Sterile inhalation suspension containing PDE-4 or PDE-3 / 4 inhibitor and preparation method and application thereof

Abstract

The invention provides a preparation method and application of a suspension containing a PDE-4 or PDE-3 / 4 inhibitor for sterile inhalation. The preparation method comprises the following steps: dispersing a PDE-4 or PDE-3 / 4 inhibitor in injection water containing an excipient, and carrying out high-pressure moist heat sterilization to obtain a PDE-4 or PDE-3 / 4 inhibitor dispersion liquid; dissolving the long-acting beta2-receptor stimulant and / or the long-acting muscarinic receptor antagonist, sterilizing and filtering to obtain a mixed solution; and mixing the PDE-4 or PDE-3 / 4 inhibitor dispersion liquid with the mixed solution, dispersing, and carrying out sterile filling. The medicinal preparation prepared by the invention is a sterile inhalation suspension, and the sterile inhalation suspension containing the PDE-4 or PDE-3 / 4 inhibitor is high in bioavailability, good in patient medication compliance and good in preparation stability.

Description

Technical Field

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

[0002] Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by incompletely reversible airflow limitation, which is usually characterized by progressive progression, accompanied by an increase in chronic inflammatory response of the airways and lungs to harmful particles or gases, including most chronic bronchitis and emphysema. As the disease progresses, it leads to airway remodeling, which eventually develops into irreversible airflow obstruction, causing patients to have difficulty breathing, lose their ability to move, and seriously affect their quality of life. In response to this increasingly serious and frequent disease, this patent combines phosphodiesterase-4 or phosphodiesterase-3 / 4 inhibitors (Phosphodiesterase-4Inhibitor, PDE-4 inhibitors or Phosphodiesterase-3 / 4, PDE-3 / 4 inhibitors) with long-acting bronchodilators to provide additional benefits of further reducing symptoms and disease exacerbation, improving patient medication compliance, and improving patient quality of life.

[0003] Currently, the main means for treating and preventing COPD and asthma include dilating bronchi and inhibiting inflammatory responses.

[0004] Commonly used drugs to inhibit inflammatory responses in the treatment of COPD include inhaled corticosteroids (ICS) and PDE-4 inhibitors. In the treatment of COPD, hormone insensitivity occurs, that is, hormone drugs cannot effectively control the progressive airway inflammation, nor can they reverse the decline in lung function caused by airway inflammation. This phenomenon causes inhaled corticosteroids to fail to achieve the expected therapeutic effect in the treatment of some frequently exacerbated COPD symptoms.

[0005] PDE-4 inhibitors are highly specific for cyclic adenosine monophosphate (cAMP) and are involved in promoting monocyte and macrophage activation, neutrophil infiltration, vasodilation and other related physiological and pathological processes. PDE-4 is associated with the hydrolysis of cAMP in a variety of inflammatory cells. Since cAMP can lead to 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 dual effects of bronchodilation and anti-inflammatory. The use of such inhibitor drugs can make up for the deficiencies in the treatment process of commonly used inhaled corticosteroids.

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

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

[0008]

[0009] Roflumilast was developed by Altana Pharma in 1993. In July 2010, the European Union approved Nycomed's once-daily oral tablet (Daxas) for marketing. It must be used in combination with other bronchodilators and is suitable for the maintenance treatment of severe COPD associated with chronic bronchitis in adult patients with a history of frequent exacerbations. It is the first drug targeting a specific phenotype of COPD. WO09501338 and CN94192659 disclose the compound, its preparation method, and its use in the treatment of airway diseases or skin diseases. Roflumilast has a wide range of anti-inflammatory effects. It can affect multiple types of cells such as neutrophils, monocytes / macrophages, endothelial cells, smooth muscle cells, etc. in vitro, and plays a role in multiple aspects of the pathogenesis of COPD, such as tobacco-induced lung inflammation, respiratory ciliary dyskinesia, emphysema, oxidative stress, pulmonary hypertension, etc.

