CN111568859B - External preparation of nitroglycerin - Google Patents
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- CN111568859B CN111568859B CN202010423456.4A CN202010423456A CN111568859B CN 111568859 B CN111568859 B CN 111568859B CN 202010423456 A CN202010423456 A CN 202010423456A CN 111568859 B CN111568859 B CN 111568859B
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Abstract
The invention relates to an external preparation of nitroglycerin, which realizes the integrated production of API and the external preparation of nitroglycerin, improves the safety, reduces the content of impurities, is beneficial to protecting the environment and reduces the waste discharge.
Description
Technical Field
The invention belongs to the field of medicaments, and particularly relates to an external preparation of nitroglycerin.
Background
Angina pectoris is a clinical syndrome with paroxysmal chest pain or chest discomfort caused by insufficient blood supply to coronary arteries, acute transient ischemia and hypoxia of cardiac muscle. Nitroglycerin can directly relax vascular smooth muscle, especially small vascular smooth muscle, to relax peripheral blood vessels, reduce peripheral resistance, reduce blood volume of return heart, reduce cardiac output, reduce cardiac load, and reduce myocardial oxygen consumption, thereby relieving angina pectoris. Nitroglycerin promotes the formation of collateral circulation. The medicine is taken by sublingual administration for 1 tablet, and the effect is achieved after 2-3 minutes, and the effect is maintained for about 30 minutes.
Nitroglycerin, also called glyceryl trinitrate, is formed by the nitration of glycerin. The reaction equation is as follows:
glyceryl trinitrate belongs to nitrate, nitrate is an important organic compound and plays a great role in the fields of war industry, medicine and energy, and polyol nitrate is used for preparing an explosive agent and a rocket propellant in the field of war industry; nitrate esters are used in the pharmaceutical field for the preparation of cardiotonic and vasodilators; alkyl nitrates are used in the petroleum processing field as promoters for the production of diesel cetane.
In the nitrate production process, the raw material nitric acid is a strong oxidizing agent, which can continuously oxidize intermediates, namely partially nitrated mononitrate and dinitrate, and can also oxidize alkyl alcohol raw materials to form CO2, H2O and N2 in a positive feedback manner, so that potential explosion risks exist. Therefore, a key step in the production of nitrate esters is to improve the safety and controllability of the nitration step. Common nitration systems currently include: concentrated nitric acid nitration, mixed acid nitration, N2O 5/organic solvent system. These nitration systems have their own advantages and disadvantages,
the yield of the concentrated nitric acid nitration is high, but the adaptability to the raw material is poor. The mixed acid nitration method has high yield, but has poor selectivity, difficult product separation and easy environmental pollution, and is not suitable for water-sensitive and acid-sensitive substances. The N2O 5/organic solvent system has mild conditions, can nitrify acid-sensitive substances or water-sensitive substances and can selectively nitrify multifunctional substances, and has the defect that the organic solvent is generally a toxic chlorinated hydrocarbon solvent. To solve these problems, the prior art discloses related art solutions.
The nobel explosive and system technology limited liability company discloses cn200580005057.x, disclosing a method for the preparation of liquid nitrates by mixing an alcohol solution with nitrating acid in a microreactor for the preparation of glycerol trinitrate or ethylene glycol dinitrate, using a microreactor or micromixer in the sub-millimeter range, which can achieve significantly higher reaction temperatures (30-50 ℃ c, rather than the usual 25-30 ℃) without increasing safety risks.
The key invention of the nobel explosive and system technology company, llc, includes microreactors. Microreactors are one of the most important areas of development in chemical synthesis today.
The microreactor is described in detail in the patent application CN200880122237.X, also from the company Olympic, Fine chemistry, DPX. The advantages of laminar flow are particularly emphasized in the discussion of microreactor publications. It is highly desirable in the prior art that the Reynolds number (Reynolds number) be significantly below 1000. Microreactors, micromixers and micro heat exchangers have been developed in Germany (i.e. IMM, Mainz and Forschungzentrum Karlsruhe) and in the United states (i.e. MIT and DuPont).
