Pharmaceutical composition, preparation method therefor and use thereof

Abstract

A pharmaceutical composition A, which comprises the following components in parts by weight: 0.2-2 parts of a compound (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical auxiliary material, wherein the pharmaceutical auxiliary material comprises 60-200 parts of an excipient and water; the excipient is selected from one or more of mannitol, maltose, fructose, lactose and glucose; and the pharmaceutical composition has a pH value of 1.5-5.0. The pharmaceutical composition has good stability, and thus has good application prospects in the preparation of a drug for preventing and / or treating respiratory diseases.

Description

A pharmaceutical composition, a preparation method thereof and application thereof

[0001] This application claims priority to Chinese patent application CN2024110722169 with a filing date of August 6, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to the field of pharmaceutical technology, in particular to a pharmaceutical composition, a preparation method thereof and application thereof. BACKGROUND

[0003] There are more than 200 drugs for treating asthma in the clinical and experimental stages in China at present. The main target points of the drugs are β2 receptor, glucocorticoid receptor, phosphodiesterase-4, genes in the leukotriene synthesis pathway, cytochrome P450 enzyme system, IL-4 / 5 receptor, etc. Although multiple target therapy drugs have been applied in the clinic, the first-line drugs for treating mild and moderate asthma are still mainly glucocorticoid combined with classic control or relieving drugs, and target therapy drugs are auxiliary. Especially for refractory asthma patients, the drug use is very limited, and the target therapy drugs also have the characteristics of limited applicable population, poor drug compliance and high price. In view of the complexity of the pathogenesis of asthma, the simple blocking of a certain cytokine does not have obvious curative effect.

[0004] SP is a polypeptide drug for treating allergic asthma, which is a new compound molecule composed of seven amino acid residues. The active structure is a peptidomimetic designed based on the HCV E2 region amino acid sequence targeting CD81, and the structure of the mimetic peptide is modified and the point position is modified according to the pharmacokinetic characteristics. Finally, SP with stable drug efficacy and long half-life is selected as a candidate drug molecule. The mechanism of action is explored by single-cell transcriptome sequencing and metabolomics analysis and other technical means, which proves that SP plays a role in anti-asthma airway inflammation by targeting CD81 to regulate immune cell metabolic function. Thus, a new peptidomimetic drug SP for treating allergic asthma with good biological activity, metabolic stability, and more suitable for non-invasive drug delivery route is found. SUMMARY

[0005] In order to overcome the defect that the types of the pharmaceutical composition for treating asthma in the prior art are limited, the present application provides a pharmaceutical composition, a preparation method thereof and application thereof. The pharmaceutical composition of the present application has good stability and good application prospect.

[0006] The present application provides a pharmaceutical composition A, which comprises the following components in parts by weight:

[0007] 0.2-2 parts of compound (I) or a pharmaceutically acceptable salt thereof,

[0008] and a pharmaceutical excipient, which includes 60-200 parts of an excipient selected from one or more of mannitol, maltose, fructose, lactose and glucose; and water; and the pH value of the pharmaceutical composition is 1.5-5.0.

[0009] In a certain aspect, the compound (I) or a pharmaceutically acceptable salt thereof is 0.5 parts, 1 part, 1.5 parts or 2 parts.

[0010] In a certain aspect, the compound (I) or a pharmaceutically acceptable salt thereof is 0.5-1.5 parts.

[0011] In a certain aspect, the pharmaceutical excipient further includes an acid; the acid is selected from one or more of acetic acid, hydrochloric acid and phosphoric acid; preferably, the acid is hydrochloric acid.

[0012] In a certain aspect, the salt is trifluoroacetate.

[0013] In a certain aspect, the pharmaceutical excipient further includes an inorganic salt and an organic salt; the inorganic salt can be sodium chloride; the organic salt can be sodium trifluoroacetate.

[0014] In a certain aspect, the pH value of the pharmaceutical composition is 3.0, 3.5, 4.0, 4.5 or 5.0.

[0015] In a certain aspect, the pH value of the pharmaceutical composition is 3.0-3.5.

