A sterile inhalation suspension containing PDE-4 or PDE-3 / 4 inhibitor, and its preparation method and application

Abstract

The application provides a preparation method and application of a sterile inhalation suspension containing a PDE-4 or PDE-3 / 4 inhibitor. The preparation method comprises dispersing the PDE-4 or PDE-3 / 4 inhibitor in injection water containing an excipient, high-pressure wet heat sterilization to obtain a PDE-4 or PDE-3 / 4 inhibitor dispersion; further comprising dissolving a long-acting beta2-receptor agonist and / or a long-acting muscarinic receptor antagonist, sterile filtration to obtain a mixed solution; mixing the PDE-4 or PDE-3 / 4 inhibitor dispersion with the mixed solution, dispersing and sterilely filling. The pharmaceutical preparation prepared by the application is a sterile inhalation suspension, the sterile inhalation suspension containing the PDE-4 or PDE-3 / 4 inhibitor has high bioavailability, good patient medication compliance and good preparation stability.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a preparation method and application of a sterile inhalation suspension containing PDE-4 or PDE-3 / 4 inhibitor. BACKGROUND

[0002] Chronic Obstructive Pulmonary Disease (COPD) is a chronic lung disease characterized by incompletely reversible airflow limitation, usually presenting a progressive characteristic, accompanied by an increase in chronic inflammatory response of airways and lungs to harmful particles or gases, including most chronic bronchitis and emphysema. With the development of the disease, it leads to airway remodeling, eventually developing into irreversible airflow obstruction, causing patients to have difficulty breathing, lose mobility, and seriously affect the quality of life. In view of this increasingly serious and frequently occurring disease, the present application provides an additional benefit of further reducing symptoms and disease exacerbation by using a combination of phosphodiesterase-4 or phosphodiesterase-3 / 4 inhibitor (PDE-4 inhibitor or PDE-3 / 4 inhibitor) and long-acting bronchodilator, improves patient medication compliance, and improves patient quality of life.

[0003] At present, the main means for treating and preventing COPD and asthma include bronchodilation and inhibition of inflammatory response.

[0004] The commonly used drugs for inhibiting inflammatory response in COPD treatment include inhaled corticosteroids (ICS) and PDE-4 inhibitors. During the treatment of COPD, hormone therapy insensitivity occurs, i.e. hormone drugs cannot effectively control the progressive development of airway inflammation, nor can they reverse the decline in lung function caused by airway inflammation. Such phenomena result in the failure of inhaled corticosteroids to achieve the expected therapeutic effect in the treatment of some frequently exacerbating COPD conditions.

[0005] PDE-4 inhibitors have high specificity for cyclic adenosine monophosphate (cAMP) and are involved in related physiological and pathological processes such as promoting monocyte and macrophage activation, neutrophil infiltration, and vasodilation. PDE-4 is related to the cAMP hydrolysis of various inflammatory cells. Since cAMP can cause bronchial smooth muscle relaxation and lung inflammation, PDE-4 inhibitors can reduce the release of inflammatory mediators, thereby inhibiting the damage to lung tissue caused by respiratory diseases such as COPD and asthma. PDE-3 / 4 inhibitors are dual-target inhibitors that can provide both bronchodilation and anti-inflammatory effects. The use of such inhibitor drugs can make up for the shortcomings of commonly used inhaled corticosteroid drugs during treatment.

[0006] Bronchodilators include short-acting and long-acting β2-receptor agonists (LABA) and long-acting muscarinic receptor antagonists (LAMA), wherein long-acting bronchodilators have a duration of action of more than 12 hours, can reduce the number of doses, improve lung function and dyspnea symptoms, improve quality of life, and reduce acute exacerbations of COPD. LABA mainly includes formoterol, salmeterol, indacaterol, olodaterol, vilanterol, carmoterol, etc., and LAMA mainly includes tiotropium bromide, glycopyrronium bromide, umclidinium bromide, aclidinium bromide, and rufinacaine.

