then, 95% (v / v) of ethanol was added slowly to the extract solution obtained to produce a final ethanol content of 69 ~ 71% (v / v), and left to stand still for 12 hours to separate the supernatant , and the supernatant was filtered. The filtrate was concentrated by removing the ethanol to obtain an extract with a relative density of 1.32 ~ 1.40. (3) Preparation of the product
[00126] The aforementioned extract of Radix Salvia miltiorrhiza and Radix Notoginseng, borneol and PEG-6000 (18 g) were well mixed and heated to a temperature of 85 ~ 90 ° C. After being melted for 20 - 120 minutes, the mixture was transferred to a drip machine tank, the temperature of which was maintained at 85 - 90 ° C to drip into liquid paraffin at 7 - 8 ° C. The pills were collected and the liquid paraffin was removed to produce the product. (4) Product features
[00127] The product was a rounded pill of dark red-brown color, with smooth surfaces, with uniform dimensions, the same color, an aroma of odor and a bitter taste. The weight of the pill was 25 mg ± 15% / pill and 3.34 ± 15% mm in diameter. Preparative Example 2
[00128] Radix Salvia miltiorrhiza (70.0 g) and Radix Notoginseng (13.7 g) coarsely crushed, were placed in an extraction tank, in which the water, with 5 times the gross weight of the drugs Radix Salvia miltiorrhiza and Radix Notoginseng was poured to cook for 2 hours for the first time, after filtration, 4 times the water was added to the drug residues to cook for 1 hour, for the second time. After filtration, the waste was discarded. After combining the material resulting from cooking, the solution was filtered and concentrated to obtain an extract of a relationship between the volume of extract (L) with the weight (kg) of the raw drugs Radix Salvia miltiorrhiza and Radix Notoginseng as 1: 0.9 - 1.1. Then, 95% (v / v) ethanol was added slowly to the extract solution obtained to produce a final ethanol content of 69 - 71% (v / v), and left to stand for 12 hours to separate the supernatant , and the supernatant was filtered. The filtrate was concentrated by removing ethanol to obtain an extract with a relative density of 1.32 - 1.40.
[00129] The aforementioned Radix extract Salvia miltiorrhiza and Radix Notoginseng, borneol (0.8) and PEG-6000 (15.5 g) were well mixed and heated to a temperature of 85 ° C. After being mixed for 30 minutes the mixture was transferred to a drip machine tank, the temperature of which was maintained at 80 ° C to drip into liquid paraffin at 7 ° C. The pills were collected and the liquid paraffin was removed to produce the product.
[00130] The product was a roundish pill with a dark red-brown color, with smooth surfaces, with uniform dimensions, the same color, an aroma of odor and a bitter taste. The weight of the pill was 25 mg ± 15% / pill and 3.34 ± 15% mm in diameter. Preparative Example 3 Radix Salvia miltiorrhiza - 96.0 g Radix Notoginseng - 1.0 g Borneol - 3.0 g PEG-6000 adjuvant - 20 g
[00131] Radix Salvia miltiorrhiza and Radix Notoginseng were extracted and the product was prepared by the same method as in Preparation Example 1 except that the temperature in the drip machine was 64 ° C and the liquid paraffin at 0 ° C.
[00132] The product was a roundish pill with a dark red-brown color, with smooth surfaces, with uniform dimensions, the same color, an aroma of odor and a bitter taste. The weight of the pill was 25 mg ± 15% / pill and 3.34 ± 15% mm in diameter. Preparative Example 4 Extract of Radix Salvia miltiorrhiza and Radix Notoginseng (prepared by a method written in Example 1) - 18 g Borneol - 3.0 g Lactitol - 45 g Pre-gelatinized starch - 20 g
[00133] The lactitol and the pre-gelatinized starch are well mixed and placed in a drip machine, in which the extract of Radix Salvia milterioriza and Radix Notoginseng and borneol were added, completely homogenized and heated in a water bath until melted in a water bath temperature of 83 ° C. At a temperature of 70 ° C, the melted solution was dripped into the silicone soda at 0 ° C at a rate of 35 pills per minute. After being formed, the pills were cleaned with absorbent paper to aspirate the methylated silicone oil that adheres to the surface of the pill. The pills were dried at low temperature to produce the product.
[00134] The mentioned product was round and smooth, with uniform size, same color and without adhesions. The pill disintegration time limit was determined according to the Chinese Pharmacopoeia (2000) monograph of the disintegration time limit. The results showed that the average time of passage through the screen without a baffle was 3.96 minutes. The time limit meets the requirements of the Chinese Pharmacopoeia. Preparative Example 5 extract of Radix Salvia miltiorrhiza and Radix Notoginseng (prepared by a method described in Example 1) - 22 g Borneol - 1.5 g Lactitol - 40 g Gum arabic - 20 g The lactitol and gum arabic were well mixed and placed in a drip machine in which the Radix Salvia miltiorrhiza and Radix Notoginseng and Borneol foral extract were added, completely homogenized and heated in a water bath until melted at a water bath temperature of 85 ° C. At water break temperature. At a temperature of 64 ° C, the molten solution was dripped into the liquid paraffin soda at 4 ° C at a rate of 40 pills per minute. After being formed, the pills were cleaned with absorbent paper to suck the liquid paraffin that adheres to the surface of the tablet. The pills were dried at low temperature to produce the product.
