Application of phentolamine mesylate in medicine for treating lung diseases

Abstract

The invention discloses application of phentolamine mesylate in a medicine for treating lung diseases, and belongs to the technical field of medicines. According to the invention, the phentolamine mesylate inhalation liquid preparation and other effective doses of medicines are combined for use, and lung diseases are jointly treated in a mode of aerosol inhalation into a body. The phentolamine mesylate provided by the invention can improve lung blood circulation and promote inflammation absorption, and other effective doses of drugs (ambroxol) can promote sputum discharge and keep the respiratory tract unobstructed. The two medicines are combined for use, so that the symptoms of child patients can be effectively relieved, the disease course is shortened, and the death rate is reduced.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to the application of phentolamine mesylate in medicines for treating lung diseases. Background Art

[0002] Due to low immunity and immature respiratory tract development, children are easily infected by pathogenic bacteria, which can cause pneumonia. Pediatric pneumonia is a common respiratory disease with an acute onset and rapid progression. It often occurs in infants and young children due to genetic, environmental, nutritional and other factors. If infants or children are not effectively treated, the disease may develop into severe pediatric pneumonia. Severe pediatric pneumonia is mainly manifested by ventilation dysfunction and fever symptoms (early stage), accompanied by hypoxemia and a high mortality rate. It is a lower respiratory tract inflammatory disease with a very high incidence in my country.

[0003] The symptoms of severe pneumonia are generally as follows: 1. Severe pneumonia may cause respiratory failure. Neurological symptoms mainly include mental depression, drowsiness or irritability. In severe cases, impaired consciousness, optic disc edema, coma, convulsions, and brain herniation may occur. Children may die from central respiratory failure. 2. Severe pneumonia can often lead to circulatory system involvement, which is manifested by weak pulse, accelerated heart rate, low and dull heart sounds, increased cyanosis, and increased lung rales. When shock and peripheral circulatory failure occur, the patient will appear pale, the skin will be gray and cold, the urine volume will decrease, the blood pressure will drop, and the capillary filling time will be prolonged.

[0004] At the same time as pneumonia occurs, the lungs may also develop acute lung injury and pulmonary edema due to inflammatory reactions. Acute lung injury (ALI) is caused by viruses, endotoxins, etc. stimulating immune cells to recruit and overactivate in the lung tissue and release excessive inflammatory factors, forming an "inflammatory factor storm" that ultimately causes a clinical critical disease with inflammatory damage to lung tissue and diffuse pulmonary interstitial and alveolar edema as the main pathological features. In recent years, acute infectious pneumonia has occurred frequently in my country, and ALI and the more serious acute respiratory distress syndrome (ARDS) are one of the main causes of death in patients. Pulmonary edema is a disease in which fluid in the blood vessels of the pulmonary parenchyma extravasates into the pulmonary interstitium or alveoli, causing physiological dysfunction, and then causing dyspnea as the main clinical manifestation. Among them, cardiogenic pulmonary edema is pulmonary edema caused by cardiovascular factors (such as heart failure) causing an increase in pulmonary vascular hydrostatic pressure. How to effectively improve inflammatory damage to lung tissue and pulmonary edema is one of the key and difficult points in the current treatment of pneumonia and ALI.

[0005] Clinically, the treatment of severe pneumonia is mainly based on the control of infection with antimicrobial drugs. The treatment is a comprehensive process, mainly symptomatic treatment. Due to the abuse of antibiotics and changes in the pathogens themselves, pathogens often become multidrug resistant. Although anti-infection has achieved certain therapeutic effects, conventional therapies are not effective and there is much room for improvement. In addition, severe pneumonia in children is often accompanied by symptoms such as thick sputum and difficulty in expectoration, which seriously affect the respiratory function of the children. Therefore, finding new combinations of therapeutic drugs is of great clinical significance.

