Pharmaceutical preparation for treating pulmonary arterial hypertension and preparation method thereof

Abstract

The invention relates to a medicinal preparation for treating pulmonary arterial hypertension as well as a preparation method and application of the medicinal preparation. Every 1000mL of liquid preparation comprises 0.3-18mg of beraprost or pharmaceutically acceptable salt thereof, 0-15g of an osmotic pressure regulator, 0.05-15g of a buffering agent, 0-0.5 g of a metal chelating agent, 0-15g of a pH regulator and water for injection. The beraprost inhalation solution is more stable in physicochemical property, higher in bioavailability, higher in safety, smaller in toxicity, smaller in irritation and higher in patient use compliance, and meets clinical medication requirements.

Description

Technical Field

[0001] This application relates to the field of medicine, and particularly to a beraprost sodium pharmaceutical preparation for treating pulmonary arterial hypertension and a preparation method thereof. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disease, mainly caused by various etiologies leading to changes in the structure and function of pulmonary blood vessels, thereby causing an increase in pulmonary vascular resistance and pulmonary artery pressure. Clinically, it often presents as dyspnea, fatigue, syncope, etc. The clinical incidence is 5 - 10 per million people, and the incidence in women is higher than that in men. If not treated in time, it can ultimately develop into right heart failure and even death.

[0003] Pulmonary arterial hypertension is usually difficult to cure. Currently, clinically, the condition is mainly controlled through drug treatment methods such as dilating the pulmonary artery and inhibiting vasoconstriction. The main treatment drugs include: calcium channel blockers such as nifedipine and diltiazem; phosphodiesterase - 5 (PDE - 5) inhibitors such as sildenafil and tadalafil; endothelin receptor antagonists such as bosentan, macitentan, and ambrisentan; guanylate cyclase agonists such as riociguat; prostacyclin drugs such as iloprost, treprostinil, and beraprost sodium. Among them, prostacyclin (PGI2) can not only dilate blood vessels and reduce pulmonary artery pressure, but also reverse pulmonary vascular remodeling, and has received increasing attention in the field of pulmonary arterial hypertension treatment and is the current mainstream drug.

[0004] Beraprost sodium was first developed by a Japanese pharmaceutical company. Currently, beraprost sodium tablets (specification: 20 / 40 μg) and sustained - release tablets (specification: 60 μg) have been marketed in Japan, South Korea, and China and are approved for the treatment of pulmonary arterial hypertension. In 2021, the Chinese Medical Association's Respiratory Disease Branch and the Chinese Medical Doctor Association's Respiratory Physician Branch jointly issued the "Chinese Guidelines for the Diagnosis and Treatment of Pulmonary Arterial Hypertension (2021 Edition)", which included beraprost sodium; in 2022, in the "ESC / ERS Guidelines for the Diagnosis and Treatment of Pulmonary Arterial Hypertension" jointly issued by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), the prostacyclin analogue beraprost drugs were also recommended for adult pulmonary arterial hypertension. Beraprost sodium has the effects of dilating blood vessels and inhibiting platelet aggregation. During clinical use, it has been found that oral administration of beraprost sodium tablets can cause side effects such as bleeding tendency, gastrointestinal irritation, palpitations, shortness of breath, and blood pressure reduction. Since pulmonary arterial hypertension requires long - term medication, long - term oral administration may cause side effects such as cardiovascular system abnormalities and digestive system abnormalities. In addition, oral administration has a strong first - pass effect in the liver and a low bioavailability. Therefore, for lung diseases, local targeted drug delivery treatment is more suitable.

[0005] In recent years, with the continuous aggravation of problems such as environmental pollution and population aging, the prevalence of respiratory diseases has also been rising continuously. The inhalation administration method has received more and more attention and recognition. For the treatment of lung diseases such as pulmonary hypertension, inhalation administration is also more suitable. Inhalation preparations use specific administration devices to disperse drugs into tiny particles such as aerosol droplets and powder mists, which are deposited in the lungs through the respiratory tract, and then directly act on the lesion site. Compared with the oral administration method, it has the following advantages: (1) The drug is directly absorbed into the blood through the lungs, with rapid onset; (2) It is a local administration, which can increase the accumulation of the drug in the lungs, increase the curative effect while reducing the toxic and side effects; (3) There is no first-pass effect and high bioavailability; (4) High patient compliance, etc. Summary of the Invention

[0006] In one or more embodiments of the present application, in view of the problems of large toxic and side effects and low bioavailability of the current oral administration of beraprost sodium tablets, a beraprost inhalation solution and its preparation method are provided. The beraprost inhalation solution has at least one of the following characteristics: more stable physical and chemical properties, higher bioavailability, higher safety, lower toxicity, lower irritation, and higher patient compliance, meeting the clinical medication needs.