[0010] Olodaterol hydrochloride is a new selective fast-acting LABA with a molecular formula of C 21 H 27 ClN2O5, the structural formula is as follows:

[0011]

[0012] Olodaterol hydrochloride was developed by Boehringer Ingelheim and launched in the United States in 2014 (trade name: Striverdi Respimat). The dosage form is an inhaled soft mist, once a day, two sprays each time. US7727984 B2 patent discloses this type of compound and its application in the treatment of COPD. Olodaterol hydrochloride has high β2-receptor selectivity, rapid onset, few cardiovascular side effects, long half-life, can maintain 24 hours of bronchial dilation, and can improve patient compliance. Experiments have shown that olodaterol hydrochloride can block the contraction of different bronchial irritants (such as histamine and methacholine), and the effect is dose-related; long-term use of olodaterol hydrochloride will not lead to β2-receptor desensitization.

[0013] Revenacin is a new type of LAMA with a molecular formula of C 35 H 43 N5O4, the structural formula is as follows:

[0014]

[0015] US7288657 B2 discloses that this type of compound is used as a long-acting muscarinic receptor antagonist; US8541451 B2 discloses two crystal forms of this type of compound. Revenacin is a new structure, non-selective, long-acting muscarinic receptor antagonist that blocks the M3-receptors in the respiratory tract, prevents acetylcholine-induced bronchoconstriction, and produces a bronchial dilation effect. In November 2018, the FDA approved Revenacin inhalation solution (trade name: Yupelri) for the maintenance treatment of chronic obstructive pulmonary disease.

[0016] The marketed products of roflumilast are orally administered, with low bioavailability and slow onset of action. They must be used in conjunction with inhaled bronchodilators, and patients have poor medication compliance. CN201710015258 discloses a roflumilast suspension for inhalation and a preparation method thereof, wherein the prepared suspension is terminally sterilized after encapsulation; CN20140006017 discloses a dosing regimen for inhalation of roflumilast N-oxide in the form of dry powder; CN201410054915 discloses a drug combination of roflumilast and tiotropium bromide in the form of dry powder inhalation; CN201410055153 discloses a drug combination of salmeterol and roflumilast in the form of dry powder inhalation; CN201410054930 discloses a drug combination of indacaterol and roflumilast in the form of dry powder inhalation; CN201410039603 discloses a roflumilast inhalation aerosol compound and a preparation method thereof.

[0017] CN201710015258 discloses a roflumilast suspension for inhalation and a preparation method thereof. The suspension consists of an active ingredient, roflumilast, a surfactant, a pH regulator, an osmotic pressure regulator, and a solvent. After the drug is prepared, terminal sterilization is performed. The high temperature causes the main component to degrade and affects the product particle size. At the same time, it causes roflumilast to crystallize, affecting the efficacy.

[0018] Currently, there is no comprehensive drug combination or formulation suitable for patients with severe chronic bronchitis-related COPD to meet the clinical needs of patients. Therefore, it is planned to develop a sterile inhalation suspension containing PDE-4 or PDE-3 / 4 inhibitors and its preparation method and application. The prepared drug preparation includes PDE-4 or PDE-3 / 4 inhibitors, long-acting β2-receptor agonists and / or long-acting muscarinic receptor antagonists, which has stable quality and can be used for once-daily nebulized inhalation treatment of severe COPD patients. Summary of the invention

[0019] The present invention aims at the problems existing in the prior art and provides a method for preparing a sterile suspension for inhalation containing a PDE-4 or PDE-3 / 4 inhibitor. The pharmaceutical preparation can be used once a day to relieve severe COPD symptoms and reduce frequent exacerbations of the disease.

