INHALATION MEDICATIONS

Abstract

The invention relates to an inhalation pharmaceutical containing N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycinate sodium or its hydrate, a pH regulator, an osmotic pressure regulator, and optionally a surfactant. The inhalation pharmaceutical of the invention is capable of improving the stability of the drug. After being finely powdered by an inhalation powdering device, the inhaled droplets are capable of maintaining good homogeneity.

Description

Pharmaceutical compositions for inhalation Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a pharmaceutical composition of sivelestat sodium or a hydrate thereof for inhalation. Background Art

[0002] Sivelestat (N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine) is a neutrophil elastase inhibitor used to treat acute lung injury or acute respiratory distress syndrome in systemic inflammatory response syndrome. Its sodium salt tetrahydrate is commonly used. Sivelestat has the following structure:

[0003]

[0004] The commercially available sivelestat sodium is an injectable formulation containing excipients such as mannitol and sodium hydroxide. Currently, sivelestat sodium is only available as an injectable formulation, requiring long-term continuous administration, such as a 24-hour infusion. Furthermore, patients with acute lung injury are often severely ill, making medication difficult to administer. Therefore, a simpler administration method is urgently needed.

[0005] Document 1 discloses a dry powder inhaler of sivelestat sodium, which is inhaled through the mouth or nose. Antistatic agents such as levodopa, cyclodextrin, sorbitol, chitin, sodium starch glycolate, and surfactants such as poloxamer and dilauroylphosphatidylcholine are added to the inhaler. The inhaler is disclosed to rapidly provide a drug effect and effectively increase medical applications. However, if the sivelestat sodium lyophilized powder for injection is used directly for inhalation, the presence of mannitol can easily cause side effects such as airway constriction and asthma, and is generally not suitable for direct inhalation, especially for direct inhalation by the human body.

[0006] Document 2 discloses a sustained-release microsphere for treating lung diseases, wherein the average particle size is 20 to 40 μm. Drugs that can be used in the sustained-release microsphere include sivelestat sodium.

[0007] Reference 3 describes a lyophilized formulation of sivelestat sodium for injection. The inactive ingredients include a pH adjuster consisting of sodium dihydrogen phosphate and sodium hydroxide, and excipients such as lactose or mannitol. Similarly, the lyophilized powder for injection is not suitable for direct inhalation, particularly in humans.

[0008] The lyophilized preparation of sivelestat sodium for injection disclosed in Document 4 contains a pH regulator selected from trisodium phosphate and its hydrate, sodium hydroxide or potassium hydroxide.

[0009] Document 5 discloses a lyophilized formulation of sivelestat sodium for injection containing anhydrous sodium carbonate and sodium chloride as pH adjusters. According to the description in Document 4, the pH of the lyophilized formulation has been shown to increase during the process, and a large amount of decomposition products is produced. After the lyophilized product was stored at 60°C for two weeks, the residual sivelestat sodium content was only 91.4%.

[0010] Existing literature reports on sivelestat sodium preparations are either lyophilized powder for injection or dry powder inhalation, and therefore the existing technologies cannot meet clinical needs. For patients, there is an urgent need for a sivelestat sodium preparation that can avoid continuous injections, is easy to use, and can achieve the desired therapeutic effect.

[0011] Document 1: CN107913261 A

[0012] Reference 2: EP291304

[0013] Document 3: CN104107172 A

[0014] Document 4: CN1263736 C

[0015] Reference 5: US7638556 B2

[0016] Summary of the Invention

[0017] The solubility of sivelestat sodium in water is less than 0.4 mg / mL, which is insufficient for use in injections or inhalers. Furthermore, sivelestat sodium is susceptible to hydrolysis in aqueous solution, producing the following structural impurity (hereinafter referred to as "Impurity A").

[0018]

[0019] Research has found that the higher the pH of the aqueous solution, the better the solubility of sivelestat sodium in the aqueous solution. However, as the pH increases, the degree of hydrolysis of sivelestat sodium significantly increases. The relationship between the solubility, pH, and degree of hydrolysis of sivelestat sodium in lyophilized injection preparations has been described in the prior art. However, the prior art does not describe any sivelestat sodium pharmaceutical compositions for inhalation, particularly pharmaceutical compositions that can be prepared as inhalation solutions.

