Sevelamer sodium inhalation powder and its use

Abstract

The present application relates to the technical field of pharmaceutical preparations, in particular to a powder aerosol intermediate composition and a preparation method thereof, a sodium ciprofloxacin inhalation powder aerosol and an application thereof. The raw and auxiliary materials of the intermediate composition include 1-7 wt% of sodium ciprofloxacin, 92-98 wt% of lactose and not more than 1% of magnesium stearate, in terms of mass percentage fraction; the D 50 of the sodium ciprofloxacin is 1-5 microns; the D 50 of the lactose is 100-150 microns. The intermediate composition can be used for preparing the sodium ciprofloxacin inhalation powder aerosol, and can realize efficient delivery of the sodium ciprofloxacin, improve the delivery efficiency of the sodium ciprofloxacin at a target site, and reduce systemic side effects. The sodium ciprofloxacin inhalation powder aerosol can be used for treating mild diseases such as cystic fibrosis, interstitial pneumonia and idiopathic pulmonary fibrosis, and thus expands the indications of the sodium ciprofloxacin.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and more specifically, to powder inhaler intermediate compositions and their preparation methods, and to cevelexta sodium inhalation powder and its application. Background Technology

[0002] Sivelestat sodium is a selective neutrophil elastase inhibitor. It inhibits the breakdown of lung junction tissue and the production of neutrophil migrating factors caused by enhanced elastase activity, and is used to treat severe conditions such as acute lung injury (ALI) with systemic inflammatory response syndrome (SIRS) or acute respiratory distress syndrome (ARDS). Since sivelestat sodium is primarily targeted at severely ill patients who are generally unable to inhale or take medication independently, current technology uses an injectable formulation, administered via intravenous infusion. However, this method of administration has a long delivery time (24 hours) and results in a low dose reaching the lung target site, accompanied by systemic toxicity. Therefore, there is an urgent need for a formulation that can increase the targeted dose of sivelestat sodium and reduce systemic side effects.

[0003] Oral inhalation formulations are a type of formulation that can directly reach the target site, have a rapid onset of action, and reduce dosage, toxicity, and adverse reactions. However, there are no oral inhalation formulations of cetelestatin sodium in the current technology, and there are many difficulties in preparing cetelestatin sodium into an oral formulation, which makes it impossible to develop or prepare oral inhalation formulations of cetelestatin sodium.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] The purpose of this invention is to provide an intermediate composition for a powder inhaler and its preparation method, as well as a cetelestat sodium inhalation powder and its application. Embodiments of this invention provide a composition that can be used to prepare a cetelestat sodium inhalation powder, enabling efficient delivery of cetelestat sodium, improving the delivery efficiency of cetelestat sodium at the target site, and reducing systemic side effects.

[0006] This invention is implemented as follows:

[0007] In a first aspect, the present invention provides a powder intermediate composition for preparing cevelexstat sodium inhalation powder, wherein the raw and excipients comprise, by weight percentage, 1-7 wt% cevelexstat sodium, 92-98 wt% lactose and no more than 1% magnesium stearate;

[0008] The D of the cevelexta sodium 50 The value is 1-5 micrometers; the D of the lactose 50 It is 100-150 micrometers.

[0009] In an optional embodiment, the raw materials include, by weight percentage, 1-7 wt% of the sodium cevelestat, 92-98 wt% of the lactose, and 0.5-1% of the magnesium stearate;

[0010] Preferably, the D of the cevelexta sodium is... 50 The value is 1.5-3 micrometers; the D of the lactose 50 It is 105-125 micrometers;

[0011] The D of the cevelexta sodium 10 The value is 0.5-1 micrometer; the D of the lactose 10 It is 40-50 micrometers;

[0012] Preferably, the D of the cevelexta sodium is... 90 The value is 3-10 micrometers; the D of the lactose 90 It is 170-210 micrometers.

[0013] In a second aspect, the present invention provides a method for preparing the powder intermediate composition for preparing cevelexta sodium inhalation powder as described in the foregoing embodiments, comprising: mixing lactose, magnesium stearate and cevelexta sodium.

[0014] In an optional embodiment, the method includes: high-speed shearing mixing of the lactose and the magnesium stearate, followed by mixing with the sodium cevelestat.

[0015] In an optional implementation, the conditions for high-speed shearing include a rotational speed of 300-3000 rpm, preferably 1000-1500 rpm.

