A pharmaceutical composition for treating myocardial ischemia and a preparation method thereof

Abstract

The present invention provides a pharmaceutical composition for treating myocardial ischemia, comprising 250-700 parts by weight of salvia miltiorrhiza, 50-150 parts by weight of notoginseng, 3-9 parts by weight of borneol, and 25-100 parts by weight of ranolazine. Another aspect of the present invention also provides an application of the pharmaceutical composition of the present invention in preparing a drug for preventing and / or treating myocardial ischemia.

Description

Technical field:

[0001] The present invention relates to the field of traditional Chinese medicine pharmaceutical preparation, and in particular to a pharmaceutical composition for treating myocardial ischemia, a preparation method thereof and an application of the pharmaceutical composition in preparing a medicine for preventing and / or treating myocardial ischemia. Background technology:

[0002] Ranolazine, chemical name (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, has the following structural formula:

[0003]

[0004] It is used to treat chronic stable angina. It has anti-anginal and anti-myocardial ischemic effects, and its specific mechanism of action is still unclear. Ranolazine is limited to patients who have not responded to anti-anginal drugs such as long-acting nitrates, calcium channel blockers, and beta-2 receptor blockers. Clinical trials have shown that male patients have better results taking ranolazine than female patients.

[0005] Salvia miltiorrhiza is also known as red ginseng, purple salvia miltiorrhiza, red root, etc. It is the root and rhizome of Salvia miltiorrhiza Bge., a plant of the Lamiaceae family. Salvia miltiorrhiza has the effects of promoting blood circulation and removing blood stasis, cooling blood and eliminating carbuncle, nourishing blood and calming the mind. It can dilate coronary arteries, increase coronary blood flow, has a significant protective effect on myocardial ischemia, and is beneficial for the prevention and treatment of angina pectoris caused by coronary heart disease. It can improve the body's microcirculation, reduce blood viscosity, and reduce platelet aggregation.

[0006] Panax notoginseng is also known as Kaihua Panax notoginseng, Ginseng Panax notoginseng, Panax notoginseng, Jinbuhuan, Panlongqi. Panax notoginseng has the effects of dispersing blood stasis and stopping bleeding, reducing swelling and relieving pain. It is mainly used to treat hemoptysis, hematemesis, epistaxis, bloody stool, metrorrhagia, bleeding due to trauma, stabbing pain in the chest and abdomen, and swelling and pain caused by falls.

[0007] Borneol is also known as borneol, orange slices, moxa slices, borneol, etc. Its chemical composition is 2-borneol, and its chemical formula is C 10 H 18 O. It has the effects of invigorating the mind, clearing away heat and dispersing toxins, improving eyesight and removing cataracts. It is mainly used to treat high fever and coma caused by fever, stroke, phlegm, convulsions and epilepsy, summer heat and dampness obstructing the clear orifices, throat paralysis and deafness, mouth sores and swollen teeth, sores, carbuncles, malnutrition and hemorrhoids, red and swollen eyes, and cataracts covering the eyes.

[0008] Chinese patent application CN111297942A discloses a compound preparation for treating myocardial ischemia, comprising ranolazine, a mixture of salvia miltiorrhiza, panax notoginseng, and borneol. The weight proportions of each component are as follows: 20-50 parts of ranolazine, 20-50 parts of a mixture of salvia miltiorrhiza, panax notoginseng, and borneol. The preparation method of the compound preparation comprises the following steps:

[0009] Step 1: Weigh each component separately and sieve for later use;

[0010] Step 2: Dissolve the adhesive in water for later use;

[0011] Step 3: Put all components except lubricant into a wet granulator, premix, add binder aqueous solution, then add water, after granulation, transfer to fluidized bed for drying, sieve and size the granules;

[0012] Step 4: Add the granulated material into a mixer, add a lubricant, and mix evenly to form an intermediate.

[0013] Step 5: Fill the intermediate into capsules to make capsules, or compress it into tablets, or prepare it into granules.

[0014] However, the application does not specifically disclose the ratio between Danshen, Panax notoginseng and Borneol, so the technical solution in the patent application is unclear and cannot be implemented. And according to the examples of the patent application, the amount of ranolazine is higher than the mixture of Danshen, Panax notoginseng and Borneol (Example 1: 250g of ranolazine, 125g of mixture of Danshen, Panax notoginseng and Borneol; Example 2: 275g of ranolazine, 100g of mixture of Danshen, Panax notoginseng and Borneol; Example 3: 300g of ranolazine, 75g of mixture of Danshen, Panax notoginseng and Borneol). Summary of the invention:

[0015] The present invention is based on the prior art, studies the dosage of salvia miltiorrhiza, panax notoginseng, borneol and ranolazine, and provides a new pharmaceutical composition for treating myocardial ischemia. The pharmaceutical composition of the present invention can reduce the dosage of ranolazine under the premise of preventing and / or treating myocardial ischemia, thereby alleviating some toxic and side effects that may exist in chemical drugs.

[0016] The pharmaceutical composition of the invention comprises 250-700 parts by weight of salvia miltiorrhiza medicinal material, 50-150 parts by weight of notoginseng medicinal material, 3-9 parts by weight of borneol and 25-100 parts by weight of ranolazine.

[0017] In the pharmaceutical composition of the present invention, the salvia miltiorrhiza and the panax notoginseng medicinal materials are extracted to obtain the salvia miltiorrhiza and panax notoginseng extract; or are directly crushed and then mixed to obtain the salvia miltiorrhiza and panax notoginseng mixture.

[0018] In one embodiment, in the pharmaceutical composition described in the present invention, the Danshen medicinal material and the Panax notoginseng medicinal material are combined and extracted according to the following method: Danshen and Panax notoginseng are decocted in water together under alkaline conditions, the decoction is filtered, the filtrate is concentrated and precipitated with alcohol, the supernatant is filtered, and ethanol is recovered to obtain an extract, namely the Danshen Panax notoginseng extract, or the extract is dried to obtain the Danshen Panax notoginseng extract.

[0019] Preferably, the Salvia miltiorrhiza and Panax notoginseng medicinal materials of the present invention are combined and extracted according to the following method:

[0020] Step (1), decocting Danshen and Panax notoginseng in water for 1-3 times under alkaline conditions, each time for 1-3 hours, filtering, and using the filtrate I for later use;

[0021] Step (2), boiling the residue with water for 1-3 times, each time for 1-3 hours, filtering, and using the filtrate II for later use;

[0022] Step (3), filtrates I and II are combined and concentrated, the concentrated solution is precipitated with alcohol, allowed to stand, the supernatant is taken, filtered, ethanol is recovered, and the extract is concentrated to obtain the Danshen Panax notoginseng extract or the extract is dried to obtain the Danshen Panax notoginseng extract.

[0023] The alkaline conditions in step (1) are not limited to one or more of sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide, the pH is 7.5-9.0, and the amount added is 1-4.5% (preferably 2.25-3%) of the medicinal material.

[0024] In step (3), 70-100% ethanol is preferably added for precipitation (optimally 95% ethanol) until the concentration is preferably (60-75%).

[0025] Most preferably, the Salvia miltiorrhiza and Panax notoginseng extract of the present invention is prepared by the following method:

[0026] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 5 times the amount of process water to each tank, heat and boil, keep boiling for about 2h±20min, and filter;

[0027] Step (2) The residue is subjected to a second extraction, 4 times the amount of water is added, heated to boiling, and kept boiling for about 1h±15min, filtered, and the residue is discarded;

[0028] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5°C) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain an extract, namely, the Salvia miltiorrhiza and Panax notoginseng extract, or the extract is dried to obtain the Salvia miltiorrhiza and Panax notoginseng extract.

[0029] In a second embodiment, in the pharmaceutical composition of the present invention, the Danshen medicinal material and the Panax notoginseng medicinal material can also be extracted by water extraction and alcohol precipitation under alkaline conditions respectively, and the obtained Danshen extract or Panax notoginseng extract can be mixed to obtain the Danshen and Panax notoginseng extract.