[00135] The mentioned product was round and smooth, with uniform size, same color and without adhesions. The pill disintegration time limit was determined according to the Chinese Pharmacopoeia (2000) monograph of the disintegration time limit. The results showed that the average time of passage through the screen without a baffle was 4.25 minutes. The time limit meets the requirements of the Chinese Pharmacopoeia. Preparative Example 6 extract of Radix Salvia miltiorrhiza and Radix Notoginseng (prepared by a method described in Example 1) - 18 g Borneol - 1.2 g Microcrystalline cellulose - 40 g talcum powder - 20 g 3% ethanol solution Polyvinylpyrrolidone (PVP) - appropriate amount A conventional method was used to prepare the tablets. Preparative Example 7 extract of Radix Salvia miltiorrhiza and Radix Notoginseng (prepared by a method described in Example 1) - 18 g Borneol - 1.2 g Gel - 50 g Glycerol - 10 g A conventional method was used to prepare the capsules. Preparative Example 8 extract of Radix Salvia miltiorrhiza and Radix Notoginseng (prepared by a method described in Example 1) - 18 g Borneol - 1.2 g Magnesium stearate - 30 g Starch - 15 g 3% ethanol solution Polyvinylpyrrolidone (PVP) - amount A conventional method was used to prepare the granules. Preparative Example 9 extract of Radix Salvia miltiorrhiza and Radix Notoginseng (prepared by a method written in Example 1) - 18 g Borneol - 1.2 g Microcrystalline cellulose - 35 g Starch - 10 g 3% ethanol solution Polyvinylpyrrolidone (PVP) - amount appropriate A conventional method was used to prepare tablets. Preparative Example 10 extract of Radix Salvia miltiorrhiza and Radix Notoginseng (prepared by a method described in Example 11) - 600 g Borneol - 5 g PEG 6000 - 2000g PEG-6000 was placed in a melting tank, heated to 90 ° C for pre -melting. The Radix Salvia miltiorrhiza and Radix Notoginseng extract was added and mixed well to form a solution. The frequency of the pneumatic vibration drippers was set to 50 Hz, and the temperature of the thermal room was maintained at 80 ° C with a steam jacket. The melting tank was vented through the air pump through the tube, which made the aforementioned solution evenly melted to flow into the drippers and fall into the cooling tunnel. The said cooling tunnel was vertical with respect to the group. The cooling air was started to bring the temperature down to -20 ° C. the angle between the intake of the cooling air and the horizontal plane was 45 °, and the cooling air was circulated inside the cooling tunnel to cool the solution that was dripped from the dripper in the form of solid pills produced by drip, which were collected in a drum through the outlet at the bottom of the tunnel (method as disclosed in Example 1 of Chinese Patent 200710060640.1). Preparative Example 11 (1) Formulation (2) Radix Salvia miltiorrhiza - 373 g (3) Radix Notoginseng - 73 g (4) Borneol - 5.0 g (5) PEG-6000 adjuvant - 182.5 g (6) Mil capsules were prepared. (2) Extraction of Radix Salvia miltiorrhiza and Radix Notoginseng:
[00136] Radix Salvia miltiorrhiza (70.0 g) and Radix Notoginseng (13.7 g) coarsely crushed, were placed in an extraction tank, in which the water, with 5 times the gross weight of the drugs Radix Salvia miltiorrhiza and Radix Notoginseng was poured to cook for 2 hours for the first time, after filtration, 4 times the water was added to the drug residues to cook for 1 hour, for the second time. After filtration, the waste was discarded. After combining the material resulting from cooking, the solution was filtered and concentrated to obtain an extract of a relationship between the volume of extract (L) with the weight (kg) of the raw drugs Radix Salvia miltiorrhiza and Radix Notoginseng as 1: 0.9 ~ 1.1. Then, 95% (v / v) of ethanol was added slowly to the extract solution obtained to produce a final ethanol content of 70% (v / v), and left to stand still for 12-24 hours to separate the supernatant , and the supernatant was filtered. The filtrate was concentrated by removing the ethanol to obtain 62.5 g of extract with a relative density of 1.32 ~ 1.40 (3) Preparation of the product
[00137] To the already mentioned extract of Radix Salvia miltiorrhiza and Radix Notoginseng, borneol and PEG-6000 were well mixed and heated to a temperature of 85 ° C. After being melted for 30 minutes, the mixture was transferred to a drip machine tank, whose temperature was maintained at 90 ° C to drip into liquid paraffin at 10 ° C. The pills were collected and the liquid paraffin was removed for loading into the capsule to produce the product. (4) Product features
[00138] The product was a capsule. The contents were round pills of black color in brownish-red, with uniform size, same color, fragrance in odor and bitter taste. Capsule weight was 250mg ± 15% / pill per capsule.