DPX fine chemistry austria diploma clearly indicates: a problem associated with the use of multiphase systems in continuous reactors, in particular in microreactors, is the mixing of the two phases. The movement of fluids through the reactor typically occurs with Taylor flow or slug flow. This results in alternating discrete zones of each phase flowing through the reactor at the same rate, allowing some degree of mass transfer.
CN200610154338.8 was filed by the board of university of california, disclosing a method for forming a chemical microreactor for mixing liquid sources such as ammonia, methanol, and butane with an appropriate amount of water and producing hydrogen fuel through a steam reforming process.
FMC ltd filed cn200680039719.x, disclosing the preparation of hydrogen peroxide by an autoxidation process via hydrogenation in a microreactor. A working solution comprising a reactive carrier compound is hydrogenated with hydrogen in a microreactor and subsequently autooxidised to form hydrogen peroxide.
CN200980120326.5 filed by international company for microfluidics discloses an apparatus, system and method that provides the use of microreactor technology to achieve desired mixing and interaction at the micro and/or molecular level between feed stream components.
CN201380010683.2 filed by corning incorporated discloses a method for oxidizing at least one alcohol group of at least one chemical compound to the corresponding carbonyl group in the presence of a buffered oxidizing hypohalous acid solution and a nitrogen oxide oxidizing catalyst, wherein the method is carried out within a microreactor.
Under the usual experimental conditions, this reaction is very dangerous: the mechanical sensitivity of the frozen nitroglycerin is higher than that of the liquid, and the mechanical sensitivity is higher when the frozen nitroglycerin is in a semi-frozen state; the explosion danger is caused by sudden cold and heat, impact and friction and when the fire is exposed and the heat is high; contact with strong acids can cause a strong reaction, causing combustion or explosion. This hazardous characteristic is the most important obstacle to nitroglycerin production.
The invention obtains unexpected progress in the aspect of continuous production of the green preparation of the nitroglycerin through hard innovation, realizes green, safe and risk-free synthesis on key API preparation, and subsequently integrally produces the combined API and the nitroglycerin preparation to develop an End to End process capable of implementing continuous production.
Disclosure of Invention
The invention relates to an external preparation of nitroglycerin, which is characterized in that: mixing concentrated sulfuric acid with fuming nitric acid through a microreactor chip (1); glycerol and dichloromethane are input into a mixer (2), mixed acid liquor of a micro-reactor chip (1) and solution of the mixer (2) are input into one or more combinations of micro-reactor chips (3), (4) and (5), reaction liquid is reserved in a micro-reactor, the reaction liquid is input into a liquid-liquid separator (6) from the micro-reactor chip, the acid liquor is input into a waste liquid processor, organic phase and water are input into the mixer (7) to be mixed and then input into a liquid-liquid separator (8), the water phase is input into the waste liquid processor, the organic phase and saturated salt solution are input into a liquid-liquid separator (9), the water phase is input into the waste liquid processor, the organic phase is connected with a molecular sieve desiccant column (10), the nitroglycerin concentration is detected through an active carbon column (11) through an ultraviolet detector (12), the dichloromethane flow rate is adjusted according to the nitroglycerin concentration and then input into a mixer (13), a nitroglycerin dichloromethane solution was obtained. Nitroglycerin dichloromethane solution was formulated.
The invention relates to an external preparation of nitroglycerin, which is characterized in that: concentrated sulfuric acid and fuming nitric acid are mixed by a microreactor chip (1) in a ratio of 1: 1, mixing at a speed ratio; glycerol and dichloromethane were mixed at a ratio of (0.2-2): (2-10) inputting the speed ratio into a mixer (2), and mixing the acid solution of the microreactor chip (1) with the solution of the mixer (2) in a ratio of (0.2-10): the speed ratio of (1-5) is input into one or more combinations of the micro-reactor chips (3), (4) and (5), the retention time of the reaction liquid in the micro-reactor is 10min to 30min, the reaction liquid is input into a liquid-liquid separator (6) from the micro-reactor chip, acid liquid is input into a waste liquid processor, organic phase and water are mixed in an input mixer (7), inputting into a liquid-liquid separator (8), inputting the water phase into a waste liquid processor, inputting the organic phase and the saturated salt solution into a liquid-liquid separator (9), inputting the water phase into the waste liquid processor, inputting the organic phase into a molecular sieve desiccant column (10), the concentration of the nitroglycerin is detected by an active carbon column (11) and an ultraviolet detector (12), the flow rate of dichloromethane was adjusted in accordance with the nitroglycerin concentration and fed to a mixer (13) to obtain a nitroglycerin dichloromethane solution of 10% concentration. Nitroglycerin dichloromethane solution was formulated.
