阅读说明：本技术 一种用于治疗心肌缺血的药物组合物及其应用 (Pharmaceutical composition for treating myocardial ischemia and application thereof ) 是由 梁颖 刘丹 于 2020-08-19 设计创作，主要内容包括：本发明公开了一种用于治疗心肌缺血的药物组合物及其应用,包括赤芍提取物和紫苏提取物或/和紫锥菊提取物,制备成临床上可接受的剂型。实验显示,本发明药物组合物对心肌缺血损伤具有保护作用,赤芍提取物和紫苏提取物二者具有协同增效的效果,可以有效治疗心肌缺血。此外,赤芍提取物和紫苏提取物和紫锥菊提取物三者协同增效治疗心肌缺血的效果更优。(The invention discloses a pharmaceutical composition for treating myocardial ischemia and application thereof, wherein the pharmaceutical composition comprises red paeony root extract and perilla extract or/and echinacea purpurea extract, and is prepared into clinically acceptable dosage forms. Experiments show that the pharmaceutical composition has a protective effect on myocardial ischemia injury, and the red peony root extract and the perilla extract have a synergistic effect, so that myocardial ischemia can be effectively treated. In addition, the red paeony root extract, the perilla extract and the echinacea extract have better effect of synergistically treating myocardial ischemia.)

1. A pharmaceutical composition for treating myocardial ischemia is characterized by comprising the following raw materials in parts by weight: red peony root extract: the perilla extract is (1-3): (1-5), preferably red peony root extract: the perilla extract is 1: (2-4).

2. The pharmaceutical composition according to claim 1, comprising the following raw materials in parts by weight: red peony root extract: the ratio of the perilla extract is 1: 3.

3. the pharmaceutical composition according to any one of claims 1-2, further comprising the following raw materials in parts by weight: echinacea purpurea extract, wherein the red peony root extract: and (3) perilla extract: the proportion of the echinacea purpurea extract is (1-3): (1-5): (0.5-1); preferably, the red peony root extract: and (3) perilla extract: the proportion of the echinacea purpurea extract is 1: 3: 0.5.

4. the preparation for treating myocardial ischemia according to any one of claims 1-3, which is prepared by conventional processes from the composition as described above into conventional solid preparations such as tablets, powders, granules, capsules, etc., into liquid preparations such as aqueous or oil suspensions or other liquid preparations such as oral preparations such as syrups, elixirs, etc.; for parenteral administration, it can be formulated into solution for injection, aqueous or oily suspension, etc.; preferably, the preparation is prepared into clinically or pharmaceutically acceptable tablets, capsules, powder, pills, granules, honey refining paste, oral liquid and the like.

5. The preparation of claim 4, wherein the weight portion ratio of the pharmaceutical composition to the adjuvant in the preparation is 1 (0.5-20).

6. The preparation according to any one of claims 4 to 5, wherein the red peony root extract and the perilla extract or/and the echinacea extract are added into an aqueous solution of soluble starch and dextrin to prepare a soft material, and the soft material is extruded, sieved and granulated to obtain a crude product; drying and granulating the crude product to obtain the granules.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the red peony root extract is prepared by the following method:

1) extraction: adding 8-10 times of 60-70% ethanol into the red paeony root coarse powder, soaking for 1-2 hours, filtering the dregs of a decoction, recovering the ethanol, adding 8-10 times of 60-70% ethanol into the dregs of a decoction again, soaking for 1-2 hours, filtering the dregs of a decoction, recovering the ethanol, repeating for three times, concentrating the filtrate under reduced pressure and vacuum into extract, and steaming at the temperature of 55-60 ℃ to obtain dry paste; 2) and (3) purification and drying: adding distilled water to the extract obtained by extraction to 4-6 times of the medicinal materials, and separating by using a macroporous resin column to obtain the red paeony root extract to be purified.

