Application of cinnamaldehyde in preparing drugs for improving tolerance of nitrate drugs, pharmaceutical composition and preparation thereof

Abstract

The present invention relates to the field of medicine, and specifically to the application of cinnamaldehyde in the preparation of a drug for improving the tolerance of nitrate drugs, a pharmaceutical composition and a preparation thereof. The inventor of the present application creatively discovered that cinnamaldehyde can solve the problem that nitroglycerin is easy to produce tolerance in the prior art, prolong the action time of nitroglycerin, and reduce the dosage of nitroglycerin, which not only expands the clinical application of nitroglycerin, but also expands the benefits, and is more in line with the current level of the pharmaceutical industry and the current status of pharmaceutical investment from the principle of pharmaceutical economics. Experimental results confirm that for experimental subjects who have developed nitroglycerin tolerance, the combined use of cinnamaldehyde and nitroglycerin has a vasodilation effect that is nearly 10% higher than the vasodilation maximum degree Emax of the vascular ring when nitroglycerin is used alone, and even if a lower nitroglycerin dosage is used, a better vasodilation effect can still be achieved, indicating that cinnamaldehyde can be used for the preparation of drugs for improving the tolerance of nitrate drugs.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to application of cinnamaldehyde in preparing a drug for improving tolerance of nitrate drugs, a drug composition and a preparation thereof. Background Art

[0002] Drug therapy is one of the important ways to treat ischemic cardiomyopathy. Whether it is angina pectoris or acute myocardial infarction, nitroglycerin (NTG) is the first choice for treatment. Studies have found that nitroglycerin activates soluble guanylate cyclase in cells by releasing nitric oxide (NO), leading to the production of guanosine 3,5-cyclic monophosphate (cGMP), promoting smooth muscle cell relaxation through dephosphorylation of myosin light chain, dilating blood vessels, and increasing perfusion of ischemic myocardium. In addition, the vasodilatory effect of nitroglycerin may be related to calcitonin gene-related peptide (CGRP). Nitroglycerin is still a classic drug for the treatment of coronary heart disease, but some patients may develop rapid tolerance to NTG after continuous use for 24 hours. The occurrence of nitroglycerin tolerance not only affects the clinical efficacy, but may also aggravate vascular endothelial damage, which is the key reason limiting its clinical use. Studies have shown that the tolerance of nitroglycerin is related to the decrease in the activity of the biotransformation enzyme acetaldehyde dehydrogenase (ALDH2), which leads to increased production of reactive oxygen species (ROS) and reduced production of calcitonin gene-related peptide (CGRP). Some studies have also found that tolerance to nitroglycerin is related to endothelial cell dysfunction, and its mechanism may be that nitroglycerin activates protein kinase C (PKC), and the activated protein kinase C phosphorylates endothelial nitric oxide synthase (eNOS) at amino acid 495, thereby inactivating it.

[0003] Cinnamaldehyde (CA) is a derivative of acrolein and the main component of the volatile oil of cassia twig or cinnamon bark. It has multiple pharmacological effects such as anti-inflammatory, anti-tumor, antibacterial, anti-diabetic, anti-obesity, and neuroprotective. It has sufficient sources, few toxic side effects, and is green and environmentally friendly. It is widely used in human medicine, food, and beauty. Summary of the invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide the use of cinnamaldehyde in the preparation of drugs for improving the tolerance of nitrate drugs, a pharmaceutical composition and a preparation thereof, which can solve the problem of easy tolerance of nitroglycerin in the prior art and expand the clinical application of nitroglycerin.

[0005] The invention provides application of cinnamaldehyde in preparing a medicine for improving tolerance of nitrate drugs.

[0006] The present invention also provides the use of cinnamaldehyde in preparing a drug for increasing the expression of calcitonin gene-related peptide. The present invention also provides the use of cinnamaldehyde in preparing a protein kinase Cα inhibitor.

[0007] In certain embodiments of the present invention, the nitrate drug is selected from one or more of nitroglycerin, isosorbide dinitrate, 5-isosorbide mononitrate or pentylenetetrazol. In certain embodiments of the present invention, the cinnamaldehyde can be replaced by cinnamon or cinnamon extract, but cinnamaldehyde is preferably used.