[0016] In a certain aspect, the excipient is selected from one or more of mannitol, maltose, lactose and glucose; preferably, the excipient is mannitol or lactose.

[0017] In a certain aspect, the content of the excipient is 100-180 parts; preferably, the content of the excipient is 101.4 parts, 140 parts or 170 parts; further preferably, the content of the excipient is 140 parts.

[0018] In a certain aspect, the pharmaceutical composition further includes 0.5-7 parts of a co-solvent and / or 2-10 parts of an amino acid; the co-solvent is preferably 0.6-6 parts; for example, 1 part, 1.1 part or 6 parts; further for example, 6 parts; the amino acid is 2 parts, 4 parts, 6 parts, 8 parts or 10 parts; for example, 2 parts.

[0019] In a certain aspect, the co-solvent is DPTA, EDTA, polysorbate 80, poloxamer 188, Span 20 or polysorbate 80+EDTA; preferably, the co-solvent is polysorbate 80, poloxamer 188, Span 20 or polysorbate 80+EDTA; further preferably, the co-solvent is poloxamer 188.

[0020] In an embodiment, the amino acid is selected from one or more of lysine, methionine, histidine, glycine, glutamine, arginine, and proline; preferably arginine or glutamine; further preferably arginine.

[0021] In an embodiment, the pharmaceutical composition has an osmolality ratio of 0.9 to 1.3.

[0022] In an embodiment, the pharmaceutical composition further comprises water; the water can be water for injection.

[0023] In an embodiment, the pharmaceutical composition comprises or consists of,

[0024] (1) the compound (I) or a pharmaceutically acceptable salt thereof, water, and an excipient; the pH value is as described in any of the preceding embodiments;

[0025] (2) the compound (I) or a pharmaceutically acceptable salt thereof, water, the excipient, a co-solvent, and the amino acid; the pH value is as described in any of the preceding embodiments; and

[0026] (3) the compound (I) or a pharmaceutically acceptable salt thereof, water, the excipient, and the amino acid; the pH value is as described in any of the preceding embodiments;

[0027] Preferably,

[0028] (1) 1 part of the compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of maltose, water, and the pH value is 4.0;

[0029] (2) 1 part of the compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of fructose, water, and the pH value is 4.0;

[0030] (3) 1 part of the compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, water, and the pH value is 4.0;

[0031] (4) 1 part of the compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of glucose, water, and the pH value is 4.0;

[0032] (5) 1 part of the compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of polysorbate 20, water, and the pH value is 4.0;

[0033] (6) 1 part of the compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of polysorbate 80, water, and the pH value is 4.0;

[0034] (7) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of poloxamer 188, water, pH 4.0;

[0035] (8) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of Span 20, water, pH 4.0;

[0036] (9) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of polysorbate + 0.1 part of EDTA, water, pH 4.0;

[0037] (10) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0;

[0038] (11) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of lysine, water, pH 4.0;

[0039] (12) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of methionine, water, pH 4.0;

[0040] (13) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, + 4 parts of arginine, 6 parts of histidine, water, pH 4.0;

[0041] (14) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of glycine, water, pH 4.0;

[0042] (15) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of proline, water, pH 4.0;

[0043] (16) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of glutamine, water, pH 4.0;

[0044] (17) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 2 parts of arginine, water, pH 5.0;

[0045] (18) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 5.0;

[0046] (19) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 6 parts of arginine, water, pH 5.0;

[0047] (20) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 8 parts of arginine, water, pH 5.0;

[0048] (21) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 10 parts of arginine, water, pH 5.0;

[0049] (22) 0.5 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0;

[0050] (23) 1.5 parts of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0;

[0051] (24) 2 parts of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0;

[0052] (25) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.0;

[0053] (26) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.5;

[0054] (27) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 4.0;

[0055] (28) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 4.5;

[0056] (29) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, 4 parts of arginine, water, pH 3.0;

[0057] (30) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, water, pH 3.0;

[0058] (31) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 170 parts of lactose, water, pH 3.0;

[0059] (32) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, water, pH 3.0;

[0060] (33) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of glucose, water, pH 3.0;

[0061] Preferably,

[0062] (1) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, water, pH 4.0;

[0063] (2) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.0;

[0064] (3) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.5;

[0065] (4) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, water, pH 3.0;

[0066] Also preferred is,

[0067] 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, water, pH 3.0.