[0030] Preferably, Danshen is boiled in water under alkaline conditions for 1-3 times, each time for 1-3 hours, filtered, the filtrates are combined and concentrated, the concentrate is precipitated with alcohol, allowed to stand, the supernatant is taken, filtered, ethanol is recovered, and the extract obtained by concentration is obtained to obtain Danshen extract, or the extract is dried to obtain Danshen extract.

[0031] Under alkaline conditions, Panax notoginseng is decocted in water for 1-3 times, each time for 1-3 hours, filtered, the filtrates are combined and concentrated, the concentrate is precipitated with alcohol, allowed to stand, the supernatant is taken, filtered, ethanol is recovered, and the extract obtained by concentration is Panax notoginseng extract, or the extract is dried to obtain Panax notoginseng extract.

[0032] The salvia miltiorrhiza extract and the panax notoginseng extract are combined to obtain the salvia miltiorrhiza and panax notoginseng extract.

[0033] The most preferred method is the Danshen extract: first put Danshen into the extraction tank, then add an appropriate amount of sodium bicarbonate (2.25% of the medicinal material), add 5 times the amount of water, boil at 100°C for 2 hours, and filter; extract the residue for the second time, add 4 times the amount of water, boil at 100°C for 1 hour, filter, and discard the residue; combine the filtrates from the two decoctions, and concentrate at 80°C to 90°C under reduced pressure to a relative density of 1.16 to 1.20 (80±1°C) or a sugar content of 48% to 52% to obtain a concentrated solution; add an appropriate amount of ethanol to the concentrated solution to adjust the alcohol content to 65% to 70% (20°C), let it stand at low temperature for 12hr to 24hr until the precipitation is complete, separate the supernatant, and discard the precipitate; concentrate the supernatant under reduced pressure to a sugar content of 82% to 88%, and obtain the Danshen extract.

[0034] Panax notoginseng extract: Panax notoginseng is crushed into particles with a diameter of less than 1.5 cm, and the crushed Panax notoginseng is first put into the extraction tank, and 5 times the amount of water is added, and the mixture is soaked for 12-15 hours. Then, an appropriate amount of sodium bicarbonate (2.25% of the medicinal material amount) is added, and the mixture is decocted at 100°C for 2 hours, and filtered; the residue is subjected to a second extraction, and 4 times the amount of water is added, and the mixture is decocted at 100°C for 1 hour, filtered, and the residue is discarded; the filtrates from the two decoctions are combined, and concentrated under reduced pressure at 80°C to 90°C to a sugar content of 18% to 28% to obtain a concentrated solution; an appropriate amount of ethanol is added to the concentrated solution to adjust the alcohol content to 65% to 70% (20°C), and the solution is allowed to stand at low temperature for 15 hours to 24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated under reduced pressure to a sugar content of 60% to 75%, and the Panax notoginseng extract is obtained.

[0035] The salvia miltiorrhiza extract and the panax notoginseng extract are combined to obtain the salvia miltiorrhiza and panax notoginseng extract.

[0036] In a third embodiment, the pharmaceutical composition of the present invention, wherein the Danshen medicinal material and the Panax notoginseng medicinal material are combined and extracted according to the following method: Danshen and Panax notoginseng are extracted together with alcohol and then with water, the extract is filtered, and the filtrate is concentrated to obtain an extract, namely the Danshen Panax notoginseng extract, or the extract is dried to obtain the Danshen Panax notoginseng extract.

[0037] Preferably, the Salvia miltiorrhiza and Panax notoginseng medicinal materials of the present invention are combined and extracted according to the following method:

[0038] Step (1), extracting Danshen and Panax notoginseng with ethanol for 1 to 3 times, each time for 1 to 3 hours, filtering, and using the filtrate I for later use;

[0039] Step (2), boiling the residue with water for 1-3 times, each time for 1-3 hours, filtering, and using the filtrate II for later use;

[0040] Step (3), the filtrate II is first concentrated and then added to the filtrate I for concentration to obtain an extract, namely the Salvia miltiorrhiza and Panax notoginseng extract, or the extract is dried to obtain the Salvia miltiorrhiza and Panax notoginseng extract.

[0041] In step (1), preferably 70-100% ethanol is added for extraction (optimally 90% ethanol).

[0042] Most preferably, the Salvia miltiorrhiza and Panax notoginseng extract of the present invention is prepared by the following method:

[0043] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set aside; put the weighed Danshen and Panax notoginseng into an extraction tank, add 4 times the amount of 90% ethanol to each tank, heat and boil, keep boiling for about 90min±20min, and filter;

[0044] Step (2) extracting the residue with water, adding 5 times the amount of water, heating to boil, keeping boiling for about 60min±15min, filtering, and discarding the residue;

[0045] Step (3) The water extract is concentrated under reduced pressure to a relative density of 1.25-1.30 (82±5° C.), and the alcohol extract is gradually added to continue concentrating to obtain an extract, namely, the Salvia miltiorrhiza and Panax notoginseng extract, or the extract is dried to obtain the Salvia miltiorrhiza and Panax notoginseng extract.

[0046] In a fourth embodiment, the pharmaceutical composition of the present invention, wherein the Danshen medicinal material is first extracted with alcohol and then with water to obtain an extract, and the Panax notoginseng medicinal material is crushed and mixed with the above extract to obtain the Danshen and Panax notoginseng extract.

[0047] Preferably, the Salvia miltiorrhiza and Panax notoginseng medicinal materials of the present invention are extracted and crushed according to the following method:

[0048] Step (1), extracting Danshen with ethanol for 1 to 3 times, each time for 1 to 3 hours, filtering, and using the filtrate I for later use;

[0049] Step (2), boiling the residue with water for 1-3 times, each time for 1-3 hours, filtering, and using the filtrate II for later use;

[0050] Step (3), filtrate II is first concentrated and then added to filtrate I for concentration to obtain an extract;

[0051] Step (4), crushing Panax notoginseng and passing through a No. 5 sieve of the pharmacopoeia to obtain fine powder;

[0052] Step (5), adding the fine powder of Panax notoginseng to the extract obtained in step (3), mixing evenly to obtain the Salvia miltiorrhiza Panax notoginseng extract or drying the extract to obtain the Salvia miltiorrhiza Panax notoginseng extract.

[0053] In step (1), preferably 70-100% ethanol is added for extraction (optimally 90% ethanol).

[0054] Most preferably, the Salvia miltiorrhiza and Panax notoginseng extract of the present invention is prepared by the following method:

[0055] Step (1) Cut the Danshen medicinal material into pieces less than 5 cm and set aside; put the weighed Danshen into an extraction tank, add 4 times the amount of 90% ethanol to each tank, heat and boil, keep boiling for about 90min±20min, and filter;

[0056] Step (2) extracting the residue with water, adding 5 times the amount of water, heating to boil, keeping boiling for about 60min±15min, filtering, and discarding the residue;

[0057] Step (3) the water extract is concentrated under reduced pressure to a relative density of 1.25-1.30 (82±5° C.), and the alcohol extract is gradually added to continue concentrating to obtain an extract;

[0058] Step (4) Grind the Radix Notoginseng medicinal material, pass it through a No. 5 sieve of the pharmacopoeia, and obtain fine powder;

[0059] Step (5) adding the fine powder of Panax notoginseng to the extract obtained in step (3), mixing them evenly, thereby obtaining the Salvia miltiorrhiza Panax notoginseng extract or drying the extract to obtain the Salvia miltiorrhiza Panax notoginseng extract.

[0060] In a fifth embodiment, in the pharmaceutical composition of the present invention, the Danshen medicinal material and the Panax notoginseng medicinal material can also be crushed separately and then mixed to obtain a Danshen and Panax notoginseng mixture.

[0061] In one embodiment, the Salvia miltiorrhiza and Panax notoginseng extract or Salvia miltiorrhiza and Panax notoginseng mixture of the present invention can be further mixed with borneol and auxiliary materials to obtain intermediate 1, and the ranolazine and auxiliary materials can be mixed to obtain intermediate 2, and the two can be layered and loaded with drugs to prepare the corresponding preparations.

