Patent Application
20230390353
The present invention relates to the field of traditional Chinese medicine preparation, especially to a pharmaceutical composition for treating myocardial ischemia, a preparation method thereof and an application in the preparation of a medicine for prevention and/or treatment of myocardial ischemia.
Ranolazine, with the chemical name (±)-N-(2, 6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]-1-piperazine acetamide, has the structural formula shown in the following figure:
It is used for treatment of chronic stable angina pectoris. It has anti-angina pectoris and anti-myocardial ischemia functions, and its specific mechanism is not clear. Ranolazine is limited to patients who are refractory to antianginal medications such as long-acting nitrates, calcium channel blockers, and beta-2 receptor blockers. Clinical trials have shown that male patients take ranolazine with better effects than female patients.
Salvia miltiorrhiza is also known as Radix salviae miltiorrhizae, HONGGEN, etc. It is the root and rhizome of Salvia miltiorrhiza Bge. Salvia miltiorrhiza has the effects of activating blood circulation and dispelling blood stasis, cooling blood and eliminating carbuncle, and nourishing blood to tranquillize the mind. It can dilate coronary artery and increase coronary blood flow, and has significant protective effect on myocardial ischemia, which is beneficial to the prevention and treatment of coronary disease and angina pectoris. It can improve the body's microcirculation, reduce blood viscosity, and reduce platelet aggregation.
Radix Notoginseng is also named Kaihua Radix Notoginseng, panax pseudoginseng, pseudo-ginseng, GINBUHUAN, PANLONGQI. Radix Notoginseng has effects of dissipating blood stasis to stop bleeding, reducing swelling and relieving pain. It mainly treats hemoptysis, hematemesis, epistaxis, hematochezia, metrorrhagia, traumatic hemorrhage, thorax and abdominal stabbing pain, and tumescent pain.
Borneolum Syntheticum is also known as borneol, Ju Pian, Ai Pian, Dipterocarp, etc. Its chemical composition is 2-camphanol, and the chemical formula is C10H18O. It has the effects of inducing reuscitation and refreshing spirit, clearing heat and removing toxic substances, and improving eyesight and removing nebula. It mainly treats calentura and unconsciousness due to high fever, apoplexy, syncope due to accumulation of phlegm, and convulsion, affecting upper orifices by heat-damp in summer, sore throat and deafness, aphtha and tooth swelling, carbuncle sore and hemorrhoid, conjunctival congestion and swelling pain, and pterygium.
Chinese patent application CN111297942A discloses a compound preparation for treating myocardial ischemia including ranolazine and a mixture consisting of Salvia miltiorrhiza, Radix Notoginseng and Borneolum Syntheticum. Herein, the parts by weight of each component are as follows: ranolazine 20-50 parts, a mixture consisting of Salvia miltiorrhiza, Radix Notoginseng, and Borneolum Syntheticum 20-50 parts. The method for preparing the compound preparation includes the following steps:
However, the application does not specifically disclose the ratio among Salvia miltiorrhiza, Radix Notoginseng and Borneolum Syntheticum, thus rendering the technical solution of the application unclear and unfeasible. In addition, it can be seen according to the embodiments of the patent application that the amount of ranolazine used is higher than that of a mixture composed of Salvia miltiorrhiza, Radix Notoginseng and Borneolum Syntheticum (Embodiment 1: ranolazine 250 g, and a mixture 125 g consisting of Salvia miltiorrhiza, Radix Notoginseng and Borneolum Syntheticum; Embodiment 2: ranolazine 275 g, and a mixture 100 g of Salvia miltiorrhiza, Radix Notoginseng and Borneolum Syntheticum; Embodiment 3: ranolazine 300 g, and a mixture 75 g of Salvia miltiorrhiza, Radix Notoginseng and Borneolum Syntheticum).
Based on the prior art, the present invention studies the dosage of Salvia miltiorrhiza, Radix Notoginseng, Borneolum Syntheticum and ranolazine to provide 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 possibly existing in chemical drugs.
The pharmaceutical composition of the present invention comprises Salvia miltiorrhiza medicinal material 250-700 parts by weight, Radix Notoginseng medicinal material 50-150 parts by weight, Borneolum Syntheticum 3-9 parts by weight, and ranolazine 25-100 parts by weight.