[0006] Phentolamine (structure as shown in formula (1)) was originally developed by Novartis and launched in the United States on January 30, 1952 under the trade name Regitine. Its indications are: 1. Used to diagnose pheochromocytoma and treat hypertension caused by it, including hypertension during surgical resection. It can also be used to assist in the diagnosis of pheochromocytoma based on the blood pressure response to this drug; 2. Treat left ventricular failure; 3. Treat norepinephrine intravenous administration spillage and prevent skin necrosis. In 1998, Repros Therapeutics developed an orally disintegrating tablet formulation of the drug for the treatment of oral disintegrating tablet formulations. In 2008, Novalar Pharmaceuticals launched a new indication for the drug in the United States under the trade name ORAVERSE, which can be used as a local dental anesthesia reversal agent for adults and adolescents. In 2023, Ocuphire launched the ophthalmic solution formulation of the drug, RYZUMVI, in the United States for the treatment of pharmacologically induced mydriasis caused by adrenergic agonists or parasympathetic nerve agents. Phentolamine is a non-selective α-receptor blocker that can lower blood pressure and vasodilation and enhance myocardial contractility by blocking α1 and α2 receptors in blood vessels. Specifically, it can improve cardiac function, accelerate vasodilation, reduce vascular resistance, and significantly reduce peripheral vascular resistance, thereby effectively promoting pulmonary blood circulation in patients with pneumonia, reducing inflammatory factors, and improving clinical symptoms and signs.

[0007]

[0008] Currently, there is no application of α-receptor blockers in the treatment of lung diseases. Considering that the pharmacological effects of phentolamine are beneficial to improving respiratory obstruction and inflammatory response caused by lung diseases, phentolamine has good prospects for use in lung diseases. Summary of the invention

[0009] The first purpose of the present invention is to propose the use of phentolamine in the preparation of medicines for treating lung diseases, which can improve pulmonary blood circulation and promote the absorption of inflammation.

[0010] The second purpose of the present invention is to propose the use of phentolamine in the preparation of a combination drug for treating lung diseases. The combined use of phentolamine and ambroxol can exert a synergistic effect and improve the therapeutic effect when treating severe pneumonia in children.

[0011] The third object of the present invention is to provide a phentolamine mesylate inhalation liquid preparation, which can use a nebulized inhalation administration method to allow phentolamine mesylate to directly enter the airway, thereby achieving targeted and efficient treatment.

[0012] In order to solve the above problems, the technical solution adopted by the present invention is as follows:

[0013] Application of phentolamine in preparing medicines for treating lung diseases.

[0014] Application of phentolamine in the preparation of a combination drug for treating lung diseases.

[0015] Furthermore, the lung disease is bronchial asthma.

[0016] Furthermore, the lung diseases include acute pneumonia, pulmonary edema, pulmonary hypertension, acute respiratory distress syndrome, acute lung injury and pulmonary fibrosis; the acute pneumonia includes mild pneumonia, viral pneumonia and severe pneumonia.

[0017] Furthermore, the phentolamine is phentolamine mesylate.

[0018] Furthermore, the other effective doses of drugs are selected from expectorants; the expectorant is selected from one of ambroxol, acetylcysteine, ambroterol and bromhexine; and the ambroxol is ambroxol hydrochloride.

[0019] Furthermore, the mass ratio of phentolamine to the combined drug is 0.25:1 to 4:1; for the human body, the dosage of phentolamine is 0.5 to 2.0 mg / kg body weight / day; and the dosage of the combined drug is 0.5 to 2.0 mg / kg body weight / day.

[0020] Furthermore, the dosage forms of the phentolamine include injections and inhalation preparations; the inhalation preparations include aerosols, powder sprays and nebulized inhalation solutions.

[0021] Furthermore, the phentolamine mesylate inhalation liquid preparation comprises an active ingredient, an isotonic agent, a metal ion complex, a pH regulator and a solvent; the active ingredient is phentolamine mesylate; the isotonic agent is mannitol; the metal ion complex is disodium ethylenediaminetetraacetate; the pH regulator is selected from one or more of acetic acid and sodium acetate; the solvent is water for injection; and the mass ratio of the active ingredient, the isotonic agent and the metal ion complex is 1:5:0.01.

