WO2018192001A1 - Compound sustained-release tablet for resisting heart failure diseases and production method - Google Patents
Compound sustained-release tablet for resisting heart failure diseases and production method Download PDFInfo
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- WO2018192001A1 WO2018192001A1 PCT/CN2017/082157 CN2017082157W WO2018192001A1 WO 2018192001 A1 WO2018192001 A1 WO 2018192001A1 CN 2017082157 W CN2017082157 W CN 2017082157W WO 2018192001 A1 WO2018192001 A1 WO 2018192001A1
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- Prior art keywords
- salt
- perindopril
- release tablet
- sustained
- compound
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
Definitions
- the invention relates to a novel anti-heart failure medical compound sustained-release tablet and preparation process.
- Mainly consists of three biologically active ingredients 20mg ⁇ 40mg ligustrazine salt, angiotensin reductase II inhibitor (ACEI) 2 ⁇ 10mg perlapril t-butylamine salt and 0.4mg ⁇ 1.8mg sulfonamide diuretic Amine, and pharmaceutical auxiliary ingredients 30mg ⁇ 50mg pharmaceutical grade hydroxypropyl methylcellulose K100M, polyvinylpyrrolidone, 10mg ⁇ 30mg, starch 60mg ⁇ 100mg, magnesium stearate 0.2mg ⁇ 0.8mg, talcum powder 0.2mg ⁇ 0.8 The composition of mg.
- the invention provides a novel anti-heart failure compound sustained-release tablet, which simultaneously improves cardiovascular and cerebrovascular diseases, regulates and stabilizes blood pressure, inhibits ventricular remodeling, improves cardiac function, and provides safe and effective drug assistance
- Heart failure is a cardiovascular disease that seriously threatens human health and life. It is due to the low blood pumping or filling function of the ventricle, the cardiac output can not meet the needs of the body's metabolism, resulting in insufficient blood perfusion of tissues and organs, as well as pulmonary circulation or systemic congestion, and the formation of various heart diseases to a serious stage.
- the clinical syndrome also known as congestive heart failure (CHF). Its pathological features are left ventricular hypertrophy or dilatation, leading to neuroendocrine disorders, abnormal circulatory function, typical dyspnea, fluid retention, edema, fatigue (especially during exercise) and other clinical symptoms, and in the course of disease development, clinical symptoms It can vary significantly or it may not match the heart function.
- Coronary heart disease is the most common cause of systolic heart failure. Active revascularization can prevent heart failure from developing and worsening. Hypertension is a common cause of diastolic (or normal ejection fraction) heart failure. Active control of blood pressure is extremely important. Decay progresses faster and induces acute heart failure. Therefore, how to treat these two heart failures is an important challenge for medical workers.
- cardiotonic drugs and diuretics are cardiotonic drugs and diuretics.
- the main reason is that the heart systolic function is weakened, the amount of bogey is reduced, and the body's needs cannot be met.
- the function of kidney urination is also affected.
- diuretic treatment but does not think that blood pressure is the cause of abnormal kidney function.
- Clinical practice has shown that the use of cardiotonic drugs and diuretics to treat heart failure is not satisfactory, mainly because the symptoms of dyspnea and limb weakness have not improved much.
- the medical community recognizes that neurohormonal dysfunction in patients with heart failure is one of the important causes of heart failure.
- an angiotensin converting enzyme inhibitor which regulates neurohormones
- ventricular remodeling that is, myocardial weight, increase in ventricular volume and changes in ventricular shape are important causes of heart failure, inhibiting ventricular weight. It is of great value to the development and improvement of heart function. This suggests that drugs with inhibition of ventricular remodeling have a greater benefit for patients with heart failure and those at high risk for heart failure.
- Perindopril is a potent and long-acting angiotensin-converting enzyme inhibitor that inhibits the breakdown of the strong peptide vasodilator, bradykinin, into inactive peptides, thereby reducing peripheral vascular resistance. Heart output and heart rate are unchanged. For the treatment of various hypertension and congestive heart failure. For patients with low renin levels or normal renin levels, perindopril can be used to treat various degrees of hypertension: mild, moderate, or severe. Reduce systolic and diastolic blood pressure in the supine and standing positions. After taking a single dose, the maximum antihypertensive effect occurred in 4-6 hours and lasted for more than 24 hours.
- Residual enzyme inhibition after 24 hours remained high (close to 80%).
- blood pressure can be normalized after 1 month of treatment and no drug resistance is produced. After stopping treatment, it does not cause blood pressure to rebound.
- perindopril has a vasodilating effect, by changing the metabolism of prostaglandins, dilating veins, reducing preload, restoring aortic elasticity and reducing left ventricular hypertrophy, reducing left ventricular and right ventricular filling pressure, increasing cardiac output and improving heart
- the index has a certain inhibition of myocardial remodeling and improves exercise endurance by reducing total peripheral vascular resistance.
- Perindopril works with its active ingredient, Perindopril, because food changes the bioavailability of its active metabolite perindopril, so perindopril tablets must be taken before meals. Perindopril is taken once a day.
- Indapamide is a sulfa diuretic that is mainly used for essential hypertension. Its antihypertensive effect is related to its improved arterial compliance and reduced arteriolar and peripheral circulation resistance. Indapamide can reverse left ventricular hypertrophy caused by hypertension.
- the mechanisms by which indapamide regulates vascular activity include: (1) impairing the contraction of vascular smooth muscle by regulating the transmembrane ion transport mechanism, particularly the transmembrane transport of calcium ions in vascular smooth muscle cells; It stimulates the synthesis of prostaglandin PGE2 and prostacyclin PGI2, both of which are vasodilators and anti-platelet factors, which inhibit vasoconstriction.
- indapamide does not affect the metabolism of blood lipids and carbohydrates, including the metabolism of triglycerides, LDL cholesterol, and HDL cholesterol. When it is depressurized, it has little or no effect on cardiac output, heart rate and heart rate. Long-term use has little effect on glomerular filtration rate or renal blood flow.
- the combination of indapamide and perindopril salt can not only significantly reduce systolic and diastolic blood pressure, but also significantly improve microcirculation, reduce proteinuria, reduce left ventricular hypertrophy, thereby reducing stroke, myocardial infarction, Mortality from diseases such as heart failure and cardiovascular death.
- the compound preparations are artificially produced antihypertensive drugs, and also have obvious defects and side effects. Therefore, how to further improve the therapeutic advantages of the compound preparation, use it to improve the important role of anti-heart failure, reduce its side effects has become the focus of our research.
- ligustrazine has the functions of expanding blood vessels, inhibiting platelet aggregation, preventing thrombosis and improving cerebral ischemia, and can effectively alleviate coronary heart disease, angina pectoris and anti-atherosclerosis, and enhance immune system function.
- ligustrazine can indirectly excite B receptor through sympathetic nerves, and has a strong heart effect, which can accelerate the heartbeat of anesthetized dogs, increase myocardial contractility, vasodilate, increase coronary blood flow, and reduce myocardial pressure.
- Oxygen consumption can protect the ischemic myocardium from reperfusion injury, improve myocardial metabolism, inhibit myocardial remodeling ventricular changes, and improve cardiac function in patients with heart failure.
- ligustrazine can also inhibit pulmonary artery contraction caused by hypoxia, and has an inhibitory effect on adrenaline-induced vasoconstriction.
- ligustrazine not only has a cardiotonic effect, but also has dilated blood vessels and reduces Myocardial oxygen consumption, improve myocardial metabolism, avoid ischemia myocardial reperfusion injury, inhibit myocardial remodeling, the combination of the two can not only play their role in improving cardiovascular disease, but also play a synergistic anti-heart failure effect.
- a technical solution for the compound sustained-release tablet is made. The main means to give full play to the purpose of drug use.
- the technical scheme of making the compound component into a sustained-release tablet is adopted.
- anti-heart failure antihypertensive agent ligustrazine salt such as hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, citrate, succinate, alaninate, Arginate salt, lysine salt, methionine salt, leucine salt, proline salt, cysteine salt
- ligustrazine salt such as hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, citrate, succinate, alaninate, Arginate salt, lysine salt, methionine salt, leucine salt, proline salt, cysteine salt
- angiotensin reductase II inhibitor perindopril salt (such as tert-butylamine salt, alanine salt, arginine salt, lysine salt, methionine salt, leucine salt, a proline salt, a cysteine salt) and a pharmaceutically acceptable salt or carrier;
- ACEI angiotensin reductase II inhibitor
- the invention relates to a compound antihypertensive anti-heart failure drug sustained-release tablet, characterized in that the main component of the pharmaceutical auxiliary used is 30 mg to 50 mg of pharmaceutical grade hydroxypropyl methylcellulose K100M, polyvinylpyrrolidone, 10mg ⁇ 30mg, starch 60mg ⁇ 100mg, magnesium stearate 0.2mg ⁇ 0.8mg, talc 0.2mg ⁇ 0.8mg.
- the invention relates to a compound antihypertensive anti-heart failure pharmaceutical preparation, characterized in that the 2-10 mg antihypertensive drug contained is an angiotensin-converting enzyme inhibitor selected from a perindopril salt compound, such as a culture medium.
- a perindopril salt compound such as a culture medium.