[0016] In an optional embodiment, the mixture with the cevelexta sodium is mixed using a three-dimensional rocking mixing method;

[0017] Preferably, the conditions for three-dimensional oscillating mixing include a rotational speed of 23-101 rpm.

[0018] In an optional embodiment, the raw material of the cevelexta sodium is further micronized before mixing.

[0019] Preferably, the micronization conditions include: a pulverizing pressure of 2 to 5 bar and an inlet air pressure of 2 to 5 bar.

[0020] Thirdly, the present invention provides a cevelexat sodium inhalation powder, comprising an inhalation device and a powder intermediate composition for preparing the cevelexat sodium inhalation powder as described in the foregoing embodiments; the powder intermediate composition is infused into the inhalation device.

[0021] In optional embodiments, the inhalation device includes any one of a single-dose capsule inhalation device, a multi-dose reservoir inhalation device, and a vesicle inhalation device, preferably a multi-dose reservoir inhalation device.

[0022] Fourthly, the present invention provides a powder intermediate composition for preparing cevelexta sodium inhalation powder as described in the foregoing embodiments, or the use of cevelexta sodium inhalation powder as described in the foregoing embodiments in the preparation of a medicament for treating mild pulmonary inflammation;

[0023] The mild pulmonary inflammation mentioned above includes one or more of cystic fibrosis, interstitial pneumonia, and idiopathic pulmonary fibrosis.

[0024] This invention offers the following advantages: Existing technologies lack oral inhalation formulations of cevelexat sodium. Oral inhalation aerosols suffer from inhalation incoordination issues, placing high demands on patient use, and require the use of environmentally unfriendly propellants, potentially leading to ozone layer depletion. Nebulized inhalers require specialized nebulizers, are inconvenient to use, and have low drug delivery efficiency; furthermore, nebulized therapy increases the risk of aerosol generation and disease transmission. Furthermore, developing adsorbed powder formulations of cevelexat sodium presents numerous challenges, such as the hygroscopicity of the active pharmaceutical ingredient or oral inhalation formulation, the appropriate aerosol particle size, the optimal FPF (particulate powder concentration), and the selection of excipients to prevent reaction with cevelexat sodium. Existing technologies lack solutions to these problems, hindering the development or manufacture of oral inhalation formulations of cevelexat sodium, particularly inhaled powder formulations.

[0025] The embodiments of this invention, by selecting specific raw materials and proportions, enable the resulting intermediate composition to be used in the preparation of inhaled powder formulations, improving the delivery efficiency of cevelexta sodium at the target site while reducing systemic side effects. Furthermore, by preparing cevelexta sodium into an inhaled powder formulation, the drug rapidly settles in the lungs upon inhalation, avoiding or reducing toxic side effects on other sites. The lungs have a large absorption surface area, high membrane permeability, and rich blood flow, resulting in rapid drug absorption. The lungs also have low enzyme activity and no first-pass effect in the liver, improving bioavailability. Compared to nebulized inhalation solutions, this eliminates the need for a nebulizer, and compared to aerosols, it eliminates the need for a propellant, making it more environmentally friendly. Attached Figure Description

[0026] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 The particle size distribution diagram of the micronized sodium cetylestradiol provided in Example 1 of the present invention;

[0028] Figure 2 This is a scanning electron microscope image of the micronized cevelexta sodium provided in Example 1 of the present invention;

[0029] Figures 3-4 Particle size distribution diagrams of different types of lactose provided in Example 2 of the present invention;

[0030] Figure 5 This is a drug deposition distribution diagram of the cevelexta sodium inhalation powder provided in Example 3 of the present invention;

[0031] Figure 6 This is a schematic diagram of the delivery dose of the cevelexta sodium inhalation powder provided in Example 3 of the present invention;

[0032] Figure 7 This is a distribution diagram of drug deposition in the sodium cevelestat inhalation powder from different types of devices provided in Example 5 of the present invention. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0034] The lungs have hundreds of millions of alveoli, providing a large absorption area; the large blood flow also facilitates drug absorption; after being absorbed by the lungs, drugs directly enter the bloodstream, avoiding the first-pass effect of the liver and improving drug bioavailability. Therefore, there are many oral inhalers containing different active ingredients on the market.