[0022] Furthermore, the preparation method is as follows: first, add water for injection, mannitol and disodium ethylenediaminetetraacetate to a liquid preparation tank, and after they are completely dissolved, add the prescribed amount of phentolamine mesylate and stir until they are completely dissolved; then, drop a pH adjuster into the solution to adjust the pH to 4.0, filter through 0.45 μm and 0.22 μm sterilizing filter membranes, and then fill and seal in a medical control bottle under nitrogen protection to obtain a phentolamine mesylate inhalation liquid preparation.

[0023] Compared with the prior art, the advantages of the present invention are as follows:

[0024] 1) The present invention adopts phentolamine mesylate and ambroxol in combination, which can exert a synergistic effect and improve the treatment effect when treating severe pneumonia in children.

[0025] 2) Phentolamine mesylate can improve pulmonary blood circulation and promote the absorption of inflammation, while ambroxol can promote sputum discharge and keep the respiratory tract open. Combining the two drugs at a certain dose can more effectively relieve the symptoms of children, shorten the course of the disease, and reduce mortality.

[0026] 3) The present invention adopts atomized inhalation administration to enable phentolamine mesylate to directly enter the airway, and has a high concentration locally in the respiratory tract, thereby achieving targeted and efficient treatment, and the dosage is small and the inhalation rate is high, which significantly improves the patient's compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a graph showing the effect of phentolamine on airway resistance after OVA-induced asthma attack in guinea pigs in Example 2;

[0028] Figure 2 This is a graph showing the rate of change of airway resistance after OVA-induced asthma attack in guinea pigs induced by phentolamine in Example 2;

[0029] Figure 3 This is a graph showing the effect of phentolamine on lung compliance after OVA-induced asthma in guinea pigs in Example 2;

[0030] Figure 4 This is a graph showing the rate of change of lung compliance of guinea pigs after an asthma attack induced by OVA in Example 2;

[0031] Figure 5 This is a diagram showing the effect of each group on lung tissue damage in ALI rats observed by HE staining in Example 3;

[0032] Figure 6 The effect of each group on the levels of TNF-α, IL-6 and IL-1β in rat serum in Example 3;

[0033] Figure 7 This is the SOD activity diagram of lung tissue in Example 3;

[0034] Figure 8 This is a graph showing the MDA content in lung tissue in Example 3;

[0035] Fig. 9 This is a graph of the GSH-Px content in lung tissue in Example 3. DETAILED DESCRIPTION

[0036] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with specific embodiments.

[0037] Unless otherwise specified, the raw materials and reagents used in the following specific embodiments are all commercially available products.

[0038] Example 1

[0039] The specific components and dosages of the phentolamine mesylate inhalation liquid preparation are shown in Table 1 below;

[0040] Table 1 Prescription of phentolamine mesylate inhalation liquid preparation

[0041]

[0042]

[0043] The preparation method of phentolamine mesylate inhalation liquid preparation is as follows:

[0044] Add 800mL (80% of the prescription amount) of water for injection into the liquid preparation tank, add the prescription amount of mannitol and disodium edetate in sequence, stir and dissolve, after complete dissolution, add the prescription amount of phentolamine mesylate, continue to stir until complete dissolution; then drop a pH adjuster into the solution, stir thoroughly until complete dissolution, adjust the pH to 4.0, add water for injection to 1000mL, filter through 0.45μm and 0.22μm sterilizing filter membranes, and fill and seal in medical control bottles under nitrogen protection to obtain a phentolamine mesylate inhalation liquid preparation, that is, 10mg / (1mL / bottle), a total of 1000 bottles.

[0045] Example 2

[0046] Application of phentolamine (in this embodiment, 10 mg / mL phentolamine mesylate injection is used for aerosol inhalation administration) in the treatment of bronchial asthma induced by guinea pig ovalbumin.