- the compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the other two biological active ingredients are 20 mg to 40 mg of ligustrazine salt and 0.4 mg to 1.8 mg of the sulfonamide diuretic indapamide. ;
- the compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the weight ratio of the three bioactive components perindopril salt compound, indapamide and ligustrazine salt is 1-5 : 0.2 to 0.9: 10 to 20 mg;
- the compound antihypertensive anti-heart failure pharmaceutical preparation of the present invention is characterized in that the described dosage form is a sustained-release tablet;
- the compound antihypertensive anti-heart failure pharmaceutical preparation of the present invention is characterized in that it is used for preparing sustained release
- the distribution ratio of each component of the tablet biochip core is:
- the compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the preparation process of the compound sustained-release preparation described above adopts a two-step preparation method of preparing a sustained release tablet core and then performing coating.
- the specific step features are
- Coating preparation process firstly configure the coating liquid, the coating liquid component: liquid A: 1%-5% ethyl cellulose ethanol solution, liquid B: 1%-4% chitosan (containing acetic acid 2 %-6%) Aqueous acetic acid solution, the mixing ratio of the two is: 8:1-2:1 Adding 2%-5% plasticizer dibutyl phthalate by weight of the mixed liquid.
- the core of the sustained release tablet is coated: 100g-600g of the core is placed in a 25cm diameter coating pan, the chip is preheated, the inclination is 40 ° C, the rotation speed of the coating pan is maintained at 40 rpm, and the coating liquid is sprayed.
- the inner diameter of the nozzle is 1 mm
- the atomization pressure of the spray gun is 0.20 MPa
- the temperature is 38 °C ⁇ 2.
- the preparation of the invention is suitable for various hypertension, especially for elderly hypertension, systolic hypertension and edema, obesity, diabetes, coronary heart disease, myocardial ischemia, ventricular hypertrophy, diastolic or systolic cardiac insufficiency ( Heart failure), atherosclerosis, myocardial infarction, etc., are also suitable for the treatment of various types of organic heart disease such as acute or chronic heart failure and congestive heart failure.
- the invention adopts Prospective, control group, single-blind and multi-center animal trials, using a fixed-dose combination of the sustained-release tablets of the present invention, were subjected to a six-month observational treatment in a mouse animal, by observing a rat model of heart failure.
- Compound sustained release tablet tablet core group is
- the core of 158.3 mg of the composite sustained release tablet was prepared according to the above formula.
- Compound sustained release tablet tablet core group is
- the core of 167.4 mg of the composite sustained release tablet was prepared according to the above formula.
- the ligustrazine hydrochloride and perindopril lysine salt in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion.
- Mix in the machine pass through 80 mesh sieve, mix well, add 15mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix.
- the diameter of the 8mm punch is controlled by a hardness of 3.0 to 6.0 kg, and finally the core of the sustained release tablet having a tablet weight of about 167.4 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
- Coating preparation process a plurality of cores having a total weight of 100 g as described above were placed in a diameter of 25 cm.
- the coating pan preheat the chip, adjust the coating pan angle to 40 ° C, start and maintain the coating pan speed 40 rpm, use the spray nozzle liquid inner diameter of 1 mm nozzle, adjust the spray gun atomization pressure to 0.20MPa, At a temperature of 38 ° C ⁇ 2, the core of the coating pan was sprayed and atomized, and the core was coated. After the coating is finished, the weight is cooled and the weight gain is 3%.
- Compound sustained release tablet tablet core group is
- the core of 168.8 mg of the composite sustained release tablet was prepared according to the above formula.
- the ligustrazine tartrate and perindopril arginine salt in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion.
- Mix in the machine pass through 80 mesh sieve, mix well, add 25mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix.
- the diameter of the 8mm punch is controlled by a hardness of 3.0 to 6.0 kg, and finally the core of the sustained release tablet having a tablet weight of about 168.8 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
- Coating preparation process a plurality of cores having a total weight of 100 g as described above were placed in a diameter of 25 cm.
- the coating pan preheat the chip, adjust the coating pan angle to 40 ° C, start and maintain the coating pan speed 40 rpm, use the spray nozzle liquid inner diameter of 1 mm nozzle, adjust the spray gun atomization pressure to 0.20MPa, At a temperature of 38 ° C ⁇ 2, the core of the coating pan was sprayed and atomized, and the core was coated. After the coating is finished, the weight is cooled and the weight gain is 3%.
- the in vitro release rate was determined according to the method prescribed by the Pharmacopoeia.
- Compound sustained release tablet tablet core group is
- the core of 162.5 mg of the composite sustained release tablet was prepared according to the above formula.
- the ligustrazine methanesulfonate and perindopril valine salt in the compound sustained-release tablet are placed in proportion to indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc.
- Mix in a mixer pass through a 80 mesh sieve, mix well, add 30 mg of the adhesive polyvinylpyrrolidone, make a soft material, then granulate through 16 mesh, dry at 50 degrees, shape, add 0.5 mg of magnesium stearate and mix.
- the tablet was pressed with a punch of 8 mm in diameter, the hardness was controlled at 3.0 to 6.0 kg, and finally, the core of the sustained-release tablet having a tablet weight of about 162.5 mg was obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
- Compound sustained release tablet tablet core group is
- the core of 167.2 mg of the composite sustained release tablet was prepared according to the above formula.
- the ligustrazine citrate and perindopril alanine salt in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion.
- Mix in the machine pass through 80 mesh sieve, mix well, add 20mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix.
- the 8mm diameter punching tablet is controlled to have a hardness of 3.0 to 6.0 kg, and finally a core of a sustained-release tablet having a tablet weight of about 167.2 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
- Compound sustained release tablet tablet core group is
- the core of 167.1 mg of the composite sustained release tablet was prepared according to the above formula.
- the ligustrazine succinate and perindopril leucine in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion.
- Mix in the machine pass through 80 mesh sieve, mix well, add 20mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix.
- the diameter of the 8mm punch is controlled by a hardness of 3.0 to 6.0 kg, and finally the core of the sustained-release tablet having a tablet weight of about 167.1 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
- Rats with early heart failure symptoms were cultured by intraperitoneal injection of doxorubicin 2.5 mg/kg twice a week for 8 weeks.
- BNP brain natriuretic peptide
- mice All heart failure model mice were divided into observation group and control group for experiment.
- the observation group was treated with compound anti-heart failure sustained-release tablets (Example 1), once a day, each time with a dose equivalent to 5 times the clinical dose of the human, once a day for 12 weeks; the control group was used, etc.
- the amount of saline was administered by gavage for parallel experiments. All rats were fed a standard diet and were given free access to water. During the experiment, the rat venous blood was taken 3 mL. After routine use for 3 months, the venous blood of the observation group was again taken to detect the molecular level of plasma BNP.
- the brain natriuretic peptide (BNP) measuring instrument was produced by Swiss Roche. Model -170, the kit is also supplied by Roche, using microparticle enzyme immunoassay.
- n number of heart failure model mice
- Average BNP pg/mL
- Control group 50 149.56 ⁇ 16.25
- Observation group 50 368.74+ ⁇ 21.32
- Heart failure scores mainly indicate the symptoms of heart failure, including myocardial ischemia, left ventricular ejection fraction, mobility, asthma, dyspnea, edema, left atrial hypertrophy, blood pressure, cardiac output, heart rate, diarrhea
- Ten heart failure symptoms such as insomnia were scored. The most serious symptom of heart failure is 100 points.
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Abstract
Disclosed are a compound sustained-release tablet for resisting heart failure diseases and a production method therefor. The tablet mainly consists of 20 mg to 40 mg of a tetramethylprazine salt, 2 mg to 10 mg of an angiotensin reductase II inhibitor (ACEI) perindopril salt, 0.4 mg to 1.8 mg of sulfamide diuretic indapamide, 30 mg to 50 mg of pharmaceutical-grade hydroxypropyl methylcellulose K100M, 10 mg to 30 mg of polyvinylpyrrolidone, 60 mg to 100 mg of starch, 0.2 mg to 0.8 mg of magnesium stearate, and 0.2 mg to 0.8 mg of talcum powder.
Description
本发明涉及到一种新的抗心力衰竭医学复方缓释片剂与制剂工艺。主要是由三种生物活性成分20mg～40mg川穹嗪盐、血管紧张素还原酶II抑制剂(ACEI)2～10mg培拉普利叔丁胺盐与0.4mg～1.8mg磺酰胺类利尿剂吲达帕胺，及药物辅料成分30mg～50mg药用级羟丙基甲基纤维素K100M，聚乙烯吡咯烷酮,10mg～30mg,淀粉60mg～100mg,硬脂酸镁0.2mg～0.8mg，滑石粉0.2mg～0.8mg所组成。本发明提供了一种新的抗心力衰竭的复方缓释片剂，同时对患者改善心脑血管病变，调节并稳定血压，抑制心室重构，改善心脏功能，提供了安全有效的药物帮助。The invention relates to a novel anti-heart failure medical compound sustained-release tablet and preparation process. Mainly consists of three biologically active ingredients 20mg ~ 40mg ligustrazine salt, angiotensin reductase II inhibitor (ACEI) 2 ~ 10mg perlapril t-butylamine salt and 0.4mg ~ 1.8mg sulfonamide diuretic Amine, and pharmaceutical auxiliary ingredients 30mg ~ 50mg pharmaceutical grade hydroxypropyl methylcellulose K100M, polyvinylpyrrolidone, 10mg ~ 30mg, starch 60mg ~ 100mg, magnesium stearate 0.2mg ~ 0.8mg, talcum powder 0.2mg ~ 0.8 The composition of mg. The invention provides a novel anti-heart failure compound sustained-release tablet, which simultaneously improves cardiovascular and cerebrovascular diseases, regulates and stabilizes blood pressure, inhibits ventricular remodeling, improves cardiac function, and provides safe and effective drug assistance.
