Pirfenidone solution for inhalation and use method thereof

Abstract

The invention discloses a pirfenidone solution for inhalation and a use method thereof, and belongs to the technical field of pulmonary fibrosis, the pirfenidone solution is prepared from the following raw materials in parts by weight: pirfenidone and an isotonic agent in a mass ratio of (10-50): 28, during preparation, a dissolving agent accounting for 80% of the dosage of the pirfenidone and the isotonic agent is measured, the solution temperature is controlled to be 40 DEG C, the solution preparation time is 60 min, the volume is fixed to 4 mL, and the solution is prepared into the solution. And filtering the solution through a polyether filter membrane, and filling into an ampoule bottle. The invention relates to a pirfenidone solution for inhalation and a use method thereof, and solves the technical problem that in the prior art, the gastrointestinal tract effect and hepatotoxicity of pirfenidone are obvious when the pirfenidone is orally taken.

Description

Technical Field

[0001] The present application relates to the technical field of pulmonary fibrosis treatment, and in particular to a pirfenidone solution for inhalation and a method for using the same. Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is considered a special manifestation of chronic progressive fibrosing interstitial pneumonia with unknown etiology. It is characterized by irreversible fibrotic destruction of lung structure, manifested as diffuse alveolar inflammation and disorder of alveolar structure and function, accompanied by a significant weakening of pulmonary ventilation function. During the onset of the disease, patients mainly present with respiratory symptoms such as dyspnea, respiratory failure, sputum, cough, and wheezing, accompanied by symptoms such as weight loss, fatigue, and loss of appetite. The prevalence and incidence of IPF increase with age, with a higher prevalence in men than in women. The prognosis of IPF is poor, and the median survival period is usually 2 to 3 years.

[0003] In 2014, the U.S. FDA officially approved pirfenidone and nintedanib for the treatment of IPF. However, the treatment method is oral. When used orally, its gastrointestinal effects and liver toxicity are obvious. Therefore, there is an urgent need for an inhaled pirfenidone solution and a method of use thereof. Summary of the invention

[0004] The purpose of the present application is to provide a pirfenidone solution for inhalation and a method for using the same, so as to solve the technical problems in the prior art of the obvious gastrointestinal effects and liver toxicity of pirfenidone when taken orally.

[0005] The present application provides a pirfenidone solution for inhalation. The pharmaceutical preparation comprises the following raw materials by weight: pirfenidone and isotonic agent in a mass ratio of 10-50:28. During preparation, a dissolving agent accounting for 80% of the amount of pirfenidone and isotonic agent is measured, the solution temperature is controlled at 40°C, the preparation time is 60min, the volume is fixed to 4mL, and the solution is filtered through a polyether filter membrane and then filled into an ampoule.

[0006] Preferably, the isotonic agent is one or more of sodium chloride, glucose and glycerol.

[0007] Preferably, the dosage of pirfenidone is 10-50 mg / vial.

[0008] Preferably, the dissolving agent is water for injection.

[0009] Preferably, the dosage of pirfenidone is 40 mg / vial.

[0010] Preferably, it is characterized in that a Philips vibrating mesh atomizer is used for atomization.

[0011] Therefore, the present application provides a pirfenidone solution for inhalation and a method for using the same, which has the following beneficial effects:

[0012] 1. Through the study of the bleomycin-induced mouse pulmonary fibrosis model, it was found that the nebulized medium-dose and high-dose pirfenidone solution can significantly reduce the mouse lung coefficient and delay the progression of pulmonary fibrosis 21 days after administration, and the effect on the lung coefficient is dose-dependent. At the same time, after treatment with pirfenidone, the damaged structures of the mouse lung tissues in the nebulized low-dose group, medium-dose group, high-dose group and oral gavage group were improved to varying degrees, the alveolar structure was more complete, the alveolar septum became thinner, and the inflammatory cells infiltrating the alveolar cavity and septum decreased. Among them, the improvement of the inhaled high-dose group was more obvious than that of the oral gavage group and the inhaled low-dose and medium-dose groups, which can reduce the deposition of collagen fibers in the mouse lung tissue and achieve the effect of treating pulmonary fibrosis;