权利要求:
Claims (28)
[0001]
1. Use of a composition of Chinese medicine comprising extract of Radix Salvia miltiorrhiza and Radix Notoginseng and Borneol, CHARACTERIZED by the fact that it is for the manufacture of a medicine for the secondary prevention of coronary heart disease in an individual diagnosed with angina pectoris grade II or grade III by the Canadian Cardiovascular Society, where the weight ratio of Radix Salvia miltiorrhiza and Radix Notoginseng to Borneol extract is (8 to 15): 1, and where the weight of Salvia mil-thiorrhiza and Radix Notoginseng extract is the dry weight, and in which the said extract of Radix Salvia miltiorrhiza and Radix Notoginseng is prepared by extracting Radix Salvia miltior-rhiza and Radix Notoginseng simultaneously.
[0002]
2. Use, according to claim 1, CHARACTERIZED by the fact that the said cardio-coronary disease is angina pectoris.
[0003]
3. Use, according to claim 1, CHARACTERIZED by the fact that said cardio-coronary disease is stable angina pectoris.
[0004]
4. Use, according to claim 1, CHARACTERIZED by the fact that the said secondary prevention is manifested in the increase of exercise tolerance.
[0005]
5. Use, according to claim 1, CHARACTERIZED by the fact that said secondary prevention is manifested in the prolonged exercise time.
[0006]
6. Use, according to claim 1, CHARACTERIZED by the fact that said secondary prevention is manifested in the delay of depression of the ST segment, or prolongation of its interval in an individual with induced stable angina pectoris.
[0007]
7. Use, according to claim 1, CHARACTERIZED by the fact that said secondary prevention is manifested in the delay in the onset of pectoral angina or prolongation of its interval in an individual with induced stable angina pectoris.
[0008]
8. Use, according to claim 1, CHARACTERIZED by the fact that said secondary prevention is manifested in the decrease in the consumption of nitro-glycerin.
[0009]
9. Use, according to claim 1, CHARACTERIZED by the fact that said secondary prevention is manifested in the reduced frequency of angina pectoris.
[0010]
10. Use, according to claim 1, CHARACTERIZED by the fact that said secondary prevention is manifested in improving the quality of life in an individual with stable angina pectoris.
[0011]
11. Use, according to claim 1, CHARACTERIZED by the fact that said composition is used in combination with β-receptor blockers.
[0012]
12. Use, according to claim 1, CHARACTERIZED by the fact that said secondary prevention is manifested in the improvement of the levels of one or more of the following biochemical parameters: B-type natriuretic peptide (BNP), C-reactive protein (CRP), lipoprotein phospholipase A2 (Lp-PLA2) and homocysteine (HCY).
[0013]
13. Use, according to claim 1, CHARACTERIZED by the fact that the said secondary prevention is manifested in the reduction of the occurrence or recurrence of serious vascular events.
[0014]
14. Use, according to claim 13, CHARACTERIZED by the fact that said serious vascular event is death.
[0015]
15. Use, according to claim 13, CHARACTERIZED by the fact that said serious vascular event is myocardial infarction.
[0016]
16. Use, according to claim 13, CHARACTERIZED by the fact that said serious vascular event is ischemic shock.
[0017]
17. Use, according to claim 13, CHARACTERIZED by the fact that said severe vascular event is a situation in which coronary artery revascularization graft, transluminal percutaneous angioplasty and / or angiocardiography is / are necessary (s ).