[0020] The pharmaceutical composition for inhalation does not contain mannitol, an excipient of the lyophilized preparation for injection. Increasing the weight ratio of sivelestat sodium or its hydrate in the pharmaceutical composition for inhalation will have a significant impact on the stability of the pharmaceutical composition for inhalation, such as an increase in the impurity content, poor uniformity of the droplets after atomization, and difficulty in controlling the droplet particle size.

[0021] To solve the above problems, the present invention provides a pharmaceutical composition for inhalation, comprising sivelestat sodium or its hydrate, a pH regulator and an osmotic pressure regulator.

[0022] The pH adjuster described in the present invention can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 2.5 mg / mL; and / or the pH adjuster can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 5 mg / mL; or the pH adjuster can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 7.5 mg / mL; or the pH adjuster can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 10.0 mg / mL; or the pH adjuster can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 15.0 mg / mL; or the pH adjuster can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 20.0 mg / mL.

[0023] The pH regulator of the present invention is a pharmaceutically acceptable acid, base and corresponding salt or a buffer system composed of any acid, base and salt. Non-limiting examples include: organic bases, organic acids and their corresponding salts, inorganic acids, inorganic bases and their corresponding salts. Inorganic acids and salts include: hydrochloric acid, phosphoric acid, phosphates, carbonates, and bicarbonates. Organic bases include: diethanolamine, triethanolamine, and tromethamine; organic acids include: acetic acid, lactic acid, citric acid, fumaric acid, tartaric acid and their corresponding salts; commonly used carbonates include: sodium carbonate, calcium carbonate, and ammonium carbonate; commonly used bicarbonates include: sodium bicarbonate and potassium bicarbonate; inorganic bases include: alkali metal hydroxides and alkaline earth metal hydroxides; phosphates include: sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate and their hydrates; commonly used alkali metal hydroxides include: sodium hydroxide and potassium hydroxide.

[0024] The pH adjuster of the present invention can adjust the pH value of the inhalation pharmaceutical composition to a range of 3.0-10.0; preferably, the pH value is in the range of 4.0-9.5; or the pH value is in the range of 5.0-9.0; or the pH value is in the range of 5.5-8.5. The pH adjuster of the present invention enables the inhalation pharmaceutical composition containing sivelestat sodium to exhibit excellent solubility properties.

[0025] The mass volume ratio (w / v, mg / mL) of the pH regulator in the solution of the present invention is in the range of 0.1-30.0 mg / mL. As a preferred embodiment, the mass volume ratio of the pH regulator of the present invention is in the range of 0.1-25.0 mg / mL. As a more preferred embodiment, the mass volume ratio of the pH regulator of the present invention is in the range of 0.5-20.0 mg / mL.

[0026] The osmotic pressure regulator of the inhalation pharmaceutical composition of the present invention includes, but is not limited to, sodium chloride, potassium chloride, glucose, calcium chloride, magnesium chloride, sorbitol, xylitol, and the like. As a preferred embodiment of the present invention, the osmotic pressure regulator is selected from sodium chloride and glucose. The osmotic pressure regulator of the present invention allows the inhalation pharmaceutical composition to have an osmotic pressure concentration of 250-450 mOsm / kg; or the osmotic pressure regulator allows the inhalation pharmaceutical composition to have an osmotic pressure concentration of 250-400 mOsm / kg; or the osmotic pressure regulator allows the inhalation pharmaceutical composition to have an osmotic pressure concentration of 250-350 mOsm / kg. Within this osmotic pressure range, the inhalation pharmaceutical composition of the present invention exhibits good stability.

[0027] The pharmaceutical composition for inhalation of the present invention may optionally contain a surfactant. The surfactant content is 0.01-10.0 mg / mL; preferably, the surfactant content is 0.01-5.0 mg / mL; and more preferably, the surfactant content is 0.01-3.5 mg / mL.