[0013] 2. Compared with the oral group, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of mice in the treatment group of inhaled pirfenidone solution were significantly reduced, indicating that the inhaled preparation group achieved significant therapeutic effects while reducing the activity of liver enzymes, alleviating the liver toxicity of pirfenidone and achieving liver protection;

[0014] 3. Reduce gastrointestinal adverse reactions: Since pulmonary administration can avoid the first-pass effect of the liver and gastrointestinal absorption, compared with oral preparations, inhaled pirfenidone solution can reduce pirfenidone's stimulation to the gastrointestinal tract and reduce the incidence of gastrointestinal adverse reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The effects of different treatment groups on the lung coefficient of mice;

[0016] Figure 2 H&E staining, Masson staining (200×), Szapiel score and Ashcroft score of lung tissues of mice in each group were compared with those of blank control group. P***<0.0001, P**<0.001, ns indicates no significance. DETAILED DESCRIPTION

[0017] The technical solution of the present invention is further illustrated by the following examples.

[0018] Example 1

[0019] Table 1 is the prescription composition of pirfenidone solution for inhalation

[0020] Table 1 Prescription composition

[0021]

[0022] During preparation, measure 80% of the amount of pirfenidone and sodium chloride in water for injection, control the solution temperature at 40°C, and prepare the solution for 60 minutes. Make up to 4 mL and filter the solution through a polyether filter membrane. Fill the solution into a 5 mL brown ampoule produced by Lunan Beite Pharmaceutical Packaging Co., Ltd., with a filling volume of 4 mL. Package it in an aluminum foil bag and atomize it with a Philips vibrating mesh nebulizer when in use.

[0023] Example 2

[0024] Table 2 is the prescription composition of the pirfenidone solution for inhalation of Example 2

[0025] Table 2 Prescription composition

[0026]

[0027] During preparation, measure 80% of the amount of pirfenidone and sodium chloride in water for injection, control the solution temperature at 40°C, and prepare the solution for 60 minutes. Make up to 4 mL and filter the solution through a polyether filter membrane. Fill the solution into a 5 mL brown ampoule produced by Lunan Beite Pharmaceutical Packaging Co., Ltd., with a filling volume of 4 mL. Package it in an aluminum foil bag and atomize it with a Philips vibrating mesh nebulizer when in use.

[0028] Example 3

[0029] Table 3 is the prescription composition of the pirfenidone solution for inhalation of Example 3

[0030] Table 3 Prescription composition

[0031]

[0032] During preparation, measure 80% of the amount of pirfenidone and sodium chloride in water for injection, control the solution temperature at 40°C, and prepare the solution for 60 minutes. Make up to 4 mL and filter the solution through a polyether filter membrane. Fill the solution into a 5 mL brown ampoule produced by Lunan Beite Pharmaceutical Packaging Co., Ltd., with a filling volume of 4 mL. Package it in an aluminum foil bag and atomize it with a Philips vibrating mesh nebulizer when in use.

[0033] According to the saturated solubility of pirfenidone, the solution concentration was investigated, and the stable solution concentration was further evaluated. The weighed pirfenidone was dissolved in distilled water, and the preparation specifications were 50mg:4mL, 45mg:4mL, and 40mg:4mL. After each concentration sample solution was prepared, it was filled into a 5mL brown ampoule with a filling volume of 4mL. Placed under strong light irradiation of 4500Lx±500Lx and high temperature of 50℃ for 30 days, the preparation concentration was screened based on content, insoluble particles, and related substances. Table 4 shows the content changes of different preparation specifications, Table 5 shows the related substances of different preparation specifications; Table 6 shows the insoluble particle inspection of different preparations.