心力衰竭是一种严重威胁人类健康与生命的心血管疾病。它是由于心室泵血或充盈功能低下，心排血量不能满足机体代谢的需要，导致组织、器官血液灌注不足，同时也出现肺循环和或体循环淤血，而形成的各种心脏病发展到严重阶段的临床综合症，也称为充血性心力衰竭(CHF)。其病理特征是左室肥厚或扩张，导致神经内分泌失常、循环功能异常，出现典型的呼吸困难、体液潴留，水肿、乏力(特别是运动时)等临床症状，而且在疾病发展过程中，临床症状可以有显著变化，也可能与心功能状况不相符。如果不治疗或治疗不及时，心功能不全的症状会不断加重，危急病人生命。冠心病均是收缩性心衰最常见病因，积极血运重建可以防止心衰发展和恶化；而高血压是舒张性(或射血分数正常)心衰常见病因，积极控制血压极其重要，否则心衰进展较快，诱发急性心衰。因此如何治疗这两种心衰是医药工作者的重要挑战。Heart failure is a cardiovascular disease that seriously threatens human health and life. It is due to the low blood pumping or filling function of the ventricle, the cardiac output can not meet the needs of the body's metabolism, resulting in insufficient blood perfusion of tissues and organs, as well as pulmonary circulation or systemic congestion, and the formation of various heart diseases to a serious stage. The clinical syndrome, also known as congestive heart failure (CHF). Its pathological features are left ventricular hypertrophy or dilatation, leading to neuroendocrine disorders, abnormal circulatory function, typical dyspnea, fluid retention, edema, fatigue (especially during exercise) and other clinical symptoms, and in the course of disease development, clinical symptoms It can vary significantly or it may not match the heart function. If left untreated or not treated, the symptoms of cardiac insufficiency will continue to worsen and the patient's life will be critical. Coronary heart disease is the most common cause of systolic heart failure. Active revascularization can prevent heart failure from developing and worsening. Hypertension is a common cause of diastolic (or normal ejection fraction) heart failure. Active control of blood pressure is extremely important. Decay progresses faster and induces acute heart failure. Therefore, how to treat these two heart failures is an important challenge for medical workers.
目前，治疗心衰药物大部分是强心药+利尿剂，主要认为是心脏收缩功能减弱，博出量降低，不能满足机体需求；同时肾脏排尿功能也受到了影响，这就需要同时进行强心和利尿治疗，但并不认为血压是引起肾脏功能异常的原因。临床实践证明单纯运用强心药和利尿剂治疗心衰的效果并不令人满意，主要是呼吸困难和四肢乏力等症状没有得到太多改善。随着科学技术的发展，医学界认识到心衰患者体内神经激素功能紊乱是导致心衰的重要原因之一。传统治疗药物只改善
了乏力、水肿等症状，却无法扭转神经激素紊乱，仍无益于降低心衰患者的死亡风险。由此，可调节神经激素的血管紧张素转换酶抑制剂(ACEI)开始广泛用于临床。近年来，随着分子生物学等技术进展，已经证明心衰发生发展的基本机制是心室重构，即心肌重量、心室容量的增加和心室形状的改变是造成心衰的重要病因，抑制心室重构对发展和改善心脏功能都具有重要的价值。这说明具抑制心室重构作用的药物对心衰患者及心衰高风险人群有较大益处。At present, most of the drugs for treating heart failure are cardiotonic drugs and diuretics. The main reason is that the heart systolic function is weakened, the amount of bogey is reduced, and the body's needs cannot be met. At the same time, the function of kidney urination is also affected. And diuretic treatment, but does not think that blood pressure is the cause of abnormal kidney function. Clinical practice has shown that the use of cardiotonic drugs and diuretics to treat heart failure is not satisfactory, mainly because the symptoms of dyspnea and limb weakness have not improved much. With the development of science and technology, the medical community recognizes that neurohormonal dysfunction in patients with heart failure is one of the important causes of heart failure. Traditional treatments only improve
The symptoms of fatigue, edema, etc., but can not reverse the neurohormonal disorder, still not help to reduce the risk of death in patients with heart failure. Thus, an angiotensin converting enzyme inhibitor (ACEI), which regulates neurohormones, has begun to be widely used clinically. In recent years, with the advancement of molecular biology and other technologies, it has been proved that the basic mechanism of heart failure development is ventricular remodeling, that is, myocardial weight, increase in ventricular volume and changes in ventricular shape are important causes of heart failure, inhibiting ventricular weight. It is of great value to the development and improvement of heart function. This suggests that drugs with inhibition of ventricular remodeling have a greater benefit for patients with heart failure and those at high risk for heart failure.
培哚普利是一种强效和长效的血管紧张素转换酶抑制剂，可以抑制强烈肽类血管扩张物质—缓激肽降解为无活性的肽类，由此使外周血管阻力降低，而心输出量和心率不变。用于治疗各种高血压与充血性心力衰竭。对于低肾素水平或正常肾素水平的患者，培哚普利均能用于治疗各种程度的高血压：轻度，中度，或重度。降低卧位和立位的收缩压和舒张压。服用单一剂量后，4－6小时出现最大降压作用，而且持续24小时以上。24小时后残留的转换酶抑制作用仍然很高(接近80％)。对于有效的患者，治疗1个月后血压可恢复正常化，而且不产生耐药性。停止治疗后，不引起血压反跳。而且培哚普利有血管扩张作用，通过改变前列腺素的代谢，扩张静脉，降低前负荷，恢复大动脉弹性并降低左室肥厚，降低左室和右室的充盈压，增加心输出量和提高心脏指数，具有一定抑制心肌重构作用，并通过降低总外围血管阻力，提高运动耐力。实践也证明它能与其他降压药或血管扩张药或利尿药合用可产生协同作用，用于治疗心力衰竭。对慢性心衰的研究显示，和其他同类药物比较，培哚普利降低血压更为缓和，极少发生突然性血压下降。Perindopril is a potent and long-acting angiotensin-converting enzyme inhibitor that inhibits the breakdown of the strong peptide vasodilator, bradykinin, into inactive peptides, thereby reducing peripheral vascular resistance. Heart output and heart rate are unchanged. For the treatment of various hypertension and congestive heart failure. For patients with low renin levels or normal renin levels, perindopril can be used to treat various degrees of hypertension: mild, moderate, or severe. Reduce systolic and diastolic blood pressure in the supine and standing positions. After taking a single dose, the maximum antihypertensive effect occurred in 4-6 hours and lasted for more than 24 hours. Residual enzyme inhibition after 24 hours remained high (close to 80%). For an effective patient, blood pressure can be normalized after 1 month of treatment and no drug resistance is produced. After stopping treatment, it does not cause blood pressure to rebound. Moreover, perindopril has a vasodilating effect, by changing the metabolism of prostaglandins, dilating veins, reducing preload, restoring aortic elasticity and reducing left ventricular hypertrophy, reducing left ventricular and right ventricular filling pressure, increasing cardiac output and improving heart The index has a certain inhibition of myocardial remodeling and improves exercise endurance by reducing total peripheral vascular resistance. Practice has also shown that it can work synergistically with other antihypertensive drugs or vasodilators or diuretics for the treatment of heart failure. Studies of chronic heart failure have shown that perindopril lowers blood pressure more slowly than other similar drugs, with a sudden onset of sudden drop in blood pressure.
培哚普利以其代谢后产生的活性成分培哚普利拉而发生作用，因为食物改变其活性代谢产物培哚普利的生物利用度，所以培哚普利片必须饭前服用。培哚普利每天服用一次。Perindopril works with its active ingredient, Perindopril, because food changes the bioavailability of its active metabolite perindopril, so perindopril tablets must be taken before meals. Perindopril is taken once a day.