[0062] Specifically, the corresponding preparations can be double-layer tablets, double-layer dropping pills, double-layer micro-pellets, etc. For example, in certain embodiments, the intermediates 1 and 2 can be made into drug-containing pill cores, tablet cores, and dropping pills, and the other can be used as drug-containing coatings to prepare double-layer tablets, double-layer dropping pills, double-layer micro-pellets, etc.

[0063] In another embodiment, the Salvia miltiorrhiza and Panax notoginseng extract or the Salvia miltiorrhiza and Panax notoginseng mixture of the present invention can also be further mixed with borneol and auxiliary materials to prepare corresponding preparations; Ranolazine is mixed with auxiliary materials to prepare corresponding preparations, and the two are combined and packaged together.

[0064] The combination packaging mentioned herein refers to mixing the two preparations and then filling them into a suitable preparation, or mixing the two preparations and bagging them in divided doses.

[0065] The corresponding preparations described therein can be in any suitable dosage form.

[0066] Preferred are tablets, capsules, granules, dripping pills, pills, oral liquids, powders, pills, ointments, emulsions, transdermal preparations, inhalation preparations and the like.

[0067] Tablets include ordinary tablets, micro tablets, etc.; capsules include hard capsules, soft capsules, etc.; pills include ordinary pills and micro pills; pills include ordinary pills and micro pills.

[0068] More preferred are drop pills, pills, tablets and capsules.

[0069] Preferably, the auxiliary materials of the present invention may contain commonly used excipients, such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents and wetting agents, and may be coated if necessary.

[0070] Suitable fillers include microcrystalline cellulose, mannitol, lactose and other similar fillers.

[0071] Suitable disintegrants include starch, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and starch derivatives such as sodium starch glycolate.

[0072] Suitable lubricants include, for example, magnesium stearate.

[0073] Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

[0074] Solid oral compositions can be prepared by conventional methods of mixing, filling, tableting, etc. Repeated mixing can be used to distribute the active substance throughout those compositions using large amounts of fillers.

[0075] The preparation of the present invention is most preferably a common dripping pill or a micro dripping pill.

[0076] The common dropping pills or micro-dropping pills described in the present invention are made of a drug active ingredient (for example, the drug composition of the present invention, a mixture of a salvia miltiorrhiza and Panax notoginseng extract or a salvia miltiorrhiza and Panax notoginseng mixture and borneol, or ranolazine) and a dropping pill matrix in a weight ratio of 1:5-5:1.

[0077] Preferably, the common dropping pills or micro-dropping pills described in the present invention are made of the active pharmaceutical ingredient and the dropping pill matrix in a weight ratio of 1:3-3:1.

[0078] Most preferably, the weight ratio of the active ingredient to the pill matrix is ​​1:1-3.

[0079] Wherein, the drop pill matrix is ​​selected from: polyethylene glycol, sorbitol, xylitol, lactitol, erythritol, poloxamer 188, polyvinyl pyrrolidone, stearic acid, maltose, starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, gum arabic, gelatin, alginic acid, dextrin, cyclodextrin, agar, lactose. Polyethylene glycol is preferred, such as solid polyethylene glycol 1000-8000; that is, one or more combinations of polyethylene glycol 1000, 2000, 3000, 4000, 6000, 8000, and the best is polyethylene glycol 6000 or 4000 or a combination of polyethylene glycol 4000-6000.

[0080] The preparation method of the common drop pills or micro drop pills of the present invention is prepared by using existing technology, such as the method disclosed in Chinese patent CN104274520 A or CN 104274518 A.

[0081] The present invention also provides use of the pharmaceutical composition of the present invention in preparing a drug for preventing and / or treating myocardial ischemia.

[0082] The pharmaceutical composition described in the present invention is superior to the existing technology (such as the use of ranolazine or a Chinese medicine composition consisting of salvia miltiorrhiza, Panax notoginseng and borneol alone) in preventing and / or treating myocardial ischemia. In addition, the pharmaceutical composition of the present invention can reduce the dosage of ranolazine while ensuring the therapeutic effect, thereby greatly reducing the possible toxic and side effects of ranolazine used alone. Specific implementation method:

[0083] Example 1

[0084] 1. The pharmaceutical composition of the present invention is composed of 1250 mg of Danshen medicinal material, 250 mg of Panax notoginseng medicinal material, 15 mg of borneol, and 500 mg of ranolazine.

[0085] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0086] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 5 times the amount of process water to each tank, heat and boil, keep boiling for about 2h±20min, and filter;

[0087] Step (2) The residue is subjected to a second extraction, 4 times the amount of water is added, heated to boiling, and kept boiling for about 1h±15min, filtered, and the residue is discarded;

[0088] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5°C) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain a salvia miltiorrhiza and Panax notoginseng extract, wherein the solid matter (excluding the amount of water, i.e., the dry weight) is about 150 mg.

[0089] 3. The Danshen and Panax notoginseng extract of the present invention, borneol and auxiliary materials are prepared into a micro-pill preparation according to the following method:

[0090] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 150mg Borneol 15mg Polyethylene glycol 6000 220mg Polyethylene glycol 4000 110mg

[0091] Polyethylene glycol 4000 and polyethylene glycol 6000 are mixed and heated to melt, and borneol and salvia miltiorrhiza and notoginseng extract are added, and an appropriate amount of purified water is added, and the mixture is fully mixed, and the mixture is vibrated and dripped, condensed, dried, coated, and screened to obtain micro-droplet pellets.

[0092] 4. The ranolazine of the present invention is prepared according to the following formula:

[0093] Ranolazine 500mg Polyethylene glycol 6000 199mg Polyethylene glycol 4000 796mg Sodium Lauryl Sulfate 5mg

[0094] Polyethylene glycol 4000 and polyethylene glycol 6000 are mixed and heated to melt, and ranolazine fine powder and sodium lauryl sulfate are added, and the mixture is fully mixed, dripped, condensed, and screened to obtain ranolazine micro-dropping pills.

[0095] 5. The above-mentioned micro-pills and ranolazine micro-pills are mixed evenly, and loaded into No. 0 gelatin capsules to obtain the pharmaceutical composition preparation of the present invention.

[0096] Example 2

[0097] 1. The pharmaceutical composition of the present invention is composed of 7000 mg of Danshen medicinal material, 1500 mg of Panax notoginseng medicinal material, 45 mg of borneol, and 500 mg of ranolazine.

[0098] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0099] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 5 times the amount of process water to each tank, heat and boil, keep boiling for about 2h±20min, and filter;

[0100] Step (2) The residue is subjected to a second extraction, 4 times the amount of water is added, heated to boiling, and kept boiling for about 1h±15min, filtered, and the residue is discarded;

[0101] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5° C.) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain a Salvia miltiorrhiza and Panax notoginseng extract, wherein the solid matter (the amount after removing the water, i.e., the dry weight) is about 450 mg.

[0102] 3. The Danshen and Panax notoginseng extract of the present invention, borneol and auxiliary materials are prepared into a micro-pill preparation according to the following method:

[0103] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 450mg Borneol 45mg Poloxamer 188 90mg Polyethylene glycol 6000 900mg

[0104] Polyethylene glycol 6000 and poloxamer 188 are mixed and heated to melt, and borneol and salvia miltiorrhiza and notoginseng extract are added, and an appropriate amount of purified water is added, and the mixture is fully mixed, and the mixture is dripped by vibration, condensed, dried, coated, and screened to obtain micro-droplet pellets.

[0105] 4. Prepare Ranolazine Micro-Pellets according to the following formula:

[0106] Ranolazine 500mg Polyethylene glycol 3350 500mg Polyethylene glycol 4000 495mg Twain 80 5mg

[0107] Polyethylene glycol 4000 and polyethylene glycol 3350 are mixed and heated to melt, and ranolazine fine powder and Tween 80 are added, and the mixture is fully mixed, dripped, condensed, and screened to obtain ranolazine micro-dropping pills.

[0108] 5. The above-mentioned micro-pills and ranolazine micro-pills are mixed evenly, and packed into a medicinal aluminum-plastic composite film bag to obtain the pharmaceutical composition preparation of the present invention.