[0007] Roflumilast is a selective PDE-4 long-acting inhibitor, with a molecular formula of C 17 H 14 Cl2F2N2O3, and a structural formula as follows:

[0008] Roflumilast was developed by Altana Pharma in 1993, and in July 2010, the European Union approved Nycomed's once-daily oral tablet (Daxas) for marketing, which must be used in combination with other bronchodilators, and is suitable for the maintenance treatment of adult patients with severe COPD related to chronic bronchitis with a history of frequent exacerbations. It is the first drug targeting specific phenotypes of COPD. WO09501338 and CN94192659 disclose the compound, the preparation method, and the application in the treatment of airway diseases or skin diseases. Roflumilast has a wide range of anti-inflammatory effects, and can affect various types of cells such as neutrophils, monocytes / macrophages, endothelial cells, and smooth muscle cells in vitro, and plays a role in many aspects of the pathogenesis of COPD, such as tobacco-induced lung inflammatory response, respiratory tract cilia movement disorder, emphysema, oxidative stress, and pulmonary hypertension.

[0009] Olodaterol hydrochloride is a new type of selective short-acting LABA, with a molecular formula of C 21 H 27 ClN2O5, and a structural formula as follows:

[0010]

[0011] Olodaterol hydrochloride was developed by Boehringer Ingelheim, and was approved in the United States in 2014 (trade name: Striverdi Respimat), which is a soft mist inhaler, once a day, twice a spray. US7727984 B2 patent discloses the compound and its application in the treatment of COPD. Olodaterol hydrochloride has high β2-receptor selectivity, rapid onset, small cardiovascular side effects, long half-life, can maintain 24 hours of bronchodilator effect, and can improve patient compliance. Experiments show that olodaterol hydrochloride can block the contraction effect of different bronchial stimulants (such as histamine and acetylcholine), and the effect is dose-dependent; long-term use of olodaterol hydrochloride will not cause β2-receptor desensitization.

[0012] Roflumilast is a new LAMA, the molecular formula is C 35 H 43 N5O4, the structure is as follows:

[0013] .

[0014] US7288657 B2 discloses that the compound is used as a long-acting muscarinic receptor antagonist; US8541451 B2 discloses two crystal forms of the compound. Roflumilast is a new structure, non-selective, long-acting muscarinic receptor antagonist, which blocks M3-receptors in the respiratory tract and prevents acetylcholine-induced bronchial constriction, resulting in bronchodilation. In November 2018, FDA approved Roflumilast inhalation solution (trade name: Yupelri) for the maintenance treatment of chronic obstructive pulmonary disease.

[0015] The marketed product of Roflumilast is for oral administration, with low bioavailability and slow onset, and must be used with inhaled bronchodilators, which has poor patient compliance. CN201710015258 discloses an inhalation Roflumilast suspension and its preparation method, which is terminally sterilized after being filled and sealed; CN20140006017 discloses a dry powder inhalation administration scheme of Roflumilast N-oxide; CN201410054915 discloses a drug combination of Roflumilast and tiotropium bromide in dry powder inhalation; CN201410055153 discloses a drug combination of salmeterol and Roflumilast in dry powder inhalation; CN201410054930 discloses a drug combination of indacaterol and Roflumilast in dry powder inhalation; CN201410039603 discloses a Roflumilast inhalation aerosol compound and its preparation method.

[0016] CN201710015258 discloses a roflumilast suspension for inhalation and a preparation method thereof, the suspension is composed of active ingredient roflumilast, surfactant, pH regulator, osmotic pressure regulator and solvent, the drug is prepared by terminal sterilization, high temperature causes degradation of the main ingredient, and affects the particle size of the product, and roflumilast crystal transformation is caused, and the drug efficacy is affected.

[0017] At present, there is no drug combination or preparation form suitable for patients with severe chronic bronchitis related COPD, and meeting the clinical needs of patients. Therefore, a sterile suspension containing PDE-4 or PDE-3 / 4 inhibitor for inhalation and its preparation method and application are developed, and the prepared drug preparation includes PDE-4 or PDE-3 / 4 inhibitor, long-acting β2-receptor agonist and / or long-acting muscarinic receptor antagonist, which is stable in quality and can be used for once-a-day nebulization inhalation treatment of severe COPD patients. SUMMARY

[0018] The present application provides a preparation method of a sterile suspension containing PDE-4 or PDE-3 / 4 inhibitor for inhalation, which can achieve once-a-day use to relieve severe COPD symptoms and reduce frequent exacerbation course.