[0020] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0021] A method for preparing a sterile inhalation suspension containing a PDE-4 or PDE-3 / 4 inhibitor, wherein the sterile inhalation suspension is a compound sterile inhalation suspension prepared from a PDE-4 or PDE-3 / 4 inhibitor and a long-acting β2-receptor agonist or a long-acting muscarinic receptor antagonist; and a tripartite sterile inhalation suspension prepared from a PDE-4 or PDE-3 / 4 inhibitor, a long-acting β2-receptor agonist and a long-acting muscarinic receptor antagonist;

[0022] The preparation method of the suspension comprises the following steps:

[0023] (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;

[0024] (2) adding the excipients to water for injection to dissolve, adjusting the pH value, adding a long-acting β2-receptor agonist and / or a long-acting muscarinic receptor antagonist, sterilizing and filtering to obtain a mixed solution;

[0025] (3) Add the PDE-4 or PDE-3 / 4 inhibitor dispersion into the mixed solution, disperse evenly, and aseptically fill to obtain a sterile inhalation suspension.

[0026] 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; the mass ratio of the excipient to the water for injection is 1:40-1:800.

[0027] 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.

[0028] Furthermore, the dispersion method in step (1) is high shear dispersion or high pressure homogenization dispersion.

[0029] Furthermore, the PDE-4 inhibitor is selected from one or more of the following compounds:

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] Preferably, the PDE-4 is the following compound;

[0039]

[0040] The PDE-3 / 4 inhibitor is selected from one or more of the following compounds:

[0041]

[0042] Preferably, the PDE-3 / 4 inhibitor is the following compound;

[0043]

[0044] 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.

[0045] Preferably, the long-acting β2-receptor agonist is olodaterol or olodaterol hydrochloride.

[0046] 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.

[0047] Preferably, the long-acting muscarinic receptor antagonist is revenacin or a pharmaceutically acceptable salt thereof.

[0048] 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.

[0049] Furthermore, in the suspension, the mass ratio of the PDE-3 / 4 inhibitor to the long-acting β2-receptor agonist 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.

[0050] Furthermore, in step (2), the pH value is adjusted to 4.0-7.0.

[0051] 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.

[0052] Furthermore, the auxiliary materials in step (2) include one or more of an isotonic agent, a buffer, and a stabilizer.

[0053] Furthermore, the isotonic agent is selected from one or more of sodium chloride, mannitol, and glucose; preferably sodium chloride;

[0054] The buffer is citric acid / sodium citrate buffer or phosphate buffer;

[0055] The stabilizer is selected from one or more of ethylenediaminetetraacetic acid, dehydrated disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate and citric acid; preferably disodium ethylenediaminetetraacetate.

[0056] Furthermore, the aseptic filling in step (3) adopts blow-fill-seal aseptic filling or aseptic filling of vials and ampoules.

[0057] Furthermore, at least 90% by volume of the particles of the suspension of the present invention 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.

[0058] Furthermore, in the suspension of the present invention, the daily inhalation dose of the PDE-4 and / or PDE-3 / 4 inhibitor 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.

[0059] Furthermore, the suspension of the present invention is administered by aerosol inhalation.

[0060] The preparation method of the present invention can also be used to prepare a sterile suspension for inhalation containing only a PDE-4 or PDE-3 / 4 inhibitor as an active ingredient.

[0061] 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:

[0062] (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;

[0063] (2) adding the excipients to water for injection and dissolving them, adjusting the pH value, sterilizing and filtering to obtain a solution;

[0064] (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.

[0065] The present invention also provides the use of the above-mentioned pharmaceutical preparation in preparing drugs for treating respiratory diseases, wherein the respiratory diseases include but are not limited to chronic obstructive pulmonary disease and all types of asthma.

[0066] Compared with the prior art, the present invention has the following beneficial effects:

[0067] (1) Oral administration of PDE-4 or PDE-3 / 4 inhibitors has low bioavailability and poor patient compliance. Currently published drug 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 have high temperatures that degrade the main components, affecting the product particle size and causing crystal transformation problems, affecting 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 plan for critically ill patients who cannot take the drug orally or cannot use dry powders, metered sprays, or soft mists.