[0109] Example 3

[0110] 1. The pharmaceutical composition of the present invention is composed of 7000 mg of Danshen medicinal material, 1500 mg of Panax notoginseng medicinal material, 45 mg of borneol, and 250 mg of ranolazine.

[0111] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0112] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 5 times the amount of process water to each tank, heat and boil, keep boiling for about 2h±20min, and filter;

[0113] Step (2) The residue is subjected to a second extraction, 4 times the amount of water is added, heated to boiling, and kept boiling for about 1h±15min, filtered, and the residue is discarded;

[0114] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5° C.) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain a Salvia miltiorrhiza and Panax notoginseng extract, wherein the solid matter (the amount after removing the water, i.e., the dry weight) is about 450 mg.

[0115] 3. The Danshen and Panax notoginseng extract of the present invention, borneol and auxiliary materials are prepared into a micro-pill preparation according to the following method:

[0116] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 450mg Borneol 45mg Polyethylene glycol 6000 990mg

[0117] The polyethylene glycol 6000 is heated and melted, and borneol and salvia miltiorrhiza and notoginseng extract are added, and an appropriate amount of purified water is added, and the mixture is fully mixed, and the mixture is vibrated and dripped, condensed, dried, coated, and screened to obtain micro-droplet pellets.

[0118] 4. Prepare ranolazine microtablets according to the following formula:

[0119] Ranolazine 250mg lactose 200mg Low substituted hydroxypropyl cellulose 20mg Polyethylene glycol 6000 20mg Sodium Lauryl Sulfate 2mg Micro powder silica gel 3mg Magnesium Stearate 5mg

[0120] Ranolazine fine powder is mixed with lactose, low-substituted hydroxypropyl cellulose, polyethylene glycol 6000 and sodium lauryl sulfate to prepare granules, the granules are fully mixed with micro-powder silica gel and magnesium stearate, and micro-tablets are pressed to obtain ranolazine micro-tablets.

[0121] 5. The above-mentioned micro-pills and ranolazine micro-tablets are sequentially loaded into No. 0 gelatin capsules to obtain the pharmaceutical composition preparation of the present invention.

[0122] Example 4

[0123] 1. The pharmaceutical composition of the present invention is composed of 1250 mg of Danshen medicinal material, 250 mg of Panax notoginseng medicinal material, 15 mg of borneol, and 250 mg of ranolazine.

[0124] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0125] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 4 times the amount of process water to each tank, heat and boil, keep boiling for about 3 hours, and filter;

[0126] Step (2) The residue is subjected to a second extraction, 5 times the amount of water is added, heated to boiling, and kept boiling for about 2 hours, filtered, and the residue is discarded;

[0127] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5°C) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain a salvia miltiorrhiza and Panax notoginseng extract, wherein the solid matter (excluding the amount of water, i.e., the dry weight) is about 150 mg.

[0128] 3. The Danshen and Panax notoginseng extract of the present invention, borneol and auxiliary materials are prepared into a micro-pill preparation according to the following method:

[0129] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 150mg Borneol 15mg Polyvinylpyrrolidone 30mg Polyethylene glycol 6000 300mg

[0130] Polyethylene glycol 6000 and polyvinyl pyrrolidone are mixed and heated to melt, and borneol and salvia miltiorrhiza and notoginseng extract are added, and an appropriate amount of purified water is added, and the mixture is fully mixed, and the mixture is vibrated and dripped, condensed, dried, coated, and screened to obtain micro-droplet pellets.

[0131] 4. Prepare ranolazine microtablets according to the following formula:

[0132] Ranolazine 250mg Microcrystalline Cellulose 300mg Pregelatinized starch 50mg Crospovidone 24mg Starch slurry 11mg Span 20 2mg Magnesium Stearate 3mg

[0133] The ranolazine fine powder is mixed evenly with microcrystalline cellulose, pregelatinized starch and cross-linked polyvinylpyrrolidone, and a mixture of starch slurry and Span 20 is added to the mixed powder as a binder to granulate, dry, sieve, add magnesium stearate, mix evenly, and tablet to obtain ranolazine microtablets.

[0134] 5. The above-mentioned micro-pills are loaded into a No. 0 gelatin capsule, and the ranolazine micro-tablets are loaded into a No. 0 gelatin capsule. The two capsules are blistered together side by side to obtain the pharmaceutical composition preparation of the present invention.

[0135] Example 5

[0136] 1. The pharmaceutical composition of the present invention is composed of 2500 mg of Danshen medicinal material, 500 mg of Panax notoginseng medicinal material, 60 mg of borneol, and 1000 mg of ranolazine.

[0137] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0138] Danshen extract: first put Danshen into the extraction tank, then add an appropriate amount of sodium bicarbonate (2.25% of the medicinal material), add 5 times the amount of water, boil at 100°C for 3 hours, and filter; extract the residue for the second time, add 5 times the amount of water, boil at 100°C for 2 hours, filter, and discard the residue; combine the filtrates of the two decoctions, and concentrate at 80°C to 90°C under reduced pressure to a relative density of 1.16 to 1.20 (80±1°C) or a sugar content of 48% to 52% to obtain a concentrated solution; add an appropriate amount of ethanol to the concentrated solution to adjust the alcohol content to 65% to 70% (20°C), let it stand at low temperature for 12hr to 24hr until the precipitation is complete, separate the supernatant, and discard the precipitate; concentrate the supernatant under reduced pressure to a sugar content of 82% to 88%, and obtain the Danshen extract.

[0139] Panax notoginseng extract: Panax notoginseng is crushed into particles with a diameter of less than 1.5 cm, and the crushed Panax notoginseng is first put into the extraction tank, and 5 times the amount of water is added, and the mixture is soaked for 12-15 hours. Then, an appropriate amount of sodium bicarbonate (2.25% of the medicinal material amount) is added, and the mixture is decocted at 100°C for 3 hours, and filtered; the residue is subjected to a second extraction, and 5 times the amount of water is added, and the mixture is decocted at 100°C for 2 hours, filtered, and the residue is discarded; the filtrates from the two decoctions are combined, and concentrated under reduced pressure at 80°C to 90°C to a sugar content of 18% to 28% to obtain a concentrated solution; an appropriate amount of ethanol is added to the concentrated solution to adjust the alcohol content to 65% to 70% (20°C), and the solution is allowed to stand at low temperature for 15 hours to 24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated under reduced pressure to a sugar content of 60% to 75%, and the Panax notoginseng extract is obtained.

[0140] The Danshen extract and the Panax notoginseng extract are combined to obtain the Danshen and Panax notoginseng extract, the solid matter (excluding the amount of water, i.e., dry weight) of which is about 200 mg.

[0141] 3. The Danshen and Panax notoginseng extract of the present invention, borneol and auxiliary materials are prepared into a micro-pill preparation according to the following method:

[0142] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 200mg Borneol 60mg Polyethylene glycol 6000 600mg

[0143] Heat and melt polyethylene glycol 6000, add borneol and salvia miltiorrhiza and Panax notoginseng extract, add appropriate amount of purified water, mix well, vibrate, drip, condense, dry, coat, screen to obtain micro-drop pellets, and put the micro-drop pellets into No. 0 capsules.

[0144] 4. Prepare Ranolazine Tablets according to the following formula:

[0145]

[0146]

[0147] Ranolazine fine powder is mixed evenly with methacrylic acid copolymer type C, microcrystalline cellulose and polyvinyl pyrrolidone, and sodium hydroxide aqueous solution is added to the above mixed powder as a binder to prepare granules. A 30% aqueous dispersion of methyl methacrylate / ethyl acrylate is added to the wet granules. The obtained granules are dried, sieved, and cross-linked sodium carboxymethyl cellulose and magnesium stearate are added. The mixture is mixed evenly and tableted to obtain ranolazine sustained-release tablets.

[0148] 5. Blister the ranolazine sustained-release tablets and micro-pill capsules in a row to obtain the pharmaceutical composition preparation of the present invention.

[0149] Example 6

[0150] 1. The pharmaceutical composition of the present invention is composed of 2500 mg of Danshen medicinal material, 1500 mg of Panax notoginseng medicinal material, 60 mg of borneol, and 375 mg of ranolazine.