[0008] The inventors of the present application creatively discovered that cinnamaldehyde can not only promote the release of calcitonin gene-related peptide (CGRP) by activating transient receptor potential channel A1 (TRPA1) receptors, but also inhibit the activity of protein kinase Cα, reverse the tolerance of nitrate drugs, reduce the dosage of nitrate drugs, and prolong the action time of nitrate drugs. The present invention uses nitroglycerin as an example to conduct experiments. The experimental results confirm that for experimental subjects who have developed nitroglycerin tolerance, the vasodilation effect of the combined use of cinnamaldehyde and nitroglycerin is nearly 10% higher than the maximum vasodilation degree Emax of the vascular ring when nitroglycerin is used alone. Even if a lower dose of nitroglycerin is used, a better vasodilation effect can still be achieved, indicating that cinnamaldehyde can be used in the preparation of drugs for improving nitrate tolerance.

[0009] The present invention provides a pharmaceutical composition, comprising cinnamaldehyde and a nitrate drug. The pharmaceutical composition of the present invention uses cinnamaldehyde and a nitrate drug in combination, and experiments are conducted using nitroglycerin as an example, and it is found that cinnamaldehyde reduces the dosage of nitroglycerin, prolongs the action time of nitroglycerin, improves nitroglycerin tolerance, and expands the clinical application of nitroglycerin.

[0010] The cinnamaldehyde and nitrate drugs of the present invention are the same as those described above and will not be described in detail. In certain embodiments of the present invention, in the pharmaceutical composition, the mass ratio of the cinnamaldehyde to the nitrate drugs is 1 to 15:1, preferably 5 to 10:1.

[0011] In one embodiment, in the pharmaceutical composition, the cinnamaldehyde is 7.5 parts by mass, and the nitrate drug is 0.5 parts by mass; alternatively, the cinnamaldehyde is 5 parts by mass, and the nitrate drug is 0.5 parts by mass; alternatively, the cinnamaldehyde is 2.5 parts by mass, and the nitrate drug is 0.5 parts by mass; alternatively, the cinnamaldehyde is 0.5 parts by mass, and the nitrate drug is 0.5 parts by mass; alternatively, the cinnamaldehyde is 4 parts by mass, and the nitrate drug is 0.5 parts by mass.

[0012] The present invention provides a method for preparing the above-mentioned pharmaceutical composition, comprising: mixing cinnamaldehyde and nitrate drugs in proportion; in one embodiment, passing cinnamaldehyde through a 100-200 mesh sieve, grinding nitroglycerin raw material drug and passing through a 150-300 mesh sieve, and mixing the sieved cinnamaldehyde and nitroglycerin raw material drug in proportion to obtain the pharmaceutical composition of the present invention. The proportion is the same as above and will not be repeated.

[0013] In one embodiment, the cinnamaldehyde is extracted from cinnamon bark, specifically comprising: taking a certain mass of cinnamon bark and grinding it, adding ethanol 1.5 to 2.5 times the mass of the cinnamon bark, and extracting it at 90 to 100° C. After the extraction stops, the extract is distilled, and then steam distilled and separated to obtain a light yellow viscous liquid, which is cinnamaldehyde. The light yellow viscous liquid is dispersed using a solid dispersion technology to obtain cinnamaldehyde.

[0014] The present invention also provides a pharmaceutical preparation, comprising the above pharmaceutical composition and pharmaceutically acceptable excipients.

[0015] In certain embodiments of the present invention, the dosage form of the pharmaceutical preparation is an oral preparation, an injection preparation or an external preparation; the oral preparation is a tablet, a capsule, a granule, a concentrated pill or a liquid; the injection preparation is a liquid injection, an injection powder or an injection tablet; the external preparation is an external solvent, an ointment, a patch, an external powder or an inhalant.

[0016] In one embodiment, the dosage form of the drug preparation is a patch, comprising a matrix, a pressure-sensitive adhesive and the drug composition of the present invention; the matrix and the pressure-sensitive adhesive are the matrix and the pressure-sensitive adhesive for drug patches well known to those skilled in the art. In one embodiment, the matrix comprises a backing film and a release material composite film; the pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive. The drug composition is the same as above and will not be described in detail.

[0017] The present invention provides a method for preparing the above-mentioned pharmaceutical preparation, comprising: mixing the above-mentioned pharmaceutical composition and pharmaceutically acceptable excipients in proportion, and preparing the pharmaceutical preparation according to the requirements of different dosage forms. In certain embodiments of the present invention, the acrylic pressure-sensitive adhesive and the above-mentioned pharmaceutical composition are mixed in proportion, and the pharmaceutical patch is prepared with the pharmaceutical patch matrix.

