An inhaled pirefenidone powder formulation, its preparation method and use

Abstract

The application discloses a pirfenidone inhalation powder, a preparation method and application thereof, and belongs to the field of pharmaceutical preparations. The pirfenidone inhalation powder comprises pirfenidone as an active ingredient and an excipient; wherein the excipient comprises any one of the following: an amino acid surface modifier, a mixture of the amino acid surface modifier and a saccharide excipient, a mixture of the amino acid surface modifier and a sugar alcohol excipient, or a mixture of the amino acid surface modifier, the saccharide excipient and the sugar alcohol excipient. The pirfenidone inhalation powder prepared by a spray drying process is used for treating lung diseases, directly delivering the medicine to an effective site, and is expected to realize the reduction of a dosing dose, the improvement of a deposition rate, and the significant improvement of a treatment effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a pirfenidone inhalation powder, its preparation method, and its application. Background Technology

[0002] Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a high mortality rate and limited treatment options. Decades of research have revealed the complex underlying pathophysiology of IPF, including alterations in many aspects of molecular and cellular physiology, such as genetics, epigenetics, microRNAs (miRNAs), developmental reprogramming, cell signaling pathways, apoptosis, metabolism, and autophagy.

[0003] Fibrosis is generally defined as the excessive pathological deposition of the extracellular matrix (ECM) during wound healing. Fibrosis is a highly coordinated process integrating multiple cell types and signaling mechanisms across organ systems. Different triggers, such as burns, infections, autoimmune disorders, surgical and non-surgical trauma, foreign bodies, and tumors, converge on similar fibrotic pathways. The wound healing process triggered by one of these factors induces an inflammatory response, ultimately recruiting fibroblasts and activating the myofibroblast subset, which deposits ECM in the form of collagen and other proteins. While wound healing typically resolves with myofibroblast apoptosis, in fibrotic disease states, pro-fibrotic activators and myofibroblasts persist.

[0004] Currently, there are three effective drugs for the treatment of idiopathic pulmonary fibrosis: nintedanib, pirfenidone, and nerandomilast. All three are currently available in oral formulations. Nerandomilast tablets were recently approved by the FDA in October 2025, but clinical data are still lacking. Pirfenidone, on the other hand, is available in oral soft capsules and tablets and is approved globally for the treatment of idiopathic pulmonary fibrosis. Although pirfenidone has significantly higher bioavailability than nintedanib, its exposure in the gastrointestinal tract and bloodstream after oral administration leads to poor tolerability, causing gastrointestinal (dyspepsia and anorexia) and dermatological (photosensitivity) side effects. Therefore, existing oral pirfenidone formulations have significant adverse reactions, and none of the current treatments have a locally administered formulation for the lungs. Clinically, there is a lack of pirfenidone formulations with better safety and stronger targeting. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a pirfenidone inhalation powder, its preparation method, and its application. The pirfenidone inhalation powder has the advantages of directly delivering the drug to the lungs, achieving a high deposition rate in the lungs, and exhibiting good storage stability.

[0006] This invention designs pirfenidone as a powder inhaler for the treatment of lung diseases, directly delivering the drug to the target site. This approach aims to reduce the dosage, increase the deposition rate, and thus significantly improve therapeutic efficacy. This strategy is of great significance for current clinical treatment of IPF.

[0007] Inhaled powder inhalers, also known as dry powder inhalers, refer to one or more medications that are delivered into the respiratory tract in dry powder form through a special inhalation device to exert systemic or local effects. They have many advantages, including high lung deposition efficiency, no propellants, low cost, and high patient compliance.

[0008] The present invention provides a pirfenidone inhalation powder formulation comprising pirfenidone as an active ingredient and an excipient; the excipient is selected from any of the following: amino acid surface modifiers, mixtures of amino acid surface modifiers and sugar excipients, mixtures of amino acid surface modifiers and sugar alcohol excipients, mixtures of amino acid surface modifiers and sugar excipients, and sugar alcohol excipients.

[0009] The amino acid surface modifier is a pharmaceutical amino acid excipient selected from one or more of leucine, L-leucyl-L-leucyl-L-leucine (abbreviated as trileucine), cysteine, tyrosine, lysine, arginine, valine, histidine, phenylalanine, threonine, glycine, and serine.

[0010] Furthermore, the amino acid surface modifier is preferably a hydrophobic amino acid excipient, wherein the hydrophobic amino acid excipient is valine, leucine (Leu), trileucine (Tri), or phenylalanine (Phe).

[0011] The leucine is L-leucine, polyleucine, D-leucine, or N-acetylleucine.