8. The pharmaceutical composition of any one of claims 1-6, wherein the perilla extract is prepared by the following method:

1) adding 30-40 times of water into dried folium Perillae, leaching for 1-2 hr at 80-90 deg.C water bath, filtering, repeatedly leaching the residue for 3-5 times, filtering, mixing the leaching solutions, adding 18% hydrochloric acid, adjusting pH to 2.0-2.5, and filtering to obtain filtrate;

2) extracting the filtrate with 2-3 times of ethyl acetate for 3 times, mixing extractive solutions, rotary evaporating to remove ethyl acetate, and vacuum drying the concentrated solution to obtain Perillae herba extract.

9. The pharmaceutical composition according to any one of claims 1 to 6, wherein the echinacea extract is prepared by the following process:

1) extraction: adding 10-15 times of 40% ethanol into Echinacea purpurea root powder, heating and reflux-extracting at 80-90 deg.C for 1-2 hr, filtering, repeatedly extracting the residue for 3-5 times, filtering, mixing filtrates, concentrating the filtrate, recovering ethanol, and concentrating the filtrate;

2) and (3) purification and drying: adding distilled water into the concentrated filtrate to 4-6 times of the medicinal materials to obtain a sample solution to be purified; taking 200ml of sample liquid to be purified, adopting an AB-8 macroporous adsorption resin column, eluting with 2-3 times of distilled water and 3-4 times of 50% ethanol respectively, collecting elution components, carrying out reduced pressure reflux on the ethanol to obtain a echinacea extract crude product, dissolving the crude product in water, adjusting the pH value of the echinacea extract crude product to 3-4 by using 5-6mol/L hydrochloric acid, extracting for 4-6 times by using ethyl acetate, concentrating and drying extract liquor, and obtaining the purified and dried echinacea extract.

10. Use of a pharmaceutical composition according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of myocardial ischemia.

Technical Field

The invention belongs to the field of pharmaceutical composition preparations, and particularly relates to a pharmaceutical composition for treating myocardial ischemia and application thereof.

Background

Myocardial ischemia (myocardial ischemia) refers to a pathological condition in which the blood perfusion of the heart is reduced, the oxygen supply of the heart is reduced, the energy metabolism of the heart muscle is abnormal, and the heart cannot work normally. The energy required by the heart activity is almost completely provided by aerobic metabolism, so even in rest, the blood oxygen intake rate of the cardiac muscle is high (about 70%), and under normal conditions, the body can regulate itself to promote relatively constant blood supply and demand and ensure the normal work of the heart. When the blood supply and demand of the myocardium are unbalanced for some reason, the myocardial ischemia is really formed. With the improvement of living standard of people, the prevalence rate of myocardial ischemia in China is on the trend of rising year by year at present, the myocardial ischemia becomes a common disease and a frequently encountered disease of middle-aged and elderly people, and some young people of 20-30 years old also have the myocardial ischemia.

The mechanism of myocardial ischemia is mainly the imbalance of supply and demand of myocardial blood, namely blood oxygen, and the accumulation of myocardial cell metabolites also occurs to aggravate the myocardial ischemia. Serious myocardial ischemia causes a series of serious damages such as complete destruction of intracellular environments such as energy substance exhaustion, acid-base imbalance, ion disorder and the like, cell membrane damage and the like to the heart. Therefore, the treatment of myocardial ischemia mainly increases myocardial oxygen supply and/or reduces myocardial oxygen consumption, so that the myocardial oxygen supply and demand reach the equilibrium state again.