[0047] In this example, an ovalbumin (OVA)-induced guinea pig asthma model was established, and phentolamine was administered by aerosol inhalation to study the improvement of phentolamine on lung compliance and airway resistance.

[0048] Due to the particularity of nebulized inhalation administration, for guinea pigs, the actual inhaled drug amount of the inhaled solution (i.e., the deposited dose) is approximately 20% of the total nebulized drug amount (i.e., the delivered dose). Therefore, in this embodiment, the guinea pig delivery dose is set to 4 / 8 / 16 mg / kg, respectively, so the lung deposition dose is 0.8 / 1.6 / 3.2 mg / kg.

[0049] Experimental methods: 25 male guinea pigs (weight 400±20g) were randomly divided into control group, model group, low-dose phentolamine group (4mg / kg), medium-dose phentolamine group (8mg / kg) and high-dose phentolamine group (16mg / kg), 5 in each group. The drug was administered by aerosol inhalation 1h before OVA challenge, and the control group and model group were gavaged with normal saline. The airway resistance (R) of guinea pigs was measured. L ) and dynamic lung compliance (C dyn ) was used to evaluate the blocking effect of phentolamine on OVA-induced bronchoconstriction in sensitized guinea pigs. A 1% grade II OVA solution was prepared with 10% aluminum hydroxide gel as solvent, and 1 mL was injected into each guinea pig intraperitoneally. After 25-35 days, the guinea pigs were challenged with antigens for lung function test. A 5g / L grade II OVA saline solution was atomized to induce panting for 30 seconds, and the MedLab biosignal acquisition and processing system recorded the changes in lung function for 30 minutes.

[0050] Evaluation index: Pulmonary function test (airway resistance R L and dynamic lung compliance C dyn ).

[0051] Experimental results: The airway resistance (R L ) and lung compliance (C dyn ) were 0.50 ± 0.15 cmH2O and 0.15 ± 0.02 mL / cmH2O (see Table 2 and Figure 1 ). After stimulation, R L The average values ​​were 4.19±1.38, 3.29±0.90, 2.52±0.30, and 2.37±0.69 cmH2O, respectively, which were 777%, 680%, 480%, and 427% higher than before stimulation (see Table 3 and Figure 2 ); 2, 5, 10, 30 min C dyn The average values ​​were 0.02±0.01, 0.03±0.01, 0.03±0.01 and 0.02±0.01 mL / cmH2O, respectively, which were reduced by 83.84%, 75.77%, 76.88% and 85.29% compared with those before stimulation (see Tables 4, 5 and Figure 3, 4 ). It shows that OVA-induced asthma in guinea pigs significantly increases airway resistance and reduces lung compliance. After 4 / 8 / 16 mg / kg of phentolamine was administered by aerosol inhalation, it inhibited bronchoconstriction in a dose-dependent manner, and showed significant effects of reducing airway resistance and improving lung compliance at 2, 5, 10, and 30 minutes after OVA stimulation, indicating that phentolamine has the effect of improving lung dynamics in OVA-induced asthma in guinea pigs.

[0052] Table 2 Effect of phentolamine on airway resistance at various time points after OVA-induced asthma attack in guinea pigs (N=5, cmH2O)

[0053] Group 0min 2min 5min 10min 30min Control group 0.43±0.07 0.44±0.05 0.50±0.07 0.42±0.11 0.39±0.04 Model Group 0.50±0.15 4.19±1.38 3.29±0.90 2.52±0.30 2.37±0.69 Low dose group 0.44±0.05 3.18±0.39 2.20±0.54 1.54±0.51 0.99±1.01 Medium dose group 0.40±0.08 2.36±1.05 2.11±0.38 1.22±0.51 0.48±0.24 High dose group 0.42±0.04 1.78±1.04 1.42±0.34 0.80±0.45 0.41±0.04

[0054] Table 3 Effect of phentolamine on the change rate of airway resistance at various time points after OVA-induced asthma attack in guinea pigs (%)

[0055]

[0056]

[0057] Note: n=5, mean±SD; * represents p<0.05 compared with the control group; ** represents p<0.01 compared with the control group.