According to the pharmaceutical composition of the present invention, the Salvia miltiorrhiza medicinal material and the Radix Notoginseng medicinal material are extracted to obtain a Salvia miltiorrhiza and Radix Notoginseng extract or directly pulverized and mixed to obtain a Salvia miltiorrhiza and Radix Notoginseng mixture.
In an embodiment, according to the pharmaceutical composition, the Salvia miltiorrhiza medicinal material and the Radix Notoginseng medicinal material are performed with merged extraction as follows: Salvia miltiorrhiza and Radix Notoginseng are decocted together with water in an alkaline condition, the decocting solution is filtered, and the filtrate is concentrated and precipitated with alcohol; the supernatant is filtered, and alcohol is recovered to obtain an extractum, that is the Salvia miltiorrhiza and Radix Notoginseng extract, or the extractum is dried to obtain the Salvia miltiorrhiza and Radix Notoginseng extract.
Preferably, the Salvia miltiorrhiza medicinal material and the Radix Notoginseng medicinal material are performed with merged extraction as follows:
The alkaline conditions described in the 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, at the pH of 7.5-9.0, with the amount added being 1-4.5% (preferably 2.25-3%) of the medicinal material.
In the step (3), it is preferably for precipitation by adding 70-100% ethanol (optimally, 95% ethanol), preferably to a concentration of 60-75% by the ethanol precipitation.
Most preferably, the Salvia miltiorrhiza and Radix Notoginseng extract of the present invention is prepared by the following method:
In the second embodiment, according to the pharmaceutical composition of the present invention, the Salvia miltiorrhiza medicinal material and the Radix Notoginseng medicinal material are respectively extracted by water extraction and alcohol precipitation under alkaline conditions, and the obtained Salvia miltiorrhiza extract and Radix Notoginseng extract are mixed to obtain the Salvia miltiorrhiza and Radix Notoginseng extract.
Preferably, the Salvia miltiorrhiza is decocted with water for 1-3 times under alkaline conditions, decocted for 1-3 hours each time, filtered; the filtrates are merged and concentrated, the concentrate is precipitated with alcohol, and allowed to stand; the supernatant is filtered, alcohol is recovered, and concentrated to obtain an extractum, that is a Salvia miltiorrhiza extract, or the extractum is dried to obtain a Salvia miltiorrhiza extract.
Under alkaline conditions, Radix Notoginseng is decocted with water for 1-3 times, decocted for 1-3 hours each time, and filtered; the filtrates are merged and concentrated, the concentrate is precipitated with alcohol, and allowed to stand; the supernatant is filtered, alcohol is recovered, and the solution is concentrated to obtain an extractum, that is a Radix Notoginseng extract, or the extractum is dried to obtain a Radix Notoginseng extract.
The Salvia miltiorrhiza extract is merged with the Radix Notoginseng extract to obtain the Salvia miltiorrhiza and Radix Notoginseng extract.
Most preferably, for the Salvia miltiorrhiza extract, firstly, Salvia miltiorrhiza is added into an extraction tank, and then an appropriate amount of sodium bicarbonate (2.25% of the amount of medicinal material) is added into the extraction tank, 5 times of water is added into the extraction tank, and the mixture is decocted at 100° C. for 2 hours and filtered; the medicinal residues are extracted for the second time, added with 4 times amount of water, decocted at 100° C. for 1 hour, filtered, and the medicinal residues are discarded. The two decocting filtrates are merged and concentrated under reduced pressure at 80° C.-90° C. to a relative density of 1.16-1.20 (80±1° C.) or a sugar degree of 48% -52% to obtain a concentrate; an appropriate amount of ethanol is added to the concentrate to adjust the ethanol content to 65% -70% (20° C.), leaving standing at low temperature for 12 hours-24 hours until the precipitation is complete; the supernatant is separated, and the precipitate is discarded; and the supernatant is concentrated under reduced pressure to 82%-88% sugar degree to obtain the Salvia miltiorrhiza extract.
Radix Notoginseng extract: the Radix Notoginseng is pulverized into particles with a diameter of 1.5 cm or less; the extraction tank is firstly charged with pulverized Radix Notoginseng, added with 5 times of water, and soaked for 12-15 hours, then added with an appropriate amount of sodium bicarbonate (2.25% of the amount of medicinal materials), decocted at 100° C. for 2 hours, and filtered; the medicinal residues are extracted for the second time, added with 4 times amount of water, decocted at 100° C. for 1 hour, filtered, and the medicinal residues are discarded. The two decocting filtrates are merged, and concentrated under reduced pressure at 80° C.-90° C. to a sugar degree of 18%-28% to obtain a concentrate; an appropriate amount of ethanol is added to the concentrate to adjust the ethanol content to 65%-70% (20° C.), leaving standing at low temperature for 15 hours-24 hours until the precipitation is complete; the supernatant is separated, and the precipitate is discarded; the supernatant is concentrated under reduced pressure to 60%-75% sugar degree, so as to obtain a Radix Notoginseng extract.