[0028] The surfactant described in the present invention is neither a nonionic surfactant nor an ionic surfactant. Non-limiting examples of optional surfactants include ethylene glycol monostearate, ethylene glycol monooleate, sodium dodecylbenzenesulfonate, sodium lauryl sulfate, glyceryl trioleate, sorbitan monolaurate, poloxamer, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polyoxyethylene castor oil. As a preferred embodiment of the present invention, the surfactant is optionally selected from sodium lauryl sulfate and polysorbate 80.

[0029] In another aspect, the present invention provides a pharmaceutical composition for inhalation, comprising sivelestat sodium or a hydrate thereof, a pH regulator, and an osmotic pressure regulator, wherein the pH regulator can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 2.5 mg / mL, and the osmotic pressure concentration of the pharmaceutical composition for inhalation is 250-400 mOsm / kg. The pharmaceutical composition for inhalation of the present invention further has at least one of the following characteristics:

[0030] ① The pH value of the pharmaceutical composition for inhalation is 3.0-10.0;

[0031] ② The total impurity content of the pharmaceutical composition for inhalation does not exceed 2.0%;

[0032] ③Optionally contains a surfactant.

[0033] On the other hand, the present invention provides a pharmaceutical composition for inhalation, which contains sivelestat sodium or its hydrate, a pH regulator, an osmotic pressure regulator and a surfactant. The pH regulator can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 2.5 mg / mL, the molar osmotic pressure concentration of the pharmaceutical composition for inhalation is 250-400 mOsm / kg, and the content of the surfactant is 0.01-10.0 mg / mL.

[0034] The inhalation pharmaceutical composition of the present invention can be administered once, twice, three times or more daily. As a preferred embodiment, each administration does not exceed 500 mg, and the total daily dosage does not exceed 2000 mg / day.

[0035] The inhalation pharmaceutical composition of the present invention is prepared by dissolving the inhalation pharmaceutical composition in a carrier and atomizing it through an existing conventional inhalation device for inhalation. Therefore, the present invention also provides a drug kit comprising a pharmaceutical composition for inhalation of sivelestat sodium or its hydrate and a dose of water, wherein the dose is 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, or more. The inhalation pharmaceutical composition of the present invention is mixed and dissolved with water, such as distilled water or water for injection, before use, and then atomized through a drug delivery device for inhalation administration. The drug delivery device can be any nebulizer capable of delivering the drug to the site of disease.

[0036] On the other hand, the present invention provides a pharmaceutical composition for inhalation that can be reconstituted within a predetermined time, and the reconstitution time is less than 60s, or less than 50s, or less than 40s, or less than 35s, or less than 30s, or less than 25s, or less than 20s. The composition contains sivelestat sodium or its hydrate, a pH regulator, an osmotic pressure regulator and optionally a surfactant. The pH regulator can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 2.5 mg / mL, the molar osmotic pressure concentration is 250-400mOsm / kg, and the content of the surfactant is 0.01-10.0 mg / mL. As a preferred embodiment of the present invention, the pharmaceutical composition is reconstituted in less than 40s; as a preferred embodiment of the present invention, the pharmaceutical composition is reconstituted in less than 30s.

[0037] Another aspect of the present invention provides an inhalation pharmaceutical composition for the treatment of lung diseases, which contains sivelestat sodium or its hydrate, a pH regulator, an osmotic pressure regulator and optionally a surfactant. The pharmaceutical composition is mixed with a carrier, such as water, physiological saline, etc., and then atomized through an inhalation dispenser and inhaled. The mass median aerodynamic diameter (MMAD) of the inhaled atomized particles (or droplets) is 0.1 to 15.0 μm; as a preferred embodiment of the present invention, the mass median aerodynamic diameter (or particle size) of the inhaled atomized particles is 0.1 to 10.0 μm; as a further preferred embodiment of the present invention, the mass median aerodynamic diameter of the inhaled atomized particles is 0.5 to 7.0 μm; as a further preferred embodiment of the present invention, the mass median aerodynamic diameter of the inhaled atomized particles is 0.5 to 5.0 μm. As a further preferred embodiment of the present invention, the proportion of the inhaled aerosolized particles with a median aerodynamic diameter of less than 5.0 μm (or the fine particle fraction) is not less than 50%; in a further preferred embodiment, the proportion of the inhaled aerosolized particles with a median aerodynamic diameter of less than 5.0 μm (or the fine particle fraction) is not less than 60%; in a further preferred embodiment, the proportion of the inhaled aerosolized particles with a median aerodynamic diameter of less than 5.0 μm (or the fine particle fraction) is not less than 70%.