[0068] In one aspect of the present application, the pharmaceutical composition A can be a solution formulation for inhalation.

[0069] In one aspect, the concentration of Compound (I) or a pharmaceutically acceptable salt thereof is (0.1-1) mg / mL; for example, 0.25 mg / mL, 0.5 mg / mL, 0.75 mg / mL or 1 mg / mL; preferably (0.25-0.75) mg / mL.

[0070] The present application provides a pharmaceutical composition B, which is obtained by freeze-drying the above pharmaceutical composition A.

[0071] The present application provides a pharmaceutical composition C, which comprises the following components in parts by weight:

[0072] 0.2-2 parts of Compound (I) or a pharmaceutically acceptable salt thereof,

[0073] and a pharmaceutical adjuvant, which comprises 60-200 parts of an excipient, wherein the pharmaceutical composition C is dissolved in water, the concentration of Compound (I) or a pharmaceutically acceptable salt thereof is (0.1-1) mg / mL, and the pH of the pharmaceutical composition C is 1.5-5.0; the Compound (I) or a pharmaceutically acceptable salt thereof and the excipient are as described in any aspect of the present application; the pharmaceutical adjuvant is as described in any aspect of the present application, except that it does not comprise water.

[0074] In one aspect, the pharmaceutical composition C is a dry powder formulation, and for example, a freeze-dried powder injection.

[0075] In one aspect, the pharmaceutical composition C is an inhalation formulation.

[0076] The present application provides a pharmaceutical composition D, which comprises 0.2-2 parts of the compound (I) or its pharmaceutically acceptable salt, and pharmaceutical adjuvants, including pH adjuster, 60-200 parts of excipient and water; the pH of the compound (I) or its pharmaceutically acceptable salt, the excipient, the pharmaceutical adjuvant and the pharmaceutical composition is as described in any of the schemes of the present application.

[0077] In a certain scheme, the pH adjuster is acid or "acid and base"; the acid is selected from one or more of acetic acid, hydrochloric acid and phosphoric acid; preferably hydrochloric acid; the base is sodium hydroxide; the hydrochloric acid can be 5 mol / L hydrochloric acid; the sodium hydroxide can be 1 mol / L sodium hydroxide.

[0078] The present application provides a preparation method of a solution preparation, in which the compound (I) or its pharmaceutically acceptable salt is dissolved to prepare a solution preparation in the presence of excipient, water and pH adjuster; the excipient, the water, the pH adjuster and the compound (I) or its pharmaceutically acceptable salt are as described in any of the schemes of the present application.

[0079] The present application provides a preparation method of a solid preparation, which is prepared by capping, semi-pressing, freeze-drying, pressing, cap rolling and packaging of the above-mentioned solution preparation.

[0080] The present application provides a pharmaceutical composition, which is the product prepared by the above-mentioned preparation method of a solution preparation or the above-mentioned preparation method of a solution preparation.

[0081] In the present application, 0.5 mg / mL of the compound (I) or its pharmaceutically acceptable salt is 1 part.

[0082] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0083] The reagents and raw materials used in the present application are commercially available.

[0084] The positive progress effect of the present application is that the present application discloses a pharmaceutical composition, its preparation method and its application. The pharmaceutical composition has good stability and has good application prospect in the preparation of drugs for preventing and / or treating respiratory diseases. DETAILED DESCRIPTION

[0085] The present application is further illustrated by the following examples, but the present application is not limited in the scope of the examples.

[0086] The experimental methods in the following examples, unless otherwise specified, are carried out according to conventional methods and conditions, or according to the instructions of the commercial product.