The Salvia miltiorrhiza extract is merged with the Radix Notoginseng extract to obtain the Salvia miltiorrhiza and Radix Notoginseng extract.
In the third embodiment, according to the pharmaceutical composition of the present invention, the Salvia miltiorrhiza medicinal material and the Radix Notoginseng medicinal material are performed with merged extraction as follows: Salvia miltiorrhiza and Radix Notoginseng are extracted with alcohol and then water, the extract is filtered, and the filtrate is concentrated to obtain an extractum, that is the Salvia miltiorrhiza and Radix Notoginseng extract, or the extractum is dried to obtain the Salvia miltiorrhiza and Radix Notoginseng extract.
Preferably, the Salvia miltiorrhiza medicinal material and the Radix Notoginseng medicinal material are performed with merged extraction as follows:
In the step (1), 70-100% ethanol extraction (optimally, 90% ethanol) is preferably performed.
Most preferably, the Salvia miltiorrhiza and Radix Notoginseng extract of the present invention is prepared by the following method:
In the fourth embodiment, according to the pharmaceutical composition of the present invention, the Salvia miltiorrhiza medicinal material is extracted with alcohol and then water to obtain an extractum, and the Radix Notoginseng medicinal material is pulverized and then mixed with the above extractum to obtain the Salvia miltiorrhiza and Radix Notoginseng extract.
Preferably, the Salvia miltiorrhiza and Radix Notoginseng of the present invention are extracted and pulverized as follows:
In the step (1), 70-100% ethanol extraction (optimally, 90% ethanol) is preferably performed. Most preferably, the Salvia miltiorrhiza and Radix Notoginseng extract of the present invention is prepared by the following method:
In the fifth embodiment, according to the pharmaceutical composition of the present invention, the Salvia miltiorrhiza medicinal material and the Radix Notoginseng medicinal material can also be pulverized respectively and then mixed to obtain the Salvia miltiorrhiza and Radix Notoginseng mixture.
In an embodiment, the Salvia miltiorrhiza and Radix Notoginseng extract or mixture of the present invention can be further mixed with Borneolum Syntheticum and excipients to prepare an intermediate 1; the ranolazine and excipients are mixed to obtain an intermediate 2; and the intermediates are loaded in different layers, and then the corresponding preparation is prepared. Specifically, the corresponding preparation is bi-layer tablet, bi-layer drop pill, bi-layer pellet or the like. For example, in certain embodiments, one of the intermediate 1 and the intermediate 2, as described above, may be formulated as a pill core having medicine, a tablet core, a drop pill, and another as a drug-containing coating, thereby forming a bi-layer tablet, a bi-layer drop pill, a bi-layer pellet, etc.
In another embodiment, the Salvia miltiorrhiza and Radix Notoginseng extract or mixture of the present invention can also be further mixed with Borneolum Syntheticum and excipients to prepare a corresponding preparation, and the ranolazine is mixed with the excipients to prepare a corresponding preparation, the two preparations are combined and packaged together.
The combination and packaged together means that the two preparations are mixed and filled into a suitable preparation, or the two preparations are mixed and bagged and packaged into a divided-dose package.
The corresponding preparation can be any suitable preparation form.
Preferred preparations include tablets, capsules, granules, drop pills, pills, oral liquid, powder, sublimed preparation, ointments, emulsion, transdermal preparation, or inhalation preparation and the like.
The tablets include common tablets, micro-tablets, etc.; the capsules include hard capsules, soft capsules and the like; the drop pills include common drop pills and micro-drop pills; and the pellet include common pills and pellets.
More preferred preparations include drop pills, pills, tablets, and capsules.
Preferably, the excipients of the present invention may contain commonly used excipients such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and may be coated if necessary.
Suitable fillers include microcrystalline cellulose, mannitol, lactose and other similar fillers.
Suitable disintegrants include starch, crospolyvinylpyrrolidone, croscarmellose sodium and starch derivatives such as sodium starch glycolate.