[0151] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0152] Danshen extract: first put Danshen into the extraction tank, then add an appropriate amount of sodium bicarbonate (2.25% of the medicinal material), add 5 times the amount of water, boil at 100°C for 2 hours, and filter; extract the residue for the second time, add 4 times the amount of water, boil at 100°C for 1 hour, filter, and discard the residue; combine the filtrates of the two decoctions, and concentrate at 80°C to 90°C under reduced pressure to a relative density of 1.16 to 1.20 (80±1°C) or a sugar content of 48% to 52% to obtain a concentrated solution; add an appropriate amount of ethanol to the concentrated solution to adjust the alcohol content to 65% to 70% (20°C), let it stand at low temperature for 12hr to 24hr until the precipitation is complete, separate the supernatant, and discard the precipitate; concentrate the supernatant under reduced pressure to a sugar content of 82% to 88%, and obtain the Danshen extract.

[0153] Panax notoginseng extract: Panax notoginseng is crushed into particles with a diameter of less than 1.5 cm, and the crushed Panax notoginseng is first put into the extraction tank, and 5 times the amount of water is added, and the mixture is soaked for 12-15 hours. Then, an appropriate amount of sodium bicarbonate (2.25% of the medicinal material amount) is added, and the mixture is decocted at 100°C for 2 hours, and filtered; the residue is subjected to a second extraction, and 4 times the amount of water is added, and the mixture is decocted at 100°C for 1 hour, filtered, and the residue is discarded; the filtrates from the two decoctions are combined, and concentrated under reduced pressure at 80°C to 90°C to a sugar content of 18% to 28% to obtain a concentrated solution; an appropriate amount of ethanol is added to the concentrated solution to adjust the alcohol content to 65% to 70% (20°C), and the solution is allowed to stand at low temperature for 15 hours to 24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated under reduced pressure to a sugar content of 60% to 75%, and the Panax notoginseng extract is obtained.

[0154] The Danshen extract and the Panax notoginseng extract were combined to obtain the Danshen and Panax notoginseng extract, the solid matter (excluding the amount of water, i.e. the dry weight) of which was about 300 mg.

[0155] 3. The Danshen and Panax notoginseng extract of the present invention, borneol and auxiliary materials are prepared into a micro-pill preparation according to the following method:

[0156] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 300mg Borneol 60mg gelatin 50mg Polyethylene glycol 4000 750mg

[0157] Polyethylene glycol 4000 and gelatin are mixed and heated to melt, borneol and salvia miltiorrhiza and Panax notoginseng extract are added, and an appropriate amount of purified water is added. The mixture is fully mixed, dripped by vibration, condensed, dried, coated, and screened to obtain micro-droplet pellets.

[0158] 4. Prepare ranolazine sustained-release microtablets according to the following formula:

[0159] Ranolazine 375mg Microcrystalline Cellulose 53mg Methacrylic acid copolymer type C 50mg Sodium hydroxide 2mg Hydroxypropyl methylcellulose 10mg Magnesium Stearate 10mg

[0160] The ranolazine fine powder is mixed evenly with methacrylic acid copolymer type C, microcrystalline cellulose and hypromellose, and an aqueous sodium hydroxide solution is added, granulated, dried, sieved, and magnesium stearate is added, mixed evenly, and then tableted and coated to obtain ranolazine sustained-release microtablets.

[0161] 5. The above-mentioned ranolazine sustained-release microtablets and micropills are sequentially loaded into No. 0 gelatin capsules to obtain the pharmaceutical composition preparation of the present invention.

[0162] Example 7

[0163] 1. The pharmaceutical composition of the present invention is composed of 1250 mg of Danshen medicinal material, 250 mg of Panax notoginseng medicinal material, 45 mg of borneol, and 250 mg of ranolazine.

[0164] 2. The mixture of Salvia miltiorrhiza and Panax notoginseng is prepared according to the following method:

[0165] The Salvia miltiorrhiza medicinal material was crushed and passed through an 80-mesh sieve.

[0166] Grind the Panax notoginseng medicinal material and pass it through an 80-mesh sieve.

[0167] The above powders are mixed to obtain a salvia miltiorrhiza and Panax notoginseng mixture.

[0168] 3. The salvia miltiorrhiza and Panax notoginseng mixture of the present invention is mixed with borneol and micro-powder silica gel to obtain a mixed powder:

[0169] Danshen Panax Notoginseng Mixture 1500mg Borneol 45mg Micro powder silica gel 8mg

[0170] 4. Prepare ranolazine microtablets according to the following formula:

[0171] Ranolazine 250mg starch 200mg Low substituted hydroxypropyl cellulose 25mg Sodium Carboxymethyl Cellulose 18mg Twain 80 2mg Magnesium Stearate 5mg

[0172] The ranolazine fine powder is mixed with starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and Tween 80, and purified water is added for granulation. The mixture is dried and granulated. Magnesium stearate is added and the mixture is mixed and then tabletted to obtain ranolazine microtablets.

[0173] 5. The mixed powder of the above-mentioned ranolazine microtablets and the mixture of salvia miltiorrhiza and Panax notoginseng is sequentially loaded into No. 0 gelatin capsules to obtain the pharmaceutical composition preparation of the present invention.

[0174] Example 8

[0175] 1. The pharmaceutical composition of the present invention is composed of 7000 mg of Danshen medicinal material, 500 mg of Panax notoginseng medicinal material, 45 mg of borneol, and 250 mg of ranolazine.

[0176] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0177] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 4 times the amount of process water to each tank, heat and boil, keep boiling for about 3 hours, and filter;

[0178] Step (2) The residue is subjected to a second extraction, 5 times the amount of water is added, heated to boiling, and kept boiling for about 2 hours, filtered, and the residue is discarded;

[0179] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5° C.) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain a Salvia miltiorrhiza and Panax notoginseng extract, wherein the solid matter (the amount after removing the water, i.e., the dry weight) is about 450 mg.

[0180] 3. The Danshen and Panax notoginseng extract of the present invention, borneol and auxiliary materials are prepared into a micro-pill preparation according to the following method:

[0181] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 450mg Borneol 45mg Xylitol 45mg Erythritol 90mg Polyethylene glycol 6000 745mg

[0182] Polyethylene glycol 6000, erythritol and xylitol are mixed and heated to melt, borneol and salvia miltiorrhiza and notoginseng extract are added, and an appropriate amount of purified water is added, and the mixture is fully mixed, vibrated and dripped, condensed, dried, coated, and screened to obtain micro-droplet pellets.

[0183] 4. Prepare ranolazine pellets according to the following formula:

[0184] Ranolazine 250mg Microcrystalline Cellulose 150mg Sucrose powder 200mg Crospovidone 38mg Span 20 2mg

[0185] The ranolazine fine powder was mixed evenly with microcrystalline cellulose, sucrose powder and cross-linked polyvinylpyrrolidone, and a soft material was prepared using a Span 20 aqueous suspension as a binder. The mixture was extruded, rolled into a round shape, dried and sieved to obtain the ranolazine microcapsules.

[0186] 5. After uniformly mixing the above-mentioned micro-pills and ranolazine micro-pills, they are loaded into No. 0 gelatin capsules to obtain a pharmaceutical composition preparation.

[0187] Example 9

[0188] 1. The pharmaceutical composition of the present invention is composed of 7000 mg of Danshen medicinal material, 500 mg of Panax notoginseng medicinal material, 45 mg of borneol, and 250 mg of ranolazine.

[0189] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0190] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 4 times the amount of process water to each tank, heat and boil, keep boiling for about 3 hours, and filter;

[0191] Step (2) The residue is subjected to a second extraction, 5 times the amount of water is added, heated to boiling, and kept boiling for about 2 hours, filtered, and the residue is discarded;

[0192] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5° C.) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain a Salvia miltiorrhiza and Panax notoginseng extract, wherein the solid matter (the amount after removing the water, i.e., the dry weight) is about 450 mg.