[0035] Existing oral inhalers mainly fall into three categories: nebulized inhalers, aerosol inhalers, and powder inhalers. Nebulized inhalers require specialized nebulizers, which are inconvenient to use and have low drug delivery efficiency. Furthermore, nebulization therapy can increase the risk of aerosol generation and disease transmission; studies have reported that viruses can be transmitted to healthcare workers who have been exposed to hospitalized COVID-19 patients who have received nebulization therapy. Aerosol inhalers are actively administered, but suffer from initiation and inhalation incoordination issues, requiring higher patient skill levels. Additionally, aerosol inhalers require environmentally unfriendly propellants, potentially leading to ozone layer depletion. In contrast, powder inhalers contain stable (solid) drugs that easily penetrate deep into lung tissue when dispersed by the inhalation device, resulting in rapid absorption, targeted delivery, and convenient portability and use. Therefore, they represent a hot research area for pulmonary drug delivery.

[0036] However, there are many problems in preparing injectable cevimestat sodium into cevimestat sodium inhalation powder, such as the hygroscopicity of the active pharmaceutical ingredient or the oral inhalation formulation to ensure its efficacy. What is the appropriate aerosol particle size for the oral inhalation formulation to ensure effective target delivery? What is the optimal FPF (Frequency Productivity) for the oral inhalation formulation, and how should excipients be selected to prevent them from reacting with cevimestat sodium? Current technologies lack solutions to these problems.

[0037] The present invention provides a powder intermediate composition for preparing cevelexta sodium inhalation powder, wherein the raw materials include 1-7 wt% cevelexta sodium, 92-98 wt% lactose and no more than 1% magnesium stearate by weight percentage.

[0038] This intermediate composition effectively solves the above problems and can be used to prepare inhaled powder, improve the delivery efficiency of cevelexat sodium at the target site, and reduce systemic side effects.

[0039] Specifically, the content of cevelexta sodium is any value between 1% and 7% wt%, such as 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, and 7 wt%.

[0040] D of cevelexta sodium 50 The value is 1-5 micrometers; preferably 1.5-3 micrometers; D 10 It is 0.5-1 micrometer; D 90 It is 3-10 micrometers in size.

[0041] The lactose content is any value between 92wt% and 98wt%, such as 92wt%, 93wt%, 94wt%, 95wt%, 96wt%, 97wt%, and 98wt%. (The text abruptly ends here, seemingly mid-sentence.) 50 100-150 micrometers; preferably 105-125 micrometers; D10 The value is 40-50 micrometers; the D content of lactose 90 It is 170-210 micrometers.

[0042] Limiting the particle size of ceftriaxone sodium and lactose is beneficial for the preparation of inhaled powder inhalers and for maximizing their efficacy.

[0043] The content of magnesium stearate is any value below 1 wt%, such as 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, and 1.0 wt%, preferably 0.5-1 wt%. Magnesium stearate can be purchased from Peter Greven under the model number LIGAMEDMF-2-V PREMIUM-MB.

[0044] In a second aspect, the present invention provides a method for preparing the powder intermediate composition for preparing cevelexta sodium inhalation powder as described in the foregoing embodiments, comprising: mixing lactose, magnesium stearate and cevelexta sodium.

[0045] First, the raw material of cevelexta sodium is micronized. The micronization conditions include: a grinding pressure of 2–5 bar and an inlet air pressure of 2–5 bar. The micronized cevelexta sodium then meets the above-mentioned D... 50 D 10 and D 90 Requirements.

[0046] The raw material for celelectostat sodium used in this embodiment of the invention is celelectostat sodium tetrahydrate, or celelectostat sodium monohydrate or celelectostat sodium dihydrate converted into celelectostat sodium tetrahydrate after being left for a period of time. Then, mixing is performed. Specifically, lactose and magnesium stearate are first mixed using a three-dimensional rocking mixing method, that is, a rotational flow-translation-inverted drop mixing method; for example, the two are added to a Turbula mixing tank for mixing, at which time the mixing speed is 23-101 rpm. Alternatively, lactose and magnesium stearate can be mixed using high-speed shear mixing, in which case the mixing speed is 300-3000 rpm, preferably 1000-1500 rpm. For example, the two are added to a GEA mixing pot for mixing.

[0047] The aforementioned Turbula mixing tank is a three-dimensional oscillating mixer manufactured by WAB AG of Switzerland, widely used in laboratory and production environments. This mixer achieves efficient mixing through harmonious rotation, translation, and inversion, making it particularly suitable for handling materials with significant differences in specific gravity, particle size, or concentration.