Suitable lubricants include, for example, magnesium stearate.
Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.
Solid oral compositions may be prepared by conventional methods of blending, filling, tableting and the like. Repeated mixing can be carried out to distribute the active substance throughout those compositions employing large amounts of fillers.
The preparation of the present invention is most preferably a common pill or a micro-drop pill.
The common drop pills or micro-drop pills of the present invention are prepared by mixing a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the present invention, or Salvia Miltiorrhiza and Radix Notoginseng extract,or the mixture of Salvia Miltiorrhiza and Radix Notoginseng extract and Borneolum Syntheticum, or ranolazine) with a drop pill base in a weight ratio of 1:5 to 5:1.
Preferably, the common drop pills or micro-drop pills of the present invention are prepared from the pharmaceutically active ingredient and the drop pill base in a weight ratio of 1:3 to 3:1.
Most preferably, it is composed of the pharmaceutically active ingredient and the dropping pill base in a weight ratio of 1:1-3.
The drop pill base is selected from one of polyethylene glycol, sorbitol, xylitol, lactitol, erythritol, poloxamer 188, polyvinylpyrrolidone, stearic acid, maltose, starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, gum arabic, gelatin, alginic acid, dextrin, cyclodextrin, agar, and lactose. Preferably, polyethylene glycols includes such as solid polyethylene glycols 1000-8000, that is, a combination of one or more of polyethylene glycols 1000, 2000, 3000, 4000, 6000, 8000, most preferably polyethylene glycol 6000 or 4000 or a polyethylene glycol 4000-6000 combination.
The preparation method of the common drop pill or micro-drop pill according to the present invention is provided by the prior art, for example, the method disclosed in Chinese patent CN104274520 A or CN 104274518 A.
The invention further provides a use of a pharmaceutical composition for preparation of a medicine for prevention and/or treatment of myocardial ischemia.
The pharmaceutical composition of the present invention is superior to the prior art (e.g., a Chinese traditional medicine consisting of Salvia Miltiorrhiza, Radix Notoginseng and Borneolum Syntheticum, or ranolazine used alone) in the prevention and/or treatment of myocardial ischemia. The pharmaceutical composition of the present invention can reduce the amount of ranolazine and greatly reduce the toxic side effects that may exist when the ranolazine is used alone while ensuring the therapeutic effect.
After mixing polyethylene glycol 4000 and polyethylene glycol 6000, the mixture is heated and melted, added with Borneolum Syntheticum, Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized, and performed with shaking and dripping, condensing, drying, coating and screening to obtain micro-drop pills.
After mixing polyethylene glycol 4000 and polyethylene glycol 6000, the mixture is heated and melted, added with ranolazine fine powder and sodium lauryl sulfate, mixed thoroughly and homogenized, and performed with dropping, condensing and screening to obtain ranolazine micro-drop pills.
After mixing polyethylene glycol 6000 and poloxamer 188, the mixture is heated and melted, added with Borneolum Syntheticum, Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized, and performed with shaking and dripping, condensing, drying, coating and screening to obtain micro-drop pills.
After mixing polyethylene glycol 4000 and polyethylene glycol 3350, the mixture is heated and melted, added with ranolazine fine powder and Tween 80, mixed thoroughly and homogenized, and performed with dropping, condensing and screening to obtain ranolazine micro-drop pills. 5, The above-mentioned micro-drop pills and ranolazine micro-drop pills are mixed uniformly and loaded into a pharmaceutical aluminum-plastic composite film bag to obtain a pharmaceutical composition preparation of the present invention.
Polyethylene glycol 6000 is heated and melted, added with Borneolum Syntheticum, Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized, and performed with shaking and dripping, condensing, drying, coating and screening to obtain micro-drop pills.
The ranolazine fine powder is mixed with lactose, low-substituted hydroxypropyl cellulose, polyethylene glycol 6000 and sodium lauryl sulfate to prepare granules, the granules are thoroughly mixed with micro-powder silica gel and magnesium stearate, and the mixture is pressed for micro-tablets to obtain ranolazine micro-tablets.
After mixing polyethylene glycol 6000 and polyvinyl pyrrolidone, the mixture is heated and melted, added with Borneolum Syntheticum, Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized, and performed with shaking and dripping, condensing, drying, coating and screening to obtain micro-drop pills.