[0018] In one embodiment, a certain mass of the above-mentioned pharmaceutical composition is taken, dissolved in ethanol with a mass of 1.5 to 2.5 times the mass of the pharmaceutical composition, and acrylic pressure-sensitive adhesive is added in proportion to mix, and then coated on a release profile composite film to form a drug-containing adhesive layer, and dried at 35 to 55° C. for 60 to 120 minutes to remove the process solvent; after laminating with a controlled release film, the film is rolled up to obtain an adhesive layer film; and then laminating with a backing film, punching and cutting to obtain a nitroglycerin cinnamaldehyde composite film.

[0019] The present invention provides the application of cinnamaldehyde in the preparation of a drug for improving the tolerance of nitrate drugs, a pharmaceutical composition and a preparation thereof. The combined use of cinnamaldehyde and nitroglycerin can solve the problem that nitroglycerin is easy to produce tolerance in the prior art, prolong the action time of nitroglycerin, reduce the dosage of nitroglycerin, not only expand the clinical application of nitroglycerin, but also expand the benefits, and is more in line with the current level of the pharmaceutical industry and the current status of pharmaceutical investment from the principle of pharmaceutical economics. The experimental results confirm that for experimental subjects who have developed nitroglycerin tolerance, the combined use of cinnamaldehyde and nitroglycerin is nearly 10% higher than the vasodilation effect of nitroglycerin alone in terms of the maximum vascular ring dilation degree Emax, and even with a lower nitroglycerin dosage, a better vasodilation effect can still be achieved, indicating that cinnamaldehyde can be used for the preparation of drugs for improving the tolerance of nitrate drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The TTC staining and statistical graph of different concentrations of cinnamaldehyde on the myocardial infarction area of ​​SD rats with myocardial ischemia-reperfusion;

[0021] Figure 2 This is the effect of cinnamaldehyde on the expression level of CK in the serum of SD rats with myocardial ischemia-reperfusion;

[0022] Figure 3 This is TTC staining and statistical graph showing the effect of cinnamaldehyde combined with CGRP specific antagonist (CGRP8-37) on myocardial infarction area in SD rats with myocardial ischemia-reperfusion. DETAILED DESCRIPTION

[0023] The present invention discloses the use of cinnamaldehyde in the preparation of a drug for improving the tolerance of nitrate drugs, a pharmaceutical composition and a preparation thereof. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It is particularly important to point out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the method and application of this article without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention.

[0024] The composition of the pharmaceutical preparation described in this specific embodiment is shown in Table 1.

[0025] Table 1

[0026] composition Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Nitroglycerin (g) 0.5 0.5 0.5 0.5 0.4 0.5 Cinnamaldehyde(g) 7.5 5 2.5 0.5 4 0 Acrylic pressure sensitive adhesive (g) 4.5 4.5 4.5 4.5 3.6 4.5 <![CDATA[Lined film (m 2 )]]> 0.5 0.5 0.5 0.5 0.5 0.5 <![CDATA[Composite film for separated profiles (m 2 )]]> 0.5 0.5 0.5 0.5 0.5 0.5 Quantity (pieces) 100 100 100 100 100 100

[0027] The present invention will be further described below in conjunction with embodiments:

[0028] Embodiments 1 to 5

[0029] According to the following steps, the pharmaceutical preparations of Examples 1 to 5 of the present invention were prepared with the compositions of the pharmaceutical preparations of Examples 1 to 5 shown in Table 1:

[0030] Step 1: Crush cinnamon bark into coarse powder, add 95% ethanol solution of twice the mass of the cinnamon bark, extract at 90°C, and stop when the color of the liquid in the extractor becomes almost transparent. Distill the ethanol contained in the extract in the recovery extractor, and then steam distill and separate the extract to obtain a light yellow viscous liquid, which is cinnamaldehyde. Use solid dispersion technology to obtain a cinnamaldehyde dispersion, and obtain a fine powder that passes through a 100-mesh sieve for later use;

[0031] Step 2: Put the nitroglycerin API into a blender and stir evenly, extract and grind to obtain fine nitroglycerin API powder that passes through a 200-mesh sieve and set aside;

[0032] Step 3: according to the proportions and amounts of Examples 1 to 5 shown in Table 1, the fine powders obtained in the above steps 1 and 2 are taken, dissolved with ethanol twice the mass of the taken fine powders, and acrylic pressure-sensitive adhesive is added to mix, stirred in a closed manner, degassed under reduced pressure, and coated on the release profile composite film to form a drug-containing adhesion layer, dried at a temperature of 35 to 55° C. for 90 minutes, and the process solvent is removed; after laminating with the controlled release film, the film is rolled up to obtain an adhesion layer film; and then laminating with the backing film to form a nitroglycerin patch; and punching and cutting are performed to obtain the nitroglycerin cinnamaldehyde compound patch (NTG / CA compound patch) of Examples 1 to 5.