[0012] Hydrophobic amino acids are a class of compounds with significantly hydrophobic side chain groups. During spray drying, they can accumulate on the surface of droplets, with their hydrophobic ends aligning outwards to form a hydrophobic coating (Zhang et al. International Journal of Pharmaceutics, 624 (2022) 122011.). This effectively reduces interparticle adhesion, improves powder dispersibility, and provides moisture protection for the powder atomizer, preventing non-dispersible aggregation and deterioration of atomization performance. The saccharide excipient is a pharmaceutical saccharide excipient in the art, selected from one or more of mannose, trehalose, lactose, hyaluronic acid, and cyclodextrin.

[0013] The sugar alcohol excipient is a pharmaceutical sugar alcohol excipient in this field, selected from one or more of xylitol, sorbitol and mannitol.

[0014] The sugar excipients and sugar alcohol excipients can increase the wettability of particles and improve powder properties.

[0015] Furthermore, the excipients of the present invention are any one of the following systems: "valine and hyaluronic acid", "phenylalanine and mannitol", "trileucine, cyclodextrin and mannitol", "leucine, trehalose and mannitol", "leucine", "leucine and trehalose", "phenylalanine", "trileucine", "leucine and mannitol", "leucine and xylitol", "trileucine and trehalose", "trileucine and mannitol".

[0016] Based on the total mass of pirfenidone inhalation powder as 100%:

[0017] The amount of the active ingredient pirfenidone is 1wt%-99wt% of the total mass of the pirfenidone inhalation powder, further 10wt%-90wt%, and even further 40wt%-90wt%, for example, 10wt%, 30wt%, 45wt%, 60wt%, 80wt%, 85wt%, and 90wt%.

[0018] The excipient is used in an amount of 1 wt% to 99 wt% of the total mass of the pirfenidone inhalation powder, further 10 wt% to 90 wt%, and even further 10 wt% to 60 wt%; for example, 2 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 22.5 wt%, 55 wt%, 75.5 wt%, 90 wt%, or 95 wt%.

[0019] Wherein: the amount of the amino acid surface modifier is 5wt%-85wt% of the total mass of the pirfenidone inhalation powder, further 5wt%-70wt%, and even further 5wt%-50wt%, for example, 5wt%, 11wt%, 15wt%, 20wt%, 22.5wt%, 30wt%, 55wt%, 75.5wt%, or 85wt%.

[0020] The excipient components and contents of the pirfenidone inhalation powder include any one of the following systems: "40wt% leucine, 20wt% mannitol and 7wt% trehalose", "20wt% trileucine, 20wt% cyclodextrin and 10wt% mannitol", "12wt% trehalose and 25wt% leucine", "40wt% leucine", "20wt% leucine", "10wt% leucine", "15wt% leucine", "5wt% leucine", "5wt% trileucine". “7wt% Trileucine”, “10wt% Trileucine”, “13wt% L-Leucyl-L-Leucyl-L-Leucine”, “27wt% Trileucine”, “95wt% Leucine and 1wt% Mannitol”, “90.5wt% Leucine and 0.5wt% Mannitol”, “45wt% Phenylalanine”, “84wt% Phenylalanine and 5.5wt% Mannitol”, “37wt% Trehalose and 14wt% Leucine”, “12wt% Trehalose and 25wt% Leucine”.

[0021] The pirfenidone inhalation powder of this invention is prepared by a spray drying process, comprising the following steps: dissolving or dispersing the active ingredient and the excipient in a solvent to obtain a spray-dried injection solution, and then spray-drying to obtain pirfenidone dry powder. The spray-dried injection solution refers to a mixture containing the active ingredient and excipient to be spray-dried, and its form can be a solution, suspension, or emulsion. The solvent can be an organic phase or a mixture of an organic phase and an aqueous phase; the organic phase is methanol, acetonitrile, or a mixture of methanol and acetone. The total solid concentration of the pirfenidone and the excipient can be 2 mg / mL-90 mg / mL, 2 mg / mL-20 mg / mL, more specifically 5 mg / mL-20 mg / mL, for example, 10 mg / mL.

[0022] The spray drying conditions can be adjusted to suit the specific model and size of the spray drying equipment used.

[0023] In this invention, the spray drying conditions, regardless of the size of the spray drying equipment, can be as follows: the inlet temperature of the spray dryer is 50℃-150℃, preferably 60℃-120℃; the outlet temperature of the spray dryer is 30℃-100℃, preferably 40℃-70℃.

[0024] In some specific embodiments, when using a small-scale spray drying device, the conditions for small-scale spray drying can be further defined as follows: the atomization pressure of the small-scale spray drying is 357 L / h-819 L / h, preferably 473 L / h-819 L / h. The feed rate of the small-scale spray drying is 1 mL / min-20 mL / min, preferably 2 mL / min-10 mL / min.