The ranolazine fine powder is mixed with microcrystalline cellulose, pregelatinized starch and crospovidone uniformly. The mixture of starch slurry and Span 20 is added as a binder to the above-mentioned mixed powder for granulation and drying. After sieving, the above resultant is added with magnesium stearate and mixed uniformly, and compressed to obtain ranolazine micro-tablets.
Salvia miltiorrhiza extract: firstly, Salvia miltiorrhiza is added into an extraction tank, and then an appropriate amount of sodium bicarbonate (2.25% of the amount of medicinal material) is added into the extraction tank, 5 times of water is added into the extraction tank, and the mixture is decocted at 100° C. for 3 hours and filtered; the medicinal residues are extracted for the second time, added with 5 times amount of water, decocted at 100° C. for 2 hours, filtered, and the medicinal residues are discarded. The two decocting filtrates are merged and concentrated under reduced pressure at 80° C.-90° C. to a relative density of 1.16-1.20 (80±1° C.) or a sugar degree of 48%-52% to obtain a concentrate; an appropriate amount of ethanol is added to the concentrate to adjust the ethanol content to 65%-70% (20° C.), leaving standing at low temperature for 12 hours-24 hours until the precipitation is complete; the supernatant is separated, and the precipitate is discarded; and the supernatant is concentrated under reduced pressure to 82%-88% sugar degree to obtain a Salvia miltiorrhiza extract.
Radix Notoginseng extract: the Radix Notoginseng is pulverized into particles with a diameter of 1.5 cm or less; the extraction tank is firstly charged with pulverized Radix Notoginseng, added with 5 times of water, and soaked for 12-15 hours, then added with an appropriate amount of sodium bicarbonate (2.25% of the amount of medicinal materials), decocted at 100° C. for 3 hours, and filtered; the medicinal residues are extracted for the second time, added with 5 times amount of water, decocted at 100° C. for 2 hours, filtered, and the medicinal residues are discarded. The two decocting filtrates are merged, and concentrated under reduced pressure at 80° C. -90° C. to a sugar degree of 18%-28% to obtain a concentrate; an appropriate amount of ethanol is added to the concentrate to adjust the ethanol content to 65%-70% (20° C.), leaving standing at low temperature for 15 hours-24 hours until the precipitation is complete; the supernatant is separated, and the precipitate is discarded; the supernatant is concentrated under reduced pressure to 60%-75% sugar degree, so as to obtain a Radix Notoginseng extract.
The Salvia miltiorrhiza extract is merged with the Radix Notoginseng extract to obtain the Salvia miltiorrhiza and Radix Notoginseng extract. The solid content (the amount of water removed, i.e., the dried weight) is about 200 mg.
After polyethylene glycol 6000 is heated and melted, it is added with Borneolum Syntheticum, Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized, and performed with shaking and dripping, condensing, drying, coating and screening to obtain micro-drop pills, and load the micro-drop pills into No. 0 capsules.
Ranolazine fine powder is mixed with methacrylic acid copolymer type C, microcrystalline cellulose and polyvinylpyrrolidone uniformly; sodium hydroxide aqueous solution is added as a binder into the above-mentioned mixed powder to prepare granules; a 30% aqueous dispersion of methyl methacrylate/ethyl acrylate is added into wet granules; the obtained granules are dried, and after sieving, added with croscarmellose sodium and magnesium stearate, mixed uniformly, and compressed to obtain ranolazine sustained-release tablets.
Salvia miltiorrhiza extract: firstly, Salvia miltiorrhiza is added into an extraction tank, and then an appropriate amount of sodium bicarbonate (2.25% of the amount of medicinal material) is added into the extraction tank, 5 times of water is added into the extraction tank, and the mixture is decocted at 100° C. for 2 hours and filtered; the medicinal residues are extracted for the second time, added with 4 times amount of water, decocted at 100° C. for 1 hour, filtered, and the medicinal residues are discarded. The two decocting filtrates are merged and concentrated under reduced pressure at 80° C.-90° C. to a relative density of 1.16-1.20 (80±1° C.) or a sugar degree of 48%-52% to obtain a concentrate; an appropriate amount of ethanol is added to the concentrate to adjust the ethanol content to 65%-70% (20°C.), leaving standing at low temperature for 12 hours-24 hours until the precipitation is complete; the supernatant is separated, and the precipitate is discarded; and the supernatant is concentrated under reduced pressure to 82%-88% sugar degree to obtain a Salvia miltiorrhiza extract.