[0007] In one or more embodiments of the present application, the liquid pharmaceutical preparation of the present application can be atomized by means of an atomizer, and the active ingredient is used to treat PAH by inhalation, with good treatment effect, higher safety, fewer side effects, and more convenient administration.

[0008] One or more embodiments of the present application provide a liquid preparation for the treatment of pulmonary hypertension. Each 1000 mL of the liquid preparation contains:

[0009] Beraprost or a pharmaceutically acceptable salt thereof 0.3 - 18 mg (such as 0.5, 1, 5, 10, 12, 15 mg); for example, the sodium salt of beraprost;

[0010] Osmotic pressure regulator 0 - 15 g, such as 3, 5, 9, 10, 13 g;

[0011] Buffer 0.05 - 15 g, such as 0.1, 1, 5, 10, 12 g;

[0012] Metal chelator 0 - 0.5 g, such as 0.1, 0.2, 0.3, 0.4 g;

[0013] pH regulator 0 - 15 g, such as 0.2, 1, 5, 10 g;

[0014] The balance is water, such as water for injection.

[0015] In one or more embodiments, the pH regulator controls the pH value of the pharmaceutical composition to 4 to 8.5 (such as 5, 6, 7).

[0016] In one or more embodiments, the pH regulator is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, potassium hydroxide.

[0017] In one or more embodiments, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, mannitol, glucose, sorbitol.

[0018] In one or more embodiments, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, calcium chloride.

[0019] In one or more embodiments, the buffer is one or more of sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, sodium acetate.

[0020] In one or more embodiments, the metal chelating agent is one or more of EDTA, EDTA-2Na.

[0021] One or more embodiments of the present application provide an inhalation liquid preparation for treating pulmonary hypertension, which comprises the liquid preparation of the present application and a pharmaceutically acceptable excipient or auxiliary material.

[0022] In one or more embodiments, the inhalation liquid preparation is an inhalation solution.

[0023] One or more embodiments of the present application provide a preparation method of the inhalation liquid preparation of the present application, which includes:

[0024] (1) For every 1000 mL of the inhalation liquid preparation, take the following components:

[0025] Beraprost or a pharmaceutically acceptable salt thereof 0.3 to 18 mg (such as 0.5, 1, 5, 10, 12, 15 mg); for example, the sodium salt of beraprost;

[0026] Osmotic pressure regulator 0 to 15 g, such as 3, 5, 9, 10, 13 g;

[0027] Buffer 0.05 to 15 g, such as 0.1, 1, 5, 10, 12 g;

[0028] Metal chelating agent 0 - 0.5 g, such as 0.1, 0.2, 0.3, 0.4 g;

[0029] pH regulator 0 - 15 g, such as 0.2, 1, 5, 10 g;

[0030] The remaining water, such as water for injection.

[0031] (2) Dissolve the buffer, optional osmotic pressure regulator, and optional metal chelator in the water, and set aside for later use;

[0032] (3) Optionally, dissolve the beraprost or its pharmaceutically acceptable salt in the solution obtained in step (2), add the pH regulator, and adjust the pH value to 4 - 8.5;

[0033] (4) Make up the volume to the full amount, and it is ready.

[0034] In one or more embodiments, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, mannitol, glucose, and sorbitol.

[0035] In one or more embodiments, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.

[0036] In one or more embodiments, the buffer is one or more of sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, and sodium acetate.

[0037] In one or more embodiments, the metal chelator is one or more of EDTA and EDTA - 2Na.

[0038] In one or more embodiments, the pH regulator is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, and potassium hydroxide.

[0039] In one or more embodiments, in step (2), add the osmotic pressure regulator, optional buffer, and optional metal chelator to 80% of the prescribed amount of water, stir until completely dissolved, and set aside for later use.

[0040] In one or more embodiments, in step (3), add the beraprost or its pharmaceutically acceptable salt to the solution obtained in step (2), stir until completely dissolved, then add the pH regulator to adjust the pH value to 4 - 8.5 and filter.