[0087] Composition of the composition:

[0088] Preparation method:

[0089] The mannitol and arginine are weighed and placed in a preparation tank, and a certain amount of water for injection is added to dissolve until completely clear. The pH of the solution is adjusted to 2.5 with 5 mol / L hydrochloric acid aqueous solution, and stirred uniformly. The SP raw material is weighed and slowly added to the above solution, and continuously stirred until completely dissolved. The pH of the solution is adjusted to 3.5 with 1 mol / L sodium hydroxide aqueous solution, and stirred uniformly. The solution is diluted to 1 ml with water for injection, stirred uniformly, and the final solution pH is adjusted to 3.5. The prepared solution is filtered through a 0.22 μm PVDF microporous filter to obtain the final solution, which is filled, stoppered and crimped to obtain the final solution preparation.

[0090] For the composition that needs to be lyophilized, after the final solution is obtained according to the above preparation method, the final lyophilized powder injection preparation is obtained through the processes of filling, semi-pressing, freeze-drying, pressing, crimping and packaging.

[0091] The pharmaceutical preparations involved in the present application all control the microorganisms and endotoxins of the materials, instruments, packaging materials and the like used, and the prepared composition solution is precision filtered to obtain the solution to be filled after terminal sterilization filtration. The materials in the whole process do not undergo high-temperature sterilization, avoiding the risk of degradation impurities generated by high temperature and improving the stability of the drug. In addition, the moisture content in the final pharmaceutical preparation obtained after freeze-drying of the solution is very low (≤5%), and the preparation is stored at 2-8°C in the dark, which is beneficial to the stability of the preparation storage.

[0092] Examples 1-8 below are prepared by the similar method of the above preparation method.

[0093] Investigation of the types of excipients in the composition of Example 1

[0094] The composition in this group contains SP raw material (0.5 mg / ml), pH adjuster (hydrochloric acid or sodium hydroxide), and excipient. The excipient can be selected from one of maltose, trehalose, fructose, sucrose, lactose, glucose, sorbitol or no excipient is added, and the addition amount of the excipient is 5% (w / v, g / mL), and the final pH of the solution is 4.0. The composition solution in this group is subjected to different temperature, light and repeated freeze-thaw -20°C test investigation. The specific implementation and results are shown in the following table.

[0095] Table 1 Stability test results under different temperature and light conditions-5 days

[0096] Table 2 Stability test results under different temperature and light conditions-10 days

[0097] Table 3 Repeated freeze-thaw test results

[0098] Data results show that under light conditions, the stability of the solution is poor in the absence of trehalose, sucrose, sorbitol and excipients. The repeated freeze-thaw test proves that lactose performs best.

[0099] Example 2 The test of the present application involves a series of compositions comparing the stability of the composition under different conditions when adding polysorbate 20 (0.05%, W / V), polysorbate 80 (0.05%, W / V), poloxamer 188 (0.3%, W / V), span 20 (0.05%, W / V), polysorbate 80 + EDTA (0.05% / 0.005%, W / V). The raw materials of the series of compositions are SP raw materials (0.5 mg / ml), excipients (lactose 5%, W / V), pH adjuster (5 mol / L hydrochloric acid or 1 mol / L sodium hydroxide) and amino acid (arginine 2 mg / ml) or absence of cosolvents, and the final pH of the solution is 4.0. The specific implementation and results are shown in the table below.

[0100] Table 4 Information on the addition of cosolvents in the prescription

[0101] Note: Test group 4 precipitated during the solution preparation process, and was not further investigated.

[0102] Table 5 Results of cosolvent test-10 days

[0103] Table 6 Results of cosolvent test-40 days

[0104] Table 7 Results of cosolvent test-2 months

[0105] Table 8 Results of repeated freeze-thaw test of cosolvent

[0106] The test data show that, compared with test group 6 without the addition of a cosolvent, the compositions with the addition of a cosolvent have no obvious difference in appearance, related substances and content determination values. From the OD 340 The test group 3 with the addition of P188 has a slight advantage over other groups with the addition of a cosolvent in terms of the OD values. The repeated freezing and thawing test results show that, at the fourth cycle, the solutions of the test groups with the addition of polysorbate 20 and P188 are clear and transparent, while the solutions of the other groups are precipitated; at the fifth cycle, only the solution of the test group with the addition of P188 is clear and transparent. It is indicated that P188 has a potential cosolvent effect in the composition and helps to improve the stability of the solution.