Radix Notoginseng extract: the Radix Notoginseng is pulverized into particles with a diameter of 1.5 cm or less; the extraction tank is firstly charged with pulverized Radix Notoginseng, added with 5 times of water, and soaked for 12-15 hours, then added with an appropriate amount of sodium bicarbonate (2.25% of the amount of medicinal materials), decocted at 100° C. for 2 hours, and filtered; the medicinal residues are extracted for the second time, added with 4 times amount of water, decocted at 100° C. for 1 hour, filtered, and the medicinal residues are discarded. The two decocting filtrates are merged, and concentrated under reduced pressure at 80° C. -90° C. to a sugar degree of 18%-28% to obtain a concentrate; an appropriate amount of ethanol is added to the concentrate to adjust the ethanol content to 65%-70% (20° C.), leaving standing at low temperature for 15 hours-24 hours until the precipitation is complete; the supernatant is separated, and the precipitate is discarded; the supernatant is concentrated under reduced pressure to 60%-75% sugar degree, so as to obtain a Radix Notoginseng extract.
The Salvia miltiorrhiza extract is merged with the Radix Notoginseng extract to obtain the Salvia miltiorrhiza and Radix Notoginseng extract. The solid content (the amount of water removed, i.e., the dried weight) is about 300 mg.
After mixing polyethylene glycol 4000 and gelatin, the mixture is heated and melted, added with Borneolum Syntheticum, the Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized, and performed with shaking and dripping, condensing, drying, coating and screening to obtain micro-drop pills.
The ranolazine fine powder is mixed with methacrylic acid copolymer type C, microcrystalline cellulose and hypromellose uniformly; the mixture is added with aqueous sodium hydroxide solution, performed with granulating, drying, and sieving, added with magnesium stearate and mixed uniformly, and then compressed and coated to obtain sustained-release ranolazine micro-tablets.
Salvia miltiorrhiza is pulverized and screened by an 80 mesh sieve.
Radix Notoginseng is pulverized and screened by an 80 mesh sieve.
The above-mentioned powders are mixed to obtain a Salvia miltiorrhiza and Radix Notoginseng mixture.
The ranolazine fine powder is mixed with starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and Tween 80 uniformly; the mixture is added with purified water to granulate, dried and granulated, added with magnesium stearate, mixed uniformly and compressed to obtain ranolazine micro-tablets.
After mixing polyethylene glycol 6000, erythritol and xylitol, the mixture is heated and melted, added with Borneolum Syntheticum, the Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized, and performed with shaking and dripping, condensing, drying, coating and screening to obtain micro-drop pills.
Ranolazine fine powder is mixed with microcrystalline cellulose, sucrose powder and crospovidone uniformly, a soft material is prepared with Span 20 water suspension as a binder, extruded and rounded, dried and sieved to obtain ranolazine pellets.
Polyethylene glycol 6000 is heated and melted, added with Borneolum Syntheticum, Salvia miltiorrhiza and Radix Notoginseng extract, and an appropriate amount of purified water, thoroughly mixed and homogenized to obtain the feed liquid of outer layer.
The polyethylene glycol 4000 is heated and melted, and the ranolazine fine powder is added and mixed thoroughly to obtain the feed liquid of inner layer.
Ranolazine fine powder is mixed with microcrystalline cellulose, sucrose powder and crospovidone uniformly, soft material is prepared with water as a binder, extruded and rounded, dried and sieved to obtain ranolazine pellets.
The Salvia miltiorrhiza and Radix Notoginseng extract is mixed with microcrystalline cellulose and Borneolum Syntheticum uniformly, the mixture is added with water to prepare granules, added with magnesium stearate, and mixed uniformly for later use.
The ranolazine fine powder is mixed with methacrylic acid copolymer type C, microcrystalline cellulose and hypromellose uniformly. The mixture is added with aqueous sodium hydroxide solution, performed with granulating, drying, and sieving, added with magnesium stearate and mixed uniformly for later use.
The Salvia miltiorrhiza and Radix Notoginseng extract is mixed with Borneolum Syntheticum, stevioside, silicon dioxide, magnesium stearate and lactose, the mixtured is pulverized and screened by a 200-mesh sieve to obtain a fine powder of Salvia miltiorrhiza and Radix Notoginseng.
The ranolazine fine powder is prepared in the following proportions.
Ranolazine is mixed with lactose, silicon dioxide and stevioside uniformly, the mixture is pulverized and screened by a 200-mesh sieve to obtain ranolazine fine powder.