Pumping the 10% nitroglycerin dichloromethane solution into a hot melt extruder, and adding lactose particles, wherein the ratio of the 10% nitroglycerin dichloromethane solution to the lactose particles is (2-20 ml): (1-20 g), granulating by adopting a wet granulation mode, and drying in vacuum to obtain green particles of nitroglycerin.
2-5 ml of 10% nitroglycerin dichloromethane solution, 20-15 g of beta-cyclodextrin and 0.1-1.0 g of polyvinylpyrrolidone; taking beta-cyclodextrin, adding a proper amount of water for injection, and stirring to completely dissolve the raw materials; slowly adding nitroglycerin solution and polyvinylpyrrolidone, stirring while adding until completely mixing, and stirring for inclusion for 2-4 h; vacuum drying to obtain green preparation of nitroglycerin;
2-20 ml of 10% nitroglycerin dichloromethane solution, 1-10 g of polyvinylpyrrolidone and 2-40 g of lactose; adding appropriate amount of water for injection, slowly adding nitroglycerin solution, polyvinylpyrrolidone and lactose, stirring while adding until completely mixing, and stirring for about 2-4 hr; vacuum freeze-drying to obtain green freeze-dried particles of nitroglycerin.
Microreactor chip (1): the microreactor consists of a set of chips, and individual chips can play a role in mixing and preheating or precooling.
The microreactor chips (3), (4) and (5) are the same chip, and the reaction time is increased by increasing the number of chips.
The temperature of the micro-reactor is controlled by the high-low temperature all-in-one machine, the heat-insulating sleeve is arranged on the outer layer of the micro-reactor, and the reaction problem of the micro-reactor can be controlled when the cooling liquid in the high-low temperature all-in-one machine flows through the heat-insulating sleeve
The micro-reactor is provided with a pressure sensor, and the pressure is controlled by controlling the flow rate.
The green granular preparation of the nitroglycerin and the green freeze-dried preparation of the nitroglycerin are prepared into the following specific preparations of the nitroglycerin according to a conventional method: injection, patch, film, aerosol, spray, cream, gel, and ointment.
The green particles of nitroglycerin, the green freeze-dried particles of nitroglycerin, the external preparation and the injection are prepared into the following specific green preparation of nitroglycerin according to a conventional method:
can be used for preparing medicine for treating or preventing coronary heart disease, angina pectoris, and myocardial infarction;
can be used for preparing medicine for treating wound. Wounds include cuts, abrasions, wounds, burns, lacerations or other accidental wounds. The wound site includes anal fissure, surgical site, trauma site, or any other injury site of the skin;
for the preparation of a medicament for the treatment or prevention of sexual dysfunction, including erectile dysfunction;
can be used for preparing medicine for treating fracture.
The invention relates to an analysis method of nitroglycerin and related substances, which comprises the following steps:
chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-water (40: 60) as mobile phase; the detection wavelength was 215 nm. And taking a proper amount of nitroglycerin reference substance and isosorbide dinitrate, adding a mobile phase for dissolving, preparing a solution containing 20 mu g of nitroglycerin and isosorbide dinitrate in each 1ml, taking 20 mu l of the solution to inject into a liquid chromatograph, recording a chromatogram, wherein the number of theoretical plates is not less than 2000 calculated according to the nitroglycerin peak, and the separation degree of the nitroglycerin peak and the isosorbide dinitrate peak is in accordance with the requirement.