[0041] In one or more embodiments, in step (4), make up the volume to the full amount, stir evenly, filter, and seal to obtain the product.

[0042] In one or more embodiments, in steps (2) - (4), the water is water for injection.

[0043] One or more embodiments of the present application provide the use of the liquid preparation of the present application or the inhalation liquid preparation of the present application in the preparation of a medicament for treating pulmonary hypertension.

[0044] The present invention provides a liquid preparation for treating pulmonary hypertension.

[0045] Further, in one or more embodiments, the liquid preparation is an inhalation liquid preparation.

[0046] Further, in one or more embodiments, the inhalation liquid preparation is an inhalation solution.

[0047] In one or more embodiments, the obtained inhalation solution can be inhaled through the mouth and nose in an atomized form through a nebulizer and deposited in the lungs.

[0048] One or more embodiments of the present application provide a preparation method of the liquid preparation of the present application, which includes:

[0049] (1) Take the following components per 1000 mL:

[0050] Beraprost or a pharmaceutically acceptable salt thereof 0.3 - 18 mg;

[0051] Osmotic pressure regulator 0 - 15 g;

[0052] Buffer 0.05 - 15 g;

[0053] Metal chelator 0 - 0.5 g;

[0054] pH regulator 0 - 15 g;

[0055] (2) Dissolve the osmotic pressure regulator, buffer and metal chelator in water for later use;

[0056] (3) Dissolve the beraprost or a pharmaceutically acceptable salt thereof in the solution obtained in step (2), and add a pH regulator to adjust the pH value to 4 - 8.5;

[0057] (4) Make up the volume with water to obtain the product.

[0058] Further, in one or more embodiments, each 1000 mL of the liquid preparation contains 0.5 - 12 mg of beraprost or a pharmaceutically acceptable salt thereof.

[0059] Further, in one or more embodiments, the pharmaceutically acceptable salt is sodium salt.

[0060] Further, in one or more embodiments, the pharmaceutical composition contains 3 - 9 g of osmotic pressure regulator.

[0061] Further, in one or more embodiments, the pharmaceutical composition comprises 0.1-10 g of a buffering agent.

[0062] Further, in one or more embodiments, the pharmaceutical composition comprises 0.1-0.4 g of a metal chelating agent.

[0063] Further, in one or more embodiments, the pharmaceutical composition comprises 0.2-10 g of a pH regulator.

[0064] Further, in one or more embodiments, the water is water for injection.

[0065] Further, in one or more embodiments, the osmotic pressure regulator is one of sodium chloride and potassium chloride.

[0066] Further, in one or more embodiments, the buffering agent is one or more of sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0067] Further, in one or more embodiments, the metal chelating agent is one of EDTA-2Na and EDTA.

[0068] Further, in one or more embodiments, the pH regulator is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, and potassium hydroxide.

[0069] In one or more embodiments, in step (2), the osmotic pressure regulator, buffering agent, and metal chelating agent are added to 80% of the prescription amount of water, stirred until completely dissolved, and reserved for use.

[0070] In one or more embodiments, in step (3), the beraprost or its pharmaceutically acceptable salt is added to the solution obtained in step (2), stirred until completely dissolved, then a pH regulator is added to adjust the pH value to 4-8.5, and then filtered.

[0071] In one or more embodiments, in step (4), water is added to make up the total volume, stirred evenly, filtered, and then filled and sealed to obtain the product.

[0072] In one or more embodiments, in steps (2)-(4), the water is water for injection.

[0073] One or more embodiments of the present application provide the use of the liquid preparation of the present application in the preparation of a drug for the treatment of pulmonary hypertension.

[0074] One or more embodiments of the present application provide a beraprost sodium inhalation solution for treating pulmonary arterial hypertension and a preparation method thereof. After being atomized by an atomizer, it can achieve inhalation administration, improve the accumulation of the drug at the lesion site, enhance the drug efficacy, reduce the toxic and side effects, and at the same time solve the problems of low bioavailability and poor compliance of traditional preparations.

[0075] In one or more embodiments, the quality indexes for evaluating the beraprost sodium inhalation solution include appearance, pH value, content, related substances, stability, aerodynamic particle size distribution after atomization, irritation, etc.