[0068] (2) The present invention optimizes the active ingredients and the 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 crystalline 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

[0069] Figure 1 is a comparison diagram of the properties of sample 1 and sample 3 in test example 3 of the present invention;

[0070] Figure 2 is a comparison diagram of the properties of sample 1 and sample 8 in test example 7 of the present invention;

[0071] Figure 3 This is a crystal form diagram of the raw material drug in Test Example 7 of the present invention;

[0072] Figure 4 This is a crystal diagram of the sample before sterilization in Test Example 7 of the present invention;

[0073] Figure 5 is a crystal diagram of sample 1 prepared in Example 1 of the present invention;

[0074] Figure 6 This is a crystal diagram of sample 8 prepared by the method disclosed in Chinese invention patent application CN201710015258.2. DETAILED DESCRIPTION

[0075] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can 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.

[0076] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0077] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. The contents described below are all by mass.

[0078] The purchase manufacturers and models of some raw materials used in the examples are as follows:

[0079] Roflumilast: Manufacturer: aladdin, batch number: L2106784;

[0080] Olodaterol hydrochloride: Manufacturer: Inke, Batch No.: PP-1;

[0081] Refenacin: Manufacturer: Medichem Batch number: F-220018;

[0082] RPL554 (Compound 50): Manufacturer: Shanghai Houbo Biotechnology Co., Ltd., batch number: 20240826.

[0083] Example 1

[0084] This example provides a method for preparing a roflumilast-olodaterol hydrochloride-revefacine suspension for sterile inhalation (roflumilast is compound 1, a PDE-4 inhibitor), and the dosage composition is shown in Table 1:

[0085] Table 1

[0086]

[0087]

[0088] Preparation process:

[0089] (1) dispersing roflumilast in a small amount of water for injection containing an excipient by high shear dispersion, sterilizing by high pressure moist heat (sterilizing at 121° C. for 15 min, the same below), and then dispersing by high shear dispersion or high pressure homogenization technology to obtain a roflumilast dispersion;

[0090] (2) adding the excipients to water for injection and stirring to dissolve, adjusting the pH value with a buffer solution, adding olodaterol hydrochloride and revenacin, dissolving, sterilizing and filtering to obtain a mixed solution;

[0091] (3) Add the dispersion of (1) above to the mixed solution of (2) above, disperse evenly, and aseptically fill by blow-fill-seal to prepare a sterile roflumilast-olodaterol hydrochloride-revefacine suspension for inhalation.

[0092] Experimental Example 1: Effect of different pH values ​​on the stability of roflumilast-olodaterol hydrochloride-revefacine suspension for inhalation

[0093] According to the components and preparation process in Example 1, roflumilast-olodaterol hydrochloride-revefanacin suspensions for inhalation with pH values ​​of 3.5, 4.0, 4.5, 5.0, and 5.5 were prepared respectively, and placed at 60° C. and accelerated conditions (40° C.±2° C., ≤25% RH) to investigate the stability of the samples. The results are shown in Tables 2 and 3:

[0094] Table 2 Stability of roflumilast-olodaterol hydrochloride-revenacin suspension for inhalation at different pH values ​​at 60°C

[0095]

[0096] Table 3 Stability of roflumilast-olodaterol hydrochloride-revefanacin suspension for inhalation at different pH values ​​under accelerated conditions (40°C ± 2°C, ≤ 25% RH)

[0097]

[0098]

[0099] 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 obvious 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 obvious change in the degradation impurities in the pH 4.0-5.0 range, and the sample had better stability at pH 4.5.

[0100] Test Example 2: Investigating the effect of stabilizers on the stability of roflumilast-olodaterol hydrochloride-revefanacin suspension for inhalation.

[0101] The roflumilast-olodaterol hydrochloride-revefacine suspension for inhalation prepared under pH 4.5 in Example 1 was used as sample 1; and according to the components and preparation process in Example 1, only disodium edetate was removed to prepare the roflumilast-olodaterol hydrochloride-revefacine suspension for inhalation, which was used as sample 2; the stability of the two samples was investigated under accelerated conditions (40°C ± 2°C, ≤ 25% RH), and the results are shown in Table 4:

[0102] Table 4 Effect of metal ion chelators on the stability of roflumilast-olodaterol hydrochloride-revefanacin suspension for inhalation

[0103]

[0104] As shown in Table 4, the stability of the samples with the addition of the stabilizer disodium ethylenediaminetetraacetate is not significantly changed compared with the samples without the addition.

