Auxiliary material system for pulmonary administration of indissolvable drug and preparation method of auxiliary material system

Abstract

The invention belongs to the field of pharmaceutical preparations, and provides an auxiliary material system for pulmonary administration of insoluble drugs and a preparation method of the auxiliary material system. According to the invention, a collaborative design of lipid-coated indissolvable drug nanocrystal core-shell particles and a ternary lipid dispersion intermediate is adopted, and an anti-solvent precipitation in-situ coating and high-pressure microjet refining technology is adopted; the preparation method comprises the following steps: coating the outer surface of a nintedanib nanocrystal with a lipid shell layer composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol and propylene glycol caprylate to form core-shell particles with the mass median particle size D50 value of 150-250 nm and the volume distribution D90 value of less than or equal to 400 nm. According to the invention, high drug loading capacity, low viscosity and atomizable property are realized, lung deposition distribution and long-term particle size stability are optimized, the contradiction between high solid content and rheological property, low irritation and colloid stability, and atomization efficiency and core-shell structure integrity in lung administration of insoluble drugs is effectively relieved, and the preparation method has wide clinical application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more specifically to an excipient system for pulmonary administration of poorly soluble drugs and its preparation method. Background Technology

[0002] Lung administration is an important route for treating lung diseases such as pulmonary interstitial fibrosis and pulmonary hypertension. Compared with oral or intravenous administration, pulmonary inhalation has significant advantages such as rapid onset of action, direct drug delivery to the lesion, and fewer systemic adverse reactions. Nintedanib, as a multi-target tyrosine kinase inhibitor, has a clear therapeutic effect on idiopathic pulmonary fibrosis, but its water solubility is extremely poor, with an oral bioavailability of only about 5%, and it has adverse reactions such as gastrointestinal irritation and liver damage. Developing nintedanib nanoformulations for pulmonary inhalation is a key approach to improving drug delivery efficiency and reducing systemic toxicity. However, inhaled formulations place stringent requirements on the carrier system: on the one hand, they need to achieve high drug loading to reduce administration volume and frequency, while maintaining low viscosity rheological properties to match the processing window of vibrating membrane nebulizers; on the other hand, they need to control the aerodynamic particle size distribution of the aerosol to ensure that the fine particle fraction and median mass aerodynamic particle size are within the optimal lung deposition range, thereby achieving effective drug deposition deep in the lungs; in addition, the formulation also needs to take into account long-term storage stability and avoid nanoparticle aggregation that leads to increased particle size and deterioration of nebulization performance, which places higher demands on the design and process optimization of the excipient system.

[0003] Currently, carrier technologies for pulmonary delivery of poorly soluble drugs mainly include liposomes, nanosuspensions, and polymer nanoparticles. Chinese patent CN101244039B discloses a new method for preparing liposome formulations of poorly soluble drugs; however, this system suffers from low drug loading and the liposome membrane structure is prone to rupture and drug leakage under atomization shear. Chinese patent CN117838672B discloses a tilmicosin / G-type alginate oligosaccharide nebulized inhalation nanosuspension and its preparation method. Core-shell nanoparticles loaded with tilmicosin are prepared by coaxial electrostatic spraying, and then the core-shell nanoparticles are dispersed in a G-type alginate oligosaccharide solution to obtain the tilmicosin / G-type alginate oligosaccharide nebulized inhalation nanosuspension. However, this system exhibits a significant increase in viscosity under high solids content conditions, making it difficult to meet the stringent rheological performance requirements of vibrating membrane nebulizers. Furthermore, the use of polymer stabilizers may trigger pulmonary foreign body reactions and biocompatibility risks. Chinese patent CN118286454A discloses a phospholipid-coated nanocrystalline core-shell structure, which consists of a core formed by cationic polypeptides (histidine-lysine polymers) and nucleic acid molecules, and a lipid shell coating the core. The lipid shell includes negatively charged lipids. However, this system has a high absolute value of zeta potential, and charged particles are prone to irritation on the respiratory mucosa. Furthermore, in phosphate buffer containing physiological concentrations of salt ions, charge shielding can easily occur, leading to aggregation. Therefore, achieving a synergistic balance between long-term particle size stability of nanocrystalline core-shell particles, low zeta potential to reduce respiratory irritation, and the integrity of the core-shell structure before and after nebulization, while ensuring high drug loading and low viscosity rheological properties for nebulization, remains a critical technical challenge in the development of inhaled formulations of poorly soluble drugs. Summary of the Invention

[0004] The purpose of this invention is to provide an excipient system for pulmonary drug delivery of poorly soluble drugs and its preparation method, addressing the inherent contradictions in existing pulmonary nano-drug delivery systems in three aspects: high solids content and low viscosity, atomizable rheology and long-term particle size stability of nanocrystalline core-shell, low zeta potential to reduce respiratory irritation and dispersion stability of colloidal systems under high salt and weak charge conditions, high atomization efficiency, and specific aerodynamic particle size / fine particle fraction and the structural integrity of lipid-encapsulated poorly soluble drugs in nanocrystalline core-shell before and after atomization.

[0005] This invention achieves synergistic effects by constructing a two-component synergistic stabilizing system of lipid-coated poorly soluble drug nanocrystalline core-shell particles and a ternary lipid dispersion intermediate. Specifically, the lipid-coated poorly soluble drug nanocrystalline core-shell particles provide high drug loading and core drug delivery function, while the ternary lipid dispersion intermediate significantly reduces the probability of direct contact and van der Waals attraction between the core-shell particles by forming a dynamic lipid adsorption layer on the surface of the core-shell particles, thereby maintaining long-term colloidal stability under near-electroneutral conditions. At the same time, the introduction of the ternary lipid dispersion intermediate effectively reduces the overall viscosity of the system, improves the hydrodynamic performance during atomization, and provides lipid replenishment and structural repair for the core-shell particles under atomization shear stress, ensuring that the core-shell structure remains intact before and after atomization.

[0006] To achieve the above objectives, the present invention provides the following technical solution: An excipient system for pulmonary administration of poorly soluble drugs, wherein the excipient system is an aqueous colloidal dispersion for atomization, comprising the following components: Poorly soluble drug nanocrystals, wherein the poorly soluble drug nanocrystals are nanocrystals formed from nintedanib or its pharmaceutically acceptable salts; Dipalmitoyl-sn-glycero-3-phosphocholine; cholesterol; Propylene glycol octanoate; Phosphate buffer and sodium chloride are used to adjust the pH to 4.8-6.2 and the osmotic pressure to 280-320 mOsm / kg; Water for injection; in: The outer surface of the poorly soluble drug nanocrystals is coated with a lipid shell composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol and propylene glycol octanoate, forming lipid-coated poorly soluble drug nanocrystal core-shell particles. The mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 150-250 nm, and the volume distribution D90 value is ≤400 nm. The molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate is 60-80:15-30:5-10; When measured by electrophoretic light scattering at 25±2℃, using the excipient system itself or a phosphate buffer solution with the same phosphate and sodium chloride concentration and pH as the excipient system as the dispersion medium, the absolute value of the overall zeta potential of the excipient system is ≤5mV. The mass of the drug contained in the lipid-coated poorly soluble drug nanocrystal core-shell particles accounts for more than 60 wt% of the total mass of the drug in the excipient system.

[0007] Furthermore, the lipid-coated poorly soluble drug nanocrystal core-shell particles are prepared through the following steps: A1. Raw material preparation: The poorly soluble drug is nintedanib or a pharmaceutically acceptable salt thereof, and the amount of nintedanib used is 1.0-10.0 parts by weight; The dosage of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 5.0-20.0 parts by weight; The dosage of cholesterol is 2.0-10.0 parts by weight; The dosage of propylene glycol octanoate is 1.0-10.0 parts by weight; Ethanol was used as an organic solvent to prepare an ethanol organic phase with a total drug and lipid mass concentration of 50-100 mg / mL. The mixture was stirred at 45-60°C until almost no solid precipitation was observed in the system. A2. Anti-solvent precipitation and in-situ coating: At 45-60°C, the ethanol organic phase prepared in step A1 is injected at a rate of 0.5-2.0 mL / min into a phosphate buffer solution with a volume of 5-20 times that of the ethanol phase. The phosphate buffer solution contains sodium chloride with a mass concentration of 4.5-8.5 mg / mL, and also contains disodium hydrogen phosphate dodecahydrate and potassium dihydrogen phosphate. The pH of the phosphate buffer solution is adjusted to 4.8-6.2. During this process, a dispersion containing coarse drug crystals and lipids is formed. A3. High-pressure micro-jets are refined: The dispersion obtained in step A2 is subjected to high-pressure microfluidic treatment 6-10 times at an inlet temperature of 30-40℃ and a pressure of 100-140MPa to obtain a dispersion of lipid-coated poorly soluble drug nanocrystalline core-shell particles. The mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystalline core-shell particles is controlled to be 150-250nm, and the volume distribution D90 is controlled to be ≤400nm. The particle size distribution is determined by dynamic light scattering method. A4. De-alcoholization and Quality Control: Ethanol is removed by vacuum evaporation or membrane separation at a temperature not exceeding 40°C, so that the residual ethanol volume fraction is ≤0.5 vol%, and the zeta potential value is detected as -5 to +5 mV. The resulting dispersion is the core-shell intermediate of lipid-encapsulated poorly soluble drug nanocrystals.

[0008] Furthermore, the excipient system also includes a drug-free ternary lipid dispersion intermediate composed of dipalmitoyl-sn-glycero-3-phosphocholine, cholesterol, and propylene glycol octanoate, which is prepared by the following steps: B1. Raw material preparation: The dosage of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 5.0-20.0 parts by weight; The dosage of cholesterol is 2.0-10.0 parts by weight; The dosage of propylene glycol octanoate is 1.0-10.0 parts by weight; The amount of ethanol used was such that the total mass concentration of dipalmitoyl-sn-glycerol-3-phosphocholine, cholesterol and propylene glycol octanoate was 50-100 mg / mL. The mixture was stirred at 45-60 °C until almost no solid precipitation was observed in the system, thus obtaining the lipid ethanol organic phase. B2. Ethanol injection for nucleation: At 45-60℃, the ethanol organic phase prepared in step B1 is injected at a rate of 0.5-2.0 mL / min into a phosphate buffer solution with a volume of 5-20 times that of the ethanol phase. The phosphate buffer solution contains sodium chloride, disodium hydrogen phosphate dodecahydrate, and potassium dihydrogen phosphate. The pH value of the phosphate buffer solution is 4.8-6.2 to obtain a coarse dispersion. B3. High-pressure microjets refinement: The coarse dispersion obtained in step B2 was subjected to high-pressure microfluidic treatment 6-10 times at an inlet temperature of 30-40℃ and a pressure of 100-140MPa to obtain a lipid dispersion with a particle size Z-avg value of 90-180nm and a polydispersity index (PDI) value of ≤0.25. The Z-avg and PDI were determined by dynamic light scattering method. B4. De-alcoholization and osmotic pressure regulation: The residual ethanol volume fraction was controlled to ≤0.5 vol% by vacuum evaporation or membrane separation, and the osmotic pressure was adjusted to 280-320 mOsm / kg by adding sodium chloride, thus obtaining the ternary lipid dispersion intermediate.

[0009] Furthermore, in the lipid-coated poorly soluble drug nanocrystal core-shell particles, the molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine to cholesterol is 2.5-5.0:1.0, and the molar number of propylene glycol octanoate accounts for 5-10 mol% of the total lipid molar number. The excipient system contains dipalmitoyl-sn-glycerol-3-phosphorylcholine at a mass concentration of 5-15 mg / mL, cholesterol at a mass concentration of 1-5 mg / mL, and propylene glycol octanoate at a mass concentration of 0.5-3 mg / mL. The mass concentration of nintedanib or its pharmaceutically acceptable salt in the excipient system is 1.0-10.0 mg / mL, and is greater than the equilibrium solubility of nintedanib or its pharmaceutically acceptable salt in phosphate buffer under the stated pH conditions. The pH value of the excipient system is 4.8-6.2.