[0076] In one or more embodiments, through the investigation of the appearance, pH value, content, related substances, stability, aerodynamic particle size distribution after atomization, irritation, etc. of the beraprost sodium inhalation solution, it is found that the beraprost sodium inhalation solution has good stability, is mild and non-irritating to the respiratory tract, and has high safety.

[0077] In one or more embodiments, a beraprost sodium inhalation solution for treating pulmonary arterial hypertension is provided, and each 1000 mL of the inhalation solution contains the following amounts of components, including:

[0078] Beraprost or its pharmaceutically acceptable salt 0.3 - 18 mg, preferably 0.5 - 12 mg;

[0079] Osmotic pressure regulator 0 - 15 g, preferably 3 - 9 g;

[0080] Buffer 0.05 - 15 g, preferably 0.1 - 10 g;

[0081] Metal chelating agent 0 - 0.5 g, preferably 0.1 - 0.4 g;

[0082] pH regulator 0 - 15 g, preferably 0.2 - 10 g;

[0083] Water to make up the total volume, preferably water for injection.

[0084] Further, in one or more embodiments, the osmotic pressure regulator is one of sodium chloride and potassium chloride.

[0085] Further, in one or more embodiments, the buffer is one or more of sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0086] Further, in one or more embodiments, the metal chelating agent is one of EDTA-2Na and EDTA.

[0087] Further, in one or more embodiments, the pH regulator is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, and potassium hydroxide.

[0088] Further, in one or more embodiments, the pH of the pharmaceutical preparation is adjusted by the regulator to 4 to 8.5.

[0089] Further, in one or more embodiments, the method for preparing the pharmaceutical preparation comprises the following steps: (1) adding the osmotic pressure regulator, buffer and metal chelating agent to 80% of the prescribed amount of water, stirring until completely dissolved, and setting aside. (2) adding the beraprost or a pharmaceutically acceptable salt thereof to the solution obtained in step (1), stirring until completely dissolved, adding a pH regulator to adjust the pH value to 4 to 8.5, and filtering. (3) making up the volume to the full amount with water, stirring evenly, filtering, and filling and sealing to obtain the beraprost sodium inhalation solution. Detailed implementation manners

[0090] The following further describes the present invention with reference to specific examples, but the examples do not limit the protection scope of the present application.

[0091] Example 1

[0092] Prescribed amount:

[0093] Components Prescription Dosage Beraprost Sodium 0.5 mg Sodium Chloride 6.5g Citric Acid 0.3g Sodium Citrate 1.8g EDTA-2Na 0.2g Sodium Bicarbonate Solution Appropriate Amount Water Make up to 1000 mL

[0094] Preparation steps:

[0095] 1. Measure 800 mL of injection water, add the prescribed amounts of sodium chloride, citric acid, sodium citrate and EDTA-2Na to the water, stir until completely dissolved, and set aside.

[0096] 2. Add the prescribed amount of beraprost sodium to the above solution, stir until completely dissolved, add a sodium bicarbonate solution under stirring conditions to adjust the pH to 4 to 8.5, and filter;

[0097] 3. Make up the injection water to 1000 mL, slowly stir evenly, filter, fill and seal to obtain the beraprost sodium inhalation solution.

[0098] Example 2

[0099] Prescribed amount:

[0100] Components Prescription Dosage Beraprost Sodium 1 mg Sodium Chloride 8g Sodium Dihydrogen Phosphate 9g Disodium Hydrogen Phosphate 1g EDTA-2Na 0.1g Hydrochloric Acid Appropriate Amount Water Make up to 1000 mL

[0101] Preparation steps:

[0102] 1. Measure 800 mL of injection water, add the prescribed amounts of sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate and EDTA-2Na to the water, stir until completely dissolved, and set aside.

[0103] 2. Add the prescribed amount of beraprost sodium to the above solution, stir until completely dissolved, then add hydrochloric acid solution under stirring to adjust the pH to 4 - 8.5, and filter;

[0104] 3. Make up to 1000 mL with injection water, stir slowly and evenly, then filter and seal to obtain the beraprost sodium inhalation solution.