At present, a plurality of medicines for clinically treating myocardial ischemia are available, and western medicines mainly comprise (1) antiplatelet medicines, which are used for preventing and treating thrombosis, preventing coronary artery and cerebral artery thromboembolism, and reducing the risks of myocardial infarction, cerebral apoplexy and cardiovascular death of patients with stable angina pectoris, such as long-term taking without contraindication, and common medicines comprise aspirin, clopidogrel and the like. (2) Beta-receptor blockers, which slow down heart rate, reduce myocardial oxygen consumption, prevent sudden death, such as metoprolol or its sustained release tablets. (3) Calcium antagonist can inhibit myocardial contraction and reduce myocardial oxygen consumption; dilating coronary artery, relieving coronary artery spasm, and improving myocardial blood supply. Common medicines include verapamil, nifedipine, etc. (4) Statins, reduce plasma cholesterol, stabilize arterial plaque, prevent plaque from shedding and forming thrombus, such as atorvastatin, rosuvastatin and the like. (5) RAS (renin-angiotensin-aldosterone system) system blockers, which prevent ventricular remodeling and improve cardiac function, such as benazepril and valsartan. (6) Nitrate drugs, expand coronary arteries and increase myocardial blood supply, such as isosorbide mononitrate. (7) Thrombolytic drug can dissolve acute thrombosis, and can be used for acute myocardial infarction. The traditional Chinese medicines are commonly seen as follows: the compound salvia miltiorrhiza dropping pill, the coronary storax pill, the quick-acting heart-saving pill and the like have a plurality of types of traditional Chinese medicines, but the types of the traditional Chinese medicines applied to the study of myocardial ischemia are few, so that the application of the traditional Chinese medicines in the myocardial ischemia treatment is screened and further researched from the traditional Chinese medicines and the classical compound, and the search for safe and effective myocardial ischemia treatment medicines is very necessary. Therefore, the invention further develops and prepares the pharmaceutical composition with good curative effect, small side effect, safety and effectiveness.

Disclosure of Invention

The invention aims to find a pharmaceutical composition with an effect of treating myocardial ischemia, and thus provides a pharmaceutical composition for treating myocardial ischemia and application thereof.

The pharmaceutical composition for treating myocardial ischemia comprises the following raw materials in parts by weight: red peony root extract: the perilla extract is (1-3): (1-5), preferably red peony root extract: the perilla extract is 1: (2-4).

More preferably, the pharmaceutical composition for treating myocardial ischemia comprises the following raw materials in parts by weight: red peony root extract: the ratio of the perilla extract is 1: 3.

more preferably, the pharmaceutical composition for treating myocardial ischemia further comprises the following raw materials in parts by weight: echinacea purpurea extract, wherein the red peony root extract: and (3) perilla extract: the proportion of the echinacea purpurea extract is (1-3): (1-5): (0.5-1), preferably red peony root extract: and (3) perilla extract: the proportion of the echinacea purpurea extract is 1: 3: 0.5.

the invention also provides a preparation with the effect of treating myocardial ischemia, which is prepared into conventional solid preparations such as tablets, powders, granules, capsules and the like according to the conventional process, and liquid preparations such as water or oil suspending agents or other liquid preparations such as syrups, elixirs and other oral preparations; for parenteral administration, it can be formulated into solution for injection, aqueous or oily suspension, etc. Preferably, the preparation is prepared into clinically or pharmaceutically acceptable tablets, capsules, powder, pills, granules, honey refining paste, oral liquid and the like.

The preparation comprises the pharmaceutical composition and the auxiliary materials, wherein the weight part ratio of the pharmaceutical composition to the auxiliary materials is 1 (0.5-20).

The invention provides a granule for treating myocardial ischemia, which is prepared by adding the red paeony root extract and the perilla extract or/and the echinacea extract into a water solution of soluble starch and dextrin to prepare a soft material, extruding, sieving and granulating the soft material to obtain a crude product; drying and granulating the crude product to obtain the granules.

The preparation method of the red peony root extract comprises the following steps:

1) extraction: adding 8-10 times of 60-70% ethanol into the red peony root coarse powder, soaking for 1-2 hours, filtering dregs of a decoction, recovering the ethanol, adding 8-10 times of 60-70% ethanol into the dregs of a decoction, soaking for 1-2 hours, filtering the dregs of a decoction, recovering the ethanol, repeatedly performing vacuum concentration on the filtrate for three times to obtain an extract, and steaming at the temperature of 55-60 ℃ to obtain a dry extract;

2) and (3) purification and drying: adding distilled water to the extract to 4-6 times of the medicinal materials to obtain a sample solution to be purified; collecting 200mL of sample liquid to be purified, adopting a D101 or AB-8 macroporous adsorption resin column, respectively eluting with 2-3 times of distilled water and 3-4 times of 30% ethanol, collecting elution components, performing reduced pressure reflux on the ethanol, drying the rest extract in a vacuum drier to obtain a purified and dried red paeony root extract, precisely weighing 0.2g of dry extract, adding methanol to a constant volume of 25mL, and determining the content of paeoniflorin to be 78.5% by an HPLC method.