[0018]
18. Use according to claim 13, CHARACTERIZED by the fact that said composition of Chinese medicine is used in combination with antiplatelet agent (s).
[0019]
19. Use, according to claim 18, CHARACTERIZED by the fact that said antiplatelet agent is aspirin.
[0020]
20. Use, according to claim 1, CHARACTERIZED by the fact that the composition of Chinese medicine comprises extract of Radix Salvia miltior-rhiza and Radix Notoginseng and Beoneol, in a weight ratio of (9 to 10): 1, in that the weight of Radix Salvia miltiorrhiza and Radix Notoginseng extract is the dry weight.
[0021]
21. Use, according to claim 20, CHARACTERIZED by the fact that said extract of Radix Salvia miltiorrhiza and Radix Notoginseng is prepared by extracting Radix Salvia miltiorrhiza and Radix Notoginseng simultaneously, and the weight ratio of the raw drugs Radix Salvia miltiorrhiza and Radix Notogin-seng, which are used as starting materials, is (3 to 7): 1.
[0022]
22. Use, according to claim 1, CHARACTERIZED by the fact that the said weight ratio of the raw drugs of Radix Salvia miltiorrhiza and Radix Notoginseng, which are used as starting materials, is (4 to 6): 1 .
[0023]
23. Use according to claim 22, CHARACTERIZED by the fact that the said weight ratio of the raw drugs of Radix Salvia miltiorrhiza and Radix Notoginseng, which are used as starting materials, is 5: 1.
[0024]
24. Use, according to claim 23, CHARACTERIZED by the fact that the said raw drugs of Radix Salvia miltiorrhiza and Radix Notoginseng are extracted with weak alkaline aqueous solution.
[0025]
25. Use, according to claim 24, CHARACTERIZED by the fact that said extract of Radix Salvia miltiorrhiza and Radix Notoginseng is prepared by a method comprising: a. extract sprayed from Radix Salvia miltiorrhiza and Radix Notoginseng with water or weak aqueous alkaline solution 2 to 3 times, in an amount of 4 to 8 times the weight of Radix Salvia miltiorrhiza and Radix Notoginseng for each time; filter, combine and properly concentrate the filtrate; B. precipitation of the alcohol by adding a high concentration of alcohol in the concentrated solution to produce a final alcohol concentration of 50 to 85% (v / v), leaving it to rest to carry out the precipitation, filter the supernatant, recover the alcohol from of the obtained supernatant and concentrate to produce the extract.
[0026]
26. Use, according to claim 25, CHARACTERIZED by the fact that the composition of Chinese medicine is still formulated in the form of a drip pill, wherein said drip pill is composed of said composition of Chinese medicine and an adjuvant , wherein said adjuvant is PEG-6000, and the weight ratio of said composition of Chinese medicine to said adjuvant is (0.2 to 0.8): 1.
[0027]
27. Use, according to claim 26, CHARACTERIZED by the fact that said adjuvant is PEG-6000, and the weight ratio of said medication relative to said adjuvant is (0.29 to 0.7): 1.
[0028]
28. Use, according to claim 26, CHARACTERIZED by the fact that said adjuvant is PEG-6000, and the weight ratio of said composition relative to said adjuvant is (0.5 to 0.6): 1.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112013002814B1|2020-10-27|use of a salvia miltiorrhiza-based composition for the secondary prevention of coronary heart disease