[0038] In another aspect, the present invention provides a pharmaceutical composition for inhalation, comprising sivelestat sodium or a hydrate thereof, a pH regulator, an osmotic pressure regulator, and a surfactant, wherein the pH regulator can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 5 mg / mL, and the molar osmotic pressure concentration of the pharmaceutical composition for inhalation is 250-400 mOsm / kg. The pharmaceutical composition for inhalation of the present invention further has at least one of the following characteristics:

[0039] ① The pH value of the inhalation pharmaceutical composition is 5.0-9.0;

[0040] ② The total impurity content of the pharmaceutical composition for inhalation does not exceed 1.5%;

[0041] ③ After the pharmaceutical composition for inhalation is atomized by a nebulizer, the particle size is 0.5 to 7.0 μm;

[0042] ④ The re-dissolution time of the pharmaceutical composition for inhalation in the solution is not more than 30s.

[0043] In another aspect, the present invention provides a method for treating a disease and use of an inhalation pharmaceutical composition in preparing a medicament for treating the disease, wherein the disease is caused by elastase and is a lung disease, including acute lung injury (ALL) or acute respiratory distress syndrome (ARDS). The method or use comprises administering a dose of the inhalation pharmaceutical composition of sivelestat sodium or its hydrate, wherein the dose does not exceed 500 mg per dose, and the total daily dose does not exceed 2000 mg / day.

[0044] In another aspect, the present invention provides a method for preparing a pharmaceutical composition for inhalation, comprising dissolving a pH regulator, an osmotic pressure regulator, sivelestat sodium and / or a surfactant in water, filling the water and then freeze-drying the mixture.

[0045] The present invention has found through experiments that surfactants are not conducive to the stability of sivelestat sodium, and the addition of surfactants will lead to an increase in the impurity content of sivelestat sodium or its hydrate in the pharmaceutical composition of the present invention. The present invention obtains a pharmaceutical composition with good stability by controlling the content of each component in the pharmaceutical composition, such as a total impurity content of no more than 2.0%, or no more than 1.5%; and the pharmaceutical composition can be redissolved and inhaled within a predetermined time (e.g., less than 30 seconds), and maintains good uniformity in the particle size range after atomization.

[0046] In patients with acute lung injury or acute respiratory distress syndrome, when inhaled sivelestat sodium or its hydrate, the particle size after atomization needs to be within a specific range (0.5-7.0 μm) to enable the drug to be deposited in the alveoli. If the particle size is too small, it is easily exhaled and loses its therapeutic effect; when the particle size is too large, the atomized particles are mainly deposited in the upper respiratory tract, affecting the absorption site of the drug. Inappropriate particle size will directly affect the absorption and therapeutic effect of the drug and increase potential side effects. Therefore, the inhalation pharmaceutical composition of the present invention not only has good stability, but also has a particle size uniformly distributed in the range of 0.5-7.0 μm after atomization by a nebulizer, which can achieve good therapeutic effects.

[0047] Explanation of terms

[0048] The "hydrate" mentioned in the present invention refers to monohydrate, dihydrate, trihydrate, tetrahydrate, etc. Preferably, sivelestat sodium exists in the form of tetrahydrate. DETAILED DESCRIPTION

[0049] The embodiments of the present invention are intended to illustrate the technical solutions of the present invention in a non-limiting manner and should not be construed as limiting the present invention. The drugs used in the present invention can be prepared by methods reported in existing literature. Unless otherwise specified, all reagents used are commercially available. The present invention uses a high-performance liquid chromatograph to determine the impurity content of the composition, a pH meter to determine the pH value of the solution, and an osmometer to measure the osmotic pressure of the solution. The term "MMAD" in the present invention refers to the mass median aerodynamic diameter.