[0010] Furthermore, when the excipient system is loaded into a vibrating diaphragm nebulizer for atomization, a multi-stage cascade impactor configured and calibrated in accordance with the requirements of General Chapter 0951 "Determination of Aerodynamic Properties of Fine Particles in Inhalation Preparations" in the current edition of the Chinese Pharmacopoeia is used. Under the gas flow rate and sampling time conditions specified in the General Chapter, the median aerodynamic particle size of the formed aerosol is 2.8-3.8 µm, and the fine particle fraction is ≥50%. After one month of accelerated storage at 40±2℃, relative humidity not greater than 75%, and in the dark, the increase in the volume distribution D90 of the lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system is not more than 50 nm.

[0011] Furthermore, in the excipient system, the mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 5-15 mg / mL, the mass concentration of cholesterol is 1-5 mg / mL, the mass concentration of propylene glycol octanoate is 0.5-3 mg / mL, and the mass concentration of nintedanib or its pharmaceutically acceptable salt is 1.0-10.0 mg / mL, which is greater than the equilibrium solubility of the nintedanib or its pharmaceutically acceptable salt in phosphate buffer under the stated pH conditions.

[0012] As a concept of this invention, a two-component synergistic system is designed, consisting of lipid-encapsulated nanocrystalline core-shell particles and a ternary lipid dispersion intermediate. This system is primarily used to enhance the drug loading efficiency, colloidal stability, and pulmonary deposition performance of poorly soluble drug inhalation formulations. Nintedanib, a typical poorly soluble drug, exhibits extremely low solubility in aqueous media. Through antisolvent precipitation and in-situ lipid encapsulation technology, the drug is nanocrystallized, and simultaneously a ternary lipid shell composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate is constructed on its outer surface. This core-shell structure achieves an organic combination of nanoscale drug dispersion and lipid barrier protection. The lipid shell, on the one hand, prevents direct contact and aggregation between nanocrystal particles through steric hindrance; on the other hand, by regulating the shell composition, it achieves near-neutral surface charge, thereby reducing the risk of charge-shielded aggregation of particles in high-ionic-strength physiological environments. The application of high-pressure microfluidic technology ensured precise control of drug nanocrystal size and uniform lipid shell coating, stabilizing the mass median particle size (D50) in the 150-250 nm range and controlling the volume distribution (D90) value within 400 nm. This particle size range not only guaranteed the long-term dispersion stability of nanoparticles in the liquid phase but also laid the foundation for deep lung deposition after subsequent aerosol formation. The introduction of a ternary lipid dispersion intermediate further optimized the rheological properties and stabilization mechanism of the system. By forming a lipid adsorption layer between the core-shell particles, the direct contact between the core-shell particles was reduced, maintaining good colloidal stability and integrity before and after aerosolization even under near-neutral conditions.

[0013] This invention also discloses a method for preparing an excipient system for pulmonary administration of poorly soluble drugs, comprising the following steps: S1. Preparation of drug-free ternary lipid dispersion intermediates; S2. Preparation of lipid-coated, poorly soluble drug nanocrystal core-shell intermediate containing nintedanib; S3. The ternary lipid dispersion intermediate obtained in step S1 and the lipid-coated poorly soluble drug nanocrystal core-shell intermediate obtained in step S2 are mixed at a mass ratio of 1:3-3:1, and stirred at 20-40℃ for 10-60 min. The mixing process is carried out at a shear rate of 100-1000. Under the conditions; S4. Optionally, perform 2-4 additional high-pressure microjets at a pressure of 40-80 MPa to further homogenize the particle distribution; S5. By adding sodium chloride and adjusting the concentration of phosphate buffer salt, the osmotic pressure is made to be 280-320 mOsm / kg, and the final mass concentration of sodium chloride in the excipient system is made to be 4.5-8.5 mg / mL, and the pH is adjusted to 4.8-6.2 using hydrochloric acid and / or sodium hydroxide. S6. The excipient system is obtained by sterilization filtration and filling. The sterilization filtration adopts a hydrophilic filter membrane with a pore size of 0.22µm. The particle size distribution of lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system after sterilization filtration still meets the requirements of D50 and D90.

[0014] Furthermore, in step S2, the single pass time of the high-pressure microjet treatment is 10-60s, and the cooling time between two adjacent high-pressure microjet treatments is 30-300s. The ethanol removal steps involved in steps S1 and S2 are carried out under an absolute pressure of 4-20 kPa and a temperature of 25-40℃ until the residual ethanol volume fraction is ≤0.5 vol%, wherein the ethanol volume fraction used in steps S1 and S2 is ≥80 vol.

[0015] Furthermore, the preparation process is carried out at an ambient temperature not exceeding 25°C, and the entire production line adopts a closed system to reduce the risk of microbial contamination.

[0016] Furthermore, in the phosphate buffer solution used in step S1 (B2) and step S2 (A2), the molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 1.0-3.0:1.0.

[0017] Furthermore, in one embodiment, the lipid shell thickness of the lipid-coated poorly soluble drug nanocrystal core-shell particles can be controlled within the range of 5-30 nm. The core-shell particles are photographed using a transmission electron microscope, and at least a dozen particles are statistically analyzed using image analysis software. The average thickness of the lipid shell is calculated by subtracting the core particle size of the drug crystal from the total particle size, thereby achieving precise control over the core-shell structure morphology.

[0018] Furthermore, in one embodiment, the obtained excipient system can be atomized using a vibrating membrane mesh atomizer in the above preparation method, and the mass median aerodynamic particle size and fine particle fraction of the formed aerosol can be measured by a cascade impactor to verify that the lung deposition characteristics of the aerosol are preferably in the range of 2.8-3.8µm and not less than 50%.

[0019] Furthermore, in one embodiment, an accelerated storage test can be conducted at 40°C to assess the storage stability of lipid-coated poorly soluble drug nanocrystal core-shell particles. The particle size distribution is periodically measured by dynamic light scattering. After one month of storage, the increase in the volume distribution D90 in the excipient system does not exceed 50 nm, thus characterizing the particle size stability of the formulation under accelerated conditions.

[0020] Furthermore, in one embodiment, the lipid dispersion intermediate may have a particle size Z-avg value of 90-180 nm and a polydispersity index (PDI) value of no more than 0.25. Through optimization of high-pressure microfluidic conditions, the lipid components form a uniformly distributed nanoscale dispersion system, providing a stable lipid source for subsequent mixing with drug nanocrystal core-shell intermediates.

[0021] Furthermore, in one embodiment, the effect of adding the ternary lipid dispersion intermediate on the particle size stability and atomization performance of the final excipient system can be examined through comparative experiments. One group of samples was prepared using a method that only contains lipid-coated poorly soluble drug nanocrystal core-shell intermediates, while the other group of samples used a combination of lipid dispersion intermediates and lipid-coated poorly soluble drug nanocrystal core-shell intermediates. By comparing the differences in particle size changes and atomization characteristics between the two groups after accelerated storage, the positive role of the ternary lipid dispersion intermediate in maintaining long-term stability can be demonstrated.

[0022] Furthermore, in one embodiment, the particle size change of lipid-coated poorly soluble drug nanocrystal core-shell particles before and after atomization can be tested. The aerosol generated by atomization is collected into a buffer solution through a suitable collection device, and then the particle size of the collected dispersion is measured using dynamic light scattering to evaluate the impact of the atomization process on the integrity of the nanocrystal core-shell particles.

[0023] Furthermore, in one embodiment, the excipient system can be fractionated and separated by ultracentrifugation or ultrafiltration, and the drug content before and after separation can be measured respectively. This allows for the estimation of the proportion of drug mass in the lipid-coated poorly soluble drug nanocrystal core-shell particles to the total drug mass in the excipient system, in order to verify that the drug loading ratio is preferably not less than 60 wt%.

[0024] As another aspect of this invention, a multi-stage preparation process path of stepwise preparation, mixing, and post-optimization is adopted, primarily to enhance the batch stability, process controllability, and product quality uniformity of lipid-encapsulated poorly soluble drug nanocrystalline core-shell particles. By preparing the drug-loaded core-shell particle intermediate and the ternary lipid dispersion intermediate independently, process parameters can be optimized for the molding characteristics of different components, avoiding mutual interference between the drug and blank lipids under the same process conditions. The preparation of the drug-loaded core-shell particle intermediate employs an antisolvent precipitation in-situ encapsulation technique. Utilizing the solubility of nintedanib in ethanol and its extremely low solubility in aqueous buffer, the rapid nucleation of drug crystals and the synchronous self-assembly and encapsulation of the lipid shell are achieved by precisely controlling the injection rate and temperature conditions of the ethanol organic phase into the phosphate buffer. The introduction of high-pressure microfluidic technology further refines coarse crystals and homogenizes the lipid shell thickness, ensuring that the median particle size (D50) of the core-shell particles is precisely controlled within the range of 150-250 nm. The independent preparation of ternary lipid dispersion intermediates focuses on the nano-dispersion of blank lipid components. By optimizing the lipid molar ratio and high-pressure microfluidic parameters, the Z-avg value of the lipid dispersion is controlled within 90-180 nm, and the polydispersity index (PDI) is ≤0.25, forming a highly homogeneous nanolipid library. The dual-intermediate mixing stage promotes the dynamic adsorption and structural rearrangement of the lipid dispersion intermediates on the surface of drug-loaded core-shell particles by controlling the mixing ratio, shear rate, and temperature conditions, forming a multi-layered lipid stability network. Optional supplementary high-pressure microfluidic treatment further optimizes the particle size distribution and lipid shell integrity. Finally, through fine adjustment of osmotic pressure and pH, as well as sterile filtration, the excipient system is ensured to meet injection-grade quality standards and atomization performance requirements.

[0025] In this invention, the synergistic mechanism between lipid-coated poorly soluble drug nanocrystal core-shell particles and ternary lipid dispersion intermediates is analyzed in detail. The lipid-coated poorly soluble drug nanocrystal core-shell particles focus on achieving high drug loading and primary stabilization of the drug nanocrystals. Through the steric hindrance effect and hydrophobic barrier of the lipid shell, direct contact between the drug nanocrystals and the aqueous medium is prevented, inhibiting crystal growth caused by Ostwald ripening, while simultaneously providing a biocompatible interface for the particle surface. The ternary lipid dispersion intermediate focuses on the overall rheological regulation and enhanced secondary stabilization of the system. Its nanoscale lipid particles form a dynamic lipid adsorption layer in the gaps between the core-shell particles. Through a competitive balance between depletion attraction and steric repulsion, the effective attraction potential energy and aggregation tendency between the core-shell particles are significantly reduced. Regarding improving particle size stability, the lipid shell of lipid-coated poorly soluble drug nanocrystal core-shell particles delays the phase transition and particle size growth of drug nanocrystals through the reduction of interfacial Gibbs free energy and the action of crystallization inhibitors. The ternary lipid dispersion intermediate maintains the shell thickness and integrity by replenishing and repairing the lipids on the surface of the core-shell particles during storage, synergistically improving particle size stability under accelerated storage conditions at 40℃. Regarding reducing system viscosity and improving atomization performance, the core-shell particles themselves form a network structure under high solid content conditions, leading to increased viscosity. The introduction of the ternary lipid dispersion intermediate breaks the particle network and reduces shear stress through dilution and lubrication effects, allowing the system to still meet the rheological window of the vibrating membrane mesh nebulizer under high drug loading conditions. Under the action of atomization shear stress, the ternary lipid dispersion intermediate is rapidly adsorbed to the damaged parts of the core-shell particle surface, repairing the lipid shell damage in real time and maintaining the integrity of the core-shell structure, ensuring the consistency of particle size distribution and zeta potential before and after atomization. In summary, lipid-encapsulated poorly soluble drug nanocrystal core-shell particles and ternary lipid dispersion intermediates achieve comprehensive optimization of poorly soluble drug inhalation formulations in terms of high drug loading, long-term stability, low viscosity atomization, and core-shell structure integrity through multi-dimensional synergy of primary stability and secondary enhancement, static barrier and dynamic repair, and drug loading function and rheological regulation.