[0193] 3. The outer layer of the double-layer dripping pill of the present invention is a layer of Danshen Panax notoginseng, and the dripping material liquid is prepared according to the following method:

[0194] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 450mg Borneol 45mg Polyethylene glycol 6000 1000mg

[0195] Heat and melt polyethylene glycol 6000, add borneol and salvia miltiorrhiza and Panax notoginseng extract, add appropriate amount of purified water, mix well and obtain outer layer liquid.

[0196] 4. The inner layer of the double-layer dropping pill is the ranolazine layer, and the dropping liquid is prepared according to the following formula:

[0197] Ranolazine 250mg Polyethylene glycol 4000 750mg

[0198] Heat and melt polyethylene glycol 4000, add ranolazine fine powder and mix thoroughly to obtain the inner layer liquid.

[0199] 5. The above-mentioned liquid is dripped into double-layer dripping pills, which are packed into a medicinal aluminum-plastic composite film bag to obtain a medicinal composition preparation.

[0200] Example 10

[0201] 1. The pharmaceutical composition of the present invention is composed of 1250 mg of Danshen medicinal material, 250 mg of Panax notoginseng medicinal material, 30 mg of borneol, and 500 mg of ranolazine.

[0202] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0203] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 4 times the amount of process water to each tank, heat and boil, keep boiling for about 3 hours, and filter;

[0204] Step (2) The residue is subjected to a second extraction, 5 times the amount of water is added, heated to boiling, and kept boiling for about 2 hours, filtered, and the residue is discarded;

[0205] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5°C) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated to obtain a salvia miltiorrhiza and Panax notoginseng extract, wherein the solid matter (excluding the amount of water, i.e., the dry weight) is about 150 mg.

[0206] 3. Prepare ranolazine pellets according to the following formula:

[0207] Ranolazine 500mg Microcrystalline Cellulose 300mg Sucrose powder 400mg Crospovidone 80mg

[0208] The ranolazine fine powder is mixed evenly with microcrystalline cellulose, sucrose powder and cross-linked polyvinylpyrrolidone, and a soft material is prepared with water as a binder. The material is extruded, rolled into a round shape, dried and sieved to obtain the ranolazine microcapsules.

[0209] 4. Suspend the borneol powder in the Salvia miltiorrhiza and Panax notoginseng extract, add water to mix, and spray it onto the fluidized ranolazine micropellets to obtain double-layer micropellets. Put the micropellets into No. 0 gelatin capsules to obtain a pharmaceutical composition preparation.

[0210] Embodiment 11

[0211] 1. The pharmaceutical composition of the present invention is composed of 2500 mg of Danshen medicinal material, 500 mg of Panax notoginseng medicinal material, 30 mg of borneol, and 500 mg of ranolazine.

[0212] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0213] Step (1) Cut the Danshen medicinal material into pieces less than 5 cm and set aside; put the weighed Danshen into an extraction tank, add 4 times the amount of 90% ethanol to each tank, heat and boil, keep boiling for about 90 minutes, and filter;

[0214] Step (2) extracting the residue with water, adding 5 times the amount of water, heating to boil, keeping boiling for about 60 minutes, filtering, and discarding the residue;

[0215] Step (3) the water extract is concentrated under reduced pressure to a relative density of 1.25-1.30 (82±5° C.), and the alcohol extract is gradually added to continue concentrating to obtain an extract;

[0216] Step (4) Grind the Radix Notoginseng medicinal material, pass it through a No. 5 sieve of the pharmacopoeia, and obtain fine powder;

[0217] Step (5) adding the fine powder of Panax notoginseng to the extract obtained in step (3), mixing evenly, drying, and crushing to obtain about 1000 mg of Salvia miltiorrhiza and Panax notoginseng extract.

[0218] 3. Prepare Danshen Sanqi Granules according to the following formula:

[0219]

[0220]

[0221] Mix the Danshen and Panax notoginseng extract with microcrystalline cellulose and borneol evenly, add water to make granules, add magnesium stearate and mix evenly, and set aside.

[0222] 4. Prepare ranolazine granules according to the following formula:

[0223] Ranolazine 500mg Microcrystalline Cellulose 71mg Methacrylic acid copolymer type C 67mg Sodium hydroxide 2.7mg Hydroxypropyl methylcellulose 14mg Magnesium Stearate 14mg

[0224] The fine powder of ranolazine is mixed evenly with methacrylic acid copolymer type C, microcrystalline cellulose and hydroxypropyl methylcellulose, and an aqueous sodium hydroxide solution is added, granulated, dried, sieved, and magnesium stearate is added to mix evenly and set aside.

[0225] 5. Press the Danshen Sanqi granules and the Ranolazine granules into double-layer tablets to obtain a pharmaceutical composition preparation.

[0226] Example 12

[0227] 1. The pharmaceutical composition of the present invention is composed of 1250 mg of Danshen medicinal material, 250 mg of Panax notoginseng medicinal material, 15 mg of borneol, and 250 mg of ranolazine.

[0228] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0229] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set them aside; weigh an appropriate amount of sodium bicarbonate (2.25-3% of the medicinal material amount), and set them aside; put the weighed Danshen, Panax notoginseng, and sodium bicarbonate into an extraction tank, add 4 times the amount of process water to each tank, heat and boil, keep boiling for about 3 hours, and filter;

[0230] Step (2) The residue is subjected to a second extraction, 5 times the amount of water is added, heated to boiling, and kept boiling for about 2 hours, filtered, and the residue is discarded;

[0231] Step (3) The extract is concentrated under reduced pressure to a relative density of 1.16-1.20 (80±5° C.) or a corresponding sugar content of 48-52% to obtain a concentrated solution; the concentrated solution is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65-70%, and the solution is allowed to stand for 12-24 hours until the precipitation is complete, and the supernatant is separated and the precipitate is discarded; the supernatant is concentrated and spray-dried to obtain a salvia miltiorrhiza and panax notoginseng extract, wherein the solid matter (the amount after removing the water, i.e., the dry weight) is about 150 mg.

[0232] 3. Prepare Danshen and Panax notoginseng fine powder according to the following formula

[0233] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 150mg Borneol 15mg lactose 60mg Silicon dioxide 15mg Stevioside 10mg Magnesium Stearate 10mg

[0234] The salvia miltiorrhiza and notoginseng extract is mixed with borneol, stevioside, silicon dioxide, magnesium stearate and lactose, and then crushed through a 200-mesh sieve to obtain salvia miltiorrhiza and notoginseng fine powder;

[0235] 4. Preparation of Ranolazine Fine Powder:

[0236] A fine powder of ranolazine was prepared according to the following proportions.

[0237] Ranolazine 250mg lactose 100mg Silicon dioxide 15mg Stevioside 10mg

[0238] Ranolazine is mixed evenly with lactose, silicon dioxide and steviol glycoside, and then crushed and passed through a 200-mesh sieve to obtain ranolazine fine powder.

[0239] 5. Evenly mix the Danshen and Panax notoginseng fine powders and the ranolazine fine powders, and put them into a plastic powder spray bottle to obtain an inhaler, i.e., the pharmaceutical composition preparation of the present invention.

[0240] Embodiment 13

[0241] 1. The pharmaceutical composition of the present invention is composed of 1250 mg of Danshen medicinal material, 250 mg of Panax notoginseng medicinal material, 15 mg of borneol, and 500 mg of ranolazine.

[0242] 2. The Danshen Panax notoginseng extract was prepared according to the following method:

[0243] Step (1) Cut the medicinal material of Danshen into pieces less than 5 cm, and crush Panax notoginseng into particles less than 1 cm, and set aside; put the weighed Danshen and Panax notoginseng into an extraction tank, add 4 times the amount of 90% ethanol to each tank, heat and boil, keep boiling for about 90min±20min, and filter;

[0244] Step (2) extracting the residue with water, adding 5 times the amount of water, heating to boil, keeping boiling for about 60min±15min, filtering, and discarding the residue;

[0245] Step (3) The water extract is concentrated under reduced pressure to a relative density of 1.25-1.30 (82±5°C), and the alcohol extract is gradually added to continue concentrating to obtain an extract, namely, a Salvia miltiorrhiza and Panax notoginseng extract, whose solid matter (excluding the amount of water, i.e., dry weight) is about 250 mg.