[0105] Example 3

[0106] Components Prescription Dosage Beraprost Sodium 2 mg Potassium Chloride 4g Citric Acid 1g Disodium Hydrogen Phosphate 2.5g EDTA 0.2g Potassium Hydroxide Solution Appropriate Amount Water Make up to 1000 mL

[0107] Preparation steps:

[0108] 1. Measure 800 mL of injection water, add the prescribed amounts of potassium chloride, citric acid, disodium hydrogen phosphate and EDTA to the water, stir until completely dissolved, and set aside.

[0109] 2. Add the prescribed amount of beraprost sodium to the above solution, stir until completely dissolved, then add potassium hydroxide solution under stirring to adjust the pH to 4 - 8.5, and filter;

[0110] 3. Make up to 1000 mL with injection water, stir slowly and evenly, then filter and seal to obtain the beraprost sodium inhalation solution.

[0111] Example 4

[0112] Components Prescription Dosage Beraprost Sodium 3 mg Sodium Chloride 7.5g Citric Acid 2g Potassium Hydrogen Phosphate 3g EDTA-2Na 0.4g Sodium Hydroxide Solution Appropriate Amount Water Make up to 1000 mL

[0113] Preparation steps:

[0114] 1. Measure 800 mL of injection water, add the prescribed amounts of sodium chloride, citric acid, dipotassium hydrogen phosphate and EDTA - 2Na to the water, stir until completely dissolved, and set aside.

[0115] 2. Add the prescribed amount of beraprost sodium to the above solution, stir until completely dissolved, then add sodium hydroxide solution under stirring to adjust the pH to 4 - 8.5, and filter.

[0116] 3. Make up to 1000 mL with injection water, stir slowly and evenly, then filter and seal to obtain the beraprost sodium inhalation solution.

[0117] Example 5

[0118] Components Prescription Dosage Beraprost Sodium 4 mg Sodium Chloride 5.5g Sodium Citrate 2.5g EDTA 0.3g Sulfuric Acid Appropriate Amount Water Make up to 1000 mL

[0119] Preparation steps:

[0120] 1. Measure 800 mL of injection water, add the prescribed amounts of sodium chloride, sodium citrate and EDTA to the water, stir until completely dissolved, and set aside.

[0121] 2. Add the prescribed amount of beraprost sodium to the above solution. After stirring until completely dissolved, add sulfuric acid solution under stirring conditions, adjust the pH to 4 - 8.5, and filter.

[0122] 3. Make up to 1000 mL with injection water. After slowly stirring evenly, filter, seal, and you will obtain the beraprost sodium inhalation solution.

[0123] Example 6

[0124] Components Prescription Dosage Beraprost Sodium 6 mg Sodium Chloride 4.5g Citric Acid 0.6g Sodium Citrate 3.0g EDTA-2Na 0.15g Sodium Hydroxide Solution Appropriate Amount Water Make up to 1000 mL

[0125] Preparation steps:

[0126] 1. Measure 800 mL of injection water. Add the prescribed amounts of sodium chloride, citric acid, sodium citrate, and EDTA - 2Na to the water. Stir until completely dissolved and set aside.

[0127] 2. Add the prescribed amount of beraprost sodium to the above solution. After stirring until completely dissolved, add sodium hydroxide solution under stirring conditions, adjust the pH to 4 - 8.5, and filter.

[0128] 3. Make up to 1000 mL with injection water. After slowly stirring evenly, filter, seal, and you will obtain the beraprost sodium inhalation solution.

[0129] Example 7

[0130] Components Prescription Dosage Beraprost Sodium 8 mg Potassium Chloride 6.0g Potassium Dihydrogen Phosphate 8g Potassium Hydrogen Phosphate 1.5g EDTA 0.1g Sodium Hydroxide Solution Appropriate Amount Water Make up to 1000 mL

[0131] Preparation steps:

[0132] 1. Measure 800 mL of injection water. Add the prescribed amounts of potassium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and EDTA to the water. Stir until completely dissolved and set aside.

[0133] 2. Add the prescribed amount of beraprost sodium to the above solution. After stirring until completely dissolved, add sodium hydroxide solution under stirring conditions, adjust the pH to 4 - 8.5, and filter.

[0134] 3. Make up to 1000 mL with injection water. After slowly stirring evenly, filter, seal, and you will obtain the beraprost sodium inhalation solution.