[0019] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0020] A preparation method of a sterile suspension containing PDE-4 or PDE-3 / 4 inhibitor for inhalation, the sterile inhalation suspension is a compound sterile inhalation suspension prepared from PDE-4 or PDE-3 / 4 inhibitor, long-acting β2-receptor agonist or long-acting muscarinic receptor antagonist; and a three-way sterile inhalation suspension prepared from PDE-4 or PDE-3 / 4 inhibitor, long-acting β2-receptor agonist and long-acting muscarinic receptor antagonist;

[0021] The preparation method of the suspension comprises the following steps:

[0022] (1) dispersing PDE-4 or PDE-3 / 4 inhibitor in water for injection containing excipients, high-pressure wet heat sterilization, and dispersing to obtain PDE-4 or PDE-3 / 4 inhibitor dispersion;

[0023] (2) dissolving the auxiliary materials in water for injection, adjusting the pH value, adding long-acting β2-receptor agonist and / or long-acting muscarinic receptor antagonist, and sterilizing and filtering to obtain a mixed solution;

[0024] (3) adding PDE-4 or PDE-3 / 4 inhibitor dispersion to the mixed solution, uniformly dispersing, and aseptically filling to obtain a sterile inhalation suspension.

[0025] Furthermore, in step (1), the mass ratio of the PDE-4 or PDE-3 / 4 inhibitor to the water for injection containing the excipient is 1:10-1:160; and the mass ratio of the excipient to the water for injection is 1:40-1:800.

[0026] Furthermore, the excipient is selected from one or more of polysorbate 20, polysorbate 80, sorbitan monolaurate, poloxamer, polyoxyethylene castor oil, polyethylene glycol, solutol HS15 and polyvinyl pyrrolidone; preferably polysorbate 80.

[0027] Furthermore, the dispersion method in step (1) is high shear dispersion or high pressure homogeneous dispersion.

[0028] Furthermore, the PDE-4 inhibitor is selected from one or more of the following compounds:

[0029]

[0030] Preferably, the PDE-4 is the following compound;

[0031]

[0032] Compound 1.

[0033] The PDE-3 / 4 inhibitor is selected from one or more of the following compounds:

[0034]

[0035] Preferably, the PDE-3 / 4 inhibitor is the following compound;

[0036]

[0037] Compound 50 Compound 51

[0038] Furthermore, the long-acting β2-receptor agonist in step (2) is selected from one or more of olodaterol, vilanterol, indacaterol, formoterol, arformoterol, carmoterol, procaterol or their corresponding pharmaceutically acceptable salts.

[0039] Preferably, the long-acting β2-receptor agonist is olodaterol or olodaterol hydrochloride.

[0040] Furthermore, the long-acting muscarinic receptor antagonist in step (2) is selected from one or more of Revefenacin, Tiotropium Bromide, Glycopyrronium Bromide, Umeclidinium, Aclidinium bromide or their corresponding pharmaceutically acceptable salts.

[0041] Preferably, the long-acting muscarinic receptor antagonist is revenacin or a pharmaceutically acceptable salt thereof.

[0042] Furthermore, in the suspension, the mass ratio of the PDE-4 inhibitor to the long-acting β2-receptor agonist is 1:0.01-1:2 and / or the mass ratio of the PDE-4 inhibitor to the long-acting muscarinic receptor antagonist is 1:0.02-1:30.

[0043] Furthermore, the mass ratio of the PDE-3 / 4 inhibitor to the long-acting β2-receptor agonist in the suspension is 3600:1-1:2 and / or the mass ratio of the PDE-3 / 4 inhibitor to the long-acting muscarinic receptor antagonist is 110:1-1:30.

[0044] Furthermore, in step (2), the pH value is adjusted to 4.0-7.0.

[0045] In some embodiments of the present invention, when the sterile inhalation suspension contains a PDE-4 inhibitor as the active ingredient, the pH value is adjusted to 4.0-5.0, preferably 4.5; when the sterile inhalation suspension contains a PDE-3 / 4 inhibitor as the active ingredient, the pH value is adjusted to 6.5-7.0, preferably 6.7.

[0046] Furthermore, the excipients in step (2) include one or more of an isotonic agent, a buffer, and a stabilizer.

[0047] Furthermore, the isotonic agent is selected from one or more of sodium chloride, mannitol, and glucose; preferably sodium chloride;

[0048] The buffer is citric acid / sodium citrate buffer or phosphate buffer;

[0049] The stabilizer is selected from one or more of ethylenediaminetetraacetic acid, dehydrated disodium ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid and citric acid; preferably disodium ethylenediaminetetraacetic acid.