The capsule contents are prepared in the following proportions:
The above-mentioned Salvia miltiorrhiza and Radix Notoginseng extract, Borneolum Syntheticum, ranolazine, hypromellose, beeswax and polysorbate 80 are successively added to soybean oil, mixed, homogenized by a colloid mill, and compressed into soft capsules to obtain a pharmaceutical composition preparation of the present invention.
CD-1 mice, male, 18-22 g, quality certificate number of experimental animals: 110011200105606931, purchased from Beijing Vital River
The proportion of the pharmaceutical composition of the present application is also obtained by screening, and the present application designs several experimental groups as follows. The Salvia miltiorrhiza and Panax notoginseng extract is prepared according to the method of Embodiment 1:
Each of the above pharmaceutical composition groups was converted to a clinically equivalent dose for mice as follows.
70 experimental animals were randomly divided into 7 groups (n=10): a normal group, a composition group 1, a composition group 2, a composition group 3, a composition group 4, a composition group 5 and a composition group 6. The mice were administered in advance for 7 days, and the mice in the normal group were administered intragastrically with equivalent distilled water. After the last dose of 60 min, the mice will be placed on the rotarod. With the rotating fatigue tester adjusted to a training state, the mice put on the rotarod were given adaptive training for 10 min, and then the rotating fatigue tester was adjusted to a test state with the rotation speed of 30 r/min. The trained mice were put on the rotarod in turn and continuously observed for 60 min, and we recorded the time that the mice continued to move on the roller without falling off.
In the total experiment, 30 min was used. When the mouse dropped from the rotarod, the channel timer was stopped, and the movement duration and the number of drops of the mouse in 30 min were calculated. The results showed that after 7 days of pre-administration, the exercise duration of mice in the administration groups was improved to different degrees, and the efficacy results were significant and were statistically different from the normal group at the proportion of Salvia miltiorrhiza, Radix Notoginseng, Borneolum Syntheticum and ranolazine being (250-700):(50-150):(3-9):(25-100) in the composition group 3 and the composition group 4.
Under the experimental conditions, each composition group can improve the duration of rotarod movement of normal mice to different degrees, and the efficacy results were significant at the proportion of Salvia miltiorrhiza, Radix Notoginseng, Borneolum Syntheticum and ranolazine being (250-700):(50-150):(3-9):(25-100) in the composition group 3 and the composition group 4.
BALB/c mice, male, 18-22 g, quality certificate number of experimental animals: 1100111911047118
Pharmaceutical composition group of the present invention (simply referred to as a composition group): it is prepared according to Embodiment 1. The daily dose converted to mice includes: traditional Chinese medicine composition (Salvia miltiorrhiza and Radix Notoginseng extract (dried weight)+Borneolum Syntheticum) 34 mg/kg and the amount of ranolazine 102 mg/kg;
The traditional Chinese medicine (Salvia miltiorrhiza and Radix Notoginseng extract (dried weight)+Borneolum Syntheticum) is prepared according to the method of Embodiment 1 of the present invention and set to 2 times the dose of the traditional Chinese medicine composition in the pharmaceutical composition of the present invention, namely 68 mg/kg;
In the ranolazine group, it is set as twice the ranolazine dose in the pharmaceutical composition group of the present invention, i.e. about 205 mg/kg;
According to the reference, 40 male mice are randomly divided into 4 groups (n=10): a normal group, a ranolazine group, a traditional Chinese medicine group and a pharmaceutical composition group of the present invention are administered in advance for 7 days, and the mice in the normal group are administered intragastrically with equivalent distilled water. Swimming tests are performed 30 min after the last administration. Mice are fixed a 5% weight of its body weight on the tail, and then placed in a large container filled with water of about 20 cm. Water should not be overfilled, so as to prevent mice from jumping out. The mice are forced to swim to exhaustion until they swim to death, and the time is recorded as the weight-bearing swimming time of the mice. See Table 5 for grouping and dose setting.
The results show that the traditional Chinese medicine group and the pharmaceutical composition group of the present invention could significantly improve the swimming time of normal mice. The results are shown in Table 6.
Under the experimental conditions, after 7 days of pre-administration, the pharmaceutical composition group of the present invention can significantly prolong the swimming time of normal mice and improve exercise endurance.
SD rats, male, 180-220 g, quality certificate number of experimental animals: 110011200109011573.