[0107] In the investigation test related to the amino acid additive involved in the present application, a series of compositions with the addition of lysine, methionine, histidine, glycine, glutamine and proline respectively are compared in terms of the stability performance under different conditions. The series of compositions contain SP (0.5 mg / ml), excipient (lactose 5%, W / V), pH regulator (5 mol / L hydrochloric acid or 1 mol / L sodium hydroxide), arginine 2 mg / ml and one of the amino acids or the absence of amino acid, and the pH of the composition solution is 4.0. The specific implementation and results are shown in the following table.

[0108] Table 9 Information of the addition of amino acids in the composition

[0109] Table 10 Investigation results of the addition of amino acids test-10 days

[0110] Table 11 Investigation results of the addition of amino acids test-40 days

[0111] Table 12 Investigation results of the addition of amino acids test-2 months

[0112] The test data show that, after 10 days of illumination, the compositions in the amino acid addition test groups are all precipitated, and the composition solution without the addition of amino acid is clear and transparent, which indicates that the amino acid has a potential risk of precipitation under the illumination condition, while the composition solutions in the other groups do not appear to be precipitated, which indicates that the illumination is not conducive to the storage of the composition. Under the condition of 40°C, the data all show that the deamidation impurity (RRT 1.25) in the test group with the addition of Gln is obviously lower than that in the test group, which indicates that the addition of Gln can reduce the increasing speed of the deamidation impurity. There is no obvious advantage of the comparison between the other test groups and test group 7.

[0113] Example 4 The present application has an investigation involving the amount of amino acid arginine added to the composition, and the stability of each composition is investigated at different amounts. The amount of the gradient includes 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml. The composition group includes SP raw materials (0.5 mg / ml), excipients (mannitol 5.07%, W / V), pH adjuster (5 mol / L hydrochloric acid or 1 mol / L sodium hydroxide), arginine. The final pH of the solution is adjusted to 5.0. Different composition samples are placed under different conditions for stability investigation. The specific implementation and results are shown in the following table.

[0114] Table 13 Arginine addition amount investigation test results-7 days

[0115] Table 14 Arginine addition amount investigation test results-15 days

[0116] The test data shows that arginine has little effect on the impurities, related substances and appearance change of SP preparation. The main effect is on the determination value of OD 340 of SP, i.e. the aggregation of SP. When the addition amount is 1 mg / ml, the determination value of OD 340 is significantly higher than that of other groups, and the difference between other groups is not obvious. Therefore, the addition amount of arginine can be 2 mg / ml-5 mg / ml.

[0117] Example 5 The present application investigates the concentration of SP raw materials in the composition, and investigates the stability of each composition solution at different SP concentrations. The composition group includes SP raw materials, excipients (lactose 5%, W / V), amino acids (arginine 2 mg / ml), pH adjuster (5 mol / L hydrochloric acid or 1 mol / L sodium hydroxide), and the final pH of the solution is adjusted to 4.0. The concentration of the raw material includes: 0.25 mg / ml, 0.5 mg / ml, 0.75 mg / ml, 1.0 mg / ml, 1.25 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 3 mg / ml. The composition group takes pH value as the pressure condition, and is placed under different conditions for stability investigation to optimize the optimal SP concentration range. The specific implementation and results are shown in the following table.

[0118] Table 15 SP concentration investigation test results

[0119] The test phenomenon indicates that the composition has the risk of precipitation under the condition of low temperature, and the lower the temperature, the easier the precipitation under the same SP concentration. SP is a polypeptide protein drug, and according to the physicochemical properties of SP, the drug needs to be stored at low temperature. The lower the concentration under refrigeration, the lower the probability of precipitation. Therefore, the SP concentration needs to be adjusted according to the situation of different compositions. In addition, the composition with SP concentration of 0.5 mg / ml (the final solution pH of the composition in this group is 3.5) was placed at 4°C for 24 months, and no opalescence and precipitation phenomenon occurred, and the stability was good. Therefore, the composition as the final preparation is the best with SP concentration of 0.5 mg / ml and pH of 3.5 or less.