[0050] Furthermore, the aseptic filling in step (3) adopts blow-fill-seal aseptic filling or aseptic filling of vials and ampoules.

[0051] Furthermore, in the suspension of the present invention, at least 90% by volume of the particles have an optical diameter of 10 μm or less, and at least 50% by volume of the particles have an optical diameter of 5 μm or less.

[0052] Furthermore, the daily inhalation dose of the PDE-4 and / or PDE-3 / 4 inhibitor in the suspension of the present invention is 10-18000 μg, the daily inhalation dose of the long-acting β2-receptor agonist is 2-20 μg, and the daily inhalation dose of the long-acting muscarinic receptor antagonist is 50-300 μg.

[0053] Furthermore, the suspension of the present invention is administered by aerosol inhalation.

[0054] The preparation method of the present invention can also be used to prepare a sterile suspension for inhalation, the active ingredient of which only contains a PDE-4 or PDE-3 / 4 inhibitor.

[0055] Furthermore, the present invention also provides a method for preparing a single suspension of a PDE-4 or PDE-3 / 4 inhibitor for sterile inhalation, comprising the following steps:

[0056] (1) dispersing the PDE-4 or PDE-3 / 4 inhibitor in water for injection containing an excipient, sterilizing by high-pressure wet heat, and dispersing to obtain a PDE-4 or PDE-3 / 4 inhibitor dispersion;

[0057] (2) Add the excipients to water for injection and dissolve, adjust the pH value, sterilize and filter to obtain a solution;

[0058] (3) Add the PDE-4 and / or PDE-3 / 4 inhibitor dispersion into the solution, disperse evenly, and aseptically fill to prepare a sterile PDE-4 and / or PDE-3 / 4 inhibitor single suspension for inhalation.

[0059] The present invention also provides the use of the above-mentioned pharmaceutical preparation in the preparation of drugs for treating respiratory diseases, wherein the respiratory diseases include but are not limited to chronic obstructive pulmonary disease and all types of asthma.

[0060] Compared with the prior art, the present invention has the following beneficial effects:

[0061] (1) Oral administration of PDE-4 or PDE-3 / 4 inhibitors has low bioavailability and poor patient compliance. Currently published pharmaceutical preparations of PDE-4 or PDE-3 / 4 inhibitors and LABA / LAMA combinations are mostly dry powders or aerosols, which also have the problem of poor patient compliance. PDE-4 or PDE-3 / 4 inhibitor suspensions prepared by terminal sterilization methods are subject to high temperatures that degrade the main components, affecting the product particle size and causing crystal transformation problems, which affects the efficacy. The present invention provides a sterile inhalation suspension comprising a PDE-4 or PDE-3 / 4 inhibitor and a long-acting β2-receptor agonist and / or a long-acting muscarinic receptor antagonist, providing a treatment option for critically ill patients who cannot take the drug orally or cannot use dry powders, metered sprays, or soft mists.

[0062] (2) The present invention optimizes the active ingredients and preparation process by combining moist heat sterilization, sterilizing filtration and aseptic filling technology. Compared with the terminal sterilization method described in the existing patents, the crystal form of the raw material drug in the prepared sample does not change significantly, and a stable sterile inhalation suspension containing a PDE-4 or PDE-3 / 4 inhibitor, a long-acting β2-receptor agonist and a long-acting muscarinic receptor antagonist can be prepared. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 is a comparison chart of the properties of Sample 1 and Sample 3 in Test Example 3 of the present invention;

[0064] Figure 2 7 is a comparison chart of the properties of Sample 1 and Sample 8 in Test Example 7 of the present invention;

[0065] Figure 3 This is a crystal form diagram of the raw material drug in Test Example 7 of the present invention;

[0066] Figure 4 This is a crystal diagram of the sample before sterilization in Test Example 7 of the present invention;

[0067] Figure 5 is a crystal diagram of sample 1 prepared in Example 1 of the present invention;

[0068] Figure 6 This is a crystal diagram of sample 8 prepared by the method disclosed in Chinese invention patent application CN201710015258.2. DETAILED DESCRIPTION

[0069] The following non-limiting examples are provided to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way. The following are merely illustrative of the scope of the present invention, and those skilled in the art may make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0070] When numerical ranges are given in the examples, it should be understood that, unless otherwise specified herein, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs.