[0135] Example 8

[0136] Components Prescription Dosage Beraprost Sodium 12 mg Sodium Chloride 6.5g Potassium Dihydrogen Phosphate 0.3g Disodium Hydrogen Phosphate 2.0g EDTA 0.15g Hydrochloric Acid Appropriate Amount Water Make up to 1000 mL

[0137] Preparation steps:

[0138] 1. Measure 800 mL of injection water. Add the prescribed amounts of sodium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate, and EDTA to the water. Stir until completely dissolved and set aside.

[0139] 2. Add the prescribed amount of beraprost sodium to the above solution. Stir until completely dissolved, then add hydrochloric acid solution under stirring conditions to adjust the pH to 4 - 8.5, and filter.

[0140] 3. Make up to 1000 mL with injection water. After slowly stirring evenly, filter, seal, and you will obtain the beraprost sodium inhalation solution.

[0141] Experimental Example 1: Determination of the properties, pH value, related substances, and content of the inhalation solution

[0142] Observe the properties of the beraprost sodium inhalation solution prepared in Examples 1 - 8, and measure the pH value, related substances, and content of the preparation. The results are shown in Table 1 below.

[0143] Table 1

[0144]

[0145] The inhalation solutions prepared in Examples 1 - 8 of the present invention are all colorless and clear liquids. The suitable pH value of the inhalation solution is generally 3 - 10. Excessive acidity or alkalinity will cause bronchospasm or cause irritation reactions such as coughing. For example, the pH is 4 - 8.5. According to this experimental example, the pH values of all inhalation preparations of the present invention are within the range of 4 - 8.5, meeting the basic requirements of the inhalation solution.

[0146] Experimental Example 2: Stability experiment of the inhalation solution

[0147] Conduct an accelerated stability study (30°C ± 2°C, RH65% ± 5%) on the inhalation solution preparation samples prepared in Examples 1 - 8. Sample at 0 and 3 months respectively, and examine the properties, pH value, related substances, and content of the samples. The results are shown in Table 2.

[0148] Table 2

[0149]

[0150] Within 3 months of acceleration, the properties, pH value, total impurities, and content of the inhalation solutions prepared in Examples 1 - 8 did not change significantly, indicating that the physicochemical stability of the liquid preparations of this application is good.

[0151] Experimental Example 3: Aerodynamic particle size distribution

[0152] Refer to the general rules in Part IV of the Chinese Pharmacopoeia (2020 Edition). Using an NGI device, the aerodynamic particle size distribution (APSD) of the inhalation solutions prepared in Example 1, Example 3, Example 4, Example 6, and Example 8 after being atomized by an Omron mesh nebulizer was measured respectively. The drug content in each layer was determined, and the mass median aerodynamic diameter (MMAD), fine particle fraction (FPF<5μm), and geometric standard deviation (GSD) were calculated. The measurement results are shown in Table 3.

[0153] Table 3

[0154]

[0155]

[0156] Research shows that droplets with a particle size of 2 - 5μm can be effectively deposited in the lungs. In this experimental example, the MMAD of the inhalation solution sample prepared after being atomized by the nebulizer is about 3μm, and the fine particle fraction (FPF<5μm) reaches more than 60%. This indicates that most of the droplets of the inhalation solution of this application can be deposited in the lungs after atomization, with higher bioavailability, thus achieving the effect of treating lung diseases.

[0157] Experimental Example 4 Respiratory Irritation Experiment

[0158] Six healthy New Zealand white rabbits (from the Experimental Animal Center of Guangzhou University of Chinese Medicine) were randomly divided into 2 groups, namely: the blank control group and the drug administration group. The blank group was given 0.9% sodium chloride injection, and the drug administration group was given the inhalation solution prepared in Example 5. Both groups were administered by aerosol inhalation, 2 times a day for 14 consecutive days. During the administration period and the recovery period, the general and local symptoms of the experimental animals were observed every day, including abnormal symptoms such as dyspnea and cough. 24 hours after the last administration, 1 animal from the drug administration group and the blank group was sacrificed. After 14 days, the remaining animals were sacrificed, and the nose, respiratory tract, and lungs of the animals were dissected to observe whether there were phenomena such as congestion and swelling.

[0159] Score according to the irritation scoring table (Table 4), and the scoring results of the anatomical examination are shown in Table 5.