The determination method comprises the following steps: taking a sample to be detected, placing the sample into a 250ml quantitative bottle, precisely adding 50ml of mobile phase, fully shaking to dissolve nitroglycerin, filtering, precisely taking 2ml of subsequent filtrate, placing the subsequent filtrate into a 50ml quantitative bottle, adding the mobile phase to dilute to a scale, shaking uniformly, precisely measuring 20 mu l, injecting into a liquid chromatograph, and recording a chromatogram; taking a proper amount of nitroglycerin as a reference substance, adding a mobile phase to prepare a solution containing 20 mu g of nitroglycerin in each 1ml, and determining by the same method: the amount of nitroglycerin contained in each tablet is calculated by the peak according to an external standard method.
The nitroglycerin has absorption to ultraviolet light and strong hydrophobicity, the main impurities of the nitroglycerin are GMN and GDN, the GMN and the GDN respectively have 1 hydroxyl and 2 hydroxyl, the hydrophobicity is weaker than that of GTN, and the GMN and the GDN have absorption to the ultraviolet light. The invention adopts High Performance Liquid Chromatography (HPLC) to analyze the related substances of nitroglycerin, and the detector is an ultraviolet detector
The invention relates to an infrared spectrum of nitroglycerin, which comprises the following components in percentage by weight:
vacuumizing the glycerol dichloromethane solution synthesized by the microreactor and the nitroglycerin ethanol solution synthesized by the flask, removing dichloromethane and ethanol, and performing infrared spectrogram test.
Test example 1:
optimization process of nitroglycerin synthesis process of microreactor
Glycerol produces Glycerol Mononitrate (GMN), glycerol dinitrate (GDN: 1, 2-GDN, 1,3-GDN) and Glycerol Trinitrate (GTN) during nitroesterification.
When nitroglycerin is prepared according to the present invention, the molar ratio of nitric acid to glycerin is preferably 3: 1-10: 1.
the reaction temperature for preparing the nitroglycerin is 5-15 ℃, and the reaction temperature is particularly preferably 10 ℃.
The reaction time for preparing nitroglycerin is 1-15 minutes, and the preferable time is 5 minutes.
According to different conditions, nitroglycerin is prepared, and a final product is analyzed by High Performance Liquid Chromatography (HPLC), wherein a detector is an ultraviolet detector.
The results of the nitroglycerin reaction in the microreactor are listed in the following table:
comparative test example 1:
the method for synthesizing nitroglycerin in the flask is as follows: adding 5mL of concentrated sulfuric acid into a 20mL flask, cooling to below 5 ℃ in an ice-water bath, adding 5mL of fuming nitric acid, keeping the temperature below 5 ℃, dropwise adding 1.5mL of glycerol within 2 minutes, keeping the temperature at 5 ℃, stirring for 30min, pouring into an aqueous solution, mixing, separating liquid, discarding an aqueous phase, adding 5mL of saturated sodium carbonate solution into an organic phase, immediately separating liquid, discarding the aqueous phase, adding 5mL of saturated sodium chloride solution into the organic phase, immediately separating liquid, discarding the aqueous phase, adding 5mL of anhydrous sodium sulfate into the organic phase, drying, adding 5mL of ethanol, and placing in a refrigerator for analysis.
The results of the flask reaction for synthesizing nitroglycerin are listed below:
test example 2
HPLC integration of nitroglycerin in microreactors
Advantageous technical Advances in the invention
The new process solves the explosive problem in the reaction process by means of a microreactor, changing the reaction mode, adding a solvent and the like: (1) the nitroglycerin is diluted by the inert solvent, so that the probability of mutual collision among nitroglycerin molecules is reduced; (2) the problem of easy explosion of nitroglycerin pipeline transportation and storage is solved. The new process adopts a micro-reactor technology, overcomes the difficulty of mixing and layering of the glycerol and the inert solvent, and solves the problem of large-scale heat release which is difficult to control in the reaction process. HPLC detection shows that the purity is over 99%.
Advantageous technical Advances in the invention
The composition of the invention can be applied to a subject and can be used for treating or preventing coronary heart disease and angina pectoris.