[0105] Example 2

[0106] This example provides a method for preparing an aseptic inhalation suspension of ensefentin-olodaterol hydrochloride-revefenacin (ensefentin is compound 50, a PDE-3 / 4 inhibitor), and the dosage composition is shown in Table 5:

[0107] Table 5

[0108]

[0109] The preparation process is the same as that in Example 1 to obtain an ensefentin-olodaterol hydrochloride-revenacin suspension, which is sample 3.

[0110] Experimental Example 3: Stability evaluation of a three-component suspension containing different types of PDE inhibitors

[0111] The raw material dispersions in sample 1 (roflumilast-olodaterol hydrochloride-revefenacin suspension) and sample 3 (encefentine-olodaterol hydrochloride-revefenacin suspension) were sterilized by high pressure wet heat and then mixed with the remaining raw material solution to observe the changes in their properties. The results are shown in the attached figure. Figure 1 shown.

[0112] As attached Figure 1 As shown, according to the preparation method of the present invention, the suspensions obtained by using different PDE inhibitors as active ingredients are all uniform suspensions. Therefore, it should be particularly noted that the stability of the sterile inhalation suspension containing PDE inhibitors prepared by the preparation process of the present invention is not affected by the type of PDE inhibitor. Subsequent examples and test examples will use "Roflumilast (Compound 1)" as the active ingredient to prepare single and compound suspensions, and study the relevant properties of the products obtained by the preparation process of the present invention.

[0113] Example 3

[0114] This example provides a method for preparing a roflumilast-olodaterol hydrochloride suspension for sterile inhalation, and the dosage composition is shown in Table 6:

[0115] Table 6

[0116] Components Single dose composition Roflumilast 0.5mg Olodaterol Hydrochloride 10 μg Citric Acid / Sodium Citrate Adjust pH to 4.5 Sodium chloride 25.5mg Disodium EDTA 0.3mg Polysorbate 80 0.5mg Water for injection 3mL

[0117] 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.

[0118] Example 4

[0119] This example provides a method for preparing a roflumilast-revefacine suspension for sterile inhalation, and the dosage composition is shown in Table 7:

[0120] Table 7

[0121]

[0122]

[0123] The preparation process of this example is the same as that of Example 1, and a roflumilast-revefacine suspension is obtained, which is Sample 5.

[0124] Example 5

[0125] This example provides a method for preparing a roflumilast single prescription suspension for sterile inhalation, and the dosage composition is shown in Table 8:

[0126] Table 8

[0127] Components Single dose composition Roflumilast 0.5mg Citric Acid / Sodium Citrate Adjust pH to 4.5 Sodium chloride 17mg Disodium EDTA 0.2mg Polysorbate 80 1mg Water for injection 2mL

[0128] Preparation process:

[0129] (1) dispersing roflumilast in water for injection containing polysorbate 80 by high shear dispersion technology, sterilizing by high pressure moist heat, and then dispersing by high shear dispersion or high pressure homogenization technology to obtain a roflumilast dispersion;

[0130] (2) adding the excipients to water for injection, stirring and dissolving, adjusting the pH value with a buffer solution, and sterilizing and filtering through a 0.22 μm filter cartridge to obtain a solution;

[0131] (3) The dispersion of (1) was added to the solution of (2) and dispersed evenly. The mixture was aseptically filled by blow-fill-seal to obtain a sterile roflumilast single prescription suspension for inhalation, which was designated as Sample 6.

[0132] Test Example 4: Effect of different dispersion media on the stability of roflumilast during high pressure wet heat sterilization

[0133] The dispersion medium (water for injection containing polysorbate 80) in Example 5 was changed to a buffer solution with a pH value of 5.0, and a roflumilast single prescription suspension was prepared in the same manner, which was 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.