[0160] Table 4

[0161] Stimulation Reaction Score No Obvious Stimulation Reaction 0 Barely Visible Congestion 1 Obviously Visible Congestion 2 Severe Congestion 3 Mucosal Damage 4

[0162] Table 5

[0163] Group 24 h after Drug Withdrawal 14 d after Drug Withdrawal Blank Group 0 0 Drug Administration Group 0 0

[0164] After the blank group and the solution prepared in Example 5 were administered by aerosol inhalation, no obvious systemic toxic reactions were observed, and no obvious irritation reactions were observed during the administration period and the recovery period, and the reaction score was 0 points. After anatomical examination, no congestion or redness was found in the nose, respiratory tract and lungs, and there was no difference compared with the blank group, indicating that the inhalation solution of the present invention has high safety, is mild to the respiratory tract and has no irritation.

Claims

1. A liquid preparation for treating pulmonary arterial hypertension, wherein each 1000 mL of the liquid preparation contains: Beraprost or a pharmaceutically acceptable salt thereof in an amount of 0.3 to 18 mg, preferably 0.5 to 12 mg; preferably, the pharmaceutically acceptable salt is a sodium salt; An osmotic pressure regulator in an amount of 0 to 15 g, preferably 3 to 9 g; A buffer in an amount of 0.05 to 15 g, preferably 0.1 to 10 g; A metal chelating agent in an amount of 0 - 0.5 g, preferably 0.1 - 0.4 g; A pH regulator in an amount of 0 - 15 g, preferably 0.2 - 10 g; The balance being water, preferably water for injection.

2. The liquid preparation according to claim 1, wherein the pH regulator controls the pH value of the pharmaceutical composition to be 4 to 8.5; preferably, the pH regulator is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, potassium hydroxide.

3. The liquid preparation according to claim 1, wherein the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, mannitol, glucose, sorbitol; preferably, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, calcium chloride.

4. The liquid preparation according to claim 1, wherein the buffer is one or more of sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, sodium acetate.

5. The liquid preparation according to claim 1, wherein the metal chelating agent is one or more of EDTA, EDTA-2Na.

6. An inhalable liquid preparation for treating pulmonary arterial hypertension, which comprises the liquid preparation according to any one of claims 1 - 5 and a pharmaceutically acceptable excipient or auxiliary material; preferably, the inhalable liquid preparation is an inhalable solution.

7. A method for preparing the inhalable liquid preparation according to claim 6, which comprises: (1) For each 1000 mL of the inhalable liquid preparation, take the following components: Beraprost or a pharmaceutically acceptable salt thereof in an amount of 0.3 to 18 mg, preferably 0.5 to 12 mg; preferably, the pharmaceutically acceptable salt is a sodium salt; An osmotic pressure regulator in an amount of 0 to 15 g, preferably 3 to 9 g; A buffer in an amount of 0.05 to 15 g, preferably 0.1 to 10 g; A metal chelating agent in an amount of 0 - 0.5 g, preferably 0.1 - 0.4 g; A pH regulator in an amount of 0 - 15 g, preferably 0.2 - 10 g; The balance being water, preferably water for injection; (2) Dissolve the buffer, the optional osmotic pressure regulator, and the optional metal chelating agent in the water and set aside; (3) Optionally, dissolve the beraprost or a pharmaceutically acceptable salt thereof in the solution obtained in step (2), add the pH regulator, and adjust the pH value to 4 to 8.5; (4) Make up the volume with water to the full amount to obtain the product.

8. The preparation method according to claim 7, wherein the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, mannitol, glucose, sorbitol; preferably, the osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, calcium chloride; Preferably, the buffer is one or more of sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, and sodium acetate; Preferably, the metal chelator is one or more of EDTA and EDTA-2Na; Preferably, the pH regulator is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, and potassium hydroxide.

9. The preparation method according to claim 7, wherein In step (2), the osmotic pressure regulator, optional buffer, and optional metal chelator are added to 80% of the prescription amount of water, and stirred until completely dissolved for standby; Preferably, in step (3), the beraprost or its pharmaceutically acceptable salt is added to the solution obtained in step (2), stirred until completely dissolved, and then the pH value is adjusted to 4-8.5 with a pH regulator, and filtered; Preferably, in step (4), water is added to the full volume, stirred evenly, filtered, and then sealed to obtain the product; Preferably, in steps (2)-(4), the water is water for injection.

10. Use of the liquid preparation according to any one of claims 1-5 or the inhalation liquid preparation according to claim 6 in the preparation of a medicament for the treatment of pulmonary hypertension.

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