[0071] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention were obtained through conventional commercial channels unless otherwise specified. The contents described below are all by mass.

[0072] The purchase manufacturers and models of some raw materials used in the examples are as follows:

[0073] Roflumilast: Manufacturer: aladdin, Batch No.: L2106784;

[0074] Olodaterol hydrochloride: Manufacturer: Inke, Batch No.: PP-1;

[0075] Revenacin: Manufacturer: Medichem Batch number: F-220018;

[0076] RPL554 (Compound 50): Manufacturer: Shanghai Houbo Biotechnology Co., Ltd., batch number: 20240826.

[0077] Example 1

[0078] This example provides a method for preparing a sterile inhalation suspension of roflumilast-olodaterol hydrochloride-revenacin (roflumilast is compound 1, a PDE-4 inhibitor). The dosage composition is shown in Table 1:

[0079] Table 1

[0080]

[0081] Preparation process:

[0082] (1) Roflumilast is dispersed in a small amount of water for injection containing an excipient by high shear dispersion, sterilized by high pressure moist heat (sterilized at 121°C for 15 min, the same below), and then dispersed by high shear dispersion or high pressure homogenization technology to obtain a roflumilast dispersion;

[0083] (2) Add the excipients to water for injection and stir to dissolve, adjust the pH value with buffer, add olodaterol hydrochloride and revenacin, dissolve, sterilize and filter to obtain a mixed solution;

[0084] (3) The dispersion of (1) is added to the mixed solution of (2) and dispersed evenly, and aseptically filled by blow-fill-seal to prepare a sterile roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation.

[0085] Experimental Example 1: Effect of Different pH Values ​​on the Stability of Roflumilast-Olodaterol Hydrochloride-Refenacin Suspension for Inhalation

[0086] According to the components and preparation process in Example 1, roflumilast-olodaterol hydrochloride-revenacin suspensions for inhalation were prepared with pH values ​​of 3.5, 4.0, 4.5, 5.0, and 5.5, respectively. The samples were placed at 60°C and under accelerated conditions (40°C ± 2°C, ≤25% RH) to investigate the stability of the samples. The results are shown in Tables 2 and 3:

[0087] Table 2 Stability of roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation at different pH values ​​at 60°C

[0088]

[0089] Table 3 Stability of roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation at different pH values ​​under accelerated conditions (40°C ± 2°C, ≤ 25% RH)

[0090]

[0091] From the results in Tables 2 and 3, it can be seen that after being placed at 60°C for 10 days, the degradation impurities of the samples at pH 3.5 and pH 5.5 increased significantly, and there was no significant change in the degradation impurities in the pH 4.0-5.0 range. After being placed under accelerated conditions (40°C ± 2°C, ≤25% RH) for 3 months, there was no significant change in the degradation impurities in the pH 4.0-5.0 range, among which the sample at pH 4.5 had better stability.

[0092] Test Example 2: Investigating the effect of stabilizers on the stability of roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation.

[0093] The roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation prepared at pH 4.5 in Example 1 was designated as Sample 1. A roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation was prepared according to the components and preparation process of Example 1, except that disodium EDTA was removed, designated as Sample 2. The stability of the two samples was investigated under accelerated conditions (40°C ± 2°C, ≤ 25% RH). The results are shown in Table 4.

[0094] Table 4 Effects of metal ion chelators on the stability of roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation

[0095]

[0096] As shown in Table 4, the stability of the samples with the addition of the stabilizer disodium edetate is not significantly changed compared with the samples without the addition of the stabilizer.

[0097] Example 2

[0098] This example provides a method for preparing an aseptic inhalation suspension of encefantine-olodaterol hydrochloride-revenacin (encefantine is compound 50, a PDE-3 / 4 inhibitor). The dosage composition is shown in Table 5:

[0099] Table 5

[0100]

[0101] The preparation process was the same as that in Example 1 to obtain an encefantine-olodaterol hydrochloride-revenacin suspension, which was designated as Sample 3.

[0102] Experimental Example 3: Stability evaluation of a tripartite suspension containing different types of PDE inhibitors

[0103] The raw material dispersions in Sample 1 (Roflumilast-Olodaterol Hydrochloride-Refenacin Suspension) and Sample 3 (Ensefentin-Olodaterol Hydrochloride-Refenacin Suspension) were sterilized by high pressure heat sterilization and then mixed with the remaining raw material solutions to observe the changes in their properties. The results are shown in the attached figure. Figure 1 shown.