[0026] Beneficial technical effects 1. Achieving a synergistic balance between high drug loading and low viscosity atomization performance: This invention utilizes a two-component design of lipid-coated poorly soluble drug nanocrystalline core-shell particles and a ternary lipid dispersion intermediate. This design optimizes the proportion of drug mass in the lipid-coated poorly soluble drug nanocrystalline core-shell particles to the total drug mass in the excipient system to over 60 wt%, significantly improving drug loading efficiency and reducing administration volume and frequency. Simultaneously, the ternary lipid dispersion intermediate, through the formation of a lipid adsorption layer and lubrication effect between the core-shell particles, helps reduce the apparent viscosity of the system under high solids content conditions, making the excipient system more likely to meet the rheological performance requirements of vibrating membrane nebulizers. This achieves the simultaneous attainment of high drug loading and optimized atomization performance.

[0027] 2. Ensuring Long-Term Particle Size Stability and Low-Irritation Interfacial Electrochemical Design: This invention, through the regulation of lipid shell composition and a near-electroneutral interface design with an absolute zeta potential of ≤5mV, inhibits Ostwald ripening and aggregation of nanocrystal particles through steric hindrance and hydrophobic barrier effects. This allows the increase in the volume distribution D90 of lipid-coated poorly soluble drug nanocrystal core-shell particles to be controlled to no more than 50nm after one month of accelerated storage at 40±2℃, exhibiting excellent long-term particle size stability. On the other hand, by controlling the system's zeta potential within a low absolute value range close to electroneutrality, it helps to weaken the electrostatic interaction between charged particles and the respiratory mucosa surface, theoretically potentially reducing the risk of local irritation. Simultaneously, in a phosphate buffer containing physiological concentrations of salt ions, it helps maintain dispersion stability under weak charge conditions, thus achieving a balance between low irritation and dispersion stability.

[0028] 3. Optimization of lung deposition characteristics and aerosol performance parameters: This invention precisely controls the median mass diameter (D50) of lipid-encapsulated poorly soluble drug nanocrystal core-shell particles to be 150-250 nm and the volume distribution (D90) to be ≤400 nm. After atomization with a vibrating membrane mesh nebulizer, an aerosol with a median mass aerodynamic particle size of 2.8-3.8 µm and a fine particle fraction of ≥50% is formed. This aerodynamic particle size range is within the preferred deep lung deposition range, significantly improving the drug deposition efficiency in the alveoli and bronchioles. At the same time, the high fine particle fraction ensures the controllability and reproducibility of the effective inhaled dose, providing precise aerosol performance assurance for the targeted delivery of poorly soluble drugs to the lungs.

[0029] 4. Ensuring the integrity of the core-shell structure and controllable drug release before and after nebulization: This invention envisions that the ternary lipid dispersion intermediate, under the shear stress of nebulization, can, to a certain extent, replenish the lipids on the surface of the lipid-coated, poorly soluble drug nanocrystal core-shell particles, which helps maintain the integrity of the lipid shell layer. Theoretically, this helps to mitigate the direct exposure of drug nanocrystals during nebulization. Maintaining a relatively consistent particle size distribution and zeta potential before and after nebulization facilitates a relatively stable drug release process in the lungs, reducing the frequency of administration and improving treatment adherence.

[0030] 5. Enhanced formulation stability and biocompatibility: The dipalmitoyl-sn-glycerol-3-phosphocholine, cholesterol, and propylene glycol octanoate used in this invention are all biocompatible endogenous or near-endogenous lipid components with excellent pulmonary safety and metabolic acceptability. By adjusting the pH to 4.8-6.2 and the osmotic pressure to 280-320 mOsm / kg, the isotonic and pH characteristics of the excipient system with the physiological environment of the lungs are ensured, reducing irritation and inflammatory response to the respiratory mucosa. At the same time, the use of sterile filtration and a closed production system ensures the microbiological quality and long-term storage stability of the formulation, meeting the stringent quality standards for injectable inhaled formulations. Attached Figure Description

[0031] Figure 1 This is a superimposed XRD diffraction pattern of Example 1 and Comparative Example 13.

[0032] Figure 2 The correlation graph shows the relationship between crystallinity and D90 increase for different samples.

[0033] Figure 3 This is a bar graph showing the drug loading ratio of different samples.

[0034] Figure 4 This is the HPLC chromatogram of Example 1.

[0035] Figure 5 The Fourier transform infrared spectrum of lipid-coated poorly soluble drug nanocrystal core-shell particles in Example 1 is shown.

[0036] Figure 6 This is a zeta potential measurement diagram of lipid-coated poorly soluble drug nanocrystal core-shell particles from Example 1.

[0037] Figure 7 This is a differential scanning calorimetry (DSC) graph of lipid-coated poorly soluble drug nanocrystal core-shell particles from Example 1. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0039] Example 1 This embodiment provides an excipient system for pulmonary administration of poorly soluble drugs. The excipient system in this embodiment is an aqueous colloidal dispersion for atomization.

[0040] Step S1: Preparation of a drug-free ternary lipid dispersion intermediate B1. Raw material preparation: Weigh 10.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 2.5 parts by weight of cholesterol, and 1.5 parts by weight of propylene glycol octanoate. Add them to 95 vol% ethanol to make the total mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate 75 mg / mL. Stir at 52 °C until there is basically no solid precipitation in the system to obtain the lipid ethanol organic phase.

[0041] B2. Ethanol Injection Nucleation: At 52°C, the ethanol organic phase prepared in step B1 was injected at a rate of 1.2 mL / min into a phosphate buffer solution with a volume 12 times that of the ethanol phase. In this embodiment, the phosphate buffer solution contains sodium chloride, disodium hydrogen phosphate dodecahydrate, and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH value of the phosphate buffer solution in this embodiment is 5.4, thus obtaining a coarse dispersion.

[0042] B3. High-pressure microjets refinement: The coarse dispersion from step B2 was subjected to eight high-pressure microjets at an inlet temperature of 35°C and a pressure of 120 MPa. The time for each pass was 35 s, and the cooling time between two adjacent high-pressure microjets was 120 s. This yielded a lipid dispersion with a Z-avg value of 135 nm and a polydispersity index (PDI) of 0.18. In this embodiment, Z-avg and PDI were determined using dynamic light scattering.

[0043] B4. De-alcoholization and osmotic pressure adjustment: Under the conditions of absolute pressure of 10 kPa and temperature of 32°C, the residual ethanol volume fraction was controlled to 0.3 vol% by vacuum evaporation, and the osmotic pressure was adjusted to 300 mOsm / kg by adding sodium chloride, thus obtaining the ternary lipid dispersion intermediate of this embodiment.

[0044] Step S2: Preparation of lipid-coated, poorly soluble drug nanocrystal core-shell intermediate containing nintedanib A1. Raw material preparation: Weigh 5.0 parts by weight of nintedanib ethanesulfonate, 8.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 2.0 parts by weight of cholesterol, and 1.2 parts by weight of propylene glycol octanoate. Use 95 vol% ethanol as the organic solvent to prepare an ethanol organic phase with a total drug and lipid concentration of 70 mg / mL. Stir at 52°C until there is basically no solid precipitation in the system.

[0045] A2. Antisolvent precipitation and in-situ coating: At 52°C, the ethanol organic phase prepared in step A1 was injected at a rate of 1.2 mL / min into a phosphate buffer solution with a volume 12 times that of the ethanol phase. The phosphate buffer solution in this embodiment contains sodium chloride with a mass concentration of 6.0 mg / mL, and contains disodium hydrogen phosphate dodecahydrate and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH of the phosphate buffer solution in this embodiment is adjusted to 5.4. During this process, a dispersion containing coarse drug crystals and lipids is formed.

[0046] A3. High-pressure microjets refinement: The dispersion obtained in step A2 is subjected to 8 high-pressure microjets at an inlet temperature of 35°C and a pressure of 120 MPa. The single pass time is 35 s, and the cooling time between two adjacent high-pressure microjets is 120 s. This yields a dispersion of lipid-coated poorly soluble drug nanocrystalline core-shell particles. In this embodiment, the mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystalline core-shell particles is controlled to be 200 nm, and the volume distribution D90 is controlled to be 300 nm. The particle size distribution in this embodiment is determined by dynamic light scattering.

[0047] A4. De-alcoholization and quality control: Ethanol was removed by vacuum evaporation under an absolute pressure of 10 kPa and a temperature of 35 °C, so that the residual ethanol volume fraction was 0.3 vol%. The zeta potential value was measured to be -2 mV. The resulting dispersion is the core-shell intermediate of lipid-encapsulated poorly soluble drug nanocrystals.

[0048] Step S3: Mixing The ternary lipid dispersion intermediate obtained in step S1 and the lipid-coated poorly soluble drug nanocrystal core-shell intermediate obtained in step S2 were mixed at a mass ratio of 2:1 and stirred at 30°C for 30 min. In this embodiment, the mixing process was carried out at a shear rate of 500... It is carried out under the following conditions.

[0049] Step S4: Supplement with high-pressure microjets Three additional high-pressure microjets were applied at a pressure of 60 MPa to further homogenize the particle distribution.

[0050] Step S5: Adjust pH and osmotic pressure By adding sodium chloride and adjusting the concentration of phosphate buffer, the osmotic pressure was made to 300 mOsm / kg, and the final mass concentration of sodium chloride in the excipient system of this embodiment was 6.5 mg / mL. The pH value was adjusted to 5.5 using hydrochloric acid and sodium hydroxide.

[0051] Step S6: Sterilization filtration and filling The excipient system of this embodiment is sterilized and filtered through a hydrophilic filter membrane with a pore size of 0.22 μm and then filled. The particle size distribution of the lipid-coated poorly soluble drug nanocrystalline core-shell particles in the excipient system after sterilization filtration still meets the requirements of D50 and D90.

[0052] The preparation process in this embodiment is carried out at an ambient temperature of 20°C, and the entire production line adopts a closed system to reduce the risk of microbial contamination.

[0053] The excipient system of this embodiment comprises the following components: poorly soluble drug nanocrystals formed from nintedanib ethanesulfonate, dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, propylene glycol octanoate, phosphate buffer, sodium chloride, and water for injection. The outer surface of the poorly soluble drug nanocrystals in this embodiment is coated with a lipid shell composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate, forming lipid-coated poorly soluble drug nanocrystal core-shell particles.

[0054] In the excipient system of this embodiment, the median particle size (D50) of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 200 nm, and the volume distribution (D90) is 300 nm. The molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate in this embodiment is 64:26:10, which meets the range requirement of 60-80:15-30:5-10. At 25±2℃, using the excipient system itself as the dispersion medium, and measured by electrophoretic light scattering, the overall zeta potential of the excipient system in this embodiment is -2 mV, with an absolute value of 2 mV.

[0055] In this embodiment, the molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine to cholesterol in the lipid-coated poorly soluble drug nanocrystal core-shell particles is 2.46:1.0, and the molar percentage of propylene glycol octanoate to total lipids is 10.0 mol%. In the excipient system of this embodiment, the mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 11.0 mg / mL, the mass concentration of cholesterol is 2.4 mg / mL, the mass concentration of propylene glycol octanoate is 0.50 mg / mL, and the mass concentration of nintedanib is 5.0 mg / mL, which is greater than the equilibrium solubility of nintedanib isosulfonate in phosphate buffer under the pH conditions of this embodiment. The pH value of the excipient system in this embodiment is 5.5, and the osmotic pressure is 300 mOsm / kg.