[0034] Table 4 shows the content changes of different preparation specifications

[0035]

[0036] Table 5 shows the related substances of different preparation specifications

[0037]

[0038] Table 6 shows the insoluble particles test of different formulation specifications

[0039]

[0040] Prepare the test samples for the influencing factor experiment, place them under the conditions of 60±2℃ / RH92.5±5% / light 4500±500Lx for 3 months to investigate their stability, wherein the determination of the content change of the above impurities can be used to evaluate the stability of the active ingredient. Table 7 is the results of the physical and chemical examination of the influencing factor test; Table 8 is the results of the insoluble particle test of the influencing factor; Table 9 is the results of the delivery rate and total delivery amount test of the influencing factor; Table 10 is the results of the APSD test of the influencing factor; Table 11 is the results of the related substance test of the influencing factor; Table 12 is the results of the physical and chemical examination of the accelerated test; Table 13 is the results of the insoluble particle test of the accelerated test; Table 14 is the results of the delivery rate and total delivery amount test of the influencing factor; Table 15 is the APSD test result of the accelerated test; Table 16 is the results of the related substance test of the influencing factor.

[0041] Table 7 Physical and chemical examination results of influencing factors test

[0042]

[0043] Table 8 Influencing factors Insoluble particle detection results

[0044]

[0045] Table 9 Test results of factors affecting delivery rate and total delivery amount

[0046]

[0047]

[0048] Table 10 APSD test results of influencing factors (Mean±SD)

[0049]

[0050] Table 11 Test results of related substances affecting factors

[0051]

[0052] Table 12 Accelerated test physical and chemical examination results

[0053]

[0054] Table 13 Accelerated test results of insoluble particles

[0055]

[0056] Table 14 Test results of factors affecting delivery rate and total delivery volume

[0057]

[0058] Table 15 Accelerated test APSD test results (Mean±SD)

[0059]

[0060] Table 16 Test results of related substances affecting factors

[0061]

[0062] From the influencing factors and the results of accelerated stability experiments, the content, insoluble particles, aerodynamic distribution, etc. of the samples after 3 months of storage all meet the quality requirements, and there is no obvious increase in related substances, which meets the quality standards, indicating that the prescription and process of the pirfenidone solution preparation for inhalation are reasonable.

[0063] Three different types of nebulizers, Philips (vibrating mesh nebulizer), Yuyue (ultrasonic nebulizer), and Bairui (jet nebulizer), were used. The aerodynamic distribution of this product and the delivery rate and total delivery volume in adult mode and child mode were measured using NGI and respiratory simulator measurement devices to find a nebulizer suitable for this product.

[0064] There are currently three types of nebulizers available on the market: ultrasonic nebulizer, jet nebulizer, and vibrating screen nebulizer. Using different nebulizers for different drug formulations (conductivity and drug viscosity) will result in different atomization rates, droplet equivalent volume particle size distributions, and drug solution temperatures in the nebulizer cup. Therefore, after an inhalation solution is developed, its applicable nebulizer device should be studied and explained.

[0065] Table 17 shows the results of the investigation of delivery rates of different nebulizers, Table 18 shows the results of the investigation of total delivery amounts of different nebulizers, and Table 19 shows the results of aerodynamic distribution of different nebulizers (n=3, mean±SD).

[0066] Table 17 Results of investigation on delivery rate of different nebulizers

[0067]

[0068] Table 18 Results of the total amount delivered by different nebulizers

[0069]

[0070] Table 19 Aerodynamic distribution results of different atomizers (n=3, mean±SD)

[0071]

[0072] It can be seen from Tables 17-19 that the total delivery volume of Yuyue is lower, and the delivery rate, recovery rate, and FPF (%) of the nebulizers of Bairui and Philips are relatively stable among the groups. In comparison, the total delivery volume of Philips is higher in the adult mode and the child mode. The Philips nebulizer is selected as the best nebulizer for this product.