吲达帕胺是一种磺胺类利尿剂，主要适用于原发性高血压。它的抗高血压作用与其改善动脉的顺应性，降低小动脉和整个外周循环阻力有关。吲达帕胺可以逆转高血压引起的左心室肥厚。吲达帕胺调节血管活动的机制包括：(1)通过调节跨膜离子转运机制，尤其是调节血管平滑肌细胞的钙离子的跨膜转运——钙内流；来削弱血管平滑肌的收缩；(2)刺激前列腺素PGE2和前列环素PGI2的合成，这两种物质为血管扩张因子和抗血小板因子，可抑制血管收缩。(3)与其它利尿
药一样，它能逆转左心室肥厚。在短期、中期、长期的抗高血压治疗中，吲达帕胺不影响不影响血脂及碳水化合物的代谢，包括甘油三酯、LDL胆固醇、HDL胆固酯的代谢。它降压时对心排血量、心率及心律影响很小甚至没有影响。长期使用对肾小球滤过率或肾血流量影响也很少。尤其是吲达帕胺与培哚普利盐形成复方制剂，不仅可明显降低收缩压和舒张压，而且可以明显改善微循环，减少蛋白尿，减轻左心室肥厚，从而降低脑卒中，心肌梗塞、心力衰竭和心血管死亡等疾病的死亡率。但该复方制剂都是人工制造的降压药物，也有着明显的缺陷与副作用。因此如何进一步提高该复方制剂治疗优势，利用其改善抗心力衰竭的重要作用，降低其副作用成为我们研究的重点。Indapamide is a sulfa diuretic that is mainly used for essential hypertension. Its antihypertensive effect is related to its improved arterial compliance and reduced arteriolar and peripheral circulation resistance. Indapamide can reverse left ventricular hypertrophy caused by hypertension. The mechanisms by which indapamide regulates vascular activity include: (1) impairing the contraction of vascular smooth muscle by regulating the transmembrane ion transport mechanism, particularly the transmembrane transport of calcium ions in vascular smooth muscle cells; It stimulates the synthesis of prostaglandin PGE2 and prostacyclin PGI2, both of which are vasodilators and anti-platelet factors, which inhibit vasoconstriction. (3) with other diuretic
Like medicine, it reverses left ventricular hypertrophy. In the short-term, medium-term, and long-term antihypertensive treatment, indapamide does not affect the metabolism of blood lipids and carbohydrates, including the metabolism of triglycerides, LDL cholesterol, and HDL cholesterol. When it is depressurized, it has little or no effect on cardiac output, heart rate and heart rate. Long-term use has little effect on glomerular filtration rate or renal blood flow. In particular, the combination of indapamide and perindopril salt can not only significantly reduce systolic and diastolic blood pressure, but also significantly improve microcirculation, reduce proteinuria, reduce left ventricular hypertrophy, thereby reducing stroke, myocardial infarction, Mortality from diseases such as heart failure and cardiovascular death. However, the compound preparations are artificially produced antihypertensive drugs, and also have obvious defects and side effects. Therefore, how to further improve the therapeutic advantages of the compound preparation, use it to improve the important role of anti-heart failure, reduce its side effects has become the focus of our research.
中药川穹是活血化瘀，行经止痛良药，被称为血中之气药，其主要成分为川穹嗪。现代药理研究表明，川穹嗪具有扩展血管，抑制血小板聚集，防治血栓形成，改善脑缺血等多种活性，可以有效缓解冠心病，心绞痛和抗动脉粥样硬化，增强免疫系统功能。更为重要的是川穹嗪可以通过交感神经，间接兴奋B受体，有强心作用，可以促使麻醉犬心跳加快，心肌收缩力加大，血管扩张，冠脉血流明显增大，降低心肌氧耗，可以使缺血心肌兔免受再灌注损伤，改善心肌代谢作用，对心肌重构心室变化有抑制作用，有利于心衰患者心脏功能改善。同时，川穹嗪也能抑制缺氧引起的肺动脉收缩，对肾上腺素引起的血管收缩有抑制作用，其对主动脉平滑肌具有松弛作用，类似于异搏停的特征，也可能是一种新的钙离子拮抗剂。但半衰期短，普通片剂需要一天多次给药(3次/天)影响患者有效使用。目前一般制成缓释片剂使用。Chuanxiong, a traditional Chinese medicine, is a medicine for promoting blood circulation and removing blood stasis. It is called a gas medicine in the blood. Its main component is ligustrazine. Modern pharmacological studies have shown that ligustrazine has the functions of expanding blood vessels, inhibiting platelet aggregation, preventing thrombosis and improving cerebral ischemia, and can effectively alleviate coronary heart disease, angina pectoris and anti-atherosclerosis, and enhance immune system function. More importantly, ligustrazine can indirectly excite B receptor through sympathetic nerves, and has a strong heart effect, which can accelerate the heartbeat of anesthetized dogs, increase myocardial contractility, vasodilate, increase coronary blood flow, and reduce myocardial pressure. Oxygen consumption can protect the ischemic myocardium from reperfusion injury, improve myocardial metabolism, inhibit myocardial remodeling ventricular changes, and improve cardiac function in patients with heart failure. At the same time, ligustrazine can also inhibit pulmonary artery contraction caused by hypoxia, and has an inhibitory effect on adrenaline-induced vasoconstriction. It has a relaxing effect on aortic smooth muscle, similar to the characteristics of heteropulsation, or it may be a new one. Calcium ion antagonist. However, the half-life is short, and the ordinary tablet needs to be administered multiple times a day (3 times/day) to affect the effective use of the patient. Currently, it is generally used as a sustained release tablet.
我们在研究药物抗心衰过程中，充分认识到西药具有疗效快，作用强，但同时副作用也很多的特点，而中药则具有疗效相对慢，但副作用低特征，如果将两者结合则互相发挥特长并能弥补其各自缺陷，这是本发明将培哚普利与吲达帕胺复合制剂与中药川穹嗪联合使用的形成新的缓释复方制剂的主要目的，一方面，培哚普利与吲达帕胺可以抑制心衰患者神经激素紊乱，而本身具有降压与扩张血管，降低左心室肥厚，抑制心肌重构作用，而川穹嗪不仅具有强心作用，也具有扩张血管，降低心肌氧耗，改善心肌代谢，避免缺血心肌再灌注损伤，对心肌重塑有抑制作用，两者组合既可以发挥各自改善心血管疾病作用，另外可发挥两者协同抗心衰作用。为了提高两者生物利用度，制成复方缓释片剂技术方案，是达
到充分发挥药物效用目的的主要手段。In the study of anti-heart failure, we fully recognize that western medicine has the effect of fast effect and strong effect, but at the same time, it has many side effects. However, traditional Chinese medicine has the characteristics of relatively slow effect, but low side effects. If the two are combined, they will play each other. The specialty is able to make up for its respective defects. This is the main purpose of the present invention to form a new sustained-release compound preparation by using the combination of perindopril and indapamide and the traditional Chinese medicine ligustrazine. On the one hand, perindopril Indapamide can inhibit neurohormonal disorders in patients with heart failure, but it has antihypertensive and dilated blood vessels, reduces left ventricular hypertrophy, and inhibits myocardial remodeling. However, ligustrazine not only has a cardiotonic effect, but also has dilated blood vessels and reduces Myocardial oxygen consumption, improve myocardial metabolism, avoid ischemia myocardial reperfusion injury, inhibit myocardial remodeling, the combination of the two can not only play their role in improving cardiovascular disease, but also play a synergistic anti-heart failure effect. In order to improve the bioavailability of the two, a technical solution for the compound sustained-release tablet is made.
The main means to give full play to the purpose of drug use.
发明内容：Summary of the invention:
本发明为了充分保证该复方组分具有治疗效果好、高效持久、安全与低毒，充分提高其生物利用度的特征，采取了将该复方组分制成缓释片剂的技术方案。In order to fully ensure that the compound component has the advantages of good therapeutic effect, high efficiency and long-lasting, safety and low toxicity, and fully improving the bioavailability, the technical scheme of making the compound component into a sustained-release tablet is adopted.
本发明所涉及的一种复方缓释片剂，其特征在于，每个片剂含有三种活性成分为：A compound sustained release tablet according to the present invention is characterized in that each tablet contains three active ingredients:
(1)20mg～40mg抗心衰降压剂川穹嗪盐(如盐酸盐，硫酸盐，磷酸盐，甲磺酸盐，酒石酸盐，柠檬酸盐，丁二酸盐，丙氨酸盐，精氨酸盐，赖氨酸盐，蛋氨酸盐，亮氨酸盐，缬氨酸盐，半胱氨酸盐)；(1) 20mg ~ 40mg anti-heart failure antihypertensive agent ligustrazine salt (such as hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, citrate, succinate, alaninate, Arginate salt, lysine salt, methionine salt, leucine salt, proline salt, cysteine salt);
(2)2mg～10mg血管紧张素还原酶II抑制剂(ACEI)培哚普利盐(如叔丁胺盐，丙氨酸盐，精氨酸盐，赖氨酸盐，蛋氨酸盐，亮氨酸盐，缬氨酸盐，半胱氨酸盐)以及药学上可以接受的各种盐或载体；(2) 2mg to 10mg angiotensin reductase II inhibitor (ACEI) perindopril salt (such as tert-butylamine salt, alanine salt, arginine salt, lysine salt, methionine salt, leucine salt, a proline salt, a cysteine salt) and a pharmaceutically acceptable salt or carrier;
(3)0.4mg～1.8mg磺胺类利尿剂吲达帕胺；(3) 0.4 mg to 1.8 mg of the sulfonamide diuretic indapamide;
本发明所涉及的一种复方降压抗心衰药物缓释片剂，其特征是，所使用的药物辅料主要组成为30mg～50mg药用级羟丙基甲基纤维素K100M，聚乙烯吡咯烷酮,10mg～30mg,淀粉60mg～100mg,硬脂酸镁0.2mg～0.8mg，滑石粉0.2mg～0.8mg。The invention relates to a compound antihypertensive anti-heart failure drug sustained-release tablet, characterized in that the main component of the pharmaceutical auxiliary used is 30 mg to 50 mg of pharmaceutical grade hydroxypropyl methylcellulose K100M, polyvinylpyrrolidone, 10mg ~ 30mg, starch 60mg ~ 100mg, magnesium stearate 0.2mg ~ 0.8mg, talc 0.2mg ~ 0.8mg.