[0134] Table 9 Effect of different dispersion media on the stability of roflumilast during high pressure wet heat sterilization

[0135]

[0136] As can be seen from Table 9, when sterilization is performed using water for injection containing polysorbate 80 as the dispersion medium, the growth of roflumilast degradation impurities is relatively small, and the prepared sample can be redispersed after sedimentation, indicating that it has a certain tolerance to high temperature, and high-pressure wet heat sterilization is suitable for the sterilization of roflumilast.

[0137] Experimental Example 5: Effects of different solid-liquid ratios and polysorbate 80 concentrations on the stability of roflumilast during high pressure wet heat sterilization

[0138] Roflumilast was dispersed in water for injection containing different concentrations of polysorbate 80 using a high shear disperser according to different solid-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.

[0139] Table 10 Effects of different solid-liquid ratios and polysorbate 80 concentrations on the stability of roflumilast during high pressure wet heat sterilization

[0140] Ratio 1 Ratio 2 Ratio 3 Ratio 4 Ratio 5 Ratio 6 Roflumilast concentration (%) 0.25 0.625 1.25 1.25 1.25 2.5 Polysorbate 80 concentration (%) 0.25 0.125 2.5 1.25 0.625 2.5 Maximum single impurity (%) 0.42 0.04 0.04 0.04 0.04 0.04 Total impurities (%) 0.51 0.12 0.17 0.12 0.10 0.11 Redispersibility Redispersible Redispersible Redispersible Redispersible Redispersible Redispersible

[0141] 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; and when the concentration of polysorbate 80 reaches above 0.125%, good dispersibility can be achieved.

[0142] Test Example 6: Stability Study of Roflumilast Suspensions for Sterile Inhalation in Different Combinations

[0143] The stability of the four suspensions (Sample 1, Sample 4, Sample 5, Sample 6) was investigated. The results are shown in Tables 11 and 12.

[0144] Table 11 Stability of different suspensions at 60°C

[0145]

[0146] Table 12 Stability of different suspensions under accelerated conditions (40°C ± 2°C, ≤ 25% RH)

[0147]

[0148] It can be seen from the results in Table 11 and Table 12 that the preparations of different compositions of roflumilast were prepared according to the screened components and processes. The roflumilast single suspension had good stability, and the combination preparations of roflumilast and olodaterol hydrochloride and / or revenacin had relatively good stability under accelerated conditions.

[0149] Test Example 7: Comparison of different sterilization methods

[0150] Chinese invention patent application CN201710015258.2 discloses a method for preparing roflumilast suspension for inhalation, in which the main sterilization method is terminal sterilization, which may affect the product quality.

[0151] According to the dosage composition of Example 1, the preparation was carried out according to the following steps (steps of Chinese invention patent application CN201710015258.2):

[0152] (1) Add the excipients to 80% of the prepared amount of water for injection and stir to dissolve;

[0153] (2) Roflumilast (micronized to D 90 less than 10 μm) was added to the above solution and stirred evenly, stirred for 30 min under a high shear homogenizer, and water for injection was added to the full amount;

[0154] (3) Adjusting pH value;

[0155] (4) Filling and terminal sterilization to prepare sample 8.

[0156] 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.

[0157] Table 13 Changes in sample degradation impurities and particle size before and after sterilization

[0158] Detection items API Before sterilization Sample 1 Sample 8 Maximum single impurity NA 0.04％ 0.05％ 0.19％ Total Miscellaneous NA 0.23％ 0.31％ 0.77％ <![CDATA[D 90 ]]> 5μm 4μm 7μm 77μm <![CDATA[D 50 ]]> 2μm 2μm 5μm 9μm <![CDATA[D 10 ]]> 1μm 1μm 2μm 3μm

[0159] As attached Figure 2 As shown, the sample is prepared according to the terminal sterilization method in Chinese invention patent application CN201710015258.2, and a large amount of flocculent crystalline substances are suspended in the drug solution; the sample prepared according to the preparation process of the present invention is a uniform white suspension.