[0120] Example 6 The present application explores the pH of the composition solution, investigates the stability of each composition under different pH conditions, the composition contains SP raw material (0.5 mg / ml), excipient (mannitol 5.07%, W / V), amino acid (arginine 2 mg / ml) and pH regulator (5 mol / L hydrochloric acid or 1 mol / L sodium hydroxide), and the pH of the solution is investigated at 3.0, 3.5, 4.0, 4.5 and 5.0. Each composition is subjected to stability investigation under different conditions of light, 40°C, 25°C and 4°C. The specific implementation and results are shown in the following table.

[0121] Table 16 Test results of composition solution pH investigation-7 days

[0122] Table 17 Test results of composition solution pH investigation-20 days

[0123] Table 18 Test results of composition solution pH investigation-1 month

[0124] The test results show that during the sample placement process, under the light condition for 1 month, except for the composition with pH of 3.0, the rest all have precipitation. Under the conditions of 25°C and 4°C for 1 month, the sample groups with pH of 3.0 and 3.5 are clear and transparent, and the rest of the sample groups all have precipitation; among them, the related substance growth rate under 25°C is obviously higher than that under 4°C. High temperature of 40°C can accelerate the degradation of each sample group, the related substance increases obviously, and the content of active ingredient decreases obviously. 340 There is no obvious change in the measured value. Therefore, the pH between 3.0 and 3.5 under the conditions of light avoidance and 4°C is beneficial to the storage of the composition.

[0125] Example 7 The present application also relates to a comparative study of SP solution and lyophilized powder formulations, and the exploration of the composition of the composition. According to the different compositions in the table, the intermediate solution is prepared, and part of the solution of each group is taken out for sub-packaging and lyophilization. The remaining solution composition of each group (group I) and the composition after lyophilization (group P) are placed in different conditions at the same time for stability investigation. The specific implementation and results are shown in the table below.

[0126] Table 19 Composition of the composition

[0127] Table 20 Lyophilization process

[0128] Table 21 Comparison test results of solution formulation and lyophilized formulation-10 days

[0129] Table 22 Comparison test results of solution formulation and lyophilized formulation-1 month

[0130] Table 23 Comparison test results of solution formulation and lyophilized formulation-2 months

[0131] The test data shows that under the same conditions, the impurities at RRT 0.95 and RRT 1.25 in the composition of the lyophilized formulation increase more slowly, and the main peak purity of the lyophilized formulation is significantly higher than that of the solution formulation after being placed at 40°C for 2 months. It is suggested that the lyophilized formulation has higher stability. 340 The measured values do not show significant differences between groups when the samples are placed for 2 months.

[0132] Example 8 The present application also relates to a long-term test investigation of lactose, mannitol and glucose as composition components. The test samples in this example are placed at 2-8°C. Sampling and testing are carried out at 0 months, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months, respectively. The specific composition and implementation are shown in the table below.

[0133] Table 24 Composition prescription composition information Note: " / " means not detected, the same below.

[0134] Table 25 Long-term stability test results-glucose prescription

[0135] Table 26 Long-term stability test results-mannitol prescription

[0136] Table 27 Long-term stability test results-lactose prescription

[0137] Conclusion: The above table data shows that the three different compositions show obvious differences in long-term storage at 2-8℃, wherein the glucose formulation appears white precipitate after 3 months, the mannitol formulation appears white precipitate after 6 months, and the lactose formulation is still clear and transparent after 24 months, and the related substances are controllable, the content, pH and sterility are within the control range. Therefore, the lactose formulation has obvious advantages in developing into a final preparation.

[0138] According to the disclosure of the present application, although the composition and method of the present application are described according to the preferred embodiments, for those skilled in the art, the composition and / or method described herein and the steps or step order of the method can be changed without departing from the concept, spirit and scope of the present application.