[0050] Reference Example 1

[0051] Referring to the method in patent CN104107172, a 40 mg / ml mannitol aqueous solution was prepared, 20 mg / ml sivelestat sodium tetrahydrate was added for dispersion, the raw material drug was dissolved in sodium dihydrogen phosphate-sodium hydroxide buffer solution, the pH of the drug solution was 7.6, 5 mL of the drug solution was filled, and the product was lyophilized.

[0052] The freeze-dried product was placed at a high temperature of 60°C to investigate its stability. The pH of the sample after reconstitution at day 0 was 7.6, with the main degradation impurity A content of 0.7% and the total impurity content of 0.8%. The sample after reconstitution at a high temperature of 60°C for 10 days had a pH of 7.6, impurity A content of 1.6%, and total impurity content of 1.8%.

[0053] Reference Example 2

[0054] Referring to the method disclosed in patent CN1263736C, a 40 mg / ml mannitol aqueous solution was prepared, 20 mg / ml sivelestat sodium tetrahydrate was dispersed, the raw material drug was dissolved in trisodium phosphate-sodium hydroxide buffer, the drug solution pH was 7.8, 5 mL of the drug solution was filled, and lyophilized.

[0055] The freeze-dried product was placed at a high temperature of 60°C to investigate its stability. The pH of the sample after reconstitution at day 0 was 7.8, with the main degradation impurity A content of 1.0% and the total impurity content of 1.3%. The sample after reconstitution at a high temperature of 60°C for 10 days had a pH of 7.9, with impurity A content of 1.5% and total impurity content of 1.7%.

[0056] Example 1

[0057] Prescription preparation process: Sodium chloride and sodium citrate are added to the aqueous solution in sequence with concentrations of 6 mg / ml and 6 mg / ml respectively, sodium hydroxide 0.17 mg / ml, and 5 mg / ml of sivelestat sodium tetrahydrate is added. Stir to dissolve and clarify, the pH of the drug solution is 7.2, fill 5 mL of the drug solution, and freeze-dry.

[0058] The freeze-dried product was placed at 60°C to investigate its stability. After reconstitution, the pH of the sample at day 0 was 7.2, the main degradation impurity A content was 0.20%, and the total impurities were 0.37%. After reconstitution at high temperature of 60°C for 10 days, the pH of the sample was 7.3, the impurity A content was 0.31%, and the total impurities content was 0.52%.

[0059] Example 2

[0060] The drug solution was prepared in the same manner as in Example 1, and 0.2 mg / ml polysorbate 80 was added, the solution was filled into 5 mL bottles, and lyophilized.

[0061] The freeze-dried product was placed at 60°C to investigate its stability. The pH of the sample after reconstitution at day 0 was 7.3, the content of the main degradation impurity A was 0.22%, and the content of total impurities was 0.38%. The pH of the sample after reconstitution at high temperature of 60°C for 10 days was 7.2, the content of impurity A was 0.72%, and the content of total impurities was 0.98%.

[0062] Example 3

[0063] Preparation process for inhalation: Sodium chloride and sodium citrate are added to the aqueous solution in sequence with concentrations of 6 mg / ml and 6 mg / ml, respectively, and sodium hydroxide is 0.34 mg / ml. Add 7.5 mg / ml of sivelestat sodium tetrahydrate, stir to dissolve and clarify, the pH of the drug solution is 7.4, fill 5 mL of the solution, and lyophilize.

[0064] Example 4

[0065] 0.2 mg / ml polysorbate 80 was added to the liquid of Example 3, and the mixture was filled and freeze-dried.

[0066] The stability results of Examples 1 to 4 and Reference Example 1 are listed in the following table:

[0067]

[0068] Note: Osmol / kg. Lyophilized samples are reconstituted with water to the desired concentration. Reconstitution time refers to the time required to reconstitute the lyophilized preparation in 5 mL of aqueous solution.