[0104] As attached Figure 1 As shown, according to the preparation method of the present invention, suspensions obtained using different PDE inhibitors as active ingredients are all uniform suspensions. Therefore, it should be noted that the stability of the sterile PDE inhibitor-containing suspension for inhalation prepared using the preparation process of the present invention is not affected by the type of PDE inhibitor. The subsequent examples and test examples will prepare single and compound suspensions using "roflumilast (Compound 1)" as the active ingredient and investigate the relevant properties of the products obtained using the preparation process of the present invention.

[0105] Example 3

[0106] This example provides a method for preparing a roflumilast-olodaterol hydrochloride suspension for sterile inhalation. The dosage composition is shown in Table 6:

[0107] Table 6

[0108]

[0109] The preparation process of this example is the same as that of Example 1, and a roflumilast-olodaterol hydrochloride suspension is obtained, which is Sample 4.

[0110] Example 4

[0111] This example provides a method for preparing a sterile roflumilast-revenacin suspension for inhalation. The dosage composition is shown in Table 7:

[0112] Table 7

[0113]

[0114] The preparation process of this example is the same as that of Example 1, and a roflumilast-revenacin suspension is obtained, which is Sample 5.

[0115] Example 5

[0116] This example provides a method for preparing a sterile roflumilast suspension for inhalation. The dosage composition is shown in Table 8:

[0117] Table 8

[0118]

[0119] Preparation process:

[0120] (1) using high shear dispersion technology to disperse roflumilast in water for injection containing polysorbate 80, sterilizing by high pressure wet heat, and then dispersing by high shear dispersion or high pressure homogenization technology to obtain a roflumilast dispersion;

[0121] (2) Add the excipients to water for injection and stir to dissolve, adjust the pH value with buffer, and sterilize and filter through a 0.22 µm filter to obtain a solution;

[0122] (3) The dispersion of (1) above was added to the solution of (2) above, dispersed evenly, and aseptically filled by blow-fill-seal to prepare a sterile roflumilast single-ingredient suspension for inhalation, which was sample 6.

[0123] Experimental Example 4: Effects of different dispersion media on the stability of roflumilast during high-pressure wet heat sterilization

[0124] Roflumilast suspension was prepared by the same method, except that the dispersion medium (water for injection containing polysorbate 80) in Example 5 was replaced with a buffer solution having a pH of 5.0. This suspension is Sample 7. The degradation of impurities in the two batches of samples after high-pressure wet heat sterilization was investigated, and the results are shown in Table 9.

[0125] Table 9 Effects of different dispersion media on the stability of roflumilast during high-pressure wet heat sterilization

[0126]

[0127] As shown in Table 9, when sterilization was performed using water for injection containing polysorbate 80 as the dispersion medium, the growth of roflumilast degradation impurities was relatively small, and the prepared sample could be redispersed after sedimentation, indicating that it has a certain tolerance to high temperature. High-pressure moist heat sterilization is suitable for the sterilization of roflumilast.

[0128] Experimental Example 5: Effects of different material-liquid ratios and polysorbate 80 concentrations on the stability of roflumilast during high-pressure wet heat sterilization

[0129] Roflumilast was dispersed in water for injection containing different concentrations of polysorbate 80 using a high shear disperser according to different material-liquid ratios. Each batch of dispersion was sterilized by high-pressure wet heat, and the degradation of impurities was investigated. The results are shown in Table 10.

[0130] Table 10 Effects of different material-liquid ratios and polysorbate 80 concentrations on the stability of roflumilast during high-pressure wet heat sterilization

[0131]

[0132] As shown in Table 10, when the concentration of roflumilast in the dispersion is increased to above 0.625%, the stability of roflumilast during high-pressure wet heat sterilization can be increased; when the concentration of polysorbate 80 reaches above 0.125%, good dispersibility can be achieved.

[0133] Test Example 6: Stability Study of Roflumilast Suspension for Sterile Inhalation in Different Combinations

[0134] The stability of four suspensions (sample 1, sample 4, sample 5, sample 6) was investigated. The results are shown in Tables 11 and 12.