[0056] When the excipient system of this embodiment was loaded into a vibrating diaphragm nebulizer for nebulization, a multi-stage cascade impactor configured and calibrated in accordance with the requirements of General Chapter 0951 "Determination of Aerodynamic Properties of Fine Particles in Inhalation Preparations" in the current edition of the Chinese Pharmacopoeia was used. Under the gas flow rate and sampling time conditions specified in the General Chapter, the median aerodynamic particle size of the formed aerosol was 3.2 μm, and the fine particle fraction was 58%. After accelerated storage for one month at 40±2℃, relative humidity not exceeding 75%, and in the dark, the increase in the volume distribution D90 of the lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system of this embodiment was 35 nm.

[0057] Example 1 Features and Application Scenarios: This example uses moderate parameter configurations. The particle size of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 200 nm, the nintedanib concentration is 5.0 mg / mL, the pH is 5.5, the osmotic pressure is 300 mOsm / kg, the dipalmitoyl-sn-glycerol-3-phosphocholine concentration is 11.0 mg / mL, the lipid component molar ratio is 64:26:10, the aerosol particle size is 3.2 μm, the fine particle fraction is 58%, and the acceleration stability is good. The parameter combination of this example has good balance and stability in terms of materials chemistry principles, the process conditions are easy to control and reproduce, and it is suitable for the routine treatment of idiopathic pulmonary fibrosis, especially for patients who require long-term stable drug administration.

[0058] Example 2 This embodiment provides an excipient system for pulmonary administration of poorly soluble drugs. The excipient system in this embodiment is an aqueous colloidal dispersion for atomization.

[0059] Step S1: Preparation of a drug-free ternary lipid dispersion intermediate B1. Raw material preparation: Weigh 15.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 2.5 parts by weight of cholesterol, and 1.8 parts by weight of propylene glycol octanoate. Add them to 95 vol% ethanol to make the total mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate 90 mg / mL. Stir at 55 °C until there is basically no solid precipitation in the system to obtain the lipid ethanol organic phase.

[0060] B2. Ethanol Injection Nucleation: At 55°C, the ethanol organic phase prepared in step B1 was injected at a rate of 1.5 mL / min into a phosphate buffer solution with a volume 15 times that of the ethanol phase. In this embodiment, the phosphate buffer solution contains sodium chloride, disodium hydrogen phosphate dodecahydrate, and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH value of the phosphate buffer solution in this embodiment is 5.7, thus obtaining a coarse dispersion.

[0061] B3. High-pressure microjets refinement: The coarse dispersion from step B2 was subjected to nine high-pressure microjets at an inlet temperature of 38°C and a pressure of 130 MPa. The time for each pass was 35 s, and the cooling time between two adjacent high-pressure microjets was 120 s. This yielded a lipid dispersion with a Z-avg value of 160 nm and a polydispersity index (PDI) of 0.22. In this embodiment, the Z-avg and PDI were determined using dynamic light scattering.

[0062] B4. De-alcoholization and osmotic pressure adjustment: Under the conditions of absolute pressure of 10 kPa and temperature of 35°C, the residual ethanol volume fraction was controlled to 0.4 vol% by vacuum evaporation, and the osmotic pressure was adjusted to 310 mOsm / kg by adding sodium chloride, thus obtaining the ternary lipid dispersion intermediate of this embodiment.

[0063] Step S2: Preparation of lipid-coated, poorly soluble drug nanocrystal core-shell intermediate containing nintedanib A1. Raw material preparation: Weigh 7.5 parts by weight of nintedanib ethanesulfonate, 10.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 2.0 parts by weight of cholesterol, and 1.5 parts by weight of propylene glycol octanoate. Use 95 vol% ethanol as the organic solvent to prepare an ethanol organic phase with a total drug and lipid mass concentration of 85 mg / mL. Stir at 55°C until there is basically no solid precipitation in the system.

[0064] A2. Antisolvent precipitation and in-situ coating: At 55°C, the ethanol organic phase prepared in step A1 was injected at a rate of 1.5 mL / min into a phosphate buffer solution with a volume 15 times that of the ethanol phase. The phosphate buffer solution in this embodiment contains sodium chloride with a mass concentration of 7.0 mg / mL, and contains disodium hydrogen phosphate dodecahydrate and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH of the phosphate buffer solution in this embodiment is adjusted to 5.7. During this process, a dispersion containing coarse drug crystals and lipids is formed.

[0065] A3. High-pressure microjets refinement: The dispersion obtained in step A2 is subjected to nine high-pressure microjets at an inlet temperature of 38°C and a pressure of 130 MPa. The single pass time is 35 s, and the cooling time between two adjacent high-pressure microjets is 120 s. This yields a dispersion of lipid-coated poorly soluble drug nanocrystalline core-shell particles. In this embodiment, the mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystalline core-shell particles is controlled to be 220 nm, and the volume distribution D90 is controlled to be 340 nm. The particle size distribution in this embodiment is determined by dynamic light scattering.

[0066] A4. De-ethanolification and quality control: Ethanol was removed by vacuum evaporation under an absolute pressure of 10 kPa and a temperature of 38 °C, so that the residual ethanol volume fraction was 0.4 vol%. The zeta potential value was measured to be +3 mV. The resulting dispersion is the core-shell intermediate of lipid-encapsulated poorly soluble drug nanocrystals.

[0067] Step S3: Mixing The ternary lipid dispersion intermediate obtained in step S1 and the lipid-coated poorly soluble drug nanocrystal core-shell intermediate obtained in step S2 were mixed at a mass ratio of 1:1 and stirred at 35°C for 45 min. In this embodiment, the mixing process was carried out at a shear rate of 750... It is carried out under the following conditions.

[0068] Step S4: Supplement with high-pressure microjets Three additional high-pressure microjets were applied at a pressure of 70 MPa to further homogenize the particle distribution.

[0069] Step S5: Adjust pH and osmotic pressure By adding sodium chloride and adjusting the concentration of phosphate buffer, the osmotic pressure was made to 310 mOsm / kg, and the final mass concentration of sodium chloride in the excipient system of this embodiment was 7.5 mg / mL. The pH value was adjusted to 5.8 using hydrochloric acid and sodium hydroxide.

[0070] Step S6: Sterilization filtration and filling The excipient system of this embodiment is sterilized and filtered through a hydrophilic filter membrane with a pore size of 0.22 μm and then filled. The particle size distribution of the lipid-coated poorly soluble drug nanocrystalline core-shell particles in the excipient system after sterilization filtration still meets the requirements of D50 and D90.

[0071] The preparation process in this embodiment is carried out at an ambient temperature of 20°C, and the entire production line adopts a closed system to reduce the risk of microbial contamination.

[0072] The excipient system of this embodiment comprises the following components: poorly soluble drug nanocrystals formed from nintedanib ethanesulfonate, dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, propylene glycol octanoate, phosphate buffer, sodium chloride, and water for injection. The outer surface of the poorly soluble drug nanocrystals in this embodiment is coated with a lipid shell composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate, forming lipid-coated poorly soluble drug nanocrystal core-shell particles.

[0073] In the excipient system of this embodiment, the median particle size (D50) of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 220 nm, and the volume distribution (D90) is 340 nm. The molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate in this embodiment is 70:21:9, which meets the range requirement of 60-80:15-30:5-10. At 25±2℃, using the excipient system itself as the dispersion medium, and measured by electrophoretic light scattering, the overall zeta potential of the excipient system in this embodiment is +3 mV, with an absolute value of 3 mV.

[0074] In this embodiment, the molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine to cholesterol in the lipid-coated poorly soluble drug nanocrystal core-shell particles is 3.33:1.0, and the molar percentage of propylene glycol octanoate to total lipids is 9.0 mol%. In the excipient system of this embodiment, the mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 13.5 mg / mL, the mass concentration of cholesterol is 2.2 mg / mL, the mass concentration of propylene glycol octanoate is 0.52 mg / mL, and the mass concentration of nintedanib is 7.5 mg / mL, which is greater than the equilibrium solubility of nintedanib isosulfonate in phosphate buffer under the pH conditions of this embodiment. The pH value of the excipient system in this embodiment is 5.8, and the osmotic pressure is 310 mOsm / kg.

[0075] When the excipient system of this embodiment was loaded into a vibrating diaphragm nebulizer for nebulization, a multi-stage cascade impactor configured and calibrated in accordance with the requirements of General Chapter 0951 "Determination of Aerodynamic Properties of Fine Particles in Inhalation Preparations" in the current edition of the Chinese Pharmacopoeia was used. Under the gas flow rate and sampling time conditions specified in the General Chapter, the median aerodynamic particle size of the formed aerosol was 3.6 μm, and the fine particle fraction was 52%. After accelerated storage for one month at 40±2℃, relative humidity not exceeding 75%, and in the dark, the increase in the volume distribution D90 of the lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system of this embodiment was 42 nm.

[0076] Example 2 Features and Application Scenarios: This example employs parameter configurations biased towards high drug loading and high lipid concentration. The particle size of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 220 nm, the nintedanib concentration is increased to 7.5 mg / mL, the pH value is 5.8, the osmotic pressure is 310 mOsm / kg, the dipalmitoyl-sn-glycerol-3-phosphocholine concentration reaches 13.5 mg / mL, the lipid component molar ratio is 70:21:9, the aerosol particle size is 3.6 μm, and the fine particle fraction is 52%. The high drug loading and high lipid concentration configuration of this example can provide stronger drug protection and drug loading capacity, and is suitable for critically ill pulmonary fibrosis patients who require high-dose drug delivery, especially suitable for clinical scenarios with rapid progression or requiring intensive treatment.

[0077] Example 3 This embodiment provides an excipient system for pulmonary administration of poorly soluble drugs. The excipient system in this embodiment is an aqueous colloidal dispersion for atomization.

[0078] Step S1: Preparation of a drug-free ternary lipid dispersion intermediate B1. Raw material preparation: Weigh 12.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 4.0 parts by weight of cholesterol, and 2.5 parts by weight of propylene glycol octanoate. Add them to 95 vol% ethanol to make the total mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate 65 mg / mL. Stir at 48 °C until there is basically no solid precipitation in the system to obtain the lipid ethanol organic phase.

[0079] B2. Ethanol Injection Nucleation: At 48°C, the ethanol organic phase prepared in step B1 was injected at a rate of 0.8 mL / min into a phosphate buffer solution with a volume 8 times that of the ethanol phase. In this embodiment, the phosphate buffer solution contains sodium chloride, disodium hydrogen phosphate dodecahydrate, and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH value of the phosphate buffer solution in this embodiment is 5.1, thus obtaining a coarse dispersion.

[0080] B3. High-pressure microjets refinement: The coarse dispersion from step B2 was subjected to seven high-pressure microjets at an inlet temperature of 32°C and a pressure of 110 MPa. The time for each pass was 35 s, and the cooling time between two adjacent high-pressure microjets was 120 s. This yielded a lipid dispersion with a Z-avg value of 110 nm and a polydispersity index (PDI) of 0.15. In this embodiment, Z-avg and PDI were determined using dynamic light scattering.

[0081] B4. De-alcoholization and osmotic pressure adjustment: Under the conditions of absolute pressure of 10 kPa and temperature of 28°C, the residual ethanol volume fraction was controlled to 0.2 vol% by vacuum evaporation, and the osmotic pressure was adjusted to 285 mOsm / kg by adding sodium chloride, thus obtaining the ternary lipid dispersion intermediate of this embodiment.

[0082] Step S2: Preparation of lipid-coated, poorly soluble drug nanocrystal core-shell intermediate containing nintedanib A1. Raw material preparation: Weigh 3.0 parts by weight of nintedanib ethanesulfonate, 10.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 3.5 parts by weight of cholesterol, and 2.0 parts by weight of propylene glycol octanoate. Use 95 vol% ethanol as the organic solvent to prepare an ethanol organic phase with a total drug and lipid mass concentration of 60 mg / mL. Stir at 48°C until there is basically no solid precipitation in the system.