[0246] 3. Preparation of capsule contents:

[0247] Prepare capsule contents according to the following proportions:

[0248] Salvia miltiorrhiza and Panax notoginseng extract (dry basis) 250mg Borneol 15mg Ranolazine 500mg Hydroxypropyl methylcellulose 50mg Soybean Oil 900mg beeswax 30mg Polysorbate 80 5mg

[0249] The above-mentioned Salvia miltiorrhiza and Panax notoginseng extract, borneol, ranolazine, hydroxypropyl methylcellulose, beeswax and polysorbate 80 are successively added to soybean oil, mixed, ground evenly by a colloid mill, and pressed into soft capsules to obtain the pharmaceutical composition preparation of the present invention.

[0250] Experimental Example 1 Screening experiment of the proportion of the drug composition of the present invention and its effect on the duration of rotarod exercise in normal mice

[0251] 1 Materials and methods

[0252] 1.1 Experimental animals

[0253] CD-1 mice, male, 18-22 g, laboratory animal quality certificate number: 110011200105606931, were purchased from Beijing Weitonglihua.

[0254] 1.2 Main instruments

[0255] Table 1. Main experimental instruments

[0256]

[0257]

[0258] 1.3 Drug grouping

[0259] The proportion of the pharmaceutical composition of the present application is also obtained through screening. The present application designed the following experimental groups, in which the Danshen Panax notoginseng extracts were prepared according to the method in Example 1:

[0260] Table 2 Grouping design of drug composition

[0261]

[0262] The above pharmaceutical compositions were converted into clinical equivalent doses for mice:

[0263] Table 3 Clinical equivalent dose conversion of each drug composition group designed by the present invention

[0264] Chinese medicine composition (Danshen and Panax notoginseng extract (dry weight) + borneol) Ranolazine Composition 1 set 303mg / kg 102mg / kg Composition 2 sets 209mg / kg 102mg / kg Composition 3 groups 135mg / kg 102mg / kg Composition 4 groups 48mg / kg 102mg / kg Composition 5 groups 48mg / kg 205mg / kg Composition 6 groups 48mg / kg 410mg / kg

[0265] 1.4 Experimental methods

[0266] 70 experimental animals were randomly divided into 7 groups (n=10): normal group, combination group 1, combination group 2, combination group 3, combination group 4, combination group 5, and combination group 6. The mice in the normal group were gavaged with an equal amount of distilled water 7 days before administration. The mice were placed on the rotating rod 60 minutes after the last administration. The fatigue rotating rod instrument was first adjusted to the training state, and the mice were placed on the rotating rod for adaptive training for 10 minutes. Then the fatigue rotating rod instrument was adjusted to the test state with a rotation speed of 30r / min. The trained mice were placed on the rotating rod in turn and observed for 60 minutes continuously. The time for the mice to continue to move on the roller without falling was recorded.

[0267] 2 Experimental results

[0268] The total experiment time was 30 minutes. When the mouse fell from the rotating rod, the channel timer stopped timing, and the mouse's exercise time and the number of falls within 30 minutes were calculated. The experimental results showed that after 7 days of pre-administration, the exercise time of the mice in the drug-administered groups increased to varying degrees. Among them, the efficacy results of Composition Group 3 and Composition Group 4, i.e., the ratio of Danshen medicinal materials, Panax notoginseng medicinal materials, borneol and ranolazine was (250-700): (50-150): (3-9): (25-100) were more obvious, and there was a statistical difference compared with the normal group.

[0269] Table 4 Effects of each combination group on the duration of rotarod exercise in normal mice

[0270]

[0271] Note: Compared with the normal group, *: P<0.05

[0272] 3 Conclusion

[0273] Under the experimental conditions, each combination group can improve the rotarod exercise time of normal mice to varying degrees. Among them, the efficacy results of combination group 3 and combination group 4, i.e., when the ratio of salvia miltiorrhiza, Panax notoginseng, borneol and ranolazine is between (250-700): (50-150): (3-9): (25-100), are more obvious.

[0274] Experimental Example 2 Effect of the pharmaceutical composition of the present invention on the weight-bearing swimming time of normal mice

[0275] 1 Experimental Materials and Methods

[0276] 1.1 Experimental animals

[0277] BALB / c mice, male, 18-22g, laboratory animal quality certificate number: 1100111911047118

[0278] 1.2 Drug grouping

[0279] The pharmaceutical composition group of the present invention (hereinafter referred to as the composition group) was prepared according to the method of Example 1. The daily dosage for mice was: the Chinese medicine composition (Danshen Panax notoginseng extract (dry weight) + borneol) 34 mg / kg; the amount of ranolazine was 102 mg / kg;

[0280] Control group:

[0281] The Chinese medicine group (Danshen Panax notoginseng extract (dry weight) + borneol) was prepared according to the method of Example 1 of the present invention, and the dosage was set to be twice of the Chinese medicine composition in the pharmaceutical composition of the present invention, i.e. 68 mg / kg;

[0282] The ranolazine group was set to be twice the ranolazine dose in the pharmaceutical composition group of the present invention, i.e., about 205 mg / kg;

[0283] 1.3 Experimental methods

[0284] According to the reference, 40 male mice were randomly divided into 4 groups (n=10): normal group, ranolazine group, Chinese medicine group, and pharmaceutical composition group of the present invention. The mice in the normal group were gavaged with an equal amount of distilled water for 7 days before the administration. A swimming test was conducted 30 minutes after the last administration. A weight of 5% of the body weight of the mice was fixed to the tail of the mice, and then the mice were placed in a large container filled with clean water of about 20 cm. The water should not be too full to prevent the mice from jumping out. The mice were forced to swim to exhaustion, and the mice swam until death. The recorded time was used as the weight-bearing swimming time of the mice. The grouping and dosage settings are shown in Table 5.

[0285] Table 5 Grouping of the drug composition of the present invention on the weight-bearing swimming endurance of normal mice

[0286]

[0287] 2 Experimental results

[0288] 2.1 Experiment on the effect of weighted swimming endurance on normal mice

[0289] The experimental results show that the Chinese medicine group and the pharmaceutical composition group of the present invention can significantly increase the swimming time of normal mice. The results are shown in Table 6.

[0290] Table 6 Effect of the pharmaceutical composition of the present invention on the weight-bearing swimming endurance of normal mice (x±s)

[0291]

[0292] *: Compared with the normal group, P<0.05

[0293] 3 Conclusion

[0294] Under the experimental conditions, after 7 days of pre-administration, the pharmaceutical composition of the present invention can significantly prolong the swimming time of normal mice and improve their exercise endurance.

[0295] Experimental Example 3 Effect of the pharmaceutical composition of the present invention on exercise duration and cardiac function in rats with myocardial ischemia

[0296] 1 Materials and methods

[0297] 1.1 Experimental animals

[0298] SD rats, male, 180-220 g, laboratory animal quality certificate number: 110011200109011573.

[0299] 1.2 Main instruments

[0300] Table 7 Main experimental instruments

[0301]

[0302] 1.3 Test substances

[0303] The pharmaceutical composition group of the present invention is set up into 2 groups:

[0304] Composition group 1: prepared according to the method of Example 2 of the present invention. The daily dosage for rats is: the Chinese medicine composition (Danshen Panax notoginseng extract (calculated on a dry basis) + borneol) is 50 mg / kg; the amount of ranolazine is 50 mg / kg;

[0305] Composition group 2: prepared according to the method of Example 3 of the present invention. The daily dosage for rats is: the Chinese medicine composition (Danshen and Panax notoginseng extract (calculated on a dry basis) + borneol) is 50 mg / kg; the amount of ranolazine is 25 mg / kg.

[0306] Control group:

[0307] The Chinese medicine group (Danshen and Panax notoginseng extract group (dry weight) + borneol) was prepared according to the method of Example 2 of the present invention, and the same dosage as the Chinese medicine composition (Danshen and Panax notoginseng extract (dry weight) + borneol) in the composition group was set, i.e., 50 mg / kg;

[0308] The ranolazine group was divided into 3 groups:

[0309] Ranolazine group 1: The dose of ranolazine administered in group 1 was set to be twice that of the ranolazine administered in group 1, i.e., 100 mg / kg.