本发明所涉及的一种复方降压抗心衰药物制剂，其特征是，所含的2～10mg降压药为血管紧张素转换酶抑制剂选自培哚普利盐类化合物，如培哚普利叔丁胺盐，培哚普利丙氨酸盐，培哚普利精氨酸盐，培哚普利赖氨酸盐，培哚普利蛋氨酸盐，培哚普利亮氨酸盐，培哚普利缬氨酸盐，培哚普利半胱氨酸盐；The invention relates to a compound antihypertensive anti-heart failure pharmaceutical preparation, characterized in that the 2-10 mg antihypertensive drug contained is an angiotensin-converting enzyme inhibitor selected from a perindopril salt compound, such as a culture medium. Pretungamine salt, perindopril alaninate, perindopril arginine, perindopril lysine, perindopril methionine, perindopril leucine, culture Plyproline salt, perindopril cysteine salt;
本发明所述的复方降压抗心衰药物制剂，其特征在于所述的另外两种生物活性成分组方为20mg～40mg川穹嗪盐和0.4mg～1.8mg磺胺类利尿剂吲达帕胺；The compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the other two biological active ingredients are 20 mg to 40 mg of ligustrazine salt and 0.4 mg to 1.8 mg of the sulfonamide diuretic indapamide. ;
本发明所述的复方降压抗心衰药物制剂，其特征在于所述的三种生物活性成分培哚普利盐类化合物、吲达帕胺与川穹嗪盐的重量含比为1～5:0.2～0.9:10～20mg；The compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the weight ratio of the three bioactive components perindopril salt compound, indapamide and ligustrazine salt is 1-5 : 0.2 to 0.9: 10 to 20 mg;
本发明所述的复方降压抗心衰药物制剂其特征在于所描述剂型为缓释片剂；The compound antihypertensive anti-heart failure pharmaceutical preparation of the present invention is characterized in that the described dosage form is a sustained-release tablet;
本发明所述的复方降压抗心衰药物制剂其特征在于所描述的用于制备缓释
片剂生物片芯各组分分配比为：The compound antihypertensive anti-heart failure pharmaceutical preparation of the present invention is characterized in that it is used for preparing sustained release
The distribution ratio of each component of the tablet biochip core is:
本发明所述的复方降压抗心衰药物制剂，其特征在于所描述复方缓释制剂的制备工艺采取了先制备缓释片剂片芯，然后再进行包衣的两步制备方法。具体步骤特征是The compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the preparation process of the compound sustained-release preparation described above adopts a two-step preparation method of preparing a sustained release tablet core and then performing coating. The specific step features are
(1)缓释片剂的片芯制备工艺：将复方缓释片剂中的川穹嗪盐、培哚普利叔丁胺盐和吲达帕胺，与上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混合均匀，加入粘合剂聚乙烯吡咯烷酮，制成软材，再经16目造粒，50度干燥，整形，加入干粒重的0.1％～0.4％硬脂酸镁混匀，采用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重100mg～250mg左右的缓释片剂的片芯。(1) Core preparation process of sustained-release tablets: the ligustrazine salt, perindopril tert-butylamine salt and indapamide in the compound sustained-release tablet, and the above-mentioned medicinal adjuvant hydroxypropylmethylcellulose Starch and talcum powder are mixed into the mixer in proportion, passed through a 80 mesh sieve, mixed evenly, and the binder polyvinylpyrrolidone is added to make a soft material, which is then granulated by 16 mesh, dried at 50 degrees, shaped, and added to dryness. The powder weight is 0.1% to 0.4% of magnesium stearate, and is compressed by a punch having a diameter of 8 mm. The hardness is controlled to be 3.0 to 6.0 kg, and finally the core of the sustained-release tablet having a tablet weight of about 100 mg to 250 mg is obtained.
(2)包衣制备工艺：首先配置包衣液，包衣液组分：A液：1％-5％乙基纤维素乙醇溶液，B液：1％-4％壳聚糖(含醋酸2％-6％)醋酸水溶液，两者混合体积比例为：8:1-2:1加入混合液体重量的2％-5％增塑剂邻苯二甲酸二丁酯。其次对缓释片剂片芯进行包衣：将100g-600g的片芯置于直径25cm的包衣锅内，预热芯片，倾角40℃，维持包衣锅转速40rpm,淋喷包衣液的喷嘴内径1mm，喷枪雾化压力0.20MPa，温度38℃±2。(2) Coating preparation process: firstly configure the coating liquid, the coating liquid component: liquid A: 1%-5% ethyl cellulose ethanol solution, liquid B: 1%-4% chitosan (containing acetic acid 2 %-6%) Aqueous acetic acid solution, the mixing ratio of the two is: 8:1-2:1 Adding 2%-5% plasticizer dibutyl phthalate by weight of the mixed liquid. Secondly, the core of the sustained release tablet is coated: 100g-600g of the core is placed in a 25cm diameter coating pan, the chip is preheated, the inclination is 40 ° C, the rotation speed of the coating pan is maintained at 40 rpm, and the coating liquid is sprayed. The inner diameter of the nozzle is 1 mm, the atomization pressure of the spray gun is 0.20 MPa, and the temperature is 38 °C ± 2.
本发明制剂适用于各种高血压，尤其是适用于老年高血压，收缩期高血压以及合并水肿，肥胖，糖尿病，冠心病，心肌缺血，心室肥厚，舒张期或喝收缩期心功能不全(心力衰竭)，动脉粥样硬化，心肌梗死等，还适用于治疗血压正常的急性或慢性心功能不全和充血性心力衰竭的各型器质性心脏疾病。本发明采用
前瞻性，设对照组，单盲和多中心动物试验，使用本发明的固定剂量配比的复方缓释片剂，在老鼠动物体内上进行了为期半年的观察治疗，通过观察心衰老鼠动物模型重要的一个生理指征——测量心衰老鼠血浆中的脑钠肽的变化(该指标被认为是检测心力衰竭病情变化的一个可靠观察指标)，证明了在各个成分剂量均小于常规治疗的剂量下，两种生物活性成分具有协同降压，抑制心肌重塑，扩张血管，治疗慢性心衰的作用。The preparation of the invention is suitable for various hypertension, especially for elderly hypertension, systolic hypertension and edema, obesity, diabetes, coronary heart disease, myocardial ischemia, ventricular hypertrophy, diastolic or systolic cardiac insufficiency ( Heart failure), atherosclerosis, myocardial infarction, etc., are also suitable for the treatment of various types of organic heart disease such as acute or chronic heart failure and congestive heart failure. The invention adopts
Prospective, control group, single-blind and multi-center animal trials, using a fixed-dose combination of the sustained-release tablets of the present invention, were subjected to a six-month observational treatment in a mouse animal, by observing a rat model of heart failure. An important physiological indication for measuring changes in brain natriuretic peptide in the plasma of heart failure rats (this indicator is considered to be a reliable indicator for detecting changes in heart failure), demonstrating that doses in each component are less than conventionally treated doses. Under the two, the two biological active ingredients have synergistic antihypertensive effect, inhibit myocardial remodeling, dilate blood vessels, and treat chronic heart failure.
下面结合实例，详细阐述本发明的具体实施过程：The specific implementation process of the present invention will be described in detail below with reference to examples:
实施例1：Example 1:
复方缓释片剂片芯组方：Compound sustained release tablet tablet core group:
按上述组方可制得158.3mg复合缓释片剂的片芯。The core of 158.3 mg of the composite sustained release tablet was prepared according to the above formula.
1.复合缓释片剂片芯制备工艺：1. Composite slow release tablet core preparation process:
将复方缓释片剂中的川穹嗪磷酸盐和培哚普利叔丁胺盐与吲达帕胺及上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混匀，加入粘合剂聚乙烯吡咯烷酮20mg，制成软材，再经16目造粒，50度干燥，整形，加入0.4mg硬脂酸镁混匀，用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重158.3mg左右的缓释片剂的片芯。取样，测量片芯药物有效成分含量及含量均匀度。Mixing ligustrazine phosphate and perindopril tert-butylamine salt in compound sustained-release tablets with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in a mixing machine After 80 mesh sieve, mix, add 20 mg of binder polyvinylpyrrolidone, make soft material, granulate by 16 mesh, dry at 50 degrees, shape, add 0.4 mg of magnesium stearate, mix with 8 mm diameter The head tablet is controlled to have a hardness of 3.0 to 6.0 kg, and finally a core of a sustained-release tablet having a tablet weight of about 158.3 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
2.复方缓释片剂包衣制备工艺：2. Preparation process of compound sustained-release tablet coating:
(1)包衣液配制：A液：2％乙基纤维素乙醇溶液，B液：4％壳聚糖(含醋酸4％)醋酸水溶液,A:B＝4:1。并加入(A+B)混合液体重量3％邻苯二甲酸二丁酯为增塑剂。
(1) Preparation of coating liquid: liquid A: 2% ethyl cellulose ethanol solution, liquid B: 4% chitosan (containing 4% acetic acid) aqueous acetic acid solution, A: B = 4:1. And adding (A + B) mixed liquid weight 3% dibutyl phthalate as a plasticizer.