[0083] A2. Antisolvent precipitation and in-situ coating: At 48°C, the ethanol organic phase prepared in step A1 was injected at a rate of 0.8 mL / min into a phosphate buffer solution with a volume 8 times that of the ethanol phase. The phosphate buffer solution in this embodiment contains sodium chloride with a mass concentration of 4.8 mg / mL, and contains disodium hydrogen phosphate dodecahydrate and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH of the phosphate buffer solution in this embodiment is adjusted to 5.1. During this process, a dispersion containing coarse drug crystals and lipids is formed.

[0084] A3. High-pressure microjets refinement: The dispersion obtained in step A2 is subjected to seven high-pressure microjets at an inlet temperature of 32°C and a pressure of 110 MPa. The single pass time is 35 s, and the cooling time between two adjacent high-pressure microjets is 120 s. This yields a dispersion of lipid-coated poorly soluble drug nanocrystalline core-shell particles. In this embodiment, the mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystalline core-shell particles is controlled to be 170 nm, and the volume distribution D90 is controlled to be 270 nm. The particle size distribution in this embodiment is determined by dynamic light scattering.

[0085] A4. De-ethanolification and quality control: Ethanol was removed by vacuum evaporation under an absolute pressure of 10 kPa and a temperature of 30 °C, so that the residual ethanol volume fraction was 0.2 vol%. The zeta potential value was measured to be -4 mV. The resulting dispersion is the core-shell intermediate of lipid-encapsulated poorly soluble drug nanocrystals.

[0086] Step S3: Mixing The ternary lipid dispersion intermediate obtained in step S1 and the lipid-coated poorly soluble drug nanocrystal core-shell intermediate obtained in step S2 were mixed at a mass ratio of 3:1 and stirred at 25°C for 20 min. In this embodiment, the mixing process was carried out at a shear rate of 300... It is carried out under the following conditions.

[0087] Step S4: Supplement with high-pressure microjets Two additional high-pressure microjets were applied at a pressure of 50 MPa to further homogenize the particle distribution.

[0088] Step S5: Adjust pH and osmotic pressure By adding sodium chloride and adjusting the concentration of phosphate buffer, the osmotic pressure was made to 285 mOsm / kg, and the final mass concentration of sodium chloride in the excipient system of this embodiment was 5.0 mg / mL. The pH value was adjusted to 5.2 using hydrochloric acid and sodium hydroxide.

[0089] Step S6: Sterilization filtration and filling The excipient system of this embodiment is sterilized and filtered through a hydrophilic filter membrane with a pore size of 0.22 μm and then filled. The particle size distribution of the lipid-coated poorly soluble drug nanocrystalline core-shell particles in the excipient system after sterilization filtration still meets the requirements of D50 and D90.

[0090] The preparation process in this embodiment is carried out at an ambient temperature of 20°C, and the entire production line adopts a closed system to reduce the risk of microbial contamination.

[0091] The excipient system of this embodiment comprises the following components: poorly soluble drug nanocrystals formed from nintedanib ethanesulfonate, dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, propylene glycol octanoate, phosphate buffer, sodium chloride, and water for injection. The outer surface of the poorly soluble drug nanocrystals in this embodiment is coated with a lipid shell composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate, forming lipid-coated poorly soluble drug nanocrystal core-shell particles.

[0092] In the excipient system of this embodiment, the median particle size (D50) of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 170 nm, and the volume distribution (D90) is 270 nm. The molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate in this embodiment is 64:26:10, which meets the range requirement of 60-80:15-30:5-10. At 25±2℃, using the excipient system itself as the dispersion medium, and measured by electrophoretic light scattering, the overall zeta potential of the excipient system in this embodiment is -4 mV, with an absolute value of 4 mV.

[0093] In this embodiment, the molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine to cholesterol in the lipid-coated poorly soluble drug nanocrystal core-shell particles is 2.46:1.0, and the molar percentage of propylene glycol octanoate to total lipids is 10.0 mol%. In the excipient system of this embodiment, the mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 14.2 mg / mL, the mass concentration of cholesterol is 3.0 mg / mL, the mass concentration of propylene glycol octanoate is 0.65 mg / mL, and the mass concentration of nintedanib is 3.0 mg / mL, which is greater than the equilibrium solubility of nintedanib isosulfonate in phosphate buffer under the pH conditions of this embodiment. The pH value of the excipient system in this embodiment is 5.2, and the osmotic pressure is 285 mOsm / kg.

[0094] When the excipient system of this embodiment was loaded into a vibrating diaphragm nebulizer for nebulization, a multi-stage cascade impactor configured and calibrated in accordance with the requirements of General Chapter 0951 "Determination of Aerodynamic Properties of Fine Particles in Inhalation Preparations" in the current edition of the Chinese Pharmacopoeia was used. Under the gas flow rate and sampling time conditions specified in the General Chapter, the median aerodynamic particle size of the formed aerosol was 2.9 μm, and the fine particle fraction was 62%. After accelerated storage for one month at 40±2℃, relative humidity not exceeding 75%, and in the dark, the increase in the volume distribution D90 of the lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system of this embodiment was 28 nm.

[0095] Example 3 Features and Application Scenarios: This example employs parameter configurations with a smaller particle size and a higher cholesterol ratio. The lipid-coated poorly soluble drug nanocrystal core-shell particles have a particle size of 170 nm, a nintedanib concentration of 3.0 mg / mL, a pH of 5.2, an osmotic pressure of 285 mOsm / kg, a dipalmitoyl-sn-glycerol-3-phosphocholine concentration of 14.2 mg / mL, a cholesterol concentration of 3.0 mg / mL, a lipid component molar ratio of 64:26:10, an aerosol particle size of 2.9 μm, and a fine particle fraction as high as 62%, exhibiting excellent accelerated stability. The small particle size and high fine particle fraction of this example enable deeper lung deposition, making it suitable for treatment needs requiring deep penetration into the alveolar region, and particularly suitable for patients with early pulmonary fibrosis or clinical applications requiring precise lung delivery.

[0096] Example 4 This embodiment provides an excipient system for pulmonary administration of poorly soluble drugs. The excipient system in this embodiment is an aqueous colloidal dispersion for atomization.

[0097] Step S1: Preparation of a drug-free ternary lipid dispersion intermediate B1. Raw material preparation: Weigh 18.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 2.0 parts by weight of cholesterol, and 1.2 parts by weight of propylene glycol octanoate. Add them to 95 vol% ethanol to make the total mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate 95 mg / mL. Stir at 58 °C until there is basically no solid precipitation in the system to obtain the lipid ethanol organic phase.

[0098] B2. Ethanol Injection Nucleation: At 58°C, the ethanol organic phase prepared in step B1 was injected at a rate of 1.8 mL / min into a phosphate buffer solution with a volume 18 times that of the ethanol phase. In this embodiment, the phosphate buffer solution contains sodium chloride, disodium hydrogen phosphate dodecahydrate, and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH value of the phosphate buffer solution in this embodiment is 6.0, and a coarse dispersion is obtained.

[0099] B3. High-pressure microjets refinement: The coarse dispersion from step B2 was subjected to 10 high-pressure microjets at an inlet temperature of 39°C and a pressure of 135 MPa. The time for each pass was 35 s, and the cooling time between two adjacent high-pressure microjets was 120 s. This yielded a lipid dispersion with a Z-avg value of 175 nm and a polydispersity index (PDI) of 0.24. In this embodiment, Z-avg and PDI were determined using dynamic light scattering.

[0100] B4. De-alcoholization and osmotic pressure adjustment: Under the conditions of absolute pressure of 10 kPa and temperature of 38°C, the residual ethanol volume fraction was controlled to 0.5 vol% by vacuum evaporation, and the osmotic pressure was adjusted to 315 mOsm / kg by adding sodium chloride, thus obtaining the ternary lipid dispersion intermediate of this embodiment.

[0101] Step S2: Preparation of lipid-coated, poorly soluble drug nanocrystal core-shell intermediate containing nintedanib A1. Raw material preparation: Weigh 9.0 parts by weight of nintedanib ethanesulfonate, 15.0 parts by weight of dipalmitoyl-sn-glycerol-3-phosphorylcholine, 2.0 parts by weight of cholesterol, and 1.0 parts by weight of propylene glycol octanoate. Use 95 vol% ethanol as the organic solvent to prepare an ethanol organic phase with a total drug and lipid mass concentration of 95 mg / mL. Stir at 58°C until there is basically no solid precipitation in the system.

[0102] A2. Antisolvent precipitation and in-situ coating: At 58°C, the ethanol organic phase prepared in step A1 was injected at a rate of 1.8 mL / min into a phosphate buffer solution with a volume 18 times that of the ethanol phase. The phosphate buffer solution in this embodiment contains sodium chloride with a mass concentration of 8.0 mg / mL, and contains disodium hydrogen phosphate dodecahydrate and potassium dihydrogen phosphate. The molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 2.0:1.0. The pH of the phosphate buffer solution in this embodiment is adjusted to 6.0. During this process, a dispersion containing coarse drug crystals and lipids is formed.

[0103] A3. High-pressure microjets refinement: The dispersion obtained in step A2 is subjected to 10 high-pressure microjets at an inlet temperature of 39°C and a pressure of 135 MPa. The single pass time is 35 s, and the cooling time between two adjacent high-pressure microjets is 120 s. This yields a dispersion of lipid-coated poorly soluble drug nanocrystalline core-shell particles. In this embodiment, the mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystalline core-shell particles is controlled to be 160 nm, and the volume distribution D90 is controlled to be 380 nm. The particle size distribution in this embodiment is determined by dynamic light scattering.

[0104] A4. De-alcoholization and quality control: Ethanol was removed by vacuum evaporation under an absolute pressure of 10 kPa and a temperature of 39 °C, so that the residual ethanol volume fraction was 0.5 vol%. The zeta potential value was measured to be +5 mV. The resulting dispersion is the core-shell intermediate of lipid-encapsulated poorly soluble drug nanocrystals.

[0105] Step S3: Mixing The ternary lipid dispersion intermediate obtained in step S1 and the lipid-coated poorly soluble drug nanocrystal core-shell intermediate obtained in step S2 were mixed at a mass ratio of 1:3 and stirred at 38°C for 55 min. In this embodiment, the mixing process was carried out at a shear rate of 900... It is carried out under the following conditions.

[0106] Step S4: Supplement with high-pressure microjets Four additional high-pressure microjets were applied at a pressure of 75 MPa to further homogenize the particle distribution.

[0107] Step S5: Adjust pH and osmotic pressure By adding sodium chloride and adjusting the concentration of phosphate buffer, the osmotic pressure was made to 315 mOsm / kg, and the final mass concentration of sodium chloride in the excipient system of this embodiment was 8.2 mg / mL. The pH value was adjusted to 6.1 using hydrochloric acid and sodium hydroxide.

[0108] Step S6: Sterilization filtration and filling The excipient system of this embodiment is sterilized and filtered through a hydrophilic filter membrane with a pore size of 0.22 μm and then filled. The particle size distribution of the lipid-coated poorly soluble drug nanocrystalline core-shell particles in the excipient system after sterilization filtration still meets the requirements of D50 and D90.

[0109] The preparation process in this embodiment is carried out at an ambient temperature of 20°C, and the entire production line adopts a closed system to reduce the risk of microbial contamination.

[0110] The excipient system of this embodiment comprises the following components: poorly soluble drug nanocrystals formed from nintedanib ethanesulfonate, dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, propylene glycol octanoate, phosphate buffer, sodium chloride, and water for injection. The outer surface of the poorly soluble drug nanocrystals in this embodiment is coated with a lipid shell composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate, forming lipid-coated poorly soluble drug nanocrystal core-shell particles.

[0111] In the excipient system of this embodiment, the median particle size (D50) of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 160 nm, and the volume distribution (D90) is 380 nm. The molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate in this embodiment is 74:17:9, which meets the range requirement of 60-80:15-30:5-10. At 25±2℃, using the excipient system itself as the dispersion medium, and measured by electrophoretic light scattering, the overall zeta potential of the excipient system in this embodiment is +5 mV, with an absolute value of 5 mV.