The compositions of the present invention may be applied to the skin of a subject for promoting wound healing, including cuts, abrasions, wounds, burns, lacerations or other accidental wounds. The wound site includes an anal fissure, a surgical site, a trauma site, or any other damaged area of the skin.
The composition of the invention can be applied to the skin of a subject for promoting the healing of bone fractures, fractures.
The compositions of the present invention may be administered to a subject, including the skin of a subject, for the treatment or prevention of sexual dysfunction, including erectile dysfunction.
Drawings
FIG. 1: scheme 1
FIG. 2: flow chart 2
FIG. 3: flow chart 3
FIG. 4: flow chart 4
FIG. 5: HPLC FIG. 1
FIG. 6: HPLC FIG. 2
FIG. 7: infrared atlas
FIG. 1 is a schematic illustration of
1. A microreactor chip; 2. a mixer;
3. a micro reactor chip, 4, 5, a micro reactor chip;
6. zaiput liquid-liquid separator; 7. a mixer, a water-gas separator and a water-gas separator,
8. a Zaiput liquid-liquid separator; 9. a liquid-liquid separator of Zaiput,
10. a molecular sieve desiccant column; 11. an activated carbon column;
12. an ultraviolet detector; 13. a mixer.
While the invention has been described in detail with reference to specific embodiments thereof, it will be apparent to one skilled in the art that it is not so limited, but is intended to cover such departures from the present disclosure as come within known, customary practice in the art to which this invention pertains. And shall also fall within the scope of the present invention.
The specific implementation mode is as follows:
example 1:
an external preparation of nitroglycerin, which is characterized in that: concentrated sulfuric acid and fuming nitric acid are mixed by a microreactor chip (1) in a ratio of 1: 1, mixing at a speed ratio; glycerol was mixed with dichloromethane at a ratio of 0.2: 2 speed ratio is input into the mixer (2), and the mixed acid liquid of the micro-reactor chip (1) and the solution of the mixer (2) are mixed in a ratio of 2: 2.75 of the speed ratio is input into the micro reactor chips (3), (4) and (5), the retention time of the reaction liquid in the micro reactor is 10min to 30min, the reaction liquid is input into the Zaiput liquid-liquid separator (6) from the micro reactor (5), the acid liquid is input into the waste liquid processor, the organic phase and the water are input into the input mixer (7) to be mixed and then input into the Zaiput liquid-liquid separator (8), the water phase is input into the waste liquid processor, the organic phase and the saturated salt solution are input into the Zaiput liquid-liquid separator (9), the water phase is input into the waste liquid processor, the organic phase is passed through the molecular sieve desiccant column (10), the nitroglycerin concentration is detected through the ultraviolet detector (12) through the activated carbon column (11), the flow rate of the dichloromethane is adjusted according to the nitroglycerin concentration and then input into the mixer (13), and the nitroglycerin dichloromethane solution with the concentration of 10% is obtained.
Example 2:
green particles of nitroglycerin
A 10% nitroglycerin dichloromethane solution (10 ml) was pumped into a hot melt extruder, 9 g of lactose particles were added, granulated using a wet granulation mode, and vacuum dried to give green nitroglycerin granules.
Example 3:
green freeze-dried granule of nitroglycerin (1)
20ml of 10% nitroglycerin dichloromethane solution, 5g of polyvinylpyrrolidone and 18 g of lactose; adding appropriate amount of water for injection, slowly adding 0% nitroglycerin dichloromethane solution, polyvinylpyrrolidone and lactose, stirring while adding until completely mixing, and stirring for about 2-4 hr; vacuum freeze-drying yielded green freeze-dried particles of nitroglycerin (1).
Example 4:
green lyophilized particles of nitroglycerin (2)
2ml of 10% nitroglycerin dichloromethane solution, 15 g of beta-cyclodextrin and 0.5 g of polyvinylpyrrolidone; taking beta-cyclodextrin, adding a proper amount of water for injection, and stirring to completely dissolve the raw materials; slowly adding nitroglycerin solution and polyvinylpyrrolidone, stirring while adding until completely mixing, and stirring for inclusion; vacuum drying gave green lyophilized particles of nitroglycerin (2).