[0310] Ranolazine Group 2: The administration dose of Ranolazine was set to be the same as that of the Composition Group 1, i.e., 50 mg / kg.

[0311] Ranolazine group 3: The administration dose of ranolazine was set to be the same as that of the composition group 2, i.e., 25 mg / kg.

[0312] 2 Experimental methods

[0313] 110 experimental animals were purchased, of which 10 animals were set as sham operation group, and 100 animals were used for left anterior descending coronary artery ligation modeling. After the modeling was completed, the surviving rats were randomly divided into solvent control group, Chinese medicine group, ranolazine group 1, ranolazine group 2, ranolazine group 3, pharmaceutical composition group 1 of the present invention, and pharmaceutical composition group 2 of the present invention according to their body weight. The therapeutic administration lasted for 28 days, and the rats in the solvent group were gavaged with an equal amount of solvent. On the 28th day of gavage of the experimental animals, 6 rats were randomly selected from each group for ultrasonic cardiography detection. The experimental animals were gavaged and administered 60 minutes after gavage on the 30th day, and the animals were sampled after the weight-bearing swimming was completed. The groups are shown in Table 8.

[0314] Table 8 Experimental grouping of the protective effect of the pharmaceutical composition of the present invention on rats with myocardial ischemia

[0315]

[0316] 3 Experimental results

[0317] 3.1 Weighted swimming duration test

[0318] On the 30th day, the experimental animals were given the drug by gavage and a weight-bearing swimming test was performed 60 minutes after the drug was administered orally. The rats were weighed and a weight of 5% of their own body weight was fixed to their tails. The rats were placed in a transparent container filled with water with an inner diameter of 19 cm, a water depth of 30 cm, and a water temperature of 25±2℃. The rats swam until exhaustion, with "loss of balance and head submerged in water for more than 10 seconds" as the exhaustion criterion. The swimming time was recorded as the weight-bearing swimming time of the rats.

[0319] Table 9 Effect of the pharmaceutical composition of the present invention on the weight-bearing swimming time of rats with myocardial ischemia

[0320]

[0321]

[0322] *: compared with the model group, P < 0.05; #: compared with the vehicle group, P < 0.05;

[0323] 3.2 Echocardiography

[0324] 60 minutes after intragastric administration on the 28th day, 6 rats were randomly selected from each group and tested for cardiac function using a portable B-ultrasound instrument to detect changes in rat cardiac ejection fraction (EF) and E / A. The experimental results showed that compared with the solvent group, the cardiac EF and E / A of the rats in the myocardial ischemia model group were significantly decreased (P < 0.05), and the cardiac EF and E / A of the rats in each drug group were improved to varying degrees.

[0325] Table 10 Effect of the pharmaceutical composition of the present invention on cardiac function in rats with myocardial ischemia

[0326]

[0327] *: compared with the model group, P < 0.05; #: compared with the vehicle group, P < 0.05;

[0328] 3.3 Detection of enzymes related to energy metabolism

[0329] The experimental results showed that compared with the solvent group, the myocardial Na + -K + -ATP, Ca 2+ -Mg 2+ -ATPase activity decreased significantly, the Chinese medicine group, the ranolazine group and the pharmaceutical composition group of the present invention could improve the two enzyme activities to different degrees, and the effect of the pharmaceutical composition group 2 of the present invention was better.

[0330] Table 11 Effect of the pharmaceutical composition of the present invention on myocardial Na + -K + -ATP, Ca 2+ -Mg 2+ - Effect of ATP activity

[0331]

[0332]

[0333] *: compared with the model group, P < 0.05; #: compared with the vehicle group, P < 0.05;

[0334] 3.4 Myocardial histopathological examination

[0335] Pathological results showed that the myocardium of rats with myocardial ischemia model showed obvious myocardial fibrosis. The administration of the pharmaceutical composition of the present invention can reduce myocardial fibrosis to varying degrees and has a certain protective effect on ischemic myocardium. The effect of using the pharmaceutical composition of the present invention in group 2 is better.

[0336] Table 12 Effects of the pharmaceutical composition of the present invention on myocardial pathology in each group

[0337]

[0338] 4 Conclusion

[0339] Under the experimental conditions, the pharmaceutical composition of the present invention can improve myocardial fibrosis and heart failure caused by myocardial ischemia, and has an effect of improving exercise endurance, especially the use of the pharmaceutical composition of the present invention in group 2 has a better effect.

Claims

1. A pharmaceutical composition for treating myocardial ischemia, characterized in that: The invention is prepared from 250-700 parts by weight of salvia miltiorrhiza medicinal material, 50-150 parts by weight of notoginseng medicinal material, 3-9 parts by weight of borneol and 25-100 parts by weight of ranolazine.

2. The pharmaceutical composition according to claim 1, characterized in that The salvia miltiorrhiza medicinal material and the panax notoginseng medicinal material are extracted to obtain a salvia miltiorrhiza and panax notoginseng extract; or they are directly crushed and mixed to obtain a salvia miltiorrhiza and panax notoginseng mixture.

3. The pharmaceutical composition according to claim 2, characterized in that The salvia miltiorrhiza medicinal material and the panax notoginseng medicinal material are combined and extracted according to the following method: salvia miltiorrhiza and panax notoginseng are decocted in water together under alkaline conditions, the decoction is filtered, the filtrate is concentrated and precipitated with alcohol, the supernatant is filtered, and ethanol is recovered to obtain an extract, namely, the salvia miltiorrhiza and panax notoginseng extract, or the extract is dried to obtain the salvia miltiorrhiza and panax notoginseng extract.

4. The pharmaceutical composition according to claim 2, characterized in that The salvia miltiorrhiza medicinal material and the panax notoginseng medicinal material are respectively extracted with water and alcohol, and the obtained salvia miltiorrhiza extract or panax notoginseng extract are mixed to obtain the salvia miltiorrhiza and panax notoginseng extract.

5. The pharmaceutical composition according to claim 2, characterized in that The salvia miltiorrhiza medicinal material and the panax notoginseng medicinal material are combined and extracted according to the following method: salvia miltiorrhiza and panax notoginseng are extracted together with alcohol and then with water, the extract is filtered, and the filtrate is concentrated to obtain an extract, namely the salvia miltiorrhiza and panax notoginseng extract, or the extract is dried to obtain the salvia miltiorrhiza and panax notoginseng extract.

6. The pharmaceutical composition according to claim 2, characterized in that The salvia miltiorrhiza medicinal material is firstly extracted with alcohol and then with water to obtain an extract; the panax notoginseng medicinal material is crushed and mixed with the extract to obtain the salvia miltiorrhiza and panax notoginseng extract.

7. The pharmaceutical composition according to claim 2, characterized in that The salvia miltiorrhiza and Panax notoginseng extract or salvia miltiorrhiza and Panax notoginseng mixture is then mixed with borneol and auxiliary materials to obtain intermediate 1; the ranolazine and auxiliary materials are mixed to obtain intermediate 2; the two are layered and loaded with drugs, and then the corresponding preparation is prepared.

8. The pharmaceutical composition according to claim 7, characterized in that The corresponding preparations can be double-layer tablets, double-layer dropping pills, or double-layer micropills.

9. The pharmaceutical composition according to claim 2, characterized in that The salvia miltiorrhiza and panax notoginseng extract or salvia miltiorrhiza and panax notoginseng mixture is then mixed with borneol and auxiliary materials to prepare a corresponding preparation; the ranolazine is mixed with auxiliary materials to prepare a corresponding preparation, and the two are combined and packaged together.

10. The pharmaceutical composition according to claim 9, characterized in that The combined packaging refers to mixing the two preparations and filling them into a suitable preparation, or mixing the two preparations and bagging them in divided doses.

11. The pharmaceutical composition according to claim 9, characterized in that The corresponding preparations are tablets, capsules, granules, pills, oral liquids, powders, pills, ointments, emulsions, transdermal preparations, and inhalation preparations.

12. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for preventing and / or treating myocardial ischemia.

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