[0135] Table 11 Stability of different suspensions at 60°C

[0136]

[0137] Table 12 Stability of different suspensions under accelerated conditions (40℃±2℃, ≤25%RH)

[0138]

[0139] From the results in Table 11 and Table 12, it can be seen that the preparations of different roflumilast compositions were prepared according to the screened components and processes. The roflumilast single suspension has good stability, and the combination preparations of roflumilast and olodaterol hydrochloride and / or revenacin have relatively good stability under accelerated conditions.

[0140] Test Example 7: Comparison of different sterilization methods

[0141] Chinese invention patent application CN201710015258.2 discloses a method for preparing roflumilast suspension for inhalation. Its main sterilization method is terminal sterilization, which may affect product quality.

[0142] According to the dosage composition of Example 1, the following steps (steps of Chinese invention patent application CN201710015258.2) were used to prepare the product:

[0143] (1) Add the excipients to 80% of the prepared injection water and stir to dissolve;

[0144] (2) Micronize roflumilast to D 90 less than 10µm) was added to the above solution and stirred evenly, stirred for 30min under high shear homogenizer, and water for injection was added to the full amount;

[0145] (3) Adjust pH value;

[0146] (4) Filling and terminal sterilization to prepare sample 8.

[0147] The particle size distribution and crystal form of the raw material Roflumilast were determined, and the properties, degradation impurities, particle size distribution and crystal form of Sample 1 and Sample 8 after sterilization were also determined. The results are shown in the attached Figure 2-6 , as shown in Table 13.

[0148] Table 13 Changes in sample degradation impurities and particle size before and after sterilization

[0149]

[0150] As attached Figure 2 As shown, the sample was prepared according to the terminal sterilization method in Chinese invention patent application CN201710015258.2, and a large amount of flocculent crystalline substances were suspended in the liquid medicine; the sample prepared according to the preparation process of the present invention was a uniform white suspension.

[0151] From the results in Table 13, it can be seen that when the sample (Sample 8) was prepared according to the terminal sterilization method in Chinese invention patent application CN201710015258.2, the degradation impurities and the particle size of the API increased significantly, and its D90 reached 77 μm, which could not meet the requirement that the particle size of the inhalation preparation was less than 10 μm. When the sample (Sample 1) was prepared according to the embodiment of the present invention, there was no significant change in the degradation impurities, no significant change in the particle size, and D90 reached 7 μm, which met the requirement that the particle size of the inhalation preparation was less than 10 μm.

[0152] As attached Figure 3-6As shown, when samples were prepared according to the terminal sterilization method in Chinese invention patent application CN201710015258.2, the crystal form of the API changed significantly; when samples were prepared according to the embodiments of the present invention, there was no crystal transformation of the API during the preparation process. In summary, the quality of the suspension prepared according to the embodiments of the present invention is significantly better than the suspension prepared according to the terminal sterilization method in Chinese invention patent application CN201710015258.2; at the same time, in this preparation process, the long-acting β2-receptor agonist and the long-acting muscarinic receptor antagonist are dissolved in the buffer solution and then mixed with roflumilast, which has no effect on the crystal form of roflumilast. Therefore, there is no crystal transformation of roflumilast during the preparation of roflumilast alone or the compound suspension of roflumilast and the long-acting β2-receptor agonist and / or the long-acting muscarinic receptor antagonist.

[0153] In summary, the present invention provides a stable, sterile single suspension for inhalation comprising a PDE-4 or PDE-3 / 4 inhibitor, or a sterile compound suspension for inhalation comprising a combination of a PDE-4 or PDE-3 / 4 inhibitor, a long-acting β2-receptor agonist, and / or a long-acting muscarinic receptor antagonist, providing a treatment option for critically ill patients who cannot take the drug orally or cannot use dry powders, metered-dose sprays, or soft mists.