[0048] Then, it is stirred with the sodium cetylpenicillin. Specifically, the mixing with the sodium cetylpenicillin is also performed using three-dimensional shaking mixing. That is, sodium cetylpenicillin can be added to the mixture of lactose and magnesium stearate. For example, after the lactose and magnesium stearate are three-dimensionally shake-mixed, half of the mixture is taken out, and then sodium cetylpenicillin is added and three-dimensionally shake-mixed. Then, the taken-out half of the mixture is added back in and three-dimensionally shake-mixed again.

[0049] Alternatively, for example, the mixture of lactose and magnesium stearate after high-speed shear mixing can be transferred to a Turbula mixing tank and cevelexta sodium can be added for three-dimensional rocking mixing, where the mixing conditions include a speed of 23-101 rpm.

[0050] Thirdly, the present invention provides a cevelexat sodium inhalation powder, comprising an inhalation device and a powder intermediate composition for preparing the cevelexat sodium inhalation powder as described in the foregoing embodiments; the powder intermediate composition is infused into the inhalation device.

[0051] The inhalation device includes any one of the following: a single-dose capsule inhalation device, a multi-dose reservoir inhalation device, and a vesicle inhalation device (single-dose or multi-dose). For example, the inhalation device can be the powder inhaler with application number CN201510373686.3, or the powder inhaler with application number CN201710946859.5, or the powder inhaler with application number CN202110886052.3, or the powder inhaler with application number CN201710947570.5.

[0052] Furthermore, the fine particle dosage of the cevelexta sodium inhalation powder provided in this embodiment of the invention reaches more than 55%.

[0053] The inhaled powder form of cetelestatin sodium provided in this invention achieves highly efficient delivery, improves the delivery efficiency of cetelestatin sodium at the target site, and reduces systemic side effects.

[0054] Furthermore, existing cevimestat sodium is an injectable form, generally used for severely ill patients, and is generally not used for mild cases such as cystic fibrosis, interstitial pneumonia, or idiopathic pulmonary fibrosis. However, in this invention, cevimestat sodium is prepared as an inhaled powder, requiring the patient to inhale it independently. In severely ill or acutely ill patients, their airway conditions may not allow for this. Therefore, this cevimestat sodium inhaled powder is generally not used for severe cases, but rather for mild cases such as cystic fibrosis, interstitial pneumonia, or idiopathic pulmonary fibrosis.

[0055] That is, the present invention provides a powder intermediate composition for preparing cevelexta sodium inhalation powder as described in the foregoing embodiments, or the use of cevelexta sodium inhalation powder as described in the foregoing embodiments in the preparation of a medicament for treating mild pulmonary inflammation; wherein, the mild pulmonary inflammation includes any one of cystic fibrosis, interstitial pneumonia, and idiopathic pulmonary fibrosis.

[0056] In other words, the cefelestat sodium inhaled powder provided in this embodiment of the invention treats patients with mild early-stage lung inflammation, preventing further aggravation of the condition. Simultaneously, as a pulmonary drug delivery formulation, the inhaled powder has the characteristics of high inhalation efficiency, good drug stability, and environmental friendliness. After inhalation, the drug directly reaches the lungs, significantly reducing the dosage compared to other drug delivery methods, thereby reducing adverse drug reactions. The drug is absorbed directly into the bloodstream through the pulmonary blood vessels, without a first-pass effect; therefore, absorption after pulmonary administration is very rapid. Compared to invasive treatments such as injections, inhaled powder treatment can reduce patient discomfort and improve treatment efficiency.

[0057] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0058] Example 1

[0059] This invention provides a method for preparing cevelexta sodium inhalation powder, comprising:

[0060] The active pharmaceutical ingredient, cefelecstat sodium, was micronized using an air jet mill to obtain a particle size D. 50 The active pharmaceutical ingredient has a particle size of approximately 2.0 μm. The particle size distribution of the micronized cevimestat sodium is shown in the image below. Figure 1 See Table 1 and the scanning electron microscope images. Figure 2 .

[0061] Table 1. Particle size distribution of micronized sodium cevelestatin

[0062] raw materials <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Span Cevelexta sodium 0.68 1.98 4.05 1.70

[0063] Weigh out 1.0064g of micronized cevelexatol sodium, 18.8016g of lactose LH100, and 0.2012g of magnesium stearate.