[0139] The above-mentioned content in the examples is not a limitation of the present application, and those skilled in the art can make various modifications or modifications to the present application without departing from the concept of the present application, and these equivalent forms also belong to the protection scope of the present application.

Claims

1. A pharmaceutical composition A, characterized by, It comprises the following components by weight: 0.2-2 parts of compound (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant comprising 60-200 parts of an excipient selected from one or more of mannitol, maltose, fructose, lactose and glucose; the pharmaceutical composition having a pH of 1.5-5.0; 2. The pharmaceutical composition A according to claim 1, wherein It meets one or more of the following conditions; (1) The compound (I) or a pharmaceutically acceptable salt thereof is 0.5 parts, 1 part, 1.5 parts or 2 parts; (2) The compound (I) or a pharmaceutically acceptable salt thereof is 0.5-1.5 parts; (3) The pharmaceutical adjuvant further comprises an acid; the acid is selected from one or more of acetic acid, hydrochloric acid and phosphoric acid; preferably hydrochloric acid; (4) The salt is trifluoroacetate; (5) The pharmaceutical adjuvant further comprises inorganic salt and organic salt; the inorganic salt can be sodium chloride; the organic salt can be sodium trifluoroacetate; (6) The pH of the pharmaceutical composition is 3.0, 3.5, 4.0, 4.5 or 5.0; (7) The pH of the pharmaceutical composition is 3.0-3.5; (8) The excipient is selected from one or more of mannitol, maltose, lactose and glucose; preferably mannitol or lactose; (9) The content of the excipient is 100-180 parts; preferably 101.4 parts, 140 parts or 170 parts; further preferably 140 parts; (10) The pharmaceutical composition further comprises 0.5-7 parts of a co-solvent and / or 2-10 parts of an amino acid; the co-solvent is preferably 0.6-6 parts; for example, 1 part, 1.1 parts or 6 parts, also for example, 6 parts; the amino acid is 2 parts, 4 parts, 6 parts, 8 parts or 10 parts, for example, 2 parts; (11) The co-solvent is DPTA, EDTA, polysorbate 80, poloxamer 188, Span 20 or polysorbate 80+EDTA; preferably polysorbate 80, poloxamer 188, Span 20 or polysorbate 80+EDTA; further preferably poloxamer 188; (12) The amino acid is selected from one or more of lysine, methionine, histidine, glycine, glutamine, arginine and proline; preferably arginine or glutamine; further preferably arginine; (13) The osmolality ratio of the pharmaceutical composition is 0.9-1.3; and (14) The pharmaceutical composition further comprises water; the water can be water for injection.

3. The pharmaceutical composition A as set forth in claim 1 or 2, wherein The pharmaceutical composition comprises or consists of any of the following schemes, (1) The compound (I) or a pharmaceutically acceptable salt thereof, water and the excipient; the pH value; (2) The compound (I) or a pharmaceutically acceptable salt thereof, water, the excipient, the co-solvent and the amino acid; the pH value; And (3) The compound (I) or a pharmaceutically acceptable salt thereof, water, the excipient and the amino acid; the pH value; Preferably, (1) 1 part of compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of maltose, water, pH 4.0; (2) 1 part of compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of fructose, water, pH 4.0; (3) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, water, pH 4.0; (4) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of glucose, water, pH 4.0; (5) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of polysorbate 20, water, pH 4.0; (6) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of polysorbate 80, water, pH 4.0; (7) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of poloxamer 188, water, pH 4.0; (8) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of Span 20, water, pH 4.0; (9) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 1 part of polysorbate + 0.1 part of EDTA, water, pH 4.0; (10) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0; (11) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of lysine, water, pH 4.0; (12) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of methionine, water, pH 4.0; (13) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, + 4 parts of arginine, 6 parts of histidine, water, pH 4.0; (14) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of glycine, water, pH 4.0; (15) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of proline, water, pH 4.0; (16) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, 6 parts of glutamine, water, pH 4.0; (17) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 2 parts of arginine, water, pH 5.0; (18) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 5.0; (19) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 6 parts of arginine, water, pH 5.0; (20) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 8 parts of arginine, water, pH 5.0; (21) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 10 parts of arginine, water, pH 5.0; (22) 0.5 parts of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0; (23) 1.5 parts of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0; (24) 2 parts of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, 4 parts of arginine, water, pH 4.0; (25) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.0; (26) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.5; (27) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 4.0; (28) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 4.5; (29) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, 4 parts of arginine, water, pH 3.0; (30) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, water, pH 3.0; (31) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 170 parts of lactose, water, pH 3.0; (32) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, water, pH 3.0; (33) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of glucose, water, pH 3.0; Preferably, (1) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 100 parts of lactose, water, pH 4.0; (2) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.0; (3) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 101.4 parts of mannitol, 4 parts of arginine, water, pH 3.5; (4) 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, water, pH 3.0; More preferably, 1 part of Compound (I) or a pharmaceutically acceptable salt thereof, 140 parts of lactose, water, pH 3.