---

BR112015011843B1|2021-04-06|COMPOSITION TO PROMOTE INTESTINAL HEALTH

---

WO2011020061A2|2011-02-17|Compositions and methods of for treating bipolar disorder

---

Chub-Uppakarn et al.2007|A randomized comparison of dexamethasone 0.15 mg/kg versus 0.6 mg/kg for the treatment of moderate to severe croup

---

WO2009070915A1|2009-06-11|Pharmaceutical compositions for treating depression and anxiety

---

CN103313717B|2015-04-29|Composition containing styraxlignolide A or the aglycone thereof as an active ingredient for preventing or treating asthma

---

PT3119201T|2018-06-15|Sildenafil solutions and methods of making and using same

---

TWI584813B|2017-06-01|The use of Salvia miltiorrhiza in the preparation of a medicament for secondary prevention of coronary heart disease

---

US20120270860A1|2012-10-25|Methods for treating or preventing alcohol-related disorders or craving-related disorders

---

WO2013004177A1|2013-01-10|Composition of active ingredient of traditional chinese medicine and use thereof

---

TW201249450A|2012-12-16|Sweet tea olive extract and manufacturing method and use thereof, as well as the composition comprising the sweet tea olive extract for prevention or treatment of melancholia

---

Chojnacki et al.2013|Influence of tianeptine on melatonin homeostasis and psychosomatic symptoms in patients with irritable bowel syndrome

---

JP2022514194A|2022-02-10|Gaboxador to reduce the risk of suicide and reduce depression quickly

---

US11058740B2|2021-07-13|Composition for preventing, alleviating or treating stress diseases, containing Platycodon grandiflorum extract as active ingredient

---

Taherzadeh et al.2020|Evaluation of sedative effects of an intranasal dosage form containing saffron, lettuce seeds and sweet violet in primary chronic insomnia: A randomized, double-dummy, double-blind placebo controlled clinical trial

---

Ghaderi et al.2017|The Effect Of Cinnamon Zeylanicum Essential Oil On Treatment Of Patients With Unipolar Nonpsychotic Major Depressive Disorder Treated With Fluoxetine

---

Al Dhamen et al.2019|Clinical uses and toxicity of Ephedra sinica: an evidence-based comprehensive retrospective review |

---

AU2018101586A4|2018-11-29|Uses of polydatin

---

WO2019114676A1|2019-06-20|New medical use of persimmon leaf extract and of preparation of persimmon leaf extract

---

US20200038413A1|2020-02-06|Methods of treating parkinson&#39;s disease using aminosterol compositions

---

Kshatriya et al.2018|Central Nervous System Stimulants and Drugs That Suppress Appetite

---

Lu et al.2019|Hypothermic properties of dexmedetomidine provide neuroprotection in rats following cerebral ischemia‑reperfusion injury

---

Haslbeck et al.2004|Diagnosis, treatment and follow-up of diabetic neuropathy

---

CN103845363B|2018-07-27|A kind of drug and preparation method thereof treated hypertension and improve small artery elasticity

---

Thomsen2013|SECTION A

同族专利:

---

公开号 | 公开日

---

JP6030556B2|2016-11-24|

---

WO2012016549A1|2012-02-09|

---

DK2601958T3|2017-07-17|

---

CN103068398A|2013-04-24|

---

EP2601958A1|2013-06-12|

---

EP2601958B1|2017-03-29|

---

KR20150107902A|2015-09-23|

---

EP2601958A4|2013-12-18|

---

AU2011288044B2|2014-07-17|

---

EA201300159A8|2014-11-28|

---

MX2013001298A|2013-03-08|

---

HK1175994A1|2013-07-19|

---

SG187715A1|2013-03-28|

---

CA2807283A1|2012-02-09|

---

AU2011288044A1|2013-02-21|

---

AU2011288044A8|2014-08-07|

---

US20130196005A1|2013-08-01|

---

CN103068398B|2015-08-19|

---

MX353834B|2018-01-31|

---

CA2807283C|2019-05-14|

---

AU2011288044B8|2014-08-07|

---

EA201300159A1|2013-11-29|

---

EA025307B1|2016-12-30|

---

JP2016183201A|2016-10-20|

---

US9072745B2|2015-07-07|

---

KR20130073938A|2013-07-03|

---

BR112013002814A2|2018-02-06|

---

NZ606595A|2014-08-29|

---

MY160768A|2017-03-15|

---

ES2624285T3|2017-07-13|

---

JP2013533292A|2013-08-22|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

GB1456323A|1974-06-06|1976-11-24|Labaz|Benzothiophenes process for preparing them and pharmaceutical compositions containing the same|

---

KR100374416B1|2000-11-14|2003-03-04|노용일|Galenic Composition For The Prevention and Treatment Of Hyperlipidemia And Anigma|

---

US8486464B2|2000-12-22|2013-07-16|Tasly Pharmaceutical Group Co. Ltd.|Herbal composition for angina pectoris, method to prepare same and uses thereof|

---

CN100475233C|2000-12-22|2009-04-08|天津天士力制药股份有限公司|Combination of Chinese traditional medicine for treating angina pectoris as well as preparation method and usage|

---

CN1161140C|2001-11-09|2004-08-11|天津天士力制药股份有限公司|Medicine for preventing and treating coronary heart disease and angina pectoris and its prepn and other use|