[0064] Place lactose and magnesium stearate into a Turbula mixing jar and mix at 101 rpm for 30 min to obtain a lactose and magnesium stearate mixture; take out about 1 / 2 of the mixture, put cevelexat sodium into a mixing pot, add the previously taken out 1 / 2 of the mixture, and mix at 101 rpm for 30 min.

[0065] The powder is quantitatively filled into the Hirakawa inhaler (see patent CN201510373686.3).

[0066] Example 2

[0067] This invention provides a method for preparing cevelexta sodium inhalation powder, comprising:

[0068] Weigh out 1.2501g of micronized cevelexatol sodium from Example 1, 396.0g of lactose SV010, and 4.0003g of magnesium stearate.

[0069] Place lactose and magnesium stearate in a GEA 1L mixing pot and mix at 1130 rpm for 9 min to obtain a mixture of lactose and magnesium stearate; take 23.7531 g of the mixture and put it together with the sodium ceftriaxone raw material into a Turbula mixing jar and mix at 72 rpm for 20 min.

[0070] The powder is metered and filled into the Hirakawa inhaler.

[0071] Example 3

[0072] This invention provides a method for preparing cevelexta sodium inhalation powder, comprising:

[0073] Weigh out 0.2508g of micronized cevelexatol sodium from Example 1, 396.0g of lactose SV010, and 4.0003g of magnesium stearate.

[0074] Place lactose and magnesium stearate in a GEA 1L mixing pot and mix at 1130 rpm for 9 min to obtain a mixture of lactose and magnesium stearate; take 24.7537 g of the mixture and put it together with the sodium cevelestat raw material into a Turbula mixing jar and mix at 72 rpm for 20 min.

[0075] The powder is metered and filled into the Hirakawa inhaler.

[0076] Example 4

[0077] This invention provides a method for preparing cevelexta sodium inhalation powder, comprising:

[0078] Weigh out 1.7501g of micronized cevelexatol sodium from Example 1, 396.0g of lactose SV010, and 4.0003g of magnesium stearate.

[0079] Place lactose and magnesium stearate in a GEA 1L mixing vessel and mix at 1130 rpm for 9 min to obtain a mixture of lactose and magnesium stearate; take 23.2524 g of the mixture and put it together with cevelexat sodium raw material into a Turbula mixing jar and mix at 72 rpm for 20 min.

[0080] The powder is metered and filled into the Hirakawa inhaler.

[0081] Comparative Example 1

[0082] This comparative example provides a method for preparing cevelexta sodium inhalation powder, including:

[0083] Weigh 1.5023g of micronized cevelexatol sodium from Example 1 and 28.5077g of lactose SV010.

[0084] Take a clean, intact 65-mesh sieve and sieve the lactose and raw drug through the 65-mesh sieve four times.

[0085] The powder is metered and filled into the Hirakawa inhaler.

[0086] Test Example 1 – Hygroscopicity Study of Active Pharmaceutical Ingredient

[0087] Two flat weighing bottles were equilibrated for 24 hours at 25℃ / 92.5%RH and 25℃ / 75%RH, respectively. The mass of each bottle was recorded as m1. A layer of cefilestat sodium raw material (unmicronized) with a thickness of about 3 mm was spread in the weighing bottle and recorded as m2. The flat weighing bottles containing the raw material were placed at 25℃ / 75%RH and 25℃ / 92.5%RH, respectively. The weighing bottles were removed on the 5th day and weighed as m3. The weighing bottles were removed on the 10th day and weighed as m4.

[0088] 5-day weight gain percentage = (m3-m2) / (m2-m1)*100%

[0089] 10-day weight gain percentage = (m4 - m2) / (m2 - m1) * 100%

[0090] The percentage of hygroscopic weight gain of cevelexostat sodium raw material is shown in the table below:

[0091]

[0092] It is evident that the active pharmaceutical ingredient is essentially non-hygroscopic, which can improve the stability of inhaled powder inhalers and avoid decomposition or clumping problems caused by moisture.

[0093] Test Example 2

[0094] The lactose LH100 (lactose) used in the above examples was tested separately. 100) and lactose SV010 ( The particle size distribution of SV010 is shown in the figure below. Figure 3 , Figure 4 and Table 2, where, Figure 3 This is a particle size distribution diagram of lactose LH100. Figure 4 This is a particle size distribution diagram of lactose SV010.