[0160] It can be seen from the results in Table 13 that the sample (Sample 8) prepared according to the terminal sterilization method in Chinese invention patent application CN201710015258.2 has significantly increased degradation impurities and the particle size of the raw material, and its D90 reaches 77 μm, which cannot meet the requirement that the particle size of the inhalation preparation is less than 10 μm; the sample (Sample 1) prepared according to the embodiment of the present invention has no obvious change in degradation impurities, no obvious change in particle size, and D90 reaches 7 μm, which meets the requirement that the particle size of the inhalation preparation is less than 10 μm.

[0161] As attached Figure 3-6 As shown, the sample was prepared according to the terminal sterilization method in Chinese invention patent application CN201710015258.2, and the crystal form of the raw material drug changed significantly; the sample was prepared according to the embodiment of the present invention, and there was no crystal transformation phenomenon of the raw material drug during the preparation process. In summary, the quality of the suspension prepared according to the embodiment of the present invention is significantly better than the suspension prepared by 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 mixed with roflumilast, which has no effect on the crystal form of roflumilast, so there is no crystal transformation phenomenon of roflumilast during the preparation of roflumilast single prescription and roflumilast and long-acting β2-receptor agonist and / or long-acting muscarinic receptor antagonist compound suspension.

[0162] In summary, the present invention provides a stable, sterile single suspension for inhalation containing a PDE-4 or PDE-3 / 4 inhibitor, or a sterile compound suspension for inhalation containing 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, to provide a treatment plan for critically ill patients who cannot be administered orally or cannot be used with dry powders, metered sprays, or soft mists.

[0163] 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) adding the excipients to water for injection to dissolve, adjusting the pH value, adding a long-acting β2-receptor agonist and / or a long-acting muscarinic receptor antagonist, sterilizing and filtering to obtain a mixed solution; (3) Add the PDE-4 or PDE-3 / 4 inhibitor dispersion into the mixed solution, disperse evenly, and aseptically fill to obtain a sterile inhalation suspension.

2. The preparation method according to claim 1, characterized in that: 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; 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.

3. The preparation method according to claim 1, characterized in that: The PDE-4 inhibitor is selected from one or more of the following compounds: Preferably, the PDE-4 inhibitor is the following compound: The PDE-3 / 4 inhibitor is selected from one or more of the following compounds: Preferably, the PDE-3 / 4 inhibitor is the following compound: The long-acting β2-receptor agonist is selected from one or more of olodaterol, vilanterol, indacaterol, formoterol, arformoterol, carmoterol, procaterol or their corresponding pharmaceutically acceptable salts; preferably olodaterol or olodaterol hydrochloride; The long-acting muscarinic receptor antagonist is selected from one or more of revenacin, tiotropium bromide, glycopyrrolate, umeclidinium bromide, aclidinium bromide or their corresponding pharmaceutically acceptable salts; preferably revenacin or its pharmaceutically acceptable salt; 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; and the pH value in step (2) is adjusted to 4.0-7.

0.

5. The preparation method according to claim 1, characterized in that: The auxiliary materials 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; preferably sodium chloride; The buffer is citric acid / sodium citrate buffer or phosphate buffer; The stabilizer is selected from one or more of ethylenediaminetetraacetic acid, dehydrated disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate and citric acid; preferably disodium ethylenediaminetetraacetate.

6. 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; preferably at least 50% by volume of the particles have an optical diameter of 5 μm or less.

7. 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) adding the excipients to water for injection and dissolving them, adjusting the pH value, sterilizing and filtering to obtain a solution; (3) Add the PDE-4 or PDE-3 / 4 inhibitor dispersion into the solution, disperse evenly, and aseptically fill to prepare a sterile PDE-4 or PDE-3 / 4 inhibitor single suspension for inhalation.

8. The preparation method according to claim 7, characterized in that: 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; 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; Step (2) adjusting the pH value to 4.0-7.0; The auxiliary materials in step (2) include one or more of an isotonic agent, a buffer and a stabilizer.

9. A sterile suspension for inhalation, characterized in that: Prepared according to the method according to any one of claims 1 to 8.

10. Use of the sterile inhalation suspension according to claim 9 in preparing a drug for treating respiratory diseases, characterized in that: The respiratory disease is chronic obstructive pulmonary disease and / or asthma.

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