[0069] The pharmaceutical composition for inhalation of the present invention can significantly improve drug stability, reduce the content of impurity A and the content of total impurities, and maintain stable pH values ​​at 0 and 10 days. The formulation containing polysorbate 80 can further shorten the reconstitution time.

[0070] Example 5

[0071] Preparation process for inhalation: Prepare 6 mg / ml sodium chloride aqueous solution, 0.5 mg / ml tromethamine, add 5 mg / ml of sivelestat sodium tetrahydrate, stir to dissolve and clarify, the drug solution pH is 7.2, fill 5 mL of the solution, and lyophilize.

[0072] The freeze-dried product was placed at 60°C to investigate its stability. After reconstitution, the pH of the sample at day 0 was 7.2, the main degradation impurity A was 0.13%, and the total impurity content was 0.25%. After reconstitution at high temperature of 60°C for 10 days, the pH of the sample was 7.2, the impurity A was 0.28%, and the total impurity content was 0.49%.

[0073] In the same preparation process, when the concentration of tromethamine was 0.242 mg / ml, the drug could not be completely dissolved and clarified.

[0074] Example 6

[0075] Preparation process for inhalation: Prepare 6 mg / ml sodium chloride aqueous solution, 10 mg / ml sodium carbonate, add 20 mg / ml of sivelestat sodium tetrahydrate, stir to dissolve and clarify, the drug solution pH is 9.0, fill 5 mL of the solution, and lyophilize.

[0076] The freeze-dried product was placed at 60°C to investigate its stability. After reconstitution, the pH of the sample at day 0 was 9.1, the content of the main degradation impurity A was 0.44%, and the content of total impurities was 0.57%. After reconstitution at high temperature of 60°C for 10 days, the pH of the sample was 9.5, the content of impurity A was 1.03%, and the content of total impurities was 1.12%.

[0077] Example 7

[0078] Preparation process for inhalation: prepare 10 mg / ml sodium bicarbonate aqueous solution, add 20 mg / ml of sivelestat sodium tetrahydrate, stir to dissolve and clarify, the drug solution pH is 8.1, fill, and freeze-dry.

[0079] Example 8

[0080] Preparation process for inhalation: Add 4 mg / ml sodium chloride and 0.2 mg / ml polysorbate 80 to the Chinese medicine solution in Example 7, stir to dissolve and clarify, the drug solution pH is 8.1, fill, and freeze-dry.

[0081] Example 9

[0082] Preparation process for inhalation: prepare 6 mg / ml sodium bicarbonate aqueous solution, add 20 mg / ml of sivelestat sodium tetrahydrate, stir to dissolve and clarify, the drug solution pH is 7.8, fill, and freeze-dry.

[0083] Example 10

[0084] Preparation process for inhalation: Add 4 mg / ml sodium chloride and 0.2 mg / ml polysorbate 80 to the Chinese medicine solution in Example 9, stir to dissolve and clarify, the drug solution has a pH of 7.8, fill, and lyophilize.

[0085] Example 11

[0086] Preparation process for inhalation: Add 8 mg / ml sodium chloride and 0.2 mg / ml polysorbate 80 to the Chinese medicine solution in Example 9, stir to dissolve and clarify, the drug solution pH is 7.8, fill, and freeze-dry.

[0087] Example 12

[0088] Preparation process for inhalation: Prepare 4 mg / ml sodium bicarbonate aqueous solution, add 10 mg / ml of sivelestat sodium tetrahydrate, stir to dissolve and clarify, the drug solution pH is 7.8, fill 5 mL of the solution, and lyophilize.

[0089] Example 13

[0090] Preparation process for inhalation: Add 4 mg / ml sodium chloride and 0.2 mg / ml polysorbate 80 to the Chinese medicine solution in Example 12, stir to dissolve and clarify, the drug solution pH is 7.8, fill 5 mL of the drug solution, and lyophilize.