[0095] Table 2. Particle size distribution of lactose

[0096] lactose <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Span LH100 47.78 120.09 200.13 1.27 SV010 47.16 107.79 179.01 1.22

[0097] The results above indicate that the particle size distribution of lactose ensures the uniformity and flowability of inhaled powder inhalers, promoting stable drug inhalation. Appropriate particle size contributes to effective drug release.

[0098] Test Example 3

[0099] The performance of the sodium cevelestat inhalation powder in Comparative Example 1 and Examples 1-4 was tested, and the results are as follows.

[0100] Table 3. Prescriptions for Comparative Examples 1, 1, and 2

[0101]

[0102] APSD detection results:

[0103] Table 4 Test Results

[0104] APSD Comparative Example 1 Example 1 Example 2 DD(μg) 435.972 443.885 469.378 FPD(μg) 182.981 202.526 276.157 FPF (%) 41.971 45.626 58.835 MMAD(μm) 2.279 2.636 2.678

[0105] As can be seen, the cevelexat sodium inhalation powder provided in this embodiment of the invention has good pulmonary drug delivery efficiency, with FPF of 45.626% and 58.835%, respectively.

[0106] Among them, APSD (Aerodynamic Particle Size Distribution) represents aerodynamic particle size distribution; DDU (Delivered-Dose Uniformity) represents delivered dose uniformity; FPF (Fine Particle Fraction) represents fine particle fraction; FPD (Fine Particle Dose) represents fine particle dose; MMAD (MassMedian Aerodynamic Diameter) represents mass median aerodynamic particle size; and DD (Delivered Dose) represents delivered dose.

[0108] Table 5 Prescriptions for Examples 2-4

[0109]

[0110] The APSD test results are shown in Table 6 below. Figure 5 .

[0111] Table 6 Test Results

[0112] APSD Example 2 Example 3 Example 4 ADP (μg) 46.480 6.395 57.770 IND(μg) 68.413 9.623 96.357 PRE(μg) 39.543 5.311 35.597 S1(μg) 8.191 1.068 11.579 S2(μg) 42.195 5.599 59.609 S3(μg) 96.688 15.258 125.666 S4(μg) 86.596 13.394 111.590 S5(μg) 42.615 6.383 51.612 S6(μg) 18.943 2.563 26.268 S7(μg) 10.712 1.231 17.161 MOC(μg) 6.193 0.668 11.122 DD(μg) 469.378 67.899 607.969 FPD(μg) 276.157 41.457 363.529 FPF (%) 58.835 61.057 59.794 MMAD(μm) 2.678 2.703 2.692

[0113] As can be seen, the different concentrations of cevelexta sodium inhalation powder provided in the embodiments of the present invention all have good pulmonary drug delivery efficiency, with an FPF of approximately 60%.

[0114] The delivery dose test results of different concentrations of cefelestat sodium inhalation powder are shown in Table 7 below. Figure 6 .

[0115] Table 7 Delivery Dosage

[0116]

[0117]

[0118] The results above show that the delivery dose of each unit is consistent and stable, which can ensure that the drug dose is consistent each time it is inhaled, thus improving the reliability and controllability of inhaled powder inhalers.

[0119] Test Example 4

[0120] The cevelexta sodium inhalation powder prepared in Example 2 was stored at 25°C / 60% RH, and samples were taken at 0 days, 3 months, and 6 months for APSD and DDU tests to determine DD, FPD, MMAD, FPF, and delivery dose at different time points. The results are shown in Tables 8 and 9.

[0121] Table 8 APSD Test Results

[0122]

[0123] Table 9 DDU Detection Results

[0124]

[0125] As shown in Tables 8 and 9, after 6 months of storage, the APSD (Aerodynamic Particle Size Distribution) and DDU (Delivery Dosage Uniformity) of the Sivelexa sodium inhalation powder showed no significant changes, indicating that the product maintained stability during storage and was not affected by environmental factors, thus maintaining stable quality.

[0126] Test Example 5

[0127] Both capsule-type and reservoir-type inhalation devices are commonly used delivery devices for inhaled powder inhalers. The powder inhaler intermediate of the cevelexostat sodium inhaler prepared in Example 2 was filled into capsules (for use with capsule-type inhalers) and Hirakawa devices, and APSD was tested.

[0128] The APSD test results are shown in Table 10 below. Figure 7 .