Example 5:
nitroglycerin green patch (1)
The weight ratio of each component
The preparation method comprises the following steps:
(1) mixing green nitroglycerin particles, low-substituted hydroxypropyl cellulose, ethanol solution (40%) of polyvinylpyrrolidone, crospovidone and borneol, and absorbing with porous material skeleton to form a nitroglycerin storage;
(2) the back lining layer of the aluminum-plastic composite membrane at the periphery of the storage is glued, sealed and attached with the polyethylene vinyl acetate controlled release membrane;
(3) the polyethylene vinyl acetate controlled release film is attached to the polyisobutylene pressure sensitive adhesive layer, and the polyisobutylene pressure sensitive adhesive layer is attached to the aluminum foil and paper composite anti-sticking layer.
Nitroglycerin green patch (2)
The weight ratio of each component
The preparation method comprises the following steps:
(1) green freeze-dried particles of nitroglycerin, low-substituted hydroxypropyl cellulose, ethanol solution (40%) of polyvinylpyrrolidone, crospovidone and borneol are mixed and absorbed by a porous material framework to form a nitroglycerin storage reservoir;
(2) the back lining layer of the aluminum-plastic composite film at the periphery of the storage is glued, sealed and attached with the polyethylene vinyl acetate controlled release film;
(3) the polyethylene vinyl acetate controlled release film is attached to a polyisobutylene pressure sensitive adhesive layer, and the polyisobutylene pressure sensitive adhesive layer is attached to an aluminum foil and paper composite anti-sticking layer.
Example 6:
green injection of nitroglycerin
The weight ratio of each component
Green lyophilized particles of nitroglycerin 5g
D-sorbitol 10g
The preparation method comprises the following steps:
adding green freeze-dried particles of D-sorbitol and nitroglycerin into water for injection, stirring until the particles are dissolved, adding 0.1% (W/V) of needle activated carbon, fully stirring, filtering to remove carbon, heating while stirring, maintaining the temperature of the liquid medicine at 40 ℃, stirring to dissolve, adjusting the pH value of the liquid medicine to 7.0 by using 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution, adding the rest of water for injection to a constant volume, sterilizing and filtering by using a 0.22 mu m microporous membrane, filling, and performing moist heat sterilization to obtain a clear solution.
Example 7:
nitroglycerin green spray (1)
The weight ratio of each component
The preparation method comprises the following steps:
adding green granules of tween-80 and nitroglycerin into ethanol, adding water for injection, stirring to dissolve, adding 0.1% (W/V) of needle activated carbon, stirring thoroughly, filtering to remove carbon, sterilizing with 0.22 μm microporous membrane, bottling, and sterilizing under humid heat to obtain clear solution.
Nitroglycerin green spray (2)
The weight ratio of each component
The preparation method comprises the following steps:
adding Tween-80 and green lyophilized granule of nitroglycerin into ethanol, adding water for injection, stirring to dissolve, adding 0.1% (W/V) of active carbon for injection, stirring thoroughly, filtering to remove carbon, sterilizing with 0.22 μm microporous membrane, bottling, and sterilizing with damp heat to obtain clear solution.
Example 8:
nitroglycerin green ointment (1)
The weight ratio of each component
The preparation method comprises the following steps:
preparation of an ointment: mixing green nitroglycerin particles, lanolin and distilled water, and mixing with white vaseline at room temperature to obtain nitroglycerin ointment.
Nitroglycerin green ointment (2)
The weight ratio of each component
The preparation method comprises the following steps:
preparation of an ointment: mixing green nitroglycerin lyophilized granule, lanolin and distilled water, and mixing with white vaseline at room temperature to obtain nitroglycerin ointment.
Example 9:
nitroglycerin green cream (1)
The weight ratio of each component
The preparation method comprises the following steps:
(1) preparing an oil phase: weighing green lecithin, cholesterol and nitroglycerin particles to prepare an oil phase;
(2) preparing an aqueous phase: weighing ethylparaben, sodium dodecyl sulfate, span-80 and glycerol, adding into sterile distilled water, stirring, dissolving, and preparing water phase;
(3) preparing a cream: adding the oil phase into the water phase under the condition of mechanical stirring, and stirring uniformly to obtain the green cream (1) of the nitroglycerin.