[0058] Table 4 Effect of phentolamine on lung compliance at various time points after OVA-induced asthma attack in guinea pigs (N=5, mL / cmH2O)

[0059] Group 0min 2min 5min 10min 30min Control group 0.14±0.01 0.16±0.03 0.16±0.02 0.16±0.02 0.15±0.03 Model Group 0.15±0.02 0.02±0.01 0.03±0.01 0.03±0.01 0.02±0.01 Low dose group 0.14±0.02 0.10±0.05 0.06±0.02 0.05±0.02 0.03±0.01 Medium dose group 0.15±0.01 0.13±0.02 0.09±0.04 0.06±0.01 0.04±0.01 High dose group 0.15±0.02 0.16±0.02 0.13±0.05 0.12±0.06 0.10±0.04

[0060] Table 5 Effect of phentolamine on lung compliance at various time points after OVA-induced asthma attack in guinea pigs (%)

[0061]

[0062] Note: n=5, mean±SD; * represents p<0.05 compared with the control group; ** represents p<0.01 compared with the control group.

[0063] Example 3

[0064] Application of phentolamine (phentolamine mesylate inhalation liquid preparation in Example 1 is used in this example) in medicine for treating lung tissue inflammation and pulmonary edema in rats with lipopolysaccharide-induced acute lung injury (ALI).

[0065] This embodiment utilizes lipopolysaccharide (LPS) to induce rat acute lung injury (ALI) model, and gives phentolamine or phentolamine combined with ambroxol to intervene, so as to evaluate the effect of single drug or drug combination on lung tissue inflammation and pulmonary edema in ALI rats. Experimental method: 32 male Wistar rats (weight 200 ± 20g) were randomly divided into control group, model group, phentolamine group (20mg / kg), phentolamine / ambroxol combined group (20mg / kg and 30mg / kg respectively), 8 in each group. Except for the control group intraperitoneal injection of normal saline, the remaining groups of rats were intraperitoneally injected with 10mg / kg LPS to induce acute lung injury. The control group and the model group were given normal saline by gavage, and the rest were given 20mg / kg phentolamine, 20mg / kg phentolamine / 30mg / kg ambroxol by group atomization inhalation, and the drug was administered once every 12h for 2 consecutive times. After the last administration, blood was collected from the heart, and the serum was separated and the levels of TNF-α, IL-6 and IL-1β were detected. The lung tissue was weighed, and then placed in an oven, and weighed again after drying to calculate the dry mass / wetmass (D / W) of the lung tissue. In addition, lung tissue sections were taken and routine HE staining was performed to observe the pathological changes of the lung tissue. Part of the lung tissue was ground into a tissue homogenate, and the supernatant was taken after centrifugation to detect the content of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the lung tissue.

[0066] Due to the particularity of aerosol inhalation administration, for rats, the actual inhaled drug amount (i.e., deposited dose) of the inhaled solution is approximately 10% of the total aerosolized drug amount (i.e., delivered dose). Therefore, the rat delivered doses of phentolamine and ambroxol in this embodiment are set to 20 and 30 mg / kg, respectively, so the rat lung deposited doses of phentolamine and ambroxol are 2 and 3 mg / kg.