[0129] Table 10 Test Results

[0130] APSD Hirakawa device capsule device ADP (μg) 46.480 3.430 IND(μg) 68.413 18.160 PRE(μg) 39.543 61.857 S1(μg) 8.191 4.123 S2(μg) 42.195 20.665 S3(μg) 96.688 40.255 S4(μg) 86.596 34.008 S5(μg) 42.615 16.735 S6(μg) 18.943 7.874 S7(μg) 10.712 4.000 MOC(μg) 6.193 1.860 DD(μg) 469.378 212.967 FPD(μg) 276.157 110.866 FPF (%) 58.835 52.910 MMAD(μm) 2.678 2.828

[0131] As can be seen, the FPF of storage-type devices is approximately 59%, while that of capsule-type devices (e.g., refer to...) With a Faster Drug Flow Rate (FPF) of approximately 53%, receptacle-type inhalers offer higher pulmonary drug delivery efficiency than capsule-type devices. This means that receptacle-type devices can deliver more fine particles of medication deep into the lungs, improving drug absorption efficiency and therapeutic effect while reducing drug waste. Furthermore, capsule-type inhalers require capsule replacement after each use, making operation more complex. In contrast, receptacle-type inhalers offer greater convenience, a larger drug storage capacity, and reduce the hassle of changing medications, increasing patient compliance and treatment effectiveness.

[0132] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A powder inhaler intermediate composition for preparing cevelexta sodium inhalation powder, characterized in that, By mass percentage, its raw and auxiliary materials include 1-7 wt% sodium cevelestat, 92-98 wt% lactose and no more than 1% magnesium stearate; The D of the cevelexta sodium 50 The value is 1-5 micrometers; the D of the lactose 50 It is 100-150 micrometers.

2. The powder intermediate composition for preparing cevelexostat sodium inhalation powder according to claim 1, characterized in that, The raw materials and excipients, by mass percentage, include 1-7 wt% of the sodium cevelestat, 92-98 wt% of the lactose, and 0.5-1% of the magnesium stearate; Preferably, the D of the cevelexta sodium is... 50 The value is 1.5-3 micrometers; the D of the lactose 50 It is 105-125 micrometers; Preferably, the D of the cevelexta sodium is... 10 The value is 0.5-1 micrometer; the D of the lactose 10 It is 40-50 micrometers; Preferably, the D of the cevelexta sodium is... 90 The value is 3-10 micrometers; the D of the lactose 90 It is 170-210 micrometers.

3. A method for preparing the powder intermediate composition for preparing cevelexta sodium inhalation powder as described in claim 1 or 2, characterized in that, include: Mix lactose, magnesium stearate, and sodium cevelestatin.

4. The preparation method according to claim 3, characterized in that, include: The lactose and magnesium stearate are mixed by high-speed shearing, and then mixed with sodium cevelestat.

5. The preparation method according to claim 4, characterized in that, The conditions for high-speed shearing include a rotational speed of 300-3000 rpm, preferably 1000-1500 rpm.

6. The preparation method according to claim 4, characterized in that, The mixture was prepared by three-dimensional rocking mixing with the sodium cevelestat. Preferably, the conditions for three-dimensional oscillating mixing include a rotational speed of 23-101 rpm.

7. The preparation method according to claim 3, characterized in that, Also includes: Before mixing, the raw material of cevelexta sodium is micronized; Preferably, the micronization conditions include: a pulverization pressure of 2–5 bar; Intake pressure 2-5 bar.

8. A sodium cevelestat inhalation powder, characterized in that, It includes an inhalation device and a powder inhaler intermediate composition for preparing cevelexta sodium inhalation powder as described in claim 1; the powder inhaler intermediate composition is infused into the inhalation device.

9. The cevelexta sodium inhalation powder according to claim 8, characterized in that, The inhalation device includes any one of a single-dose capsule inhalation device, a multi-dose reservoir inhalation device, and a vesicle inhalation device, preferably a multi-dose reservoir inhalation device.

10. The use of a powder intermediate composition for preparing cevelexta sodium inhalation powder as described in claim 1 or 2, or the use of cevelexta sodium inhalation powder as described in claim 8, in the preparation of a medicament for treating mild pulmonary inflammation; in, The mild pulmonary inflammation includes one or more of cystic fibrosis, interstitial pneumonia, and idiopathic pulmonary fibrosis.

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