The pharmaceutical composition group of the present invention is set as two groups in total:
Composition Group 1: it was prepared according to the method of Embodiment 2 of the present invention. The daily doses converted to rats were the traditional Chinese medicine (Salvia miltiorrhiza Radix and Notoginseng extract (calculated by dried weight)+Borneolum Syntheticum) of 50 mg/kg and the amount of ranolazine of 50 mg/kg;
Composition Group 2: it was prepared according to the method of Embodiment 3 of the present invention. The daily doses converted to rats were the traditional Chinese medicine (Salvia miltiorrhiza Radix Notoginseng extract (calculated by dried weight)+Borneolum Syntheticum) of 50 mg/kg and the amount of ranolazine of 25 mg/kg.
The traditional Chinese medicine group (the Salvia miltiorrhiza and Radix Notoginseng extract (dried weight)+Borneolum Syntheticum) was prepared according to the method of Embodiment 2 of the present invention, with the same administration dose as that of the traditional Chinese medicine (Salvia miltiorrhiza and Radix Notoginseng extract (dried weight)+Borneolum Syntheticum) in the composition group, i.e., 50 mg/kg;
The ranolazine group was divided into three groups:
Ranolazine group 1: the dose of ranolazine was set to twice the ranolazine administration dose in the composition group 1, i.e., 100 mg/kg.
Ranolazine group 2: the dose of ranolazine was set to the same of the ranolazine administration dose in the composition group 1, i.e., 50 mg/kg.
Ranolazine group 3: the dose of ranolazine was set to the same of the ranolazine administration dose in the composition group 2, i.e., 25 mg/kg.
110 experimental animals were purchased, of which 10 animals were set as a sham-operation group, and 100 animals were used for modeling left anterior descending coronary artery ligation. After modeling, surviving rats were randomly divided into a vehicle control group, a traditional Chinese medicine group, a ranolazine group 1, a ranolazine group 2, a ranolazine group 3, a pharmaceutical composition group 1 of the present invention and a pharmaceutical composition group 2 of the present invention according to body weight. After therapeutic administration for 28 days, the rats from the vehicle control group were given the same amount of menstruum by gavage. On the 28th day of intragastric administration, 6 rats in each group were randomly selected for echocardiography. After intragastric administration of 60 min on Day 30, a weight-bearing swimming test was performed, and animal samples were taken after the end of weight-bearing swimming. The groups are shown in Table 8.
After intragastric administration of 60 min on Day 30, the experimental animals were subjected to the weight-bearing swimming test. After weighing, the rats, fixed a 5% weight of its body weight on the tail were placed in a transparent container filled with water with an inner diameter of 19 cm and a water depth of 30 cm. The water temperature was 25±2° C. The rats swimming to exhaustion were judged by the standard of losing balance and the head submerged for more than 10 seconds. The time of swimming was recorded as the time of weight-bearing swimming.
#compared with the vehicle group, P < 0.05;
After intragastric administration of 60 min on Day 28, 6 rats in each group were randomly selected, and the cardiac function was detected by a portable b-ultrasound instrument. The changes of cardiac ejection fraction (EF) and E/A were detected. The experimental results showed that compared with the vehicle group, the heart EF and E/A of rats in the myocardial ischemia model group were significantly decreased (P<0.05), and the heart EF and E/A of rats in each administration group were improved to varying degrees.
#compared with the vehicle group, P < 0.05;
The experimental results showed that compared with the vehicle group, the enzyme activity of the animal myocardial Na+—K+ATP and Ca2+—Mg2+-ATP in the model group were significantly decreased, and the activity of these two enzymes in the traditional Chinese medicine group, the ranolazine group and the pharmaceutical composition group of the present invention could be improved in different degrees, and the effect of the pharmaceutical composition group 2 was better.
#compared with the vehicle group, P < 0.05;
Pathological results showed that the myocardium of rats with myocardial ischemia model showed significant fibrosis. The administration of the pharmaceutical composition of the present invention could reduce myocardial fibrosis to varying degrees, causing a certain protective effect on the ischemic myocardium, and the effect of the pharmaceutical composition group 2 of the present invention was better.
Under the experimental conditions, the pharmaceutical composition of the present invention has the effect of improving myocardial fibrosis and cardiac insufficiency caused by myocardial ischemia, and has the effect of improving exercise endurance. Especially, the effect of the pharmaceutical composition group 2 of the present invention is better.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111136641.6 | Sep 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/116975 | 9/5/2022 | WO |