[0025] The pirfenidone inhalation powder of the present invention is used to treat pulmonary fibrosis, especially idiopathic pulmonary fibrosis, by delivering the drug directly to the lungs through inhalation.

[0026] The pirfenidone inhalation powder of the present invention can be in the form of a single-dose capsule inhalation powder.

[0027] The size of the single-dose capsules, according to conventional art, can generally be any of the following: size 0, 1, 2, 3, or 4. The material of the single-dose capsules can be gelatin or hydroxypropyl methylcellulose (HPMC).

[0028] The particle size D of the pirfenidone inhalation powder obtained in this invention is... 50 The diameter is 1.64 μm-4.25 μm, preferably 1.65 μm-2.87 μm. The in vitro drug deposition rate (FPF) is 17.23%-68.32%; the aerodynamic mass median diameter (MMAD) is 2.93 μm-6.49 μm, preferably 2.93 μm-6.29 μm.

[0029] The optimal formulation of pirfenidone inhalation powder in this invention, after being stored at 25°C and 10% humidity for 90 days, has a particle size D... 50 Stable (after storage D) 50 The change is less than 5%.

[0030] The beneficial effects of this invention are as follows: The pirfenidone inhaled powder of this invention delivers the drug directly to the lungs, achieving a high local drug concentration in the lungs, reducing systemic drug exposure, and mitigating toxic side effects. Through spray drying, the appropriate particle size (1μm-5μm), morphology, and precise aerodynamic parameters were further designed to maximize deposition in the lungs. Developing pirfenidone into an inhalable powder is of great significance in addressing the current predicament of lacking more ideal new compounds for clinical IPF treatment. Attached Figure Description

[0031] Figure 1 X-ray powder diffraction patterns of the pirfenidone inhalation powder prepared in Examples 1-9 and Comparative Example 1.

[0032] Figure 2DSC thermal images of the pirfenidone inhalation powder prepared in Examples 1-9 and Comparative Example 1.

[0033] Figure 3 The images show the in vitro deposition of pirfenidone inhalation powder prepared in Examples 1-9 and Comparative Example 1.

[0034] Figure 4 Scanning electron microscope (SEM) images of the pirfenidone inhalation powder prepared in Examples 1-9 and Comparative Example 1.

[0035] Figure 5 The stability test results of the pirfenidone inhalation powder prepared in Examples 1-5 after 90 days of storage are shown in the figure; where **P<0.01, ***P<0.001, ****P<0.0001, and ns indicate no statistical difference. Detailed Implementation

[0036] The present invention is further illustrated below by way of embodiments, but these embodiments are not intended to limit the invention to their scope. Experimental methods not specifically described in the following embodiments are performed according to conventional methods and conditions, or as selected according to the product instructions. Those skilled in the art should understand that the embodiments are merely illustrative of the invention and should not be considered as specific limitations thereof. Based on common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain the present invention. All reagents and raw materials used in the present invention are commercially available.

[0037] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for descriptive purposes only and is not intended to limit the invention. The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion. "A plurality of" as used herein refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships may exist.

[0038] The active substance and excipients are dissolved or dispersed in a solvent to form a spray-dried injection solution (solution or suspension). The spray-dried injection solution is then spray-dried in a spray dryer to obtain a dry powder, thus obtaining pirfenidone inhalation powder.

[0039] Pirfenidone: Appears as a pale yellow powder, odorless, and with good stability. Molecular formula: C 12 H 11 NO; Molecular weight: 185.22; Melting point: 108.2℃; CAS Registry No.: 53179-13-8; Soluble in water, methanol, ethanol or dimethyl sulfoxide.

[0040] Example 1

[0041] A method for preparing pirfenidone inhalation powder, the specific steps of which are as follows:

[0042] 60 wt% pirfenidone (PFD) and 40 wt% leucine (LEU) were dissolved in pure water to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 90 ℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 2 mL / min.

[0043] Example 2

[0044] A method for preparing pirfenidone inhalation powder, the specific steps of which are as follows:

[0045] 55 wt% pirfenidone and 45 wt% phenylalanine (PHE) were dissolved in methanol to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 120 ℃, the atomizing gas flow rate was 473 L / h, and the feed rate was 8 mL / min.

[0046] Example 3

[0047] A method for preparing pirfenidone inhalation powder, the specific steps of which are as follows:

[0048] 93 wt% pirfenidone and 7 wt% trileucine (Tri) were dissolved in methanol to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 150 ℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 10 mL / min.