[0112] In this embodiment, the molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine to cholesterol in the lipid-coated poorly soluble drug nanocrystal core-shell particles is 4.35:1.0, and the molar percentage of propylene glycol octanoate to total lipids is 8.5 mol%. In the excipient system of this embodiment, the mass concentration of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 14.8 mg / mL, the mass concentration of cholesterol is 1.8 mg / mL, the mass concentration of propylene glycol octanoate is 0.50 mg / mL, and the mass concentration of nintedanib is 9.0 mg / mL, which is greater than the equilibrium solubility of nintedanib isosulfonate in phosphate buffer under the pH conditions of this embodiment. The pH value of the excipient system in this embodiment is 6.1, and the osmotic pressure is 315 mOsm / kg.

[0113] When the excipient system of this embodiment was loaded into a vibrating diaphragm nebulizer for nebulization, a multi-stage cascade impactor configured and calibrated in accordance with the requirements of General Chapter 0951 "Determination of Aerodynamic Properties of Fine Particles in Inhalation Preparations" in the current edition of the Chinese Pharmacopoeia was used. Under the gas flow rate and sampling time conditions specified in the General Chapter, the median aerodynamic particle size of the formed aerosol was 3.7 μm, and the fine particle fraction was 51%. After accelerated storage for one month at 40±2℃, relative humidity not exceeding 75%, and in the dark, the increase in the volume distribution D90 of the lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system of this embodiment was 48 nm.

[0114] Example 4 Features and Application Scenarios: This example employs a configuration close to the boundaries of multiple parameter ranges. The particle size D50 of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 160 nm (close to the lower limit), and the D90 is 380 nm (close to the upper limit). The nintedanib concentration reaches 9.0 mg / mL (close to the upper limit), the pH value is 6.1 (close to the upper limit), the osmotic pressure is 315 mOsm / kg, the sodium chloride concentration is 8.2 mg / mL (close to the upper limit), the dipalmitoyl-sn-glycerol-3-phosphorylcholine concentration is 14.8 mg / mL, the lipid component molar ratio is 74:17:9, the number of high-pressure microjets is 10 (reaching the upper limit), the aerosol particle size is 3.7 μm, and the fine particle fraction is 51%. This example, by selecting a combination close to the boundaries of parameter ranges, fully demonstrates the feasibility and stability of the excipient system within a wide parameter window, verifies the flexibility and robustness of the technical solution, and is suitable for the treatment of acute pulmonary fibrosis requiring high drug loading and rapid onset of action, as well as for patient groups with good pH tolerance.

[0115] Comparative Example 1: Basically the same as Example 1, except that the mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 140 nm, the volume distribution D90 is 260 nm, and the amounts of other components and preparation conditions remain unchanged.

[0116] Comparative Example 2: It is basically the same as Example 1, except that the mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 270 nm, the volume distribution D90 is 450 nm, and the amounts of other components and preparation conditions remain unchanged.

[0117] Comparative Example 3: It is basically the same as Example 1, except that the molar ratio of dipalmitoyl-sn-glycerol-3-phosphocholine, cholesterol and propylene glycol octanoate is adjusted to 55:30:15, while the amounts of other components and preparation conditions remain unchanged.

[0118] Comparative Example 4: It is basically the same as Example 1, except that the molar ratio of dipalmitoyl-sn-glycerol-3-phosphocholine, cholesterol and propylene glycol octanoate is adjusted to 85:12:3, while the amounts of other components and preparation conditions remain unchanged.

[0119] Comparative Example 5: It is basically the same as Example 1, except that the overall zeta potential of the excipient system is -12mV, which is achieved by adjusting the lipid composition ratio. Specifically, the amount of cholesterol is increased to 3.5 parts by mass, and the amount of dipalmitoyl-sn-glycerol-3-phosphocholine is reduced to 6.5 parts by mass, while other conditions remain unchanged.

[0120] Comparative Example 6: Basically the same as Example 1, except that the pH value was adjusted to 4.2, the molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate in the phosphate buffer was adjusted to 0.5:1.0, and the amounts of other components and preparation conditions remained unchanged.

[0121] Comparative Example 7: Basically the same as Example 1, except that the pH value was adjusted to 6.8, the molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate in the phosphate buffer was adjusted to 4.0:1.0, and the amounts of other components and preparation conditions remained unchanged.

[0122] Comparative Example 8: Basically the same as Example 1, except that the osmotic pressure is 250 mOsm / kg, the mass concentration of sodium chloride is adjusted to 3.5 mg / mL, and the amounts of other components and preparation conditions remain unchanged.

[0123] Comparative Example 9: Basically the same as Example 1, except that the osmotic pressure is 350 mOsm / kg, the mass concentration of sodium chloride is adjusted to 10.0 mg / mL, and the amounts of other components and preparation conditions remain unchanged.

[0124] Comparative Example 10: Basically the same as Example 1, except that the mass concentration of nintedanib is 0.5 mg / mL, and the mass ratio of the lipid-coated poorly soluble drug nanocrystal core-shell intermediate to the ternary lipid dispersion intermediate is adjusted to 1:5, while other preparation conditions remain unchanged.

[0125] Comparative Example 11: It is basically the same as Example 1, except that the mass concentration of nintedanib is 12.0 mg / mL, and the mass ratio of the lipid-coated poorly soluble drug nanocrystal core-shell intermediate to the ternary lipid dispersion intermediate is adjusted to 4:1. Other preparation conditions remain unchanged.

[0126] Comparative Example 12: It is basically the same as Example 1, except that the pressure of the high-pressure microjet treatment is 80 MPa and the number of treatments is 4, resulting in a median particle size D50 of 320 nm and a volume distribution D90 of 520 nm for lipid-coated poorly soluble drug nanocrystal core-shell particles, while the amount of other components remains unchanged.

[0127] Comparative Example 13: It is basically the same as Example 1, except that the ternary lipid dispersion intermediate prepared in step S1 is omitted. Only the lipid-encapsulated poorly soluble drug nanocrystal core-shell intermediate prepared in step S2 is used. The subsequent pH and osmotic pressure adjustment, sterile filtration and filling are carried out directly. Other preparation conditions remain unchanged.

[0128] Characterization and performance testing Particle size distribution determination of lipid-coated poorly soluble drug nanocrystalline core-shell particles: This experiment used lipid-coated poorly soluble drug nanocrystalline core-shell particles as the test object to evaluate the mass median particle size (D50) and volume distribution (D90) of the core-shell particles. The test principle was based on dynamic light scattering, which utilizes the intensity fluctuations of scattered light caused by Brownian motion of particles and calculates the hydrodynamic diameter using photon correlation spectroscopy. The experimental method involved taking an appropriate amount of the excipient system, diluting it to a suitable concentration with phosphate buffer solution of the same pH and osmotic pressure as the formulation, and measuring the particle size using a Malvern Zetasizer Nano ZS particle size analyzer at 25±2℃ with a detection angle of 173°. Each sample was measured in triplicate. Key parameters included test temperature 25±2℃, refractive index 1.45, absorption coefficient 0.001, dispersion medium viscosity 0.89 mPa·s, and sample concentration adjusted to a count rate of 200-400 kcps. Data processing employed the Cumulants method and multi-peak fitting algorithm to calculate Z-avg, polydispersity index (PDI), median particle size (D50), and volume distribution (D90), expressed as the arithmetic mean ± standard deviation of three measurements.

[0129] Zeta potential determination of excipient system: This experiment used the excipient system as the test object to evaluate the surface charge characteristics of colloidal particles and confirm that the absolute value of the zeta potential meets the requirement of ≤5mV. The test principle is based on electrophoretic light scattering, which causes charged particles to migrate directionally by applying an electric field. The electrophoretic mobility is calculated based on the Doppler frequency shift, and then the zeta potential is converted according to the Smoluchowski equation. The experimental method is as follows: an appropriate amount of excipient system is taken and diluted to a suitable concentration with phosphate buffer with the same pH and osmotic pressure as the formulation. The zeta potential is measured at 25±2℃ using a Malvern Zetasizer Nano ZS zeta potential analyzer, using a folded capillary electrophoresis cell. Each sample is measured in triplicate. Key parameters include test temperature 25±2℃, electric field strength approximately 20V / cm, sample concentration adjusted to a count rate of 100-300kcps, dielectric constant 78.5, and viscosity 0.89mPa·s. Data processing employed the Henry equation and the Smoluchowski approximation to calculate the ζ potential, which was expressed as the arithmetic mean ± standard deviation of three measurements, in mV.

[0130] pH and osmotic pressure determination of the excipient system: This experiment used the excipient system as the test object to verify that the pH value of the excipient system conformed to the range of 4.8-6.2 and the osmotic pressure conformed to the range of 280-320 mOsm / kg, ensuring compatibility with physiological conditions. The testing principle was that pH measurement was based on the glass electrode method, which calculates the pH value by measuring the potential difference generated by the hydrogen ion activity. Osmotic pressure measurement was based on the freezing point depression method, utilizing the principle that the freezing point depression of a solution is proportional to the osmotic molar concentration. The experimental method was as follows: pH measurement was performed using a pH meter calibrated with standard buffer solution, directly measuring the excipient system at 25±2℃; osmotic pressure measurement was performed using a freezing point osmoremeter, taking 50 μL of sample and measuring the freezing point within the range of -40℃ to 0℃, with each sample measured in triplicate. Key parameters included pH meter accuracy ±0.01, standard buffer solution pH 4.00, 6.86, 9.18; osmoremeter accuracy ±2 mOsm / kg, calibration solution 300 mOsm / kg. Data processing is expressed as the arithmetic mean ± standard deviation of three measurements. pH has no unit, and osmotic pressure is in mOsm / kg.

[0131] Determination of Mass Median Aerodynamic Size (MMAD) and Fine Particle Fraction (FPF) of Aerosols: This experiment uses aerosols formed after the excipient system is atomized by a vibrating membrane nebulizer as the test object. The purpose is to evaluate its pulmonary deposition characteristics and confirm that the mass median aerodynamic size (MMAD) meets the requirements of 2.8-3.8 μm and the fine particle fraction (FPF) ≥ 50%. The test principle is based on a multi-stage cascaded impactor that utilizes the inertial impaction effect of aerosols of different sizes at different flow rates to collect them in stages and weigh them to calculate MMAD and FPF. The experimental method involves loading the excipient system into a vibrating membrane nebulizer, using an ACI or NGI configured and calibrated according to General Chapter 0951 of the Chinese Pharmacopoeia, collecting aerosols at a flow rate of 28.3 L / min or 60 L / min, with sampling time determined according to the nebulizer output rate. Each collection plate and filter membrane is eluted with a suitable solvent, and the drug content is determined by HPLC. The standard is General Chapter 0951 of the current edition of the Chinese Pharmacopoeia, Part IV, "Determination of Aerodynamic Properties of Fine Particles in Inhaled Preparations". Key parameters included flow rates of 28.3±5% L / min or 60±5% L / min, cutoff particle sizes corresponding to each stage, temperatures of 20-25℃, and relative humidity of 40-60%. Data processing was used to calculate the percentage of drug deposition at each stage, and the cumulative distribution curve was fitted to the MMAD. The FPF was defined as the percentage of the total deposition in particles with a diameter ≤5μm.

[0132] Accelerated stability testing of the excipient system: This experiment used the excipient system as the test object to evaluate the increase in the volume distribution (D90) of lipid-encapsulated poorly soluble drug nanocrystal core-shell particles after one month of storage at 40±2℃, relative humidity not exceeding 75%, and in the dark. The test principle simulates the long-term storage process under accelerated aging conditions, and the particle size change is monitored using dynamic light scattering. The increase in D90 reflects the degree of particle aggregation or crystal growth. The experimental method involved dispensing the excipient system into sealed glass bottles and storing them for one month in a stability test chamber at 40±2℃, relative humidity not exceeding 75%, and in the dark. Samples were taken at 0, 7, 14, and 30 days, and the D90 was measured according to Experiment 1. The increase in D90 at 30 days relative to 0 days was calculated. Key parameters included temperature 40±2℃, relative humidity ≤75%, darkness protection, sampling time points of 0, 7, 14, and 30 days, and a minimum of three batches of samples. Data processing calculates D90 increase = D90(30 days) - D90(0 days), unit nm, taking the arithmetic mean ± standard deviation of 3 batches of samples, requiring an increase ≤ 50 nm.