(2)包衣制备工艺：将上述连续制备的总重为100g的多个片芯置于直径25cm的包衣锅内，预热芯片，调整包衣锅倾角为40℃，开动并维持包衣锅转速40rpm,使用淋喷包衣液的内径为1mm的喷嘴，调节喷枪雾化压力为0.20MPa，温度38℃±2，对包衣锅内片芯进行喷淋雾化，对片芯进行包衣。包衣完毕后冷却称重，增重3％即可。(2) Coating preparation process: the above-mentioned continuously prepared plurality of cores having a total weight of 100 g were placed in a coating pan having a diameter of 25 cm, preheating the chip, adjusting the inclination angle of the coating pan to 40 ° C, starting and maintaining the coating The rotation speed of the pan is 40 rpm, and the nozzle with the inner diameter of 1 mm of the spray coating liquid is used to adjust the atomization pressure of the spray gun to 0.20 MPa, and the temperature is 38 ° C ± 2, and the core of the coating pan is sprayed and atomized, and the core is packaged. clothes. After the coating is finished, the weight is cooled and the weight gain is 3%.
实施例2：Example 2:
复方缓释片剂片芯组方：Compound sustained release tablet tablet core group:
按上述组方可制得167.4mg复合缓释片剂的片芯。The core of 167.4 mg of the composite sustained release tablet was prepared according to the above formula.
1.复合缓释片剂片芯制备工艺：1. Composite slow release tablet core preparation process:
将复方缓释片剂中的川穹嗪盐酸盐和培哚普利赖氨酸盐与吲达帕胺及上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混匀，加入粘合剂聚乙烯吡咯烷酮15mg，制成软材，再经16目造粒，50度干燥，整形，加入0.3mg硬脂酸镁混匀，用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重167.4mg左右的缓释片剂的片芯。取样，测量片芯药物有效成分含量及含量均匀度。The ligustrazine hydrochloride and perindopril lysine salt in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion. Mix in the machine, pass through 80 mesh sieve, mix well, add 15mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix. The diameter of the 8mm punch is controlled by a hardness of 3.0 to 6.0 kg, and finally the core of the sustained release tablet having a tablet weight of about 167.4 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
2.复方缓释片剂包衣制备工艺：2. Preparation process of compound sustained-release tablet coating:
(1)包衣液组方：A液：3％乙基纤维素乙醇溶液，B液：5％壳聚糖(含醋酸4％)醋酸水溶液，A:B＝6:1。并加入(A+B)混合液体重量3％邻苯二甲酸二丁酯为增塑剂；(1) Coating liquid group: Liquid A: 3% ethyl cellulose ethanol solution, liquid B: 5% chitosan (containing 4% acetic acid) aqueous acetic acid solution, A: B = 6:1. And adding (A + B) mixed liquid weight 3% dibutyl phthalate as a plasticizer;
(2)包衣制备工艺：将上述连续制备的总重为100g的多个片芯置于直径25cm
的包衣锅内，预热芯片，调整包衣锅倾角为40℃，开动并维持包衣锅转速40rpm,使用淋喷包衣液的内径为1mm的喷嘴，调节喷枪雾化压力为0.20MPa，温度38℃±2，对包衣锅内片芯进行喷淋雾化，对片芯进行包衣。包衣完毕后冷却称重，增重3％即可。(2) Coating preparation process: a plurality of cores having a total weight of 100 g as described above were placed in a diameter of 25 cm.
In the coating pan, preheat the chip, adjust the coating pan angle to 40 ° C, start and maintain the coating pan speed 40 rpm, use the spray nozzle liquid inner diameter of 1 mm nozzle, adjust the spray gun atomization pressure to 0.20MPa, At a temperature of 38 ° C ± 2, the core of the coating pan was sprayed and atomized, and the core was coated. After the coating is finished, the weight is cooled and the weight gain is 3%.
实施例3：Example 3:
复方缓释片剂片芯组方：Compound sustained release tablet tablet core group:
按上述组方可制得168.8mg复合缓释片剂的片芯。The core of 168.8 mg of the composite sustained release tablet was prepared according to the above formula.
1.复合缓释片剂片芯制备工艺：1. Composite slow release tablet core preparation process:
将复方缓释片剂中的川穹嗪酒石酸盐和培哚普利精氨酸盐盐与吲达帕胺及上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混匀，加入粘合剂聚乙烯吡咯烷酮25mg，制成软材，再经16目造粒，50度干燥，整形，加入0.3mg硬脂酸镁混匀，用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重168.8mg左右的缓释片剂的片芯。取样，测量片芯药物有效成分含量及含量均匀度。The ligustrazine tartrate and perindopril arginine salt in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion. Mix in the machine, pass through 80 mesh sieve, mix well, add 25mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix. The diameter of the 8mm punch is controlled by a hardness of 3.0 to 6.0 kg, and finally the core of the sustained release tablet having a tablet weight of about 168.8 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
2.复方缓释片剂包衣制备工艺：2. Preparation process of compound sustained-release tablet coating:
(1)包衣液配制：A液：2％乙基纤维素乙醇溶液，B液：4％壳聚糖(含醋酸4％)醋酸水溶液，A:B＝7:1。并加入(A+B)混合液体重量3％邻苯二甲酸二丁酯为增塑剂；(1) Preparation of coating liquid: liquid A: 2% ethyl cellulose ethanol solution, liquid B: 4% chitosan (containing 4% acetic acid) aqueous acetic acid solution, A: B = 7:1. And adding (A + B) mixed liquid weight 3% dibutyl phthalate as a plasticizer;
(2)包衣制备工艺：将上述连续制备的总重为100g的多个片芯置于直径25cm
的包衣锅内，预热芯片，调整包衣锅倾角为40℃，开动并维持包衣锅转速40rpm,使用淋喷包衣液的内径为1mm的喷嘴，调节喷枪雾化压力为0.20MPa，温度38℃±2，对包衣锅内片芯进行喷淋雾化，对片芯进行包衣。包衣完毕后冷却称重，增重3％即可。按药典所规定的方法，测定其体外释放度。(2) Coating preparation process: a plurality of cores having a total weight of 100 g as described above were placed in a diameter of 25 cm.
In the coating pan, preheat the chip, adjust the coating pan angle to 40 ° C, start and maintain the coating pan speed 40 rpm, use the spray nozzle liquid inner diameter of 1 mm nozzle, adjust the spray gun atomization pressure to 0.20MPa, At a temperature of 38 ° C ± 2, the core of the coating pan was sprayed and atomized, and the core was coated. After the coating is finished, the weight is cooled and the weight gain is 3%. The in vitro release rate was determined according to the method prescribed by the Pharmacopoeia.
实施例4：Example 4:
复方缓释片剂片芯组方：Compound sustained release tablet tablet core group:
按上述组方可制得162.5mg复合缓释片剂的片芯。The core of 162.5 mg of the composite sustained release tablet was prepared according to the above formula.
1.复合缓释片剂片芯制备工艺：1. Composite slow release tablet core preparation process:
将复方缓释片剂中的川穹嗪甲磺酸盐和培哚普利缬氨酸盐与吲达帕胺及上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混匀，加入粘合剂聚乙烯吡咯烷酮30mg，制成软材，再经16目造粒，50度干燥，整形，加入0.5mg硬脂酸镁混匀，用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重162.5mg左右的缓释片剂的片芯。取样，测量片芯药物有效成分含量及含量均匀度。The ligustrazine methanesulfonate and perindopril valine salt in the compound sustained-release tablet are placed in proportion to indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc. Mix in a mixer, pass through a 80 mesh sieve, mix well, add 30 mg of the adhesive polyvinylpyrrolidone, make a soft material, then granulate through 16 mesh, dry at 50 degrees, shape, add 0.5 mg of magnesium stearate and mix. The tablet was pressed with a punch of 8 mm in diameter, the hardness was controlled at 3.0 to 6.0 kg, and finally, the core of the sustained-release tablet having a tablet weight of about 162.5 mg was obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
2.复方缓释片剂包衣制备工艺：2. Preparation process of compound sustained-release tablet coating:
(1)包衣液配制：A液：2％乙基纤维素乙醇溶液，B液：4％壳聚糖(含醋酸4％)醋酸水溶液，A:B＝5:1。并加入(A+B)混合液体重量3％邻苯二甲酸二丁酯为增塑剂；(1) Preparation of coating liquid: liquid A: 2% ethyl cellulose ethanol solution, liquid B: 4% chitosan (containing 4% acetic acid) aqueous acetic acid solution, A: B = 5:1. And adding (A + B) mixed liquid weight 3% dibutyl phthalate as a plasticizer;
(2)包衣制备工艺：将上述连续制备的总重为100g的多个片芯置于直径25cm的包衣锅内，预热芯片，调整包衣锅倾角为40℃，开动并维持包衣锅转速40rpm,
使用淋喷包衣液的内径为1mm的喷嘴，调节喷枪雾化压力为0.20MPa，温度38℃±2，对包衣锅内片芯进行喷淋雾化，对片芯进行包衣。包衣完毕后冷却称重，增重3％即可。按药典所规定的方法，测定其体外释放度。(2) Coating preparation process: the above-mentioned continuously prepared plurality of cores having a total weight of 100 g were placed in a coating pan having a diameter of 25 cm, preheating the chip, adjusting the inclination angle of the coating pan to 40 ° C, starting and maintaining the coating The pot rotates at 40 rpm.
Using a nozzle with an inner diameter of 1 mm of the spray coating liquid, the atomization pressure of the spray gun was adjusted to 0.20 MPa, and the temperature was 38 ° C ± 2, and the core of the coating pan was spray-sprayed to coat the core. After the coating is finished, the weight is cooled and the weight gain is 3%. The in vitro release rate was determined according to the method prescribed by the Pharmacopoeia.