[0067] Evaluation indicators:

[0068] (1) Gross observation after lung injury: After lung injury, large areas of hemorrhage and exudation can be seen with the naked eye, which can directly reflect the degree of lung injury;

[0069] (2) Lung tissue dry mass / wet mass ratio (D / W): The lung wet / dry weight ratio is a direct indicator of pulmonary edema and a sensitive indicator of the severity of lung injury. After acute lung injury (ALI) occurs, a large amount of fluid infiltrates into the alveoli and interstitium, causing the weight of the lung to increase, while the dry weight of the lung is not affected. The rats were killed, the trachea was cut off, the whole lung was taken out, the wet weight was measured, and then the lung was placed in a 65°C incubator to dry. After 24 hours, the lung was taken out and the dry weight was measured to calculate the lung wet / dry weight ratio;

[0070] (3) Observation of histopathological sections: The left lung was fixed with 4% paraformaldehyde, and then the lung tissue was routinely dehydrated, embedded in paraffin, sliced ​​(5 μm thick), and stained with HE. HE staining lung histology evaluation can intuitively reflect the degree of lung injury. ALI histopathology is mainly manifested by the infiltration of alveolar neutrophils and red blood cells and the formation of transparent membranes on the alveolar wall. After HE staining, the inflammatory cell infiltration, edema and damage of the entire left lung tissue can be observed under a low-power microscope to evaluate the distribution of lung damage; while under a high-power microscope, the alveolar structure can be identified, and the degree of lung injury can be evaluated and scored.

[0071] Scoring method: Six visual fields were used to score hemorrhage and edema.

[0072] 0 points: No damage

[0073] 1 point: <25% of the injured area

[0074] 2 points: 25% to 50% of the damaged area

[0075] 3 points: 50% to 75% of the damaged area

[0076] 4 points: > 75% of the injured area

[0077] (4) Detection of the expression level of marker inflammatory factors: The left lobe trachea was dissected, endobronchial intubation was performed, and bronchoalveolar lavage was performed three times with 1 mL of pre-cooled sterile saline, for a total of 3 mL. The bronchoalveolar lavage fluid (BALF) was collected into a sterile centrifuge tube and centrifuged at 1500 r / min for 10 min. The supernatant was collected and stored at -80°C. The content of cytokines such as TNF-α, IL-6 and IL-1β in the alveolar lavage fluid was detected using an ELISA kit. The content of SOD, MDA and GSH-Px in lung tissue was detected by spectrophotometer.

[0078] (5) Cell count in alveolar lavage fluid (BALF):

[0079] After blood was collected from the rats, the chest was opened, the mediastinum was separated, and 3 ml of normal saline was drawn from the tracheal tube and pushed into the lungs. The lavage fluid was drawn out after repeated lavage for 3 times each time. The alveolar lavage fluid was centrifuged at 4°C and 3000r / min for 15 minutes, and the supernatant was taken and stored at -80°C for subsequent detection. The precipitate was rinsed with PBS and then stained with Diff-Quik staining solution. Cell classification was performed under an optical microscope to observe neutrophils, macrophages and lymphocytes.

[0080] Experimental results:

[0081] (1) Gross observation after lung injury: The lung tissue of the control group was light pink, smooth and elastic. Compared with the control group, the lung tissue of the model group showed large-area hemorrhage and exudation, edema, increased volume and decreased elasticity. After treatment, the lung tissue of the phentolamine group and the phentolamine / ambroxol combination group showed less congestion, reduced volume and gradually restored elasticity.

[0082] (2) Dry-to-wet ratio of lung tissue: As shown in Table 7, compared with the control group, the D / W ratio of lung tissue in the model group was significantly decreased, while the D / W ratio of lung tissue in the phentolamine group and the phentolamine / ambroxol combination group was significantly increased.

[0083] (3) Observation of tissue pathology sections: Figure 5 As shown in the figure, the lung tissue morphology of rats in the control group was normal, the alveolar pores were intact, and clear capillary networks, a small number of red blood cells, fibroblasts and macrophages were visible in the alveolar septa. The lung tissue structure of rats in the model group was destroyed, the alveolar pores became larger, the alveolar walls thickened, the fibroblasts increased, a large number of red blood cells and white blood cells infiltrated the alveolar cavity, the macrophages increased, the interstitial edema was severe, and focal alveolar hemorrhage occurred. The morphological structure of the lung tissue of rats in the phentolamine group was restored to a certain extent, but the alveolar wall was thickened, the number of inflammatory cells was significantly reduced, but a large number of red blood cells were still visible, and the interstitial edema was reduced. The lung tissue structure of rats in the phentolamine / ambroxol combination group was further improved, the alveolar pores were relatively intact, the alveolar walls were thinned, the number of inflammatory cells was further reduced, red blood cells were occasionally seen, and the interstitial edema was not obvious.