[0133] Determination of Nintedanib Content and Drug Loading Ratio: This experiment used the excipient system as the test object to determine the total mass concentration of nintedanib in the excipient system and to evaluate the proportion of drug mass in lipid-encapsulated poorly soluble drug nanocrystal core-shell particles to the total drug mass using ultracentrifugation. The test principle is based on high-performance liquid chromatography (HPLC), utilizing the difference in partition coefficients of different components between the stationary and mobile phases to achieve separation and quantification. Ultracentrifugation separates the core-shell particles from the free drug. The experimental method was as follows: Total drug content was determined by methanol demulsification extraction, using a C18 column, with acetonitrile-phosphate buffer gradient elution as the mobile phase, a detection wavelength of 310 nm, and external standard method for quantification. Drug loading ratio was determined by ultracentrifugation at 100,000 g for 60 minutes to separate the supernatant and precipitate, and the contents of free drug and core-shell encapsulated drug were measured separately, and the ratio was calculated. Key parameters included column temperature 35℃, flow rate 1.0 mL / min, injection volume 20 μL, ultracentrifugation temperature 4℃, rotation speed 100,000 g, and time 60 minutes. Data processing expressed the total drug content as mg / mL. The drug loading ratio was calculated as (core-shell encapsulated drug mass / total drug mass) × 100%. The average value ± standard deviation of three parallel determinations was taken.

[0134] Figure 1 The image shows a superimposed XRD diffraction pattern of Example 1 and Comparative Example 13. The characterization method involved Cu Kα radiation powder X-ray diffraction to determine the diffraction curves within the 2θ 5–35° range, followed by pseudo-Voigt peak fitting and smoothing. Fixed parameters included the same batch of nintedanib isosulfonate crystals, the same instrument and test scan rate, sample pH of approximately 5.5, and osmotic pressure of approximately 300. The parameters varied were the formulation and process: Example 1 was an optimized nanocrystalline core-shell system, and Comparative Example 13 was a system with decreased crystallinity due to different drug loading strategies. The results showed that Example 1 had higher main diffraction peak intensities and relatively sharper peak shapes at approximately 12.5°, 18.3°, and 24.7°, with an estimated crystallinity of approximately 78%. Comparative Example 13 showed significantly lower peak intensities and increased peak widths, corresponding to a crystallinity of approximately 45%. Furthermore, in the stability test, the D90 increase in Comparative Example 13 was significantly greater than that in Example 1, indicating that maintaining a high crystallinity nanocrystalline core is beneficial for suppressing particle size growth and maintaining atomization performance.

[0135] Figure 2 A correlation plot of crystallinity vs. D90 increase was generated. The characterization method involved XRD refinement to obtain the crystallinity of different samples and correlation analysis with the D90 increase after accelerated storage at 40°C for 1 month. Fixed parameters included identical nystatinibu crystal form, consistent lipid class, pH and osmotic pressure controlled at 5.2–5.8 and approximately 300 ppm. Within the specified range, the stability testing conditions were uniform. The varying parameters were the sample formulation and process, with five representative examples selected: Example 1, Example 3, and Comparative Examples 1, 11, and 13. The results showed that when the crystallinity retention rate was 75–80% (Examples 1 and 3), the D90 increase was controlled at 28–35 nm. However, when the crystallinity decreased to 60%, 55%, and 45% (Comparative Examples 1, 11, and 13), the D90 increase rose to 52, 85, and 125 nm respectively, showing a clear negative correlation. This demonstrates that maintaining a high degree of crystallinity in the nanocrystal nucleus is a key factor in controlling particle size migration and atomized particle size stability.

[0136] Figure 3 The bar chart shows the drug loading ratio. The characterization method involved ultracentrifugation to separate the free drug from the particulate phase, followed by quantitative calculation of the drug loading ratio using HPLC. Fixed parameters included consistent batches of nintedanib raw materials, identical lipid types, and the same chromatographic conditions, centrifugation speed, and time. Variations included formulation strategy and drug concentration: Examples 1–4 employed a dual-intermediate strategy and moderate drug concentration, resulting in drug loading ratios of 64–72%. Comparative Examples 10, 11, and 13, representing insufficient drug loading, excessively high drug concentration, or improper intermediate use, had drug loading ratios of approximately 45%, 68%, and 48%, respectively. The results indicate that Examples 1–4 maintained stable particle size and atomization performance while ensuring a high drug loading ratio. Samples with excessively low drug loading or improper drug loading processes exhibited poor subsequent stability and atomization performance, demonstrating that a dual-intermediate strategy and a suitable drug loading ratio window design are fundamental to achieving a balance between high drug loading and stability.

[0137] Figure 4The HPLC chromatogram is shown. Characterization was performed using reversed-phase high-performance liquid chromatography (RP-HPLC) at a fixed mobile phase and flow rate, detecting the supernatant after centrifugation and the reconstituted precipitate. Drug content was quantified by the peak area at a retention time of approximately 4.5 min. Fixed parameters were maintained for the formulation and preparation process of Example 1, with consistent centrifugation conditions, injection volume, and detection wavelength. Variations were in the sample state: the supernatant represented free drug, and the reconstituted precipitate represented drug encapsulated in the core-shell particles; the peak areas of the two were significantly different. Results showed that the free drug peak area was smaller, corresponding to a lower free drug fraction, while the particle phase peak area was significantly larger, indicating that most of the drug existed in an encapsulated form. The calculated drug loading ratio was approximately 68%, and the total recovery rate was close to 100%. This demonstrates that the optimized core-shell structure can effectively enrich the drug within the lipid-coated nanocrystals under given formulation conditions, reducing the proportion of free drug and improving stability and nebulization delivery efficiency.

[0138] Figure 5 The image shows the Fourier transform infrared spectrum of lipid-coated poorly soluble drug nanocrystal core-shell particles from Example 1, with the parameter set to a nintedanib isosulfonate mass concentration of 5.0%. Dipalmitoyl-sn-glycerol-3-phosphocholine mass concentration 11.0 Cholesterol concentration 2.4 Propylene glycol octanoate concentration 0.50 Phosphate buffer solution, pH 5.5, osmotic pressure 300. The molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate in the system was 64:26:10. The changing parameter represents the transition of the drug from a molecularly dissolved state to a solid form of lipid-encapsulated, poorly soluble drug nanocrystal core-shell particles. The spectrum is between approximately 2920 and 2850 nm. The lipid alkyl C–H stretching vibration is characterized at 1740. Near the ester group C=O stretching absorption, at 1240 and 1080 The region shows vibrational signals of phosphate ester groups P=O and P–O–C. At the same time, the aromatic ring and hydrogen bond-related peak positions of nintedanib ethanesulfonate show slight shifts and changes in peak shape compared with the active pharmaceutical ingredient. This indicates that the drug is embedded in a lipid shell composed of dipalmitoyl-sn-glycero-3-phosphorylcholine, cholesterol, and propylene glycol octanoate and forms a stable non-covalent interaction with it. This demonstrates from the molecular vibrational level that the lipid-encapsulated nanocrystalline core-shell structure of the poorly soluble drug has been formed and the drug-lipid interface environment has been effectively regulated.

[0139] Figure 6 This is a zeta potential measurement graph of lipid-coated poorly soluble drug nanocrystal core-shell particles from Example 1, with the parameter fixed at a nintedanib isosulfonate mass concentration of 5.0. Dipalmitoyl-sn-glycerol-3-phosphocholine mass concentration 11.0 Cholesterol concentration 2.4 Propylene glycol octanoate concentration 0.50 Phosphate buffer solution, pH 5.5, osmotic pressure 300. The final mass concentration of sodium chloride is 6.5%. The median particle size (D50) of the lipid-encapsulated poorly soluble drug nanocrystalline core-shell particles was 200 nm, and the volume distribution (D90) was 300 nm. The variation parameter was the distribution of the electrokinetic potential of the particles in the system. The zeta potential distribution exhibited a narrow single peak around -2.0 ± 0.5 mV, without obvious multi-peaks or long tails. This indicates that under moderate ionic strength and weakly acidic pH conditions, the net surface charge of the particles was close to neutral and uniformly distributed. This is beneficial for reducing the risk of electrostatic aggregation and adhesion in the aqueous colloidal dispersion environment for pulmonary injection, while maintaining moderate colloidal stability. Combined with the result that D50 and D90 only increased slightly by 35 nm during long-term storage, this indicates that the weakly negative potential level achieved a balance between sedimentation stability and biocompatibility under the ionic strength and lipid composition conditions of this system. This supports the rationality of the structure and interface regulation strategy of this nanocrystalline core-shell system in pulmonary drug delivery scenarios.

[0140] Figure 7 This is a differential scanning calorimetry (DSC) chromatogram of lipid-coated poorly soluble drug nanocrystal core-shell particles from Example 1, with the parameter set to a nintedanib isosulfonate mass concentration of 5.0%. Dipalmitoyl-sn-glycerol-3-phosphocholine mass concentration 11.0 Cholesterol concentration 2.4 Propylene glycol octanoate concentration 0.50 The molar ratio of lipid components is 64:26:10, the pH value of the formulation is 5.5, and the osmotic pressure is 300. The particle size distribution (D50) is 200 nm, the volume distribution (D90) is 300 nm, the median aerodynamic particle size is 3.2 μm, and the fine particle fraction is 58%. The variation parameter is the heat flux behavior as a function of temperature during the heating process. The heat flux curve shows a smooth endothermic peak in the region of approximately 45 to 55 °C, corresponding to the melting transformation of the dipalmitoyl-sn-glycerol-3-phosphorylcholine lipid shell chain. The peak shape is slightly wider than that of the pure lipid system, indicating that cholesterol and propylene glycol octanoate ester synergistically regulate the order and fluidity of the lipid bilayer. A drug-related endothermic peak appears near approximately 130 to 150 °C, with the peak position slightly shifted relative to the melting peak of the active pharmaceutical ingredient. This indicates that the partial crystalline phase of nintedanib is subject to crystal form constraint or lattice defect regulation in the nanocrystalline core-shell structure, thereby reducing the sharpness of the macroscopic melting peak. Thermal analysis results show that the phase transition temperature of the lipid shell is significantly different from the formulation's usage temperature range. At the same time, the drug crystals are in a thermodynamically stable state at the nanoscale. This is consistent with the results that the D90 only increases by 35 nm and the aerosol fine particle fraction remains stable at around 58% under accelerated storage conditions. From the perspective of thermal behavior, this lipid-encapsulated poorly soluble drug nanocrystal core-shell system has good physical stability and structural reproducibility under pulmonary administration conditions.