Nitroglycerin green cream (2)
The weight ratio of each component
The preparation method comprises the following steps:
(1) preparing an oil phase: weighing green lecithin, cholesterol and nitroglycerin freeze-dried particles, and preparing an oil phase;
(2) preparing an aqueous phase: weighing ethylparaben, sodium dodecyl sulfate, span-80 and glycerol, adding into sterile distilled water, stirring, dissolving, and preparing water phase;
(3) preparing a cream: adding the oil phase into the water phase under the condition of mechanical stirring, and stirring uniformly to obtain the green cream (2) of the nitroglycerin.
Example 10:
randomly dividing 4 rats into two groups, establishing a reperfusion model of isolated rat cardiac myocardial ischemia, applying nitroglycerin group (2 in the used group) and not using nitroglycerin group (2 in the control group) in the low-flow ischemia period, perfusing through green particles of nitroglycerin (1 × 10(-3) mmol/L nitroglycerin, and bicarbonate buffer solution) and perfusing through the control group only using bicarbonate buffer solution, and inspecting isolated rat cardiac myocardial ischemia reperfusion injury. The control group of cardiomyocytes showed severe mitochondrial vacuolar degeneration and rupture of the myocardial fibers. The myocardial cells of the drug group have no mitochondrial vacuole degeneration and no rupture of myocardial fibers. The conclusion of the above experimental data is that: the green nitroglycerin particles can obviously improve the bad reconstruction of the heart of the rat with heart failure after myocardial infarction, effectively protect the heart function, and can prevent or treat myocardial infarction, coronary heart disease and angina.
Example 11:
randomly dividing 4 rats into two groups, and a control group (Mayinglong musk hemorrhoid ointment); administration group (nitroglycerin green cream (1) group). Both groups are topically applied 2 times daily at a dose of 1mg each time. Before administration, anal resting pressure was measured for both groups, and then 1 hour after administration, anal rectal resting pressure (cmH2O) was measured and the mean value calculated.
| Group of | Before |
1 hour after administration |
| Control group | 5.35 | 5.21 |
| Test group | 5.42 | 3.68 |
Example 12:
four rats were divided into two groups at random, and after molding, group A was a blank control group (glycerin), and group B was applied with green cream (1) of nitroglycerin at 0.1mg/Kg/d for 4 weeks. X-ray examination was performed 2 and 4 weeks after surgery to evaluate callus growth. Compared with the blank control group, the low dose group formed more trabeculae 2 weeks after the operation, and the trabeculae fused into slices at the low dose group 4 weeks after the operation were woven to form bone.
Example 13:
four rats were randomly divided into two groups and the wounds were painted with 50% glacial acetic acid 1 time/day for 1 week. The administration group is respectively 0.1mg/Kg/d of nitroglycerin green cream (1) and a blank control group (glycerin) which are applied to the skin for 4 weeks according to the calculation of each square centimeter. The dressing change is started on the next day of molding for each group, the ointment is directly coated on the wound surface, a layer of film is covered on the wound surface after dressing change for 2 groups, the film is fixed by a medical adhesive tape, and the dressing change is carried out until the wound surface is healed. The average healing time of the administration group was (11.5) d, and the average healing time of the blank control group was (18.5) d.
Example 14:
four rats were randomly divided into two groups and the wounds were painted with 50% glacial acetic acid 1 time/day for 1 week. The administration group is nitroglycerin green cream (1)0.1mg/Kg/d applied to the skin for 4 weeks and a blank control group (glycerin) respectively according to the calculation of each square centimeter. The dressing change is started on the next day of molding for each group, the ointment is directly coated on the wound surface, a layer of film is covered on the wound surface after dressing change for 2 groups, the film is fixed by a medical adhesive tape, and the dressing change is carried out until the wound surface is healed. The average healing time of the administration group was (11.5) d, and the average healing time of the blank control group was (18.5) d.