[0084] (4) Detection of expression levels of marker inflammatory factors: Figure 6 , 7 As shown in Figures 8, 9 and Table 6, compared with the control group, the lung index of the rats in the model group was reduced, the serum TNF-α, IL-6, and IL-1β levels were significantly increased, the SOD and GSH-Px levels in the lung tissue were reduced, and the MDA content was increased; compared with the model group, the above symptoms and indicators in each treatment group were significantly improved, among which the phentolamine combined with ambroxol group was the most significant. This shows that phentolamine combined with ambroxol can inhibit inflammatory response, resist oxidative damage, reduce pulmonary edema, and prevent and treat acute lung injury.

[0085] Table 6 Summary of biochemical indicators (N=8)

[0086]

[0087] Note: * represents P < 0.05 compared with the control group; △ represents P < 0.05 compared with the model group; # represents P < 0.05 compared with the phentolamine group.

[0088] Table 7 Wet / dry mass ratio of rat lung tissue (N=8)

[0089]

[0090]

[0091] Note: * represents P < 0.05 compared with the control group; △ represents P < 0.05 compared with the model group; # represents P < 0.05 compared with the phentolamine group.

[0092] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Application of phentolamine in the preparation of medicines for treating lung diseases.

2. The use of phentolamine in the preparation of a combination drug for the treatment of lung diseases.

3. The use according to claim 1 or 2, characterized in that: The lung disease is bronchial asthma.

4. The use according to claim 1 or 2, characterized in that: The lung diseases include acute pneumonia, pulmonary edema, pulmonary hypertension, acute respiratory distress syndrome, acute lung injury and pulmonary fibrosis; the acute pneumonia includes mild pneumonia, viral pneumonia and severe pneumonia.

5. The use according to claim 1 or 2, characterized in that: The phentolamine is phentolamine mesylate.

6. The use according to claim 2, characterized in that: The combined drug is selected from an expectorant; the expectorant is selected from one of ambroxol, acetylcysteine, ambroxol and bromhexine; and the ambroxol is ambroxol hydrochloride.

7. The use according to claim 2, characterized in that: The mass ratio of phentolamine to the combined drug is 0.25:1-4:1; for human body, the dosage of phentolamine is 0.5-2.0 mg / kg body weight / day; the dosage of the combined drug is 0.5-2.0 mg / kg body weight / day.

8. The use according to claim 2, characterized in that: The dosage forms of phentolamine include injection and inhalation preparations; the inhalation preparations include aerosol, powder inhalation and nebulized inhalation solution.

9. A phentolamine mesylate inhalation liquid preparation, characterized in that: The invention comprises an active ingredient, an isotonic agent, a metal ion complex, a pH regulator and a solvent; the active ingredient is phentolamine mesylate; the isotonic agent is mannitol; the metal ion complex is disodium ethylenediaminetetraacetate; the pH regulator is selected from one or more of acetic acid and sodium acetate; the solvent is water for injection; and the mass ratio of the active ingredient, the isotonic agent and the metal ion complex is 1:5:0.

01.

10. The phentolamine mesylate inhalation liquid preparation according to claim 9, characterized in that: The preparation method is as follows: first, add water for injection, mannitol and disodium ethylenediaminetetraacetate into a liquid preparation tank, and after the solution is completely dissolved, add the prescribed amount of phentolamine mesylate, and stir until it is completely dissolved; then, drop a pH adjuster into the solution to adjust the pH to 4.0, filter through 0.45 μm and 0.22 μm sterilizing filter membranes, and then fill and seal in a medical control bottle under nitrogen protection to obtain a phentolamine mesylate inhalation liquid preparation.

Images