[0141] As can be seen from the performance of the embodiments and comparative examples in Table 1, the four embodiments are significantly superior to the comparative examples in most key performance indicators, demonstrating the superiority of the technical solution of the present invention. The median particle size D50 of embodiments 1-4 is in the range of 160-220nm, and the volume distribution D90 is in the range of 270-380nm, all of which meet the requirements of 150-250nm and ≤400nm in the claims, and the narrow particle size distribution is conducive to uniform lung deposition; while the D50 of comparative example 1 is 140nm, which is below the lower limit, and the D50 of comparative examples 2 and 12 are 270nm and 320nm, respectively, which exceed the upper limit, and the D90 is as high as 450nm and 520nm, resulting in excessively large aerosol particle size (4.2-4.8μm) and a significant decrease in the fraction of fine particles (28-38%), which is not conducive to deep lung deposition. The absolute value of the ζ potential in the embodiment is controlled within the range of 2-5mV, which meets the low potential requirement of ≤5mV. However, the absolute value of the ζ potential in comparative examples 3 and 5 is as high as 8.5-12mV, resulting in a significant increase in the acceleration stability D90 (65-82nm), far exceeding the 50nm control standard. The pH (5.2-6.1), osmotic pressure (285-315 mOsm / kg), aerosol MMAD (2.9-3.7 μm), and fine particle fraction (51-62%) of the examples were all within reasonable ranges. However, the pH values ​​of Comparative Examples 6 and 7 deviated to 4.2 and 6.8, and the osmotic pressures of Comparative Examples 8 and 9 deviated to 250 and 350 mOsm / kg, all of which led to decreased stability. The drug concentration of Comparative Example 10 was too low (0.5 mg / mL), resulting in a drug loading ratio of only 45%. The drug concentration of Comparative Example 11 was too high (12.0 mg / mL), leading to deterioration of stability (D90 increase of 85 nm). The process parameters of Comparative Example 12 were insufficient, resulting in excessively large particle size and a serious decrease in atomization performance. The lack of a ternary lipid dispersion intermediate in Comparative Example 13 led to a significant deterioration in long-term stability (D90 increase of 125 nm) and a low drug loading ratio (48%). In summary, this invention, by precisely controlling the particle size, lipid composition ratio, interfacial potential, pH, and osmotic pressure of lipid-encapsulated poorly soluble drug nanocrystal core-shell particles, combined with the synergistic stabilizing effect of ternary lipid dispersion intermediates and optimized high-pressure microfluidic process, successfully achieves a comprehensive balance of high drug loading, low irritation, long-term particle size stability, and optimized lung deposition distribution, which is significantly better than the comparative examples of deviations from individual factors.

[0142] Table 1 Performance comparison data between the examples and comparative examples

[0143] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. An excipient system for pulmonary administration of poorly soluble drugs, characterized in that, The excipient system is an aqueous colloidal dispersion for atomization, comprising the following components: Poorly soluble drug nanocrystals, wherein the poorly soluble drug nanocrystals are nanocrystals formed from nintedanib or its pharmaceutically acceptable salts; Dipalmitoyl-sn-glycero-3-phosphocholine; cholesterol; Propylene glycol octanoate; Phosphate buffer and sodium chloride are used to adjust the pH to 4.8-6.2 and the osmotic pressure to 280-320 mOsm / kg; Water for injection; in: The outer surface of the poorly soluble drug nanocrystals is coated with a lipid shell composed of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol and propylene glycol octanoate, forming lipid-coated poorly soluble drug nanocrystal core-shell particles. The mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystal core-shell particles is 150-250 nm, and the volume distribution D90 value is ≤400 nm. The molar ratio of dipalmitoyl-sn-glycerol-3-phosphorylcholine, cholesterol, and propylene glycol octanoate is 60-80:15-30:5-10; When measured by electrophoretic light scattering at 25±2℃, using the excipient system itself or a phosphate buffer solution with the same phosphate and sodium chloride concentration and pH as the excipient system as the dispersion medium, the absolute value of the overall zeta potential of the excipient system is ≤5mV. The mass of the drug loaded in the lipid-coated poorly soluble drug nanocrystal core-shell particles accounts for more than 60 wt% of the total mass of the drug in the excipient system.

2. The excipient system as described in claim 1, characterized in that, The lipid-coated, poorly soluble drug nanocrystalline core-shell particles are prepared through the following steps: A1. Raw material preparation: The poorly soluble drug is nintedanib or a pharmaceutically acceptable salt thereof, and the amount of nintedanib used is 1.0-10.0 parts by weight; The dosage of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 5.0-20.0 parts by weight; The dosage of cholesterol is 2.0-10.0 parts by weight; The dosage of propylene glycol octanoate is 1.0-10.0 parts by weight; Ethanol was used as an organic solvent to prepare an ethanol organic phase with a total drug and lipid mass concentration of 50-100 mg / mL. The mixture was stirred at 45-60°C until almost no solid precipitation was observed in the system. A2. Anti-solvent precipitation and in-situ coating: At 45-60°C, the ethanol organic phase prepared in step A1 is injected at a rate of 0.5-2.0 mL / min into a phosphate buffer solution with a volume of 5-20 times that of the ethanol phase. The phosphate buffer solution contains sodium chloride with a mass concentration of 4.5-8.5 mg / mL, and also contains disodium hydrogen phosphate dodecahydrate and potassium dihydrogen phosphate. The pH of the phosphate buffer solution is adjusted to 4.8-6.

2. During this process, a dispersion containing coarse drug crystals and lipids is formed. A3. High-pressure micro-jets are refined: The dispersion obtained in step A2 is subjected to high-pressure microfluidic treatment 6-10 times at an inlet temperature of 30-40℃ and a pressure of 100-140MPa to obtain a dispersion of lipid-coated poorly soluble drug nanocrystalline core-shell particles. The mass median particle size D50 of the lipid-coated poorly soluble drug nanocrystalline core-shell particles is controlled to be 150-250nm, and the volume distribution D90 is controlled to be ≤400nm. The particle size distribution is determined by dynamic light scattering method. A4. De-alcoholization and Quality Control: Ethanol is removed by vacuum evaporation or membrane separation at a temperature not exceeding 40°C, so that the residual ethanol volume fraction is ≤0.5 vol%, and the zeta potential value is detected as -5 to +5 mV. The resulting dispersion is the core-shell intermediate of lipid-encapsulated poorly soluble drug nanocrystals.

3. The excipient system as described in claim 1, characterized in that, The excipient system also includes a drug-free ternary lipid dispersion intermediate composed of dipalmitoyl-sn-glycero-3-phosphorylcholine, cholesterol, and propylene glycol octanoate, which is prepared by the following steps: B1. Raw material preparation: The dosage of dipalmitoyl-sn-glycerol-3-phosphorylcholine is 5.0-20.0 parts by weight; The dosage of cholesterol is 2.0-10.0 parts by weight; The dosage of propylene glycol octanoate is 1.0-10.0 parts by weight; The amount of ethanol used was such that the total mass concentration of dipalmitoyl-sn-glycerol-3-phosphocholine, cholesterol and propylene glycol octanoate was 50-100 mg / mL. The mixture was stirred at 45-60 °C until almost no solid precipitation was observed in the system, thus obtaining the lipid ethanol organic phase. B2. Ethanol injection for nucleation: At 45-60℃, the ethanol organic phase prepared in step B1 is injected at a rate of 0.5-2.0 mL / min into a phosphate buffer solution with a volume of 5-20 times that of the ethanol phase. The phosphate buffer solution contains sodium chloride, disodium hydrogen phosphate dodecahydrate, and potassium dihydrogen phosphate. The pH value of the phosphate buffer solution is 4.8-6.2 to obtain a coarse dispersion. B3. High-pressure microjets refinement: The coarse dispersion obtained in step B2 was subjected to high-pressure microfluidic treatment 6-10 times at an inlet temperature of 30-40℃ and a pressure of 100-140MPa to obtain a lipid dispersion with a particle size Z-avg value of 90-180nm and a polydispersity index (PDI) value of ≤0.

25. The Z-avg and PDI were determined by dynamic light scattering method. B4. De-alcoholization and osmotic pressure regulation: The residual ethanol volume fraction was controlled to ≤0.5 vol% by vacuum evaporation or membrane separation, and the osmotic pressure was adjusted to 280-320 mOsm / kg by adding sodium chloride, thus obtaining the ternary lipid dispersion intermediate.

4. The excipient system as described in claim 1, characterized in that, The molar ratio of dipalmitoyl-sn-glycero-3-phosphorylcholine to cholesterol in the lipid-coated poorly soluble drug nanocrystal core-shell particles is 2.5-5.0:1.0, and the molar number of propylene glycol octanoate accounts for 5-10 mol% of the total lipid molar number. The excipient system contains dipalmitoyl-sn-glycerol-3-phosphorylcholine at a mass concentration of 5-15 mg / mL, cholesterol at a mass concentration of 1-5 mg / mL, and propylene glycol octanoate at a mass concentration of 0.5-3 mg / mL. The mass concentration of nintedanib or its pharmaceutically acceptable salt in the excipient system is 1.0-10.0 mg / mL, and is greater than the equilibrium solubility of nintedanib or its pharmaceutically acceptable salt in phosphate buffer under the stated pH conditions. The pH value of the excipient system is 4.8-6.

2.

5. The excipient system as described in claim 1, characterized in that, When the excipient system is loaded into a vibrating diaphragm nebulizer for nebulization, a multi-stage cascade impactor configured and calibrated in accordance with the requirements of General Chapter 0951 "Determination of Aerodynamic Properties of Fine Particles in Inhalation Preparations" in the current edition of the Chinese Pharmacopoeia, under the gas flow rate and sampling time conditions specified in the General Chapter, is used to determine that the median aerodynamic particle size of the formed aerosol is 2.8-3.8 µm and the fine particle fraction is ≥50%. After one month of accelerated storage at 40±2℃, relative humidity not greater than 75%, and in the dark, the increase in the volume distribution D90 of the lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system is not more than 50 nm.

6. The excipient system as described in claim 1, characterized in that, The excipient system contains dipalmitoyl-sn-glycerol-3-phosphorylcholine at a mass concentration of 5-15 mg / mL, cholesterol at a mass concentration of 1-5 mg / mL, propylene glycol octanoate at a mass concentration of 0.5-3 mg / mL, and nintedanib or a pharmaceutically acceptable salt thereof at a mass concentration of 1.0-10.0 mg / mL, which is greater than the equilibrium solubility of the nintedanib or a pharmaceutically acceptable salt thereof in phosphate buffer under the stated pH conditions.

7. A method for preparing an excipient system for pulmonary administration of poorly soluble drugs as described in any one of claims 1-6, characterized in that, Includes the following steps: S1. Preparation of drug-free ternary lipid dispersion intermediates; S2. Preparation of lipid-coated, poorly soluble drug nanocrystal core-shell intermediate containing nintedanib; S3. The ternary lipid dispersion intermediate obtained in step S1 and the lipid-coated poorly soluble drug nanocrystal core-shell intermediate obtained in step S2 are mixed at a mass ratio of 1:3-3:1, and stirred at 20-40℃ for 10-60 min. The mixing process is carried out at a shear rate of 100-1000. Under the conditions; S4. By adding sodium chloride and adjusting the concentration of phosphate buffer salt, the osmotic pressure is made to be 280-320 mOsm / kg, and the final mass concentration of sodium chloride in the excipient system is made to be 4.5-8.5 mg / mL, and the pH is adjusted to 4.8-6.2 using hydrochloric acid and / or sodium hydroxide. S5. The excipient system is obtained by sterilization filtration and filling. The sterilization filtration adopts a hydrophilic filter membrane with a pore size of 0.22µm. The particle size distribution of lipid-coated poorly soluble drug nanocrystal core-shell particles in the excipient system after sterilization filtration still meets the requirements of D50 and D90.

8. The preparation method according to claim 7, characterized in that: In step S2, the single pass time of the high-pressure microjet treatment is 10-60s, and the cooling time between two adjacent high-pressure microjet treatments is 30-300s. The ethanol removal steps involved in steps S1 and S2 are carried out under an absolute pressure of 4-20 kPa and a temperature of 25-40℃ until the residual ethanol volume fraction is ≤0.5 vol%. The ethanol volume fraction used in both steps S1 and S2 is ≥80 vol%. After step S3 and before step S4, the process further includes step S3': performing 2-4 additional high-pressure microjet treatments at a pressure of 40-80 MPa to further homogenize the particle distribution.

9. The preparation method according to claim 7, characterized in that: The preparation process is carried out at an ambient temperature not exceeding 25°C, and the entire production line adopts a closed system to reduce the risk of microbial contamination.

10. The preparation method according to claim 7, characterized in that, In the phosphate buffer solution used in step S1 (B2) and step S2 (A2), the molar ratio of disodium hydrogen phosphate dodecahydrate to potassium dihydrogen phosphate is 1.0-3.0:1.0.

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