[0033] According to the pharmacopoeia release determination method, the release of nitroglycerin and cinnamaldehyde of the nitroglycerin-cinnamaldehyde composite patches prepared in Examples 1 to 5 can reach more than 70% after 12 hours.

[0034] Comparative Example 1

[0035] The difference from Examples 1 to 5 is that in step 3, the pharmaceutical preparation is prepared according to the proportions and amounts of Comparative Example 1 shown in Table 1 to obtain a nitroglycerin patch (NTG patch).

[0036] Example 6 Test on the effect of cinnamaldehyde (CA) on the tolerance of nitroglycerin (NTG)

[0037] After one week of adaptive feeding, SD rats weighing 250-300g were randomly divided into 7 groups, 6 rats in each group, and the weight of the rats was weighed and recorded, and set as normal control group, NTG patch group and NTG / CA compound patch groups 1-5, respectively, wherein the NTG patch group used 5mg / d of the NTG patch of comparative example 1, and the NTG / CA compound patch groups 1-5 used the NTG / CA compound patches of Examples 1-5, respectively. The rats were anesthetized with pentobarbital, the hair between the scapulae on the back of the chest was removed, and the patch was attached to the site and fed for 3 days; the rats in the normal control group were subjected to similar operations, but the NTG patch was not used.

[0038] After the rats were killed, the thoracic aorta was quickly dissected out and placed in a Krebs solution bath filled with 95% O2 + 5% CO2. The surrounding connective tissue was removed and cut into a single ring segment of about 5 mm in length to connect to the tension transducer. The aortic ring was first contracted with potassium chloride solution to test its vitality, and then rinsed twice in Krebs solution. The ring was contracted with 1 μmol / L phenylephrine to obtain a stable tension, and then different concentrations of NTG, i.e., 30nmol / L to 30 μmol / L NTG, were added to observe the vascular dilation response and record the maximum dilation degree of the vascular ring. The result data were expressed as mean ± standard deviation, and the inter-group comparison was performed by variance analysis. P < 0.01 was considered to be significantly different. The results are shown in Table 2:

[0039] Table 2

[0040] Group Emax(%) Normal control group 97.1±1.3 NTG / CA compound patch group 1 95.2±2.0 NTG / CA compound patch group 2 96.6±1.1 NTG / CA compound patch group 3 96.2±1.9 NTG / CA compound patch group 4 90.5±0.8 NTG / CA compound patch group 5 96.4±2.3 NTG patch group 80.7±1.4

[0041] As shown in the results in Table 2, compared with the normal control group, the diastolic response of the aortic rings of SD rats in the NTG patch group to NTG was significantly weakened (P < 0.01), indicating that the continuous use of the NTG patch has produced tolerance; the responsiveness of the aortic rings of SD rats in NTG / CA compound patch groups 1 to 5 to NTG was significantly enhanced compared with that in the NTG patch group (P < 0.01), indicating that CA can significantly reduce the tolerance to NTG; the responsiveness of the aortic rings of SD rats in NTG / CA compound patch group 5 to NTG was significantly enhanced compared with that in the NTG patch group (P < 0.01), indicating that the combined use of cinnamaldehyde can achieve a better diastolic response effect while reducing the dosage of nitroglycerin.

[0042] Example 2 Test on the protective effect of cinnamaldehyde on myocardial injury

[0043] The effect of cinnamaldehyde on myocardial infarction area of ​​SD rats with myocardial ischemia-reperfusion was tested as follows:

[0044] After one week of adaptive feeding, SD rats weighing 250-300 g were randomly divided into 4 groups. The rats were weighed and set as sham operation group, model group and experimental group, respectively. The experimental group included 20 mg / kg CA group and 50 mg / kg CA group (CA was purchased from Anergy).