[0073] Depend on Figure 1 It can be seen that the lung coefficient of mice in the model group (0.0187±0.13) was higher than that of mice in the normal group (0.005±0.09). The lung coefficients of the nebulized medium dose (0.0127±0.006) and nebulized high dose groups (0.006±0.014) were significantly reduced 21 days after administration, indicating that the pulmonary fibrosis of mice was improved and the progression of pulmonary fibrosis was delayed. At the same time, we found that the effect of pirfenidone nebulization group on the lung coefficient was dose-dependent.

[0074] The effect of inhaled pirfenidone on the pathology of mouse lung tissue was observed by H&E staining and Masson staining analysis and scoring. Figure 2 It can be seen that after treatment with pirfenidone, the damaged structures of the lung tissues of mice in the four groups of aerosol low-dose group, aerosol medium-dose group, aerosol high-dose group, and pirfenidone gavage group were improved to varying degrees. At the same time, the alveolar structure was relatively intact, the alveolar septum became thinner, and the inflammatory cells infiltrating the alveolar cavity and septum decreased. The improvement of the high-dose inhalation group was more obvious than that of the gavage group and the low-dose and medium-dose inhalation groups. In the Masson staining analysis, compared with the blank control group, the lung structure of the model group completely disappeared, the alveolar septum changed significantly, and a large area of ​​blue-stained collagen fiber deposition could be observed, indicating that the mice had obvious symptoms of pulmonary fibrosis; and after treatment with pirfenidone, the collagen fibers deposited in the lung tissues of mice decreased, among which the high-dose inhalation group decreased significantly, the alveolar structure was intact, and there was no fibrotic mass in the field of vision. Analysis of the results of H&E staining and Masson staining showed that inhaled pirfenidone can reduce collagen fiber deposition in mouse lung tissue, improve disordered alveolar structure, reduce inflammatory cell infiltration, and achieve the effect of treating pulmonary fibrosis.

[0075] In Table 20, compared with the blank group, the activities of AST and ALT in the serum of mice in the oral gavage group were significantly increased (P<0.05); compared with the oral gavage group, the levels of AST and ALT in the inhalation treatment group were significantly reduced. The inhalation preparation group can achieve significant therapeutic effects while reducing the activity of liver enzymes, reducing the liver toxicity of pirfenidone, and achieving liver protection.

[0076] Table 20 Contents of AST and ALT in liver (n=3, mean±SD)

[0077]

[0078] Compared with the blank control group, P***<0.0001, compared with the model group, P#<0.05, P##<0.01.

[0079] Therefore, the present application provides a pirfenidone solution for inhalation and a method for using the same, which solves the technical problems in the prior art of the obvious gastrointestinal effects and liver toxicity of pirfenidone when used orally.

[0080] In the description of this specification, the description with reference to the terms "an experimental example", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the experimental example or example are included in at least one experimental example or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same experimental example or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more experimental examples or examples in a suitable manner.

[0081] Finally, it should be noted that the above experimental examples are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred experimental examples, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A pirfenidone solution for inhalation, characterized in that The pharmaceutical preparation comprises the following raw materials by weight: pirfenidone and isotonic agent in a mass ratio of 10-50:

28. During preparation, 80% of the amount of pirfenidone and isotonic agent is measured, the solution temperature is controlled at 40°C, the preparation time is 60 minutes, the volume is fixed to 4 mL, and the solution is filtered through a polyether filter membrane and then filled into an ampoule bottle.

2. A pirfenidone solution for inhalation according to claim 1, characterized in that The isotonic agent is one or more of sodium chloride, glucose, and glycerol.

3. A pirfenidone solution for inhalation according to claim 1, characterized in that: The dosage of pirfenidone is 10-50 mg / vial.

4. A pirfenidone solution for inhalation according to claim 1, characterized in that: The solvent is water for injection.

5. A pirfenidone solution for inhalation according to claim 1, characterized in that: The dosage of pirfenidone is pirfenidone 40 mg / vial.

6. The method for using the pirfenidone solution for inhalation according to any one of claims 1 to 5, characterized in that: Nebulization was performed using a Philips vibrating mesh nebulizer.

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