0.

4. The pharmaceutical composition A according to claim 1, wherein which satisfies one or both of the following conditions; (1) the pharmaceutical composition A can be a solution preparation for inhalation; and (2) the concentration of Compound (I) or a pharmaceutically acceptable salt thereof is (0.1-1) mg / mL; for example, 0.25 mg / mL, 0.5 mg / mL, 0.75 mg / mL or 1 mg / mL; preferably (0.25-0.75) mg / mL.

5. A pharmaceutical composition B, characterized by, which is obtained by freeze-drying the pharmaceutical composition A according to any one of claims 1 to 4.

6. A pharmaceutical composition C, characterized by, which comprises the following components in the amounts by weight: 0.2-2 parts of Compound (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant, the pharmaceutical composition C being dissolved in water, the pH of the pharmaceutical composition C being 1.5-5.0 when the concentration of Compound (I) or a pharmaceutically acceptable salt thereof is (0.1-1) mg / mL; The compound (I) or a pharmaceutically acceptable salt thereof and the excipient are as described in any one of claims 1 to 4. The pharmaceutical adjuvant is as described in any one of claims 1 to 4, except that it does not contain water.

7. The pharmaceutical composition C according to claim 6, wherein It satisfies one or more of the following conditions: (1) The pharmaceutical composition C is a dry powder preparation, for example a freeze-dried powder injection preparation; (2) The pharmaceutical composition C is an inhalation preparation.

8. A pharmaceutical composition D, characterized in that, It contains 0.2 to 2 parts of the compound (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant, which includes a pH adjuster, 60 to 200 parts of an excipient, and water; The compound (I) or a pharmaceutically acceptable salt thereof, the excipient, the pharmaceutical adjuvant, and the pH of the pharmaceutical composition are as described in any one of claims 1 to 4.

9. The pharmaceutical composition D according to claim 8, wherein The pH adjuster is an acid or an "acid and base"; the acid is selected from one or more of acetic acid, hydrochloric acid, and phosphoric acid; preferably, it is hydrochloric acid; the base is sodium hydroxide; the hydrochloric acid can be 5 mol / L hydrochloric acid; the sodium hydroxide can be 1 mol / L sodium hydroxide.

10. A method for preparing a solution formulation, characterized by, The compound (I) or a pharmaceutically acceptable salt thereof is dissolved in the presence of an excipient, water, and a pH adjuster to prepare a solution preparation; the excipient, the water, the pH adjuster, and the compound (I) or a pharmaceutically acceptable salt thereof are as described in any one of claims 1 to 4.

11. A method of preparing a solid formulation, characterized by, The solution preparation of claim 10 is subjected to capping, semi-pressing, freeze-drying, pressing, cap rolling, and packaging to prepare a solid preparation.

12. A pharmaceutical composition, characterized by, The pharmaceutical composition is a method for preparing the solution preparation of claim 10 or a product prepared by the method for preparing the solution preparation of claim 10. The pharmaceutical composition is a method for preparing the solution preparation of claim 10 or a product prepared by the method for preparing the solution preparation of claim 10.

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