Slow-release sivelestat composition and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and particularly provides a sustained-release sivelestat pharmaceutical composition and a preparation method thereof, and the pharmaceutical composition comprises sivelestat and phospholipid. The sivelestat which is insoluble in water is used as an active component, the phospholipid is used as a stabilizer, and the particles are excellent in aerodynamic performance, good in stability and simple in preparation process. After being inhaled, the medicine stays in the lung for a long time, and has a very good slow-release effect and a very good industrialization prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a cevelexat composition and its preparation method. Background Technology

[0002] Sivelestat sodium inhibits neutrophil elastase activity and is an effective drug for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) accompanied by systemic inflammatory response syndrome. Clinical studies have shown that sivelestat sodium can effectively reduce lung injury scores, improve lung function, shorten mechanical ventilation time and intensive care unit hospital stay in ARDS patients, and reduce mortality.

[0004] Current research on cefelestat sodium primarily focuses on systemic administration. However, systemic administration results in low local drug concentrations, necessitating higher doses and increasing toxicity and side effects, while also increasing the financial burden on patients. Because the lungs have a rich blood supply and a large absorption area, inhaled cefelestat sodium can rapidly enter the bloodstream, achieving an onset of action similar to intravenous administration. Furthermore, inhalation allows the drug to reach deep into the terminal bronchioles and alveoli, resulting in fewer side effects compared to systemic administration.

[0005] Cevelexostat sodium aqueous solution has poor stability and is prone to hydrolysis; therefore, it is formulated as a powder for injection. The production of powder for injection requires a long freeze-drying process, which results in time-consuming and costly production. Furthermore, powder for injection lacks a sustained-release effect and requires continuous intravenous administration over 24 hours, leading to poor patient compliance.

[0006] CN117982414A, CN114681435A, CN107913261A, and CN104107172A all disclose inhaled formulations of cevelexat sodium, all using cevelexat sodium as a raw material, and none of them contain sustained-release materials. They are easily metabolized and eliminated, failing to achieve a long-term sustained-release effect in the lungs. To achieve the same efficacy as continuous intravenous injection, theoretically continuous inhalation is required, which would lead to inconvenience in clinical use.

[0007] CN116115589A discloses an inhaled cevelexostat sodium pharmaceutical composition and its preparation method. This composition uses distearylphosphatidylethanolamine-polyethylene glycol, which has a sustained-release function, as a key excipient, solving the problems of low drug solubility and poor stability. However, it does not mention any sustained-release efficacy. Furthermore, the composition uses a large amount of sustained-release material, 10 to 40 times the amount of the drug. The preparation process is relatively complex, requiring separate dissolution, mixing, followed by vacuum evaporation to form a drug-containing lipid film, reconstitution with water, addition of the excipient mannitol, and finally freeze-drying. Summary of the Invention

[0008] In view of the above-mentioned technological status, this invention aims to provide a cevelexta sustained-release granule, using cevelexta, which is poorly soluble in water, as the active ingredient and phospholipids as a stabilizer. The granules exhibit excellent aerodynamic performance, good stability, and a simple preparation process. After inhalation, the drug has a long residence time in the lungs, demonstrating excellent sustained-release effects and promising industrialization prospects.

[0009] Unlike cevimestat sodium, cevimestat has low solubility in water, good stability, and a slow dissolution rate. Coating the particle surface with a layer of phospholipids not only further delays drug release but also improves biocompatibility. After nebulization, the particles have a long residence time in the lungs and are released slowly.

[0010] The present invention provides a sustained-release pharmaceutical composition containing cevelexatrol, the pharmaceutical composition comprising cevelexatrol and phospholipids.

[0011] In this invention, as one embodiment, the cevelex and phospholipids form a solid dispersion.

[0012] In this invention, as one embodiment, the mass ratio of cevelexatol to phospholipid is 1:1 to 1:6, preferably 1:3 to 1:5.

[0013] As an example, the ratios can be 1:1, 1:2, 1:3, 1:4, 1:5, or 1:6.