---

CN1202103C|2002-05-23|2005-05-18|天津天士力制药股份有限公司|Preparation method of red sageroot total phenolic acid and its use|

---

CN100339085C|2003-09-23|2007-09-26|天津天士力制药股份有限公司|Combination of Chinese traditional medicine for curing cardiovascular and cerebrovascular diseases|

---

CN100450501C|2004-03-17|2009-01-14|天津天士力制药股份有限公司|Chinese medicine preparation for treating cardiovascular and cerebrovascular diseases and preparing process thereof|

---

CN100404041C|2004-06-30|2008-07-23|天津天士力制药股份有限公司|Medicinal composition for treating coronary heart disease|

---

CN1785249B|2004-12-06|2011-03-23|天津天士力制药股份有限公司|Novel use of medicine composition containing red-rooted salvia|

---

CN1919248B|2005-08-24|2011-04-27|天津天士力制药股份有限公司|Traditional Chinese medicinal formulation for treating cardiovascular and cerebrovascular disease|

---

US9072745B2|2010-08-06|2015-07-07|Tasly Pharmaceutical Group Co., Ltd|Use of Salvia miltiorrhiza composition in preparing drugs for secondary prevention of coronary heart disease|US20110025830A1|2009-07-31|2011-02-03|3Dmedia Corporation|Methods, systems, and computer-readable storage media for generating stereoscopic content via depth map creation|

---

WO2011014419A1|2009-07-31|2011-02-03|3Dmedia Corporation|Methods, systems, and computer-readable storage media for creating three-dimensionalimages of a scene|

---

US9072745B2|2010-08-06|2015-07-07|Tasly Pharmaceutical Group Co., Ltd|Use of Salvia miltiorrhiza composition in preparing drugs for secondary prevention of coronary heart disease|

---

US8274552B2|2010-12-27|2012-09-25|3Dmedia Corporation|Primary and auxiliary image capture devices for image processing and related methods|

---

EA034240B1|2013-07-11|2020-01-21|Тасли Фармасьютикал Груп Ко., Лтд.|Formulation of traditional chinese medicine in form of a micro drop pill and preparation method thereof|

---

US9999630B2|2013-07-11|2018-06-19|Tasly Pharmaceutical Group Co., Ltd.|Traditional chinese medicine composition, and preparation and application thereof|

---

CN104418744B|2013-08-29|2017-03-01|天士力制药集团股份有限公司|A kind of new salvianolic acid compound T, Preparation Method And The Use|

---

CN104435525A|2014-09-01|2015-03-25|周风华|Traditional Chinese medicine composition for preventing and treating bacterial endocarditis and preparation method of traditional Chinese medicine composition|

---

CN104800520A|2015-04-16|2015-07-29|刘瑜|Red traditional Chinese medicine package for treating heart and small intestine diseases|

---

CN104840900A|2015-06-08|2015-08-19|刘云平|Traditional Chinese medicine for treating palpitation|

---

JP6520510B2|2015-07-15|2019-05-29|富士ゼロックス株式会社|INFORMATION PROCESSING APPARATUS AND INFORMATION PROCESSING PROGRAM|

---

CN104998216A|2015-08-19|2015-10-28|鄢明亮|Traditional Chinese medicine tea bag for preventing and treating palpitation and preparation method|

---

CN107137665B|2017-06-02|2020-11-24|烟台大学|Traditional Chinese medicine composition for preventing and treating myocardial fibrosis and application thereof|

---

CN107714857A|2017-12-01|2018-02-23|王章琳|A kind of Chinese medicine composition for treating cardiovascular and cerebrovascular diseases and preparation method thereof|

---

KR102127706B1|2018-08-29|2020-06-29|윤화순|Preparation for improving blood circulation comprising mixed oriental medicinal extracts|

---

KR102127726B1|2018-08-29|2020-06-29|윤화순|Preparation for improving blood circulation comprising mixed oriental medicinal extracts|

---

CN111297942A|2019-12-23|2020-06-19|卓和药业集团有限公司|Compound preparation for treating myocardial ischemia and preparation method thereof|

法律状态:
2018-03-13| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2019-07-16| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

---

2019-09-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-04-14| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2020-10-27| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 08/08/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

CN201010253344.5|2010-08-06|

---

CN201010253344|2010-08-06|

---

PCT/CN2011/078128|WO2012016549A1|2010-08-06|2011-08-08|Use of salvia miltiorrhiza composition in preparing drugs for secondary prevention of coronary heart disease|

---