实施例5：Example 5:
复方缓释片剂片芯组方：Compound sustained release tablet tablet core group:
按上述组方可制得167.2mg复合缓释片剂的片芯。The core of 167.2 mg of the composite sustained release tablet was prepared according to the above formula.
1.复合缓释片剂片芯制备工艺：1. Composite slow release tablet core preparation process:
将复方缓释片剂中的川穹嗪柠檬酸盐和培哚普利丙氨酸盐与吲达帕胺及上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混匀，加入粘合剂聚乙烯吡咯烷酮20mg，制成软材，再经16目造粒，50度干燥，整形，加入0.3mg硬脂酸镁混匀，用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重167.2mg左右的缓释片剂的片芯。取样，测量片芯药物有效成分含量及含量均匀度。The ligustrazine citrate and perindopril alanine salt in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion. Mix in the machine, pass through 80 mesh sieve, mix well, add 20mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix. The 8mm diameter punching tablet is controlled to have a hardness of 3.0 to 6.0 kg, and finally a core of a sustained-release tablet having a tablet weight of about 167.2 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
2.复方缓释片剂包衣制备工艺：2. Preparation process of compound sustained-release tablet coating:
(1)包衣液配制：A液：2％乙基纤维素乙醇溶液，B液：4％壳聚糖(含醋酸4％)醋酸水溶液，A:B＝8:1。并加入(A+B)混合液体重量2％～5％邻苯二甲酸二丁酯为增塑剂；(1) Preparation of coating liquid: liquid A: 2% ethyl cellulose ethanol solution, liquid B: 4% chitosan (containing 4% acetic acid) aqueous acetic acid solution, A: B = 8:1. And adding (A+B) mixed liquid weight 2% to 5% dibutyl phthalate as a plasticizer;
(2)包衣制备工艺：将上述连续制备的总重为100g的多个片芯置于直径25cm的包衣锅内，预热芯片，调整包衣锅倾角为40℃，开动并维持包衣锅转速40rpm,使用淋喷包衣液的内径为1mm的喷嘴，调节喷枪雾化压力为0.20MPa，温度
38℃±2，对包衣锅内片芯进行喷淋雾化，对片芯进行包衣。包衣完毕后冷却称重，增重3％即可。按药典所规定的方法，测定其体外释放度。经检测，累积释放百分率与时间的平方根符合Higuchi方程。(2) Coating preparation process: the above-mentioned continuously prepared plurality of cores having a total weight of 100 g were placed in a coating pan having a diameter of 25 cm, preheating the chip, adjusting the inclination angle of the coating pan to 40 ° C, starting and maintaining the coating The rotation speed of the pan is 40 rpm, and the nozzle with the inner diameter of 1 mm of the spray coating liquid is used to adjust the atomization pressure of the spray gun to 0.20 MPa.
At 38 ° C ± 2, the core of the coating pan was sprayed and atomized, and the core was coated. After the coating is finished, the weight is cooled and the weight gain is 3%. The in vitro release rate was determined according to the method prescribed by the Pharmacopoeia. Upon detection, the cumulative release percentage and the square root of time are in accordance with the Higuchi equation.
实施例6：Example 6
复方缓释片剂片芯组方：Compound sustained release tablet tablet core group:
按上述组方可制得167.1mg复合缓释片剂的片芯。The core of 167.1 mg of the composite sustained release tablet was prepared according to the above formula.
1.复合缓释片剂片芯制备工艺：1. Composite slow release tablet core preparation process:
将复方缓释片剂中的川穹嗪琥珀酸盐和培哚普利亮氨酸盐与吲达帕胺及上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混匀，加入粘合剂聚乙烯吡咯烷酮20mg，制成软材，再经16目造粒，50度干燥，整形，加入0.3mg硬脂酸镁混匀，用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重167.1mg左右的缓释片剂的片芯。取样，测量片芯药物有效成分含量及含量均匀度。The ligustrazine succinate and perindopril leucine in the compound sustained-release tablet are mixed with indapamide and the above-mentioned medicinal auxiliary materials hydroxypropylmethylcellulose, starch and talc in proportion. Mix in the machine, pass through 80 mesh sieve, mix well, add 20mg of binder polyvinylpyrrolidone, make soft material, then granulate by 16 mesh, dry at 50 degrees, shape, add 0.3mg magnesium stearate and mix. The diameter of the 8mm punch is controlled by a hardness of 3.0 to 6.0 kg, and finally the core of the sustained-release tablet having a tablet weight of about 167.1 mg is obtained. Sampling, measuring the content of the active ingredient of the core drug and the uniformity of the content.
2.复方缓释片剂包衣制备工艺：2. Preparation process of compound sustained-release tablet coating:
(1)包衣液配制：A液：2％乙基纤维素乙醇溶液B液：4％壳聚糖(含醋酸4％)醋酸水溶液，A:B＝6:1。并加入(A+B)混合液体重量2％～5％邻苯二甲酸二丁酯为增塑剂；(1) Preparation of coating liquid: Liquid A: 2% ethyl cellulose ethanol solution B solution: 4% chitosan (containing 4% acetic acid) aqueous acetic acid solution, A: B = 6:1. And adding (A+B) mixed liquid weight 2% to 5% dibutyl phthalate as a plasticizer;
(2)包衣制备工艺：将上述连续制备的总重为100g的多个片芯置于直径25cm的包衣锅内，预热芯片，调整包衣锅倾角为40℃，开动并维持包衣锅转速40rpm,使用淋喷包衣液的内径为1mm的喷嘴，调节喷枪雾化压力为0.20MPa，温度38℃±2，
对包衣锅内片芯进行喷淋雾化，对片芯进行包衣。包衣完毕后冷却称重，增重3％即可。按药典所规定的方法，测定其体外释放度，累积释放百分率与时间的平方符合Higuchi方程。(2) Coating preparation process: the above-mentioned continuously prepared plurality of cores having a total weight of 100 g were placed in a coating pan having a diameter of 25 cm, preheating the chip, adjusting the inclination angle of the coating pan to 40 ° C, starting and maintaining the coating The rotation speed of the pan is 40 rpm, and the nozzle with the inner diameter of 1 mm of the spray coating liquid is used to adjust the atomization pressure of the spray gun to 0.20 MPa, and the temperature is 38 ° C ± 2 .
The core of the coating pan is sprayed and atomized, and the core is coated. After the coating is finished, the weight is cooled and the weight gain is 3%. The in vitro release was determined according to the method prescribed by the Pharmacopoeia. The cumulative release percentage and the square of time are in accordance with the Higuchi equation.
抗心衰复方缓释片剂效果测定：Anti-heart failure compound sustained-release tablet effect determination:
1.心衰老鼠模型建立：1. Establishment of a heart failure mouse model:
通过尾静脉注射阿霉素2.5mg/kg,每周2次，连续8周，培育出早期心衰症状老鼠。Rats with early heart failure symptoms were cultured by intraperitoneal injection of doxorubicin 2.5 mg/kg twice a week for 8 weeks.
2.脑钠肽(BNP)水平测定：2. Determination of brain natriuretic peptide (BNP) levels:
将所有心衰模型老鼠分为观察组与对照组进行实验。观察组以复方抗心衰缓释片剂(实施例1)进行治疗，以每天一次，每次以相当于人临床剂量5倍的剂量灌胃，每天一次，连续12周；对照组则采用等量生理盐水灌胃方式，作平行实验。所有大鼠均按标准饲料饲养，自由饮水。实验时，取大鼠静脉血3mL.并进行常规服用3个月后再次留取观察组静脉血3mL进行血浆BNP的分子水平的检测，脑钠肽(BNP)测定仪器为瑞士罗氏公司产的E-170型号，试剂盒亦由罗氏公司提供，使用微粒子酶免疫分析法检测。All heart failure model mice were divided into observation group and control group for experiment. The observation group was treated with compound anti-heart failure sustained-release tablets (Example 1), once a day, each time with a dose equivalent to 5 times the clinical dose of the human, once a day for 12 weeks; the control group was used, etc. The amount of saline was administered by gavage for parallel experiments. All rats were fed a standard diet and were given free access to water. During the experiment, the rat venous blood was taken 3 mL. After routine use for 3 months, the venous blood of the observation group was again taken to detect the molecular level of plasma BNP. The brain natriuretic peptide (BNP) measuring instrument was produced by Swiss Roche. Model -170, the kit is also supplied by Roche, using microparticle enzyme immunoassay.
统计学方法本研究采用SPSS 21.0统计软件进行统计学处理，计量资料以(X±s)表示，结果比较：两组间关系采用两样本t检验，多组数据采用单因素方差分析，相关分析采用pearson或spearman相关检验.其中数据P<0.05为差异具有统计学意义。最终实验结果如下：Statistical Methods This study used SPSS 21.0 statistical software for statistical processing. The measurement data were expressed as (X±s). The results were compared. The relationship between the two groups was analyzed by two-sample t-test. The data of multiple groups were analyzed by one-way ANOVA. Pearson or spearman correlation test. The data P < 0.05 was considered statistically significant. The final experimental results are as follows:
表1治疗前对照组与观察组血液BNP水平比较Table 1 Comparison of blood BNP levels between control group and observation group before treatment
| n(心衰模型老鼠数目)n (number of heart failure model mice) | 平均BNP(pg/mL)Average BNP (pg/mL) | |
| 对照组Control group | 5050 | 149.56±16.25149.56±16.25 |
| 观察组Observation group | 5050 | 368.74+±21.32368.74+±21.32 |
观察组治疗前后血浆BNP水平浓度变化比较，可以看出，观察组治疗前与
治疗后12周内血浆BNP水平浓度差异均具有统计学意义(P<0.05)，其下降程度与病情改善程度为正相关(r＝0.786)。Comparison of changes in plasma BNP levels before and after treatment in the observation group, it can be seen that the observation group before treatment and
There was a statistically significant difference in plasma BNP levels between the 12 weeks after treatment (P<0.05), and the degree of decline was positively correlated with the degree of improvement (r=0.786).