The preparation method of the perilla extract comprises the following steps:

1) adding 30-40 times of water into dried folium Perillae, leaching for 1-2 hr at 80-90 deg.C water bath, filtering, repeatedly leaching the residue for 3-5 times, filtering, mixing the leaching solutions, adding 18% hydrochloric acid, adjusting pH to 2.0-2.5, and filtering to obtain filtrate;

2) extracting the filtrate with 2-3 times of ethyl acetate for 3 times, mixing extractive solutions, rotary evaporating to remove ethyl acetate, and vacuum drying the concentrated solution to obtain Perillae herba extract.

The preparation method of the echinacea purpurea extract comprises the following steps:

1) extraction: adding 10-15 times of 40% ethanol into Echinacea purpurea root powder, heating and reflux-extracting at 80-90 deg.C for 1-2 hr, filtering, repeatedly extracting the residue for 3-5 times, filtering, mixing filtrates, concentrating the filtrate, recovering ethanol, and concentrating the filtrate;

2) and (3) purification and drying: adding distilled water into the concentrated filtrate to 4-6 times of the medicinal materials to obtain a sample solution to be purified; taking 200ml of sample liquid to be purified, adopting an AB-8 macroporous adsorption resin column, eluting with 2-3 times of distilled water and 3-4 times of 50% ethanol respectively, collecting elution components, carrying out reduced pressure reflux on the ethanol to obtain a echinacea extract crude product, dissolving the crude product in water, adjusting the pH value of the echinacea extract crude product to 3-4 by using 5-6mol/L hydrochloric acid, extracting for 4-6 times by using ethyl acetate, concentrating and drying extract liquor, and obtaining the purified and dried echinacea extract.

The red peony root of the invention: is the dry root of Paeonia lactiflora pall or Paeonia veitchii Szechwan of Ranunculaceae, and has effects of clearing heat and cooling blood, removing blood stasis and relieving pain. Mainly comprises terpenes, tannins, flavones, glycosides thereof, volatile oils and the like, and the main active component is total paeony glycoside which mainly comprises monoterpene compounds such as paeoniflorin, albiflorin, hydroxyl paeoniflorin, benzoylpaeoniflorin and the like, wherein the contents of the paeoniflorin and the albiflorin are high.

The use of red peony root is relatively rare, usually in the form of compound or re-using red peony root. The red paeony root is mainly combined with 13 traditional Chinese medicines of white paeony root, rehmannia root, tree peony bark, rhubarb, baical skullcap root, amur corktree bark, immature bitter orange, nutgrass galingale rhizome, danshen root, Szechuan lovage rhizome, Chinese angelica tail, giant knotweed rhizome and liquoric root to respectively play the efficacies of reinforcing and reducing diarrhea, nourishing yin to dissipate blood stasis, cooling blood and activating blood, clearing heat and removing blood stasis, clearing liver and promoting bile flow, cooling blood and stopping dysentery, promoting qi and activating blood, promoting qi to relieve pain, activating blood and stimulating menstrual flow, promoting blood circulation to break stagnation, removing blood stasis and relieving.

Perilla frutescens is an annual herb of Perilla of Labiatae, has various medicinal and edible effects, and folium Perillae has antipyretic, cold dispelling, cough relieving and phlegm eliminating effects. Besides various vitamins and minerals, the health food also contains various bioactive substances such as perillaldehyde, eugenol, threone, perillyl alcohol, limonene, citral, polyphenol and the like. The perilla extract is known to have antioxidant activity, antibacterial action and antipyretic action, and has certain influence on blood sugar, and the current researches are mainly in the aspects of anti-inflammation, antivirus, tumor inhibition and the like, and the researches on the aspect of treating myocardial ischemia are less.