[0045] Except for the sham operation group, the SD rats in the other groups were ligated with the anterior descending coronary artery to establish the myocardial ischemia-reperfusion model. In the sham operation group, the SD rats only opened the chest cavity and fully exposed the heart, without ligating the anterior descending coronary artery. After the myocardial ischemia-reperfusion model was established, the experimental groups were intraperitoneally injected with cinnamaldehyde (solvent was normal saline) at a dose of 20 mg / kg and 50 mg / kg, respectively, and the sham operation group was intraperitoneally injected with an equal amount of normal saline.

[0046] The specific operations of establishing the myocardial ischemia-reperfusion model in SD rats and the experiment on the effect of myocardial infarction area are as follows:

[0047] Step 1: SD rats were anesthetized by intraperitoneal injection of 3% 50 mg / kg sodium pentobarbital, and then their teeth and limbs were fixed on a mouse board;

[0048] Step 2: Cut the neck skin of the SD rat, bluntly separate the muscles, expose the trachea, make a T-shaped incision on the trachea, insert the ventilator hose into the rat trachea, thread and fix it, and connect the animal ventilator. The ventilator is set to a tidal volume of about 25 mL / kg and a frequency of 50 times per minute;

[0049] Step 3: Use a razor to shave the chest hair of the SD rat, cut the skin between the 3rd and 4th intercostal spaces on the left side, use forceps to bluntly separate the muscle tissue, use flat-head scissors to remove the ribs, and fully expose the heart;

[0050] Step 4: Remove the pericardium, squeeze out the heart quickly, use the obvious left coronary vein between the pulmonary artery cone and the left atrial appendage as a landmark, wrap the leather loop with 5.0 suture thread to ligate the left anterior descending branch of the coronary artery, quickly restore the position of the heart, and ligate it;

[0051] Step 5: Observe while performing step 4. If the apex of the heart turns white, it means myocardial ischemia is successful. The ischemia lasts for 1 hour.

[0052] Step 6: 5 minutes before reperfusion, the control group was given an equal dose of normal saline, and the experimental group was given the above dose of cinnamaldehyde, and then the leather ring and ligature were cut open to resume perfusion for 3 hours;

[0053] Step 7: All groups of mice were moved into 4% paraformaldehyde for fixation for 24 hours and then photographed; the necrotic area was not stained and appeared white because there was no dehydrogenase, while the non-necrotic area was stained red because it contained dehydrogenase.

[0054] Image J was used to calculate the myocardial infarction area, and GraphPad Prism 9 software was used to calculate the statistical results. Figure 1 As shown, Figure 1 The TTC staining and statistical graph of different concentrations of cinnamaldehyde on the myocardial infarction area of ​​SD rats with myocardial ischemia-reperfusion. Figure 1 Compared with the model group, ##p<0.01, n=6; Figure 1 It can be seen that the hearts of SD rats in the sham operation group were all red, with no infarcted area; the myocardial infarction area of ​​SD rats in the model group was significantly increased compared with that in the sham operation group, proving that the myocardial ischemia-reperfusion model was successfully established; in the CA group, the myocardial infarction area of ​​SD rats in the 20 mg / kg CA group was not significantly different from that in the model group, and the myocardial infarction area of ​​SD rats in the 50 mg / kg CA group was significantly reduced compared with that in the model group, with a significant difference.

[0055] The results show that cinnamaldehyde can reduce the area of ​​myocardial infarction caused by myocardial ischemia-reperfusion and has a protective effect on the myocardium. Therefore, when cinnamaldehyde is used in combination with nitroglycerin, it may also play a certain anti-myocardial ischemia effect and enhance the therapeutic effect on ischemic cardiomyopathy.

[0056] The effect of cinnamaldehyde on the expression level of serum creatine kinase (CK) was tested as follows:

[0057] After the ischemia-reperfusion surgery in step 6, blood was collected from the apex of the heart, centrifuged at 3000 rpm and 4°C for 10 min, and the supernatant was collected and stored at -80°C;

[0058] Serum CK activity was determined as follows: 10 mL of R2 reagent was used to dissolve a bottle of R1 reagent to prepare a working solution, 4 μL of serum was added to 200 μL of CK reagent kit working solution, and incubated at 37°C for 2 min. The wavelength of the microplate reader was set to 340 nm, and the absorbance A0, A1, A2, A3, and A4 were read at 0, 1, 2, 3, and 4 min, respectively. The change in average absorbance per minute (△A) was calculated, and the concentration of CK in serum was calculated according to the following formula:

[0059]

[0060] Note: △A = change in average absorbance; extinction coefficient = 6.3;

[0061] Vt: total reaction volume = 2.5 mL;

[0062] Vs: Sample volume = 50 μL.