[0049] Example 4

[0050] A method for preparing pirfenidone inhalation powder, the specific steps of which are as follows:

[0051] 87 wt% of pirfenidone and 13 wt% of trileucine were dissolved in a mixture of methanol and acetone (in any ratio) to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 60 °C, the atomizing gas flow rate was 473 L / h, and the feed rate was 6 mL / min.

[0052] Example 5

[0053] A method for preparing pirfenidone inhalation powder, the specific steps of which are as follows:

[0054] 73 wt% pirfenidone and 27 wt% trileucine were dissolved in acetonitrile to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 90 ℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 6 mL / min.

[0055] Example 6

[0056] 98 wt% pirfenidone and 2 wt% leucine were dissolved in a mixed solvent of pure water and ethanol in any proportion to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 90 ℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 10 mL / min.

[0057] Example 7

[0058] 95 wt% pirfenidone and 5 wt% leucine were dissolved in a mixed solvent of pure water and ethanol in any proportion to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 90 ℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 10 mL / min.

[0059] Example 8

[0060] 90 wt% pirfenidone and 10 wt% leucine were dissolved in a mixed solvent of pure water and ethanol in any proportion to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 90 ℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 10 mL / min.

[0061] Example 9

[0062] 85 wt% pirfenidone and 15 wt% leucine were dissolved in a mixed solvent of pure water and ethanol in any proportion to obtain a sample solution. The solution was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 90 ℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 10 mL / min.

[0063] Comparative Example 1

[0064] A method for preparing pirfenidone inhalation powder, the specific steps of which are as follows:

[0065] Pirfenidone was dissolved in pure water to obtain a sample solution, which was then spray-dried to prepare a dry powder and evaluated. The inlet temperature of the spray drying equipment was 90℃, the atomizing gas flow rate was 819 L / h, and the feed rate was 6 mL / min.

[0066] The performance of the pirfenidone inhalation powder prepared in the above embodiments and comparative examples was tested, and the test results are as follows:

[0067] 1. X-ray powder diffraction measurement:

[0068] The XRD measurement process is as follows: Take an appropriate amount of the powder sample to be tested, place it in the groove of the sample plate of the X-ray powder diffraction analyzer, gently scrape it flat, insert it into the slot of the instrument, and detect the XRD diffraction pattern under the conditions of copper Kα rays, tube voltage of 40kV, current of 30mA, and diffraction angle 2θ of 5°-45°.

[0069] XRD analysis was performed on the pirfenidone powder samples prepared in Examples 1-9 and Comparative Example 1. The results are as follows: Figure 1 As shown, the crystal form of the powdered pirfenidone obtained in each embodiment has not changed, and the crystal form of the pirfenidone active pharmaceutical ingredient has been maintained.

[0070] 2. DSC measurement:

[0071] Differential Scanning Calorimetry (DSC) was used to analyze the crystallization state of the active pharmaceutical ingredient. The specific procedure was as follows: An empty aluminum crucible was placed on a balance, tare it, and a small amount of the sample powder (approximately 3 mg) was accurately weighed into the crucible. A hole was punched in the crucible lid, and the perforated lid was placed on top of the crucible containing the sample. The lid was then tightened with a capping device. The DSC sample preparation was complete. The instrument, cold trap, and computer were turned on in sequence. The nitrogen valve was opened to approximately 0.1 MPa. The scanning temperature program was set as follows: heating from -40℃ to 120℃ at a heating rate of 20℃ / min.

[0072] DSC analysis was performed on the pirfenidone powder samples prepared in Examples 1-9 and Comparative Example 1. The results are as follows: Figure 2 As shown. The results indicate that the melting peak of pirfenidone active pharmaceutical ingredient is at 109°C, and the melting peak of the powdered pirfenidone obtained in each example did not change.

[0073] 3. Particle size determination:

[0074] The particle size distribution of pirfenidone powder was determined by laser diffraction. An R1 lens with a detection range of 0.1 / 0.18-35µm was selected. The dispersion method was RODOS dry dispersion, and the dispersion pressure was 3 bar. The triggering conditions were: data collection started when the occlusion was greater than 4% and the refractive index was greater than 1%, and the test ended after 5 seconds or 2 seconds after the refractive index was lower than 1%. The data exchange frequency was 100ms. Each sample was measured in triplicate, and the results are shown in Table 1.

[0075] Examples 1, 3, 4, and 5 of D 90 Less than 5 μm, and D in Example 1 90 Smaller particle size, meeting the requirements for drug delivery to the lungs.

[0076] Table 1. Particle size distribution of pirfenidone inhalation powder prepared in each example.

[0077]