Echinacea purpurea is a plant of the family Compositae of the order Chrysanthemum. The main active ingredients of the perennial herb, the capitula, the natural plant with the immune function comprise polysaccharide, various alkyl amide compounds, caffeic acid derivatives, flavonoids, volatile oil and the like, and researches show that the echinacea can enhance the resistance of the body to bacterial and viral infection by stimulating the immune system of the body, has the function of antibiotics, is used for relieving allergic symptoms, is used for treating skin infection for a long time, and does not find the research on the aspect of treating myocardial ischemia.

The invention adopts natural plant medicines as raw materials, adopts the comprehensive effect of various traditional Chinese medicines to treat myocardial ischemia, has no toxic or side effect, and does not generate dependence.

Pharmacological experiments and clinical observation show that the red paeony root extract and the perilla extract have certain effects on treating myocardial ischemia. Different from the prior art, the red paeony root is usually used in a heavy dosage when being used in combination, and the effect is best when the dosage is selected to be low, particularly the combination ratio of the red paeony root to the red paeony root is 1: the treatment effect is better when 3, the disease is not easy to relapse after healing, and the treatment course is short. In addition, the purple coneflower extract is added into the red paeony root extract and the purple perilla extract, so that the effect of treating myocardial ischemia is more remarkable.

The formula composition of the preparation is obtained by screening in a large amount, the preparation is optimized by optimization treatment, and in order to achieve optimization, the inventor does a large amount of work, and compared experiments, screening experiments and animal experiments prove that the preparation has a remarkable effect on improving myocardial ischemia compared with the prior art, so the preparation has prominent substantive, specific and remarkable progress.

Detailed Description

The specific preparation method of the red peony root extract comprises the following steps:

1) extraction: adding 10 times of 70% ethanol into radix Paeoniae Rubra coarse powder, soaking for 1 hr, filtering the residue, recovering ethanol, adding 10 times of 70% ethanol into the residue, soaking for 1 hr, filtering the residue, recovering ethanol, repeating for three times, vacuum concentrating the filtrate under reduced pressure to obtain extract, and steaming at 60 deg.C to obtain dry extract.

2) And (3) purification and drying: adding distilled water to the extract obtained by extraction to 4 times of the medicinal materials to obtain a sample solution to be purified; collecting 200mL of sample liquid to be purified, adopting a D101 macroporous adsorption resin column, eluting with 3 times of distilled water and 3 times of 30% ethanol respectively, collecting elution components, refluxing the ethanol under reduced pressure, drying the rest extract in a vacuum drier to obtain a purified and dried red paeony root extract, precisely weighing 0.2g of dry extract, adding methanol to a constant volume of 25mL, and measuring the content of paeoniflorin to be 78.5% by an HPLC method.

The preparation method of the perilla extract comprises the following steps:

1) adding 40 times of water into dry folium Perillae, leaching for 1 hr in 90 deg.C water bath, filtering, repeatedly leaching the residue for 3 times, filtering and mixing the leaching solutions, adding 18% hydrochloric acid to adjust pH to 2.0-2.5, and filtering to obtain filtrate;

2) extracting the filtrate with 2 times of ethyl acetate for 3 times, mixing extractive solutions, rotary evaporating to remove ethyl acetate, and vacuum drying the concentrated solution to obtain Perillae herba extract.

The preparation method of the echinacea purpurea extract comprises the following steps:

1) extraction: adding 15 times of 40% ethanol into Echinacea purpurea root powder, heating and reflux-extracting at 90 deg.C for 2 hr, filtering, repeatedly extracting the residue for 5 times, filtering, mixing filtrates, concentrating, recovering ethanol, and concentrating the filtrate;

2) and (3) purification and drying: adding distilled water into the concentrated filtrate to 4 times of the medicinal materials to obtain a sample solution to be purified; taking 200ml of sample liquid to be purified, adopting an AB-8 macroporous adsorption resin column, eluting with 3 times of distilled water and 4 times of 50% ethanol respectively, collecting elution components, carrying out reduced pressure reflux on the ethanol to obtain a echinacea extract crude product, dissolving the echinacea extract crude product in water, adjusting the pH value of the echinacea extract crude product to 3 by using 6mol/L hydrochloric acid, extracting the echinacea extract product for 6 times by using ethyl acetate, and concentrating and drying extract liquor to obtain the purified and dried echinacea extract.