[0091] Example 14

[0092] Preparation process for inhalation: Add 8 mg / ml sodium chloride and 0.2 mg / ml polysorbate 80 to the Chinese medicine solution in Example 12, stir to dissolve and clarify, the drug solution pH is 7.8, fill 5 mL of the drug solution, and lyophilize.

[0093] The stability results of Examples 7 to 14 are listed in the following table:

[0094]

[0095] Example 15

[0096] Preparation process for inhalation: Prepare 0.4 mg / ml sodium hydroxide aqueous solution, add 9 mg / ml sodium chloride, add 10 mg / ml of sivelestat sodium tetrahydrate, stir to dissolve and clarify, the drug solution pH is 7.3, fill 5 mL of the solution, and lyophilize.

[0097] Example 16

[0098] Preparation process for inhalation: Add 0.2 mg / ml polysorbate 80 to the Chinese medicine solution in Example 15, stir to dissolve and clarify, the pH of the drug solution is 7.3, fill 5 mL of the drug solution, and lyophilize.

[0099] Example 17

[0100] Preparation process for inhalation: Prepare 1.1 mg / ml sodium hydroxide aqueous solution, add 9 mg / ml sodium chloride, 0.2 mg / ml polysorbate 80, and 20 mg / ml sivelestat sodium tetrahydrate. Stir to dissolve and clarify. The pH of the drug solution is 7.8. Fill 5 mL of the drug solution and lyophilize.

[0101] The stability results of Examples 15 to 17 are listed in the following table:

[0102]

[0103] The ratio of raw materials and excipients in the prescription was adjusted, 4 ml was filled, and freeze-dried to prepare the prescriptions of Examples 18 to 20; 2.5 ml was filled, and freeze-dried to obtain the prescriptions of Examples 21-22, as shown below.

[0104]

[0105]

[0106] Example 23

[0107] Atomization characteristics experiment

[0108] The particle size determination method of the present invention adopts the drug solution after reconstitution of the freeze-dried samples of Reference Example 1, Example 9, Example 10, and Example 11 with water, and atomizes them with a PARI eflow model nebulizer. The mass median aerodynamic diameter (MMAD) is measured using a new generation pharmaceutical cascade impactor (NGI) at a flow rate of 15 L / min. The results show that the MMAD results are 8.047 μm, 3.921 μm, 2.005 μm, and 2.056 μm, respectively, indicating that the pharmaceutical composition for inhalation in the embodiment of the present invention can obtain a particle size that meets pharmaceutical requirements, and when the composition contains polysorbate 80, the particle size distribution after atomization is more uniform.

[0109] Examples 18-22 were reconstituted in 4 ml of water. In addition to MMAD, the aerosol characteristics were measured for two parameters: total drug delivery percentage and fine particle fraction. The total drug delivery percentage refers to the proportion of the drug delivered through the nozzle after aerosolization into the nebulizer cup; the fine particle fraction refers to the proportion of delivered drug particles with a diameter less than 5 μm.

[0110]

[0111] Animal experiments

[0112] A comparison of lung exposure in SD rats was conducted after a single injection of 5 mg / kg and an inhalation of 5 mg / kg using the formulation in Example 19. Compared to the marketed injection, inhalation increased lung exposure by 20.5 times, significantly prolonging the duration of effective lung concentration.

[0113]

[0114] The inhalation pharmaceutical composition of the present invention exhibits excellent stability, and the particles maintain uniformity after atomization by an atomizer. It can be used for inhalation therapy of patients with lung diseases, avoiding the need for 24-hour continuous infusion and significantly improving medication convenience. Animal experiments have shown that the inhalation composition of the present invention significantly increases drug concentration and AUC values ​​in the lungs compared to injection.

Claims

1. A pharmaceutical composition for inhalation, comprising sivelestat sodium or its hydrate, a pH regulator and an osmotic pressure regulator, wherein the pH regulator can make the solubility of sivelestat sodium in the pharmaceutical composition not less than 2.5 mg / mL, and the molar osmotic pressure concentration of the pharmaceutical composition for inhalation is 250-450 mOsm / kg.

2. The pharmaceutical composition for inhalation according to claim 1, further comprising at least one of the following features: ① The pH value of the pharmaceutical composition for inhalation is 3.0-10.0; ② After the inhalation pharmaceutical composition is atomized by an atomizing device, the particle size is 0.1 to 10.0 μm; ③Optionally contains a surfactant.

3. The pharmaceutical composition for inhalation according to claim 1, wherein the pH regulator can make the solubility of sivelestat sodium or its hydrate in the pharmaceutical composition not less than 5 mg / mL.

4. The pharmaceutical composition for inhalation according to claim 1, wherein the pH adjuster makes the pH value of the aqueous solution of the pharmaceutical composition for inhalation be 5.0-9.0 and / or the pH value be 5.5-8.

5.

5. The pharmaceutical composition for inhalation according to claim 1, wherein the molar osmotic pressure concentration of the pharmaceutical composition for inhalation is 250-400 mOsm / kg, preferably the molar osmotic pressure concentration is 250-350 mOsm / kg.

6. The pharmaceutical composition for inhalation according to claim 1, wherein the particle size of the pharmaceutical composition for inhalation is 0.5 to 7.0 μm after being atomized by an atomizer.

7. The pharmaceutical composition for inhalation according to claim 1, which is prepared by dissolving the composition in a carrier and atomizing the composition through an atomizing device for inhalation administration. The pharmaceutical composition for inhalation according to claim 1 , wherein the carrier is water.

9. The pharmaceutical composition for inhalation according to claim 1, wherein the content of the pH regulator is 0.1-30.0 mg / mL; preferably, the content is 0.1-25.0 mg / mL.

10. The pharmaceutical composition for inhalation according to claim 1, wherein the content of the surfactant is 0.01-10.0 mg / mL; preferably 0.01-5.0 mg / mL.

11. A pharmaceutical composition for inhalation, comprising sivelestat sodium or its hydrate, a pH regulator, and an osmotic pressure regulator, wherein the pH regulator can make the solubility of sivelestat sodium or its hydrate in the pharmaceutical composition not less than 5 mg / mL, the molar osmotic pressure concentration of the pharmaceutical composition for inhalation is 250-400 mOsm / kg, and the pharmaceutical composition for inhalation has at least one of the following characteristics: ① The pH value of the pharmaceutical composition for inhalation is 5.0-9.0; ② After the inhalation pharmaceutical composition is atomized by an atomizer, the particle size is 0.5 to 7.0 μm; ③ Optionally contain a surfactant.

12. The pharmaceutical composition for inhalation according to claim 1 or 11, wherein the osmotic pressure regulator is selected from sodium chloride and glucose.

13. The pharmaceutical composition for inhalation according to claim 1 or 11, wherein the surfactant is selected from sodium lauryl sulfate and Tween 80.

14. A pharmaceutical composition for inhalation, comprising sivelestat sodium or its hydrate, a pH regulator, an osmotic pressure regulator and a surfactant, wherein the pH regulator can make the solubility of sivelestat sodium or its hydrate in the pharmaceutical composition not less than 5 mg / mL, the molar osmotic pressure concentration of the pharmaceutical composition for inhalation is 250-350 mOsm / L, and the pH value of the pharmaceutical composition is 5.0-9.

0.

15. A pharmaceutical composition for inhalation, comprising sivelestat sodium or its hydrate, a pH regulator, an osmotic pressure regulator and a surfactant, in, The content of pH regulator is 0.1-25.0 mg / mL, the content of surfactant is 0.01-5.0 mg / mL, the molar osmotic pressure concentration is 250-350 mOsm / L, and the pH value is 5.0-9.

0.

16. The pharmaceutical composition for inhalation according to claim 14 or 15, wherein the osmotic pressure regulator is sodium chloride and the surfactant is polysorbate 80.

17. Use of a pharmaceutical composition for inhalation in preparing a drug for treating a disease, wherein the drug composition for inhalation is mixed with water and then atomized through an inhalation dosing device and then inhaled, wherein the disease is a lung disease.