表2经过三个月治疗后观察组血液BNP水平浓度变化Table 2 Changes in blood BNP levels in the observation group after three months of treatment
心衰积分主要表示的是对心衰疾病症状打分，含心肌是否缺血，左室射血分数，活动能力，气喘呼吸困难，水肿，左心房心肌肥厚，血压，心排血量，心率，腹泻失眠等10种心衰症状给予打分。心衰症状最严重值为满分100分。Heart failure scores mainly indicate the symptoms of heart failure, including myocardial ischemia, left ventricular ejection fraction, mobility, asthma, dyspnea, edema, left atrial hypertrophy, blood pressure, cardiac output, heart rate, diarrhea Ten heart failure symptoms such as insomnia were scored. The most serious symptom of heart failure is 100 points.
从该表看出，经过复方缓释片剂治疗，老鼠血浆BNP浓度显著下降，心衰积分也逐渐回落，证明复方缓释片剂治疗心衰具有较为显著作用特征。
It can be seen from the table that after treatment with compound sustained-release tablets, the plasma BNP concentration of the mice decreased significantly, and the heart failure scores gradually decreased. It proved that the compound sustained-release tablets have a significant effect on the treatment of heart failure.
Claims (8)
- 本发明所涉及的一种复方缓释片剂，其特征在于每个片剂含有三种活性成分为A compound sustained release tablet according to the present invention, characterized in that each tablet contains three active ingredients(1)20mg～40mg抗心衰降压剂川穹嗪盐(如盐酸盐，硫酸盐，磷酸盐，甲磺酸盐，酒石酸盐，柠檬酸盐，丁二酸盐，丙氨酸盐，精氨酸盐，赖氨酸盐，蛋氨酸盐，亮氨酸盐，缬氨酸盐，半胱氨酸盐)；(1) 20mg ~ 40mg anti-heart failure antihypertensive agent ligustrazine salt (such as hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, citrate, succinate, alaninate, Arginate salt, lysine salt, methionine salt, leucine salt, proline salt, cysteine salt);(2)2mg～10mg血管紧张素还原酶II抑制剂(ACEI)培哚普利盐类化合物(如叔丁胺盐，丙氨酸盐，精氨酸盐，赖氨酸盐，蛋氨酸盐，亮氨酸盐，缬氨酸盐，半胱氨酸盐)以及药学上可以接受的各种盐或载体；(2) 2mg ~ 10mg angiotensin reductase II inhibitor (ACEI) perindopril salt compounds (such as tert-butylamine salt, alanine salt, arginine salt, lysine salt, methionine salt, leucine a salt, a proline salt, a cysteine salt) and a pharmaceutically acceptable salt or carrier;(3)0.4-1.8mg磺酰胺类利尿剂吲达帕胺；(3) 0.4-1.8 mg sulfonamide diuretic indapamide;
- 本发明所涉及的一种复方缓释片剂，其特征是所使用的药物辅料主要组成为：30mg～50mg药用级羟丙基甲基纤维素K100M，聚乙烯吡咯烷酮,10mg～30mg,淀粉60mg～100mg,硬脂酸镁0.2mg～0.8mg，滑石粉0.2mg～0.8mg。The invention relates to a compound sustained-release tablet characterized in that the main component of the pharmaceutical auxiliary used is: 30 mg to 50 mg of pharmaceutical grade hydroxypropyl methylcellulose K100M, polyvinylpyrrolidone, 10 mg to 30 mg, starch 60 mg ~100mg, magnesium stearate 0.2mg ~ 0.8mg, talc 0.2mg ~ 0.8mg.
- 本发明所涉及的一种复方缓释片剂，其特征是所含的2～10mg降压药为血管紧张素转换酶抑制剂选自培哚普利盐类化合物，如培哚普利叔丁胺盐，培哚普利丙氨酸盐，培哚普利精氨酸盐，培哚普利赖氨酸盐，培哚普利蛋氨酸盐，培哚普利亮氨酸盐，培哚普利缬氨酸盐，培哚普利半胱氨酸盐；The invention relates to a compound sustained-release tablet characterized in that the 2-10 mg antihypertensive drug contained is an angiotensin converting enzyme inhibitor selected from a perindopril salt compound, such as perindopril tert-butylamine salt. , perindopril alanine, perindopril arginine, perindopril lysine, perindopril methionine, perindopril leucine, perindopril Acid salt, perindopril cysteine salt;
- 本发明所涉及的一种复方缓释片剂，其特征是所述的另外两种生物活性成分组方为20mg～40mg川穹嗪盐和0.4～1.8mg磺酰胺类利尿剂吲达帕胺；The present invention relates to a compound sustained-release tablet, characterized in that the other two biologically active ingredients are 20 mg to 40 mg of ligustrazine salt and 0.4 to 1.8 mg of a sulfonamide diuretic indapamide;
- 本发明所涉及的一种复方缓释片剂，其特征是所述的三种生物活性成分培哚普利盐类、吲达帕胺与川穹嗪盐重量含比为1～5:0.2～0.9:10～20mg；The invention relates to a compound sustained-release tablet, characterized in that the weight ratio of the three bioactive components perindopril salt, indapamide and ligustrazine salt is 1-5:0.2~ 0.9: 10 ~ 20mg;
- 本发明所涉及的一种复方降压抗心衰药物制剂其特征在于所描述剂型为缓释片剂。A compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the described dosage form is a sustained release tablet.
- 本发明所述的复方降压抗心衰药物制剂其特征在于所描述的用于制备缓释片剂片芯各组分分配比为：The compound antihypertensive anti-heart failure pharmaceutical preparation of the present invention is characterized in that the distribution ratio of each component described for preparing the sustained-release tablet core is:
- 本发明所述的复方降压抗心衰药物制剂其特征在于所描述复方缓释制剂的制备工艺采取了先制备缓释片剂片芯，然后再进行包衣的两步制备方法。具体步骤特征是：The compound antihypertensive anti-heart failure pharmaceutical preparation according to the present invention is characterized in that the preparation process of the compound sustained-release preparation described above adopts a two-step preparation method of preparing a sustained release tablet core and then performing coating. The specific steps are:(1)缓释片剂的片芯制备工艺：将复方缓释片剂中的川穹嗪盐、培哚普利叔丁胺盐和吲达帕胺，与上述药用辅料羟丙基甲基纤维素、淀粉、滑石粉按比例放入混合机内混合，过80目筛，混合均匀，加入粘合剂聚乙烯吡咯烷酮，制成软材，再经16目造粒，50度干燥，整形，加入干粒重的0.1％～0.4％硬脂酸镁混匀，采用直径8mm冲头压片，硬度控制在3.0～6.0kg,最后获得片重100mg～250mg左右的缓释片剂的片芯。(1) Core preparation process of sustained-release tablets: the ligustrazine salt, perindopril tert-butylamine salt and indapamide in the compound sustained-release tablet, and the above-mentioned medicinal adjuvant hydroxypropylmethylcellulose Starch and talcum powder are mixed into the mixer in proportion, passed through a 80 mesh sieve, mixed evenly, and the binder polyvinylpyrrolidone is added to make a soft material, which is then granulated by 16 mesh, dried at 50 degrees, shaped, and added to dryness. The powder weight is 0.1% to 0.4% of magnesium stearate, and is compressed by a punch having a diameter of 8 mm. The hardness is controlled to be 3.0 to 6.0 kg, and finally the core of the sustained-release tablet having a tablet weight of about 100 mg to 250 mg is obtained.(2)包衣制备工艺：首先配制包衣液，包衣液组分：A液：1％-5％乙基纤维素乙醇溶液，B液：1％-4％壳聚糖(含醋酸2％-6％)醋酸水溶液，两者混合体积比例为：8:1-2:1加入混合液体重量的2％-5％增塑剂邻苯二甲酸二丁酯。其次，对缓释片剂片芯进行包衣：将100g-600g的片芯置于直径25cm的包衣锅内，预热芯片，倾角40℃，维持包衣锅转速40rpm,淋喷包衣液的喷嘴内径1mm，喷枪雾化压力0.20MPa，温度38℃±2。 (2) Coating preparation process: firstly prepare coating liquid, coating liquid component: liquid A: 1%-5% ethyl cellulose ethanol solution, liquid B: 1%-4% chitosan (containing acetic acid 2 %-6%) Aqueous acetic acid solution, the mixing ratio of the two is: 8:1-2:1 Adding 2%-5% plasticizer dibutyl phthalate by weight of the mixed liquid. Next, the sustained release tablet core is coated: 100g-600g core is placed in a 25cm diameter coating pan, the chip is preheated, the inclination is 40 ° C, the coating pan speed is maintained at 40 rpm, and the spray coating liquid is sprayed. The inner diameter of the nozzle is 1 mm, the atomization pressure of the spray gun is 0.20 MPa, and the temperature is 38 °C ± 2.
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