[0154] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a sterile inhalation suspension containing a PDE-4 or PDE-3 / 4 inhibitor, characterized in that: The steps include: (1) dispersing the PDE-4 or PDE-3 / 4 inhibitor in water for injection containing an excipient, sterilizing by high-pressure wet heat, and dispersing to obtain a PDE-4 or PDE-3 / 4 inhibitor dispersion; (2) Add the excipients to water for injection and dissolve them, adjust the pH value, add a long-acting β2-receptor agonist and / or a long-acting muscarinic receptor antagonist, sterilize and filter to obtain a mixed solution; (3) Adding the PDE-4 or PDE-3 / 4 inhibitor dispersion to the mixed solution, dispersing evenly, and aseptically filling to prepare a sterile inhalation suspension; The mass ratio of the PDE-4 or PDE-3 / 4 inhibitor to the water for injection containing the excipient is 1:10-1:160; the mass ratio of the excipient to the water for injection is 1:40-1:160; The PDE-4 inhibitor is ; The PDE-3 / 4 inhibitor is ; The long-acting β2-receptor agonist is olodaterol or olodaterol hydrochloride; The long-acting muscarinic receptor antagonist is revenacin or a pharmaceutically acceptable salt thereof; The excipient is one or more of polysorbate 20, polysorbate 80 and sorbitan monolaurate; When step (1) is a PDE-4 inhibitor, the pH value is adjusted to 4.0-5.0 in step (2); when step (1) is a PDE-3 / 4 inhibitor, the pH value is adjusted to 6.5-7.0 in step (2).

2. The preparation method according to claim 1, characterized in that The excipient is polysorbate 80.

3. The preparation method according to claim 1, characterized in that The mass ratio of the PDE-4 inhibitor to the long-acting β2-receptor agonist in the suspension is 1:0.01-1:2 and / or the mass ratio of the PDE-4 inhibitor to the long-acting muscarinic receptor antagonist is 1:0.02-1:30; the mass ratio of the PDE-3 / 4 inhibitor to the long-acting β2-receptor agonist in the suspension is 3600:1-1:2 and / or the mass ratio of the PDE-3 / 4 inhibitor to the long-acting muscarinic receptor antagonist is 110:1-1:

30.

4. The preparation method according to claim 1, characterized in that The dispersion method in step (1) is high shear dispersion or high pressure homogenization dispersion.

5. The preparation method according to claim 1, characterized in that The excipients in step (2) include one or more of an isotonic agent, a buffer, and a stabilizer; The isotonic agent is selected from one or more of sodium chloride, mannitol and glucose; The buffer is citric acid / sodium citrate buffer or phosphate buffer; The stabilizer is selected from one or more of ethylenediaminetetraacetic acid, dehydrated disodium ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid and citric acid.

6. The preparation method according to claim 5, characterized in that The isotonic agent is sodium chloride; the stabilizer is disodium edetate.

7. The preparation method according to claim 1, characterized in that At least 90% by volume of the particles of the suspension have an optical diameter of 10 μm or less.

8. The preparation method according to claim 7, characterized in that At least 50% by volume of the particles of the suspension have an optical diameter of 5 μm or less.

9. A method for preparing a single suspension of a PDE-4 or PDE-3 / 4 inhibitor for sterile inhalation, comprising the following steps: (1) dispersing the PDE-4 or PDE-3 / 4 inhibitor in water for injection containing an excipient, sterilizing by high-pressure wet heat, and dispersing to obtain a PDE-4 or PDE-3 / 4 inhibitor dispersion; (2) Add the excipients to water for injection and dissolve, adjust the pH value, sterilize and filter to obtain a solution; (3) adding the PDE-4 or PDE-3 / 4 inhibitor dispersion to the solution, dispersing it evenly, and aseptically filling it to prepare a sterile PDE-4 or PDE-3 / 4 inhibitor single suspension for inhalation; In step (1), the mass ratio of the PDE-4 or PDE-3 / 4 inhibitor to the water for injection containing the excipient is 1:10-1:160, and the mass ratio of the excipient to the water for injection is 1:40-1:160; The PDE-4 inhibitor is ; The PDE-3 / 4 inhibitor is ; The excipient is one or more of polysorbate 20, polysorbate 80 and sorbitan monolaurate; When step (1) is a PDE-4 inhibitor, the pH value is adjusted to 4.0-5.0 in step (2); when step (1) is a PDE-3 / 4 inhibitor, the pH value is adjusted to 6.5-7.0 in step (2).

10. The preparation method according to claim 9, characterized in that The excipients in step (2) include one or more of an isotonic agent, a buffer and a stabilizer.

11. The preparation method according to claim 9, characterized in that The excipient is polysorbate 80.

12. A sterile suspension for inhalation, characterized in that Prepared according to the method according to any one of claims 1 to 11.

13. Use of the sterile inhalation suspension according to claim 12 in preparing a medicament for treating respiratory diseases, characterized in that: The respiratory disease is chronic obstructive pulmonary disease and / or asthma.

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