Example 15:
four rats are randomly divided into two groups, a blank group (glycerin) and a nitroglycerin green cream group (1), a stimulation electrode of a multi-purpose instrument for physiological experiments is placed at the root of the penis of the rat, local electric stimulation is given, the current intensity is 1.5mA, and the time from the stimulation to the penis erection is counted as the penis erection latency period.
Glycerol and nitroglycerin green cream (1) (0.1mg/Kg) was given at an administration amount of 5 mg/body, applied to the surface of penis, followed by local electrical stimulation at an electric current intensity of 1.5mA, and the time from the initiation of stimulation to penile erection was counted as penile erection latency.
The nitroglycerin green cream (1) obviously shortens the erection latent period of the penis of a rat by 30 percent.
Example 16:
Peak Number，X(cm-1)，Y(％T)
1，3437.02，64.96
2，2918.54，69.
3，1645.46，58.06
4，1428.09，72.64
5，1275.55，55.65
6，1009.74，71.00
7，838.78，65.70
8，764.16，56.08
9.750.04，51.02。
Claims (2)
1. the cream of nitroglycerin is characterized in that
The weight ratio of each component
Nitroglycerin particles 5g
Lecithin 95g
Cholesterol 95g
Span-802 g
Glycerol 40g
Sodium dodecyl sulfate 2g
Proper amount of sterile distilled water
1g of ethylparaben
The preparation method comprises the following steps:
(1) preparing an oil phase: weighing lecithin, cholesterol and nitroglycerin particles to prepare an oil phase;
(2) preparing a water phase: weighing ethylparaben, sodium dodecyl sulfate, span-80 and glycerol, adding into sterile distilled water, stirring, dissolving, and preparing water phase;
(3) preparing a cream: adding the oil phase into the water phase under mechanical stirring, and stirring to obtain cream of nitroglycerin;
the preparation method of the nitroglycerin particles comprises the following steps:
the ratio of the 10% nitroglycerin dichloromethane solution to the lactose is 2-20 ml: 1-20 g;
pumping the nitroglycerin dichloromethane solution with the concentration of 10% into a hot melt extruder, adding lactose, granulating by adopting a wet granulation mode, and drying in vacuum to obtain nitroglycerin granules;
the preparation method of the 10% nitroglycerin dichloromethane solution comprises the following steps: concentrated sulfuric acid and fuming nitric acid are mixed by a microreactor chip (1) in a ratio of 1: 1, mixing at a speed ratio; mixing glycerol with dichloromethane at a ratio of 0.2-2: inputting the mixed acid solution of the micro-reactor chip (1) and the solution of the mixer (2) into the mixer (2) in a speed ratio of 2-10, wherein the mixed acid solution of the micro-reactor chip (1) and the solution of the mixer (2) are mixed in a ratio of 0.2-10: 1-5 of speed ratio is input into one or more combinations of the micro-reactor chips (3), (4) and (5), the retention time of the reaction liquid in the micro-reactor is 10 minutes to 30 minutes, the reaction liquid is input into a liquid-liquid separator (6) from a micro-reactor chip, acid liquid is input into a waste liquid processor, organic phase and water are mixed in an input mixer (7), inputting into a liquid-liquid separator (8), inputting the water phase into a waste liquid processor, inputting the organic phase and the saturated salt solution into a liquid-liquid separator (9), inputting the water phase into the waste liquid processor, inputting the organic phase into a molecular sieve desiccant column (10), the concentration of the nitroglycerin is detected by an active carbon column (11) and an ultraviolet detector (12), regulating the flow rate of dichloromethane according to the concentration of nitroglycerin, inputting the mixture into a mixer (13) to obtain a nitroglycerin dichloromethane solution with the concentration of 10 percent;
the reaction temperature of the nitroglycerin is 5-15 ℃;
the reaction time for preparing the nitroglycerin is 10-30 minutes;
the molar ratio of the nitric acid to the glycerol is 6:1-10: 1.
2. A nitroglycerin cream according to claim 1, for use in the preparation of a medicament for promoting fracture healing, wound healing, and penile erection.
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