[0063] The results are as follows Figure 2 As shown, Figure 2This is the effect of cinnamaldehyde on the expression level of CK in the serum of SD rats with myocardial ischemia-reperfusion. Figure 2 Compared with the model group, #p<0.05, n=6; Figure 2 It can be seen that the serum creatine kinase (CK) level of SD rats in the 20mg / kg CA group in the experimental group was not significantly different from that in the model group; the serum CK level of SD rats in the 50mg / kg CA group was significantly lower than that in the model group. This result shows that 50mg / kg cinnamaldehyde can significantly reduce the serum CK level in rats with myocardial ischemia-reperfusion. The above results all prove that cinnamaldehyde has a protective effect on myocardial damage.

[0064] Example 3 Mechanism of the Effect of Cinnamaldehyde on Nitroglycerin Tolerance (CGRP)

[0065] The experiment of promoting CGRP release by cinnamaldehyde was carried out as follows:

[0066] After one week of adaptive feeding, SD rats weighing 250-300g were randomly divided into 4 groups, 6 rats in each group, and the rats were weighed and set as sham operation group, model group and experimental group respectively; except for the sham operation group, the remaining SD rats were established with myocardial ischemia reperfusion model according to the method of steps 1 to 5 of Example 2. The experimental group was further divided into CA experimental group and CA+CGRP8-37 experimental group, wherein the CA experimental group was administered with intraperitoneal injection of 50mg / kg CA, the CA+CGRP8-37 experimental group was administered with intraperitoneal injection of 50mg / kg CA and intravenous injection of 1mg / kg CGRP8-37, and the sham operation group was intraperitoneally injected with an equal amount of normal saline. Specifically, the CA experimental group and the sham operation group were given the above drugs 5min before reperfusion; the CA+CGRP8-37 experimental group was given CGRP8-37 10min before reperfusion, and CA was given 5min before reperfusion.

[0067] The results are as follows Figure 3 As shown, Figure 3 To show the TTC staining and statistical graph of the effect of cinnamaldehyde combined with CGRP specific antagonist (CGRP8-37) on myocardial infarction area in SD rats with myocardial ischemia-reperfusion, Figure 3 Compared with the model group, ##p<0.01, n=6; Figure 3It can be seen that the hearts of SD rats in the sham operation group were all red, with no infarcted area; the myocardial infarction area of ​​SD rats in the model group was significantly increased compared with the sham operation group, proving that the myocardial ischemia-reperfusion model was successfully established; compared with the model group, the myocardial infarction area of ​​the CA experimental group was significantly reduced; compared with the CA experimental group, the myocardial infarction area of ​​the CA+CGRP8-37 experimental group was increased, and the anti-myocardial ischemia-reperfusion injury effect was significantly weakened, indicating that cinnamaldehyde plays an anti-myocardial ischemia-reperfusion injury role by promoting the release of CGRP. The results show that cinnamaldehyde can promote the release of CGRP, thereby improving myocardial ischemia.

[0068] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. Application of cinnamaldehyde in the preparation of drugs for improving nitroglycerin tolerance; The mass ratio of the cinnamaldehyde to the nitroglycerin drug is 5-15:

1.

2. A pharmaceutical composition comprising cinnamaldehyde and nitroglycerin; The mass ratio of the cinnamaldehyde to the nitroglycerin is 5-15:

1.

3. The pharmaceutical composition according to claim 2, characterized in that The cinnamaldehyde is 7.5 parts by mass, and the nitroglycerin is 0.5 parts by mass; Alternatively, the cinnamaldehyde is 5 parts by mass and the nitroglycerin is 0.5 parts by mass; Alternatively, the cinnamaldehyde is 2.5 parts by mass, and the nitroglycerin is 0.5 parts by mass; Alternatively, the cinnamaldehyde is 4 parts by mass and the nitroglycerin is 0.4 parts by mass.

4. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 2 to 3 and a pharmaceutically acceptable excipient.

5. The pharmaceutical preparation according to claim 4, characterized in that The dosage form of the pharmaceutical preparation is an oral preparation, an injection preparation or an external preparation.

6. The pharmaceutical preparation according to claim 4, characterized in that The oral preparation is a tablet, capsule, granule, concentrated pill or liquid; The injection preparation is a liquid injection, a powder for injection or a tablet for injection; The external preparation is an external solvent, ointment, patch, external powder or inhalant.

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