[0014] In this invention, as one embodiment, the pharmaceutical composition comprises cevelexatil, phospholipids, and an aqueous solution, wherein the aqueous solution is free of organic solvents. The aqueous solution is selected from water for injection, physiological saline, or glucose solution.

[0015] In this invention, as one embodiment, the composition containing the above-mentioned aqueous solution contains, by weight of composition, 0.05-5% cevelexatol, preferably 0.1-3.0%; and 0.15-1.5% phospholipids, preferably 0.3-1.0%.

[0016] As an example, the percentage of cefotaxime can be 0.05%, 0.07%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%. 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.1%, 4.3%, 4.4%, 4.5%, 4.7%, 4.8%, 4.9%, or 5.0%; the proportion of phospholipids can be 0.15%, 0.17%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.25%, 0.26%, 0.27%, 0.28%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%.

[0017] In this invention, as one embodiment, the pharmaceutical composition includes cevelex, phospholipids, and a desiccant, wherein it does not contain organic solvents.

[0018] In this invention, as one embodiment, the composition containing the desiccant contains 5-40% sevilostat, preferably 10-30%, based on the amount of the composition.

[0019] As an example, the percentages could be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40%.

[0020] In this invention, as one embodiment, the composition contains 2.5-50% phospholipids by weight, preferably 5-42%, more preferably 10-37.5%, and even more preferably 15-35%.

[0021] As an example, the percentage could be 2.5%, 2.6%, 2.7%, 2.9%, 3%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

[0022] In this invention, as one embodiment, the desiccant accounts for 25-75%, preferably 40-60%.

[0023] As an example, the percentages could be 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, or 75%.

[0024] In this invention, as one embodiment, the phospholipid is selected from one, two or more combinations of egg yolk lecithin, soybean lecithin, and synthetic phospholipids, preferably egg yolk lecithin.

[0025] In this invention, as one embodiment, the desiccant is one, two, or a combination of two or more of the following: fructose, xylitol, maltitol, erythritol, povidone, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, poloxamer, lactose, glucose, sucrose, trehalose, mannitol, and sorbitol; preferably, one, two, or a combination of two or more of the following: lactose, glucose, sucrose, trehalose, mannitol, and sorbitol; more preferably, mannitol.

[0026] In this invention, as one embodiment, the pharmaceutical composition comprises:

[0027] composition Prescription 1 (by weight) Sivirex 1.0 Egg yolk lecithin 0.5 and Mannitol 1.0

[0028] composition Prescription 2 (by weight) Sivirex 1.0 Egg yolk lecithin 1.0 and Mannitol 1.0

[0029] composition Prescription 3 (parts by weight) Sivirex 1.0 Egg yolk lecithin 2.0 and Mannitol 1.0

[0030] composition Prescription 4 (parts by weight) Sivirex 1.0 Egg yolk lecithin 3.0 and Mannitol 2.0

[0031] composition Prescription 5 (parts by weight) Sivirex 1.0 Egg yolk lecithin 3.0 and Mannitol 4.0

[0032] composition Prescription 6 (by weight) Sivirex 1.0 Egg yolk lecithin 3.0 and Mannitol 6.0

[0033] composition Prescription 7 (parts by weight) Sivirex 1.0 Egg yolk lecithin 5.0 and Mannitol 6.0

[0034] composition Prescription 8 (by weight) Sivirex 1.0 Egg yolk lecithin 5.0 and Mannitol 18.0

[0035] composition Prescription 9 (by weight) Sivirex 1.0 Egg yolk lecithin 0.25 and Mannitol 8.75

[0036]

[0037]

[0038] In this invention, as one embodiment, the dosage form of the pharmaceutical composition is a lyophilized powder injection, a powder inhaler (dry powder inhaler), an aerosol, or a suspension.

[0039] This invention provides a method for preparing a pharmaceutical composition containing cetirizine, the method comprising the following steps:

[0040] (1) Cefalexin and phospholipids were directly ground to obtain a drug-phospholipid solid dispersion;

[0041] (2) Add water for injection to the solid dispersion and mix well (preferably by pressure homogenization) to obtain a suspension;

[0042] In this invention, as one embodiment, the method includes the following steps:

[0043] (3) The suspension obtained in step (2) is spray-dried or a desiccant is added to the suspension, mixed evenly, and then spray-dried to obtain dry powder particles.

[0044] In this invention, as one of the implementation schemes, the method includes the following steps (2): homogenization refers to homogenization 1 to 10 times at a pressure of 200 to 1000 bar; preferably, homogenization 6 times at a pressure of 700 bar.

[0045] In this invention, as one of the embodiments, the method includes the following step (3) in which the spray drying temperature is 90-110°C.

[0046] In this invention, as one embodiment, the dry powder particles can be further prepared with pharmaceutically acceptable excipients to obtain a powder inhaler (inhalable dry powder) or an aerosol.

[0047] The present invention also provides a reconstituted formulation, wherein the reconstituted formulation comprises the dry powder granules prepared in the present invention and water for injection, physiological saline for injection or glucose solution for injection.

[0048] The present invention also provides the use of a sustained-release pharmaceutical composition containing cevelexat or a reconstituted formulation thereof or a formulation prepared by the method of the present invention in the preparation of a medicament for treating inflammatory responses, bronchiectasis, acute lung injury or acute respiratory distress syndrome.

[0049] The advantages of this invention are:

[0050] 1) The preparation process is simple and easy to industrialize.

[0051] 2) The preparation process uses a high-pressure homogenization method, resulting in a relatively stable suspension.

[0052] 3) In addition to its sustained-release effect, cevelexatil suspension containing phospholipids can treat respiratory diseases more effectively than other formulations.

[0053] 4) After inhalation, the lung exposure is large and the release is sustained, which is significantly better than the nebulized inhalation of cevelexta sodium powder injection solution. Attached Figure Description

[0054] Figure 1 Scanning electron microscope image of cevelexat dry powder raw material;

[0055] Figure 2 Scanning electron microscope image of the suspension particles before high-pressure homogenization of prescription 1;

[0056] Figure 3 Scanning electron microscope image of the suspension particles after high-pressure homogenization of prescription 1;

[0057] Figure 4 Scanning electron microscope image of the dry powder particles of prescription 4;

[0058] Figure 5 Scanning electron microscope image of the dry powder particles of prescription 5;

[0059] Figure 6 Chromatogram of prescription 5 on day 0;

[0060] Figure 7 Chromatogram of prescription 5 after 10 days of light exposure;

[0061] Figure 8 Chromatogram of prescription 5 after 10 days at 40℃;

[0062] Figure 9 Chromatogram of prescription 5 after 10 days at 60℃;

[0063] Figure 10 Chromatogram of cevelexostat sodium suspension on day 0;

[0064] Figure 11Chromatogram of cevelexostat sodium suspension after 10 days of light exposure;

[0065] Figure 12 Chromatogram of cevelexostat sodium suspension after 10 days at 40°C;

[0066] Figure 13 Chromatogram of cevelexostat sodium suspension after 60℃ for 10 days; Detailed Implementation

[0067] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.

[0068] Example 1: Test of solubility of cevelexatil

[0069] Preparation of cevelexatil: Dissolve 40g of cevelexatil sodium in 5L of water for injection by stirring. Then adjust the pH of the solution to 3.0 with 5% dilute hydrochloric acid, and cevelexatil precipitates out. Filter, wash, and dry at 60℃ to obtain cevelexatil powder.

[0070] Take 50 ml of water for injection (pH 6.8), add 5 mg of cevelexat dry powder, stir at room temperature (-25℃) for 48 h, and then filter. Analyze the filtrate for drug concentration; the result is 0.0278 mg / ml. At pH 6.8, the solubility of cevelexat sodium is 11.2 mg / ml. Compared to cevelexat sodium, the solubility of cevelexat in water is significantly reduced.

[0071] Example 2: Screening of lecithin dosage

[0072] The prescription is designed as follows:

[0073]

[0074] Preparation of cevelexta suspension:

[0075] (1) Place cevelex and phospholipids in a mortar and grind them until they are uniformly mixed to obtain a drug-phospholipid solid dispersion.

[0076] (2) Add 200 ml of physiological saline to the solid dispersion, stir and disperse evenly to obtain a coarse suspension;

[0077] (3) Homogenize the crude suspension at 700 bar for 6 times to obtain a suspension;

[0078] Preparation of cevelexta dry powder:

[0079] (1) Add mannitol to the suspension obtained in step (3) above, stir magnetically at 1000 rpm to dissolve, and then spray dry at 110°C to obtain the product.

[0080] After spray drying, it was found that the powders of Formula 3 and Formula 4 (lecithin content 50%) adhered to the cyclone separator relatively severely. As the lecithin content decreased, the powder adhesion to the cyclone separator gradually improved.

[0081] The suspensions of prescriptions 10 and 11 showed good stability, with no significant sedimentation after 3 hours and a sedimentation volume ratio of 1. Both suspensions remained opaque after being left at room temperature for 30 days. There was no sedimentation at the bottom of the suspension of prescription 10, while the suspension of prescription 11, due to its high drug concentration, showed some sedimentation at the bottom, but it could be shaken to become uniform.

[0082] To analyze the effect of different phospholipid / drug ratios on drug release, appropriate amounts of powders from formulations 1, 2, 5, and 7 were selected, and a certain amount of water for injection was added. The mixture was stirred and dispersed evenly to prepare a suspension with a drug concentration of 5.0 mg / ml. 1.0 ml of each suspension was placed in a dialysis tube (molecular weight cutoff 300 kD) and then subjected to in vitro dissolution. The specific method is as follows:

[0083] Dissolution method Paddle technique, 50 rpm Dissolution medium pH 6.8 phosphate buffer Medium volume 900ml medium temperature 37±0.5℃ Sampling volume 10ml Sampling time point 0.5h, 1h, 2h, 4h, 8h, 12h Should we replenish the media? yes Sample processing and analysis methods After passing through a 0.22 μm filter membrane, the sample is then subjected to high-performance liquid chromatography (HPLC) for detection.

[0084] The results are as follows:

[0085] 0.5h(％) 1h(％) 2h(％) 4h(％) 8h(％) 12h(％) Prescription 1 44.1 74.5 92.7 100.4 100.8 99.8 Prescription 2 28.9 53.5 81.5 86.3 88.1 88.4 Prescription 5 14.7 26.9 43.2 58.1 65.0 65.9 Prescription 7 13.4 22.2 38.9 50.2 56.3 58.5

[0086] The dissolution results showed that as the amount of phospholipid increased, the proportion of phospholipid coated on the particle surface also increased. Due to the hydrophobicity of phospholipids, the drug dissolution rate slowed down. Specifically, when the amount of phospholipid was 0.5 times that of the drug (Formula 1), complete dissolution occurred after 4 hours. When the amount of phospholipid was 1 times that of the drug (Formula 2), the dissolution rate remained essentially unchanged after 4 hours, not exceeding 90%. When the amount of phospholipid was 3 times that of the drug (Formula 5), ​​the dissolution rate remained essentially unchanged after 8 hours, not exceeding 70%. When the amount of phospholipid was 5 times that of the drug (Formula 7), the slowing trend in the dissolution rate lessened, and the dissolution rate did not exceed 60% after 12 hours. With increasing phospholipid dosage, the release gradually slowed down, achieving a sustained-release effect. When the mass ratio of phospholipid to drug was greater than 1:1, the drug exhibited a sustained-release effect, with the best effect observed when the mass ratio was 3:1 to 5:1.

[0087] Example 3: Particle morphology characterization

[0088] To further analyze the morphology of cevelexta particles, a small amount of the suspension from formulation 1 before and after high-pressure homogenization was dropped onto a glass slide and allowed to air dry. This suspension, along with the cevelexta dry powder particles, was then analyzed using scanning electron microscopy. The results are shown in the attached figure. Figures 1-3 As shown.

[0089] Scanning electron microscopy results show that cevelestat particles are rod-shaped, with most ranging in length from 1 to 10 μm. Figure 1After being manually ground, the particles are broken into particles of varying lengths. Figure 2 After further high-pressure homogenization, the particles are all short rod-shaped or spherical, and their surfaces are coated with a phospholipid layer. Figure 3 Analysis using a Nano ZS90 particle size analyzer showed that the average particle size was 730.7 nm.

[0090] To further investigate the effect of different lecithin dosages on the morphology of the dry powder particles, scanning electron microscopy (SEM) was performed on dry powder particles from formulation 4 (50% lecithin) and formulation 5 (37.5% lecithin). The results are shown in the attached figure. Figures 4-5 As shown.

[0091] The results show that after spray drying, the dry powder is mostly composed of spherical, wrinkled particles, with most primary particles smaller than 5 μm. When the lecithin content is high, the powder particles are prone to agglomeration and deformation. As the lecithin content decreases, particle agglomeration is alleviated.

[0092] Example 4: Stability Comparison

[0093] To compare the stability of cevelectin and cevelectin sodium in water, 1.0 g of cevelectin sodium and 1.0 g of lecithin were added to 50 ml of water for injection, homogenized, and then dispensed into 5 ml vials. Separately, 1.0 g of Formula 5 dry powder was added to 50 ml of water for injection, shaken, and dispersed, then dispensed into 5 ml vials. The samples were placed in an oven at 40°C, an oven at 60°C, and a light chamber, respectively, for 10 days. Related substances were then analyzed using the following methods:

[0094]

[0095]

[0096] Solvent: Ethanol: Water (1:1)

[0097] Test solution: Prepare a solution of approximately 1 mg / ml.

[0098] Self-control solution: Take 1 ml of the test solution into a 100 ml volumetric flask, dilute to volume with solvent, and shake well.

[0099] The results are shown in the table below and attached. Figures 6-13 As shown:

[0100] 0 days 40℃ - 10 days 60℃ - 10 days 10 days of sunlight Prescription 5 0.63 0.74 0.84 0.62 Civelestat sodium suspension 0.76 20.05 47.86 4.19

[0101] Note: After 10 days of light exposure, the sodium cevelestat suspension turned into a brown suspension, while the other samples were white to off-white suspensions.

[0102] The results above show that cevelexatol has significantly improved stability in water compared to cevelexatol sodium.

[0103] Example 5: Atomization Performance Measurement

[0104] Mass median aerodynamic diameter (MMAD) is the most important critical mass attribute of oral inhaled formulations. Larger particles (MMAD > 10 μm) are usually filtered in the upper respiratory tract or nasopharynx due to inertial impaction; particles of 5–10 μm can reach the proximal lower respiratory tract; particles of 1–5 μm are transported through the airways to the peripheral airways and alveoli; and particles smaller than 0.5 μm are exhaled.

[0105] The aerodynamic particle size distribution of Formula 5 dry powder and its water-redispersible suspension (0.5 mg / ml) was determined using a new generation pharmaceutical impactor (NGI). The dry powder was mixed with twice the amount of lactose and then filled into capsules, each containing 1.0 mg of drug. Separately, 16 mg of the dry powder was added to 4 ml of water for injection, shaken to disperse evenly, achieving a drug concentration of 0.5 mg / ml. 2.0 ml of this solution was then nebulized. Following pharmacopoeia standard procedures, the specific results are as follows:

[0106] dry powder Dry powder water redispersibility MMAD(μm) 3.6 3.3 <![CDATA[FPF1(%)]]> 54.0 72.9 <![CDATA[FPF2(%)]]> 46.8 32.6

[0107] FPF1: The percentage of the total drug delivered from the drug delivery device by particles with an aerodynamic diameter of less than 5 μm.

[0108] FPF2: The percentage of the mass of particles with an aerodynamic diameter of less than 5 μm relative to the labeled amount of the drug.

[0109] The results show that both the dry powder and the dry powder redispersible suspension have suitable MMAD. The percentage of particles smaller than 5 μm in the total amount of drug delivered from the drug delivery device exceeds 50%, and the percentage of particles smaller than 5 μm in the amount of drug labeled exceeds 30%, indicating that they are suitable for inhalation administration and have a high deposition rate in the lungs.

[0110] Example 6: Investigation of Lung Tissue Exposure

[0111] The exposure levels of cevelexatase suspension particles and cevelexatase sodium solution in the lungs were compared and examined under different time conditions.

[0112] Samples and reagents:

[0113]

[0114] 6.1 Sample Preparation

[0115] Cevelexatil suspension: Take 320mg of prescription 5 dry powder, add 40ml of physiological saline, shake to disperse evenly, and a suspension of 1.0mg / ml is obtained.

[0116] Cevelexostat sodium solution: Take 2.0g of cevelexostat sodium raw material and 4.0g of mannitol, add 80.0g of water for injection, stir to suspend evenly, then slowly add 5% sodium hydroxide solution dropwise until the system becomes clear and transparent. Then add water to 100.0g (pH 8.20). Filter the solution through a 0.22μm filter membrane, then dispense into vials, filling each vial with 5.0ml, and then freeze-dry to obtain lyophilized powder (prescription same as commercially available powder for injection). Before use, add water for injection to each vial of lyophilized powder to 5.0ml, then dilute with physiological saline to 1.0mg / ml to obtain cevelexostat sodium solution.

[0117] 6.2 Laboratory Animals

[0118] Experimental animals: 40 male SD rats, weighing 220-240g.

[0119] Laboratory animal husbandry and management: Two rats were kept in each cage and fed maintenance diet with free access to food and water via water bottles.

[0120] Animal grouping and administration: Before administration, animals were randomly divided into two groups of 20 each, with 5 animals in each group at each time point, and administration was carried out by airway nebulization.

[0121] Dosage: 1 mg / kg.

[0122] Animals were anesthetized with isoflurane at 0.5h, 1h, 4h and 12h after administration. Blood was drawn from the abdominal aorta after anesthesia, and the animals were euthanized and lung tissue samples were collected.

[0123] 6.3 Tissue Sample Processing

[0124] Diluent 1: Weigh about 5g of potassium oxalate monohydrate, add an appropriate amount of ultrapure water to dissolve it, mix well, and prepare a 250mg / ml potassium oxalate aqueous solution.

[0125] Diluent 2: Weigh about 10g of citric acid, add an appropriate amount of ultrapure water to dissolve it, mix well, and prepare a 500mg / ml citric acid aqueous solution.

[0126] Preparation of homogenate: Take 400ml of physiological saline, add 16ml of diluent 1 and 8ml of diluent 2 to it to obtain a homogenate containing 10mg / ml citric acid and 10mg / ml potassium oxalate.

[0127] After the lung tissue was collected, it was weighed immediately, and a homogenizing solution was added (the mass-to-volume ratio of lung tissue to homogenizing solution was 1:4 (g / ml)). The homogenization was then carried out immediately on an ice bath, and the matrix was stored below -20°C.

[0128] 6.4 Tissue Sample Analysis

[0129] Take 50 μl of lung tissue homogenate and add 200 μl of acetonitrile (containing 20 ng / ml of phenytoin sodium). -1 Vortex for 2 min, centrifuge at 45000 rpm and 4℃ for 15 min, take 10 μl of the supernatant and add 190 μl of acetonitrile / water (1:1) for dilution, and perform LC-MS / MS mass spectrometry analysis.

[0130] The results of pulmonary exposure to cevelexatil suspension are as follows:

[0131]

[0132] The results of pulmonary exposure to cevelexta sodium solution are as follows:

[0133]

[0134]

[0135] The results show that the pulmonary exposure of cevelexstat suspension after inhalation is high and the sustained-release effect is good. The pulmonary drug exposure at 0.5 h is 4.9 times that of cevelexstat sodium solution, at 1 h it is 19.4 times, and at 12 h it is 375 times.

[0136] In summary, experiments have demonstrated that cevelectin exhibits low solubility, slow dissolution rate, and good stability. In rats, nebulized administration via the airway results in high pulmonary exposure and a good sustained-release effect, significantly superior to cevelectin sodium solution.

Claims

1. A sustained-release pharmaceutical composition containing cevelexatil, characterized in that, The pharmaceutical composition includes cevelexatil and phospholipids.

2. The pharmaceutical composition according to claim 1, characterized in that, The cevelex and phospholipids form a solid dispersion.

3. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of cevelex to phospholipid is 1:1 to 1:6, preferably 1:3 to 1:

5.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The pharmaceutical composition comprises cevelexatil, phospholipids, and an aqueous solution, wherein no organic solvents are contained.

5. The pharmaceutical composition according to claim 3, characterized in that, In the composition, the proportion of cevelexat is 0.05-5%, preferably 0.1-3.0%, and the proportion of phospholipids is 0.15-1.5%, preferably 0.3-1.0%, based on the mass of the composition.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition includes cevelex, phospholipids, and a desiccant, and does not contain organic solvents.

7. The pharmaceutical composition according to claim 6, characterized in that, In the composition, by weight of the composition, cevelexatin accounts for 5-40%, preferably 10-30%; phospholipids account for 2.5-50%, preferably 5-42%, more preferably 10-37.5%, and even more preferably 15-35%.

8. The pharmaceutical composition according to claim 7, characterized in that, The phospholipid is selected from egg yolk lecithin, soybean lecithin, or synthetic phospholipids, or a combination of two or more of them, preferably egg yolk lecithin.

9. The pharmaceutical composition according to claim 6, characterized in that, The desiccant comprises 25-75%, preferably 40-60%.

10. The pharmaceutical composition according to claim 9, characterized in that, The desiccant is one, two, or a combination of two or more of the following: fructose, xylitol, maltitol, erythritol, povidone, polyethylene glycol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, poloxamer, lactose, glucose, sucrose, trehalose, mannitol, and sorbitol; preferably, one, two, or a combination of two or more of the following: lactose, glucose, sucrose, trehalose, mannitol, and sorbitol; more preferably, mannitol.

11. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition include: or 。 12. A formulation comprising the pharmaceutical composition according to claims 1 to 11, characterized in that, The dosage form is a lyophilized powder injection, a powder mist, an aerosol, or a suspension.

13. A method for preparing the pharmaceutical composition according to any one of claims 1 to 11, characterized in that, The method includes the following steps: (1) Cefalexin and phospholipids were directly ground to obtain a drug-phospholipid solid dispersion; (2) Add water for injection to the solid dispersion and mix well (preferably by pressure homogenization) to obtain a suspension.

14. The method for preparing the pharmaceutical composition according to claim 13, characterized in that, The method includes the following steps: (3) Spray dry the suspension obtained in step (2) or add a desiccant to the suspension, mix well and then spray dry to obtain dry powder particles.

15. The preparation method according to claim 13, characterized in that, The method includes the following steps (2): homogenization refers to homogenization 1 to 10 times under a pressure of 200 to 1000 bar; preferably, homogenization 6 times under a pressure of 700 bar.

16. The preparation method according to claim 14, characterized in that, The method includes the step (3) in which the spray drying temperature is 90-110℃.

17. A reconstituted formulation, characterized in that, The reconstituted formulation includes the dry powder granules prepared according to any one of claims 14 to 16 and water for injection, physiological saline for injection, or glucose solution for injection.

18. The use of the pharmaceutical composition according to any one of claims 1 to 12, the reconstituted formulation according to claim 17, or the formulation prepared by any one of claims 13 to 16 in the treatment of inflammatory reactions, bronchiectasis, acute lung injury, or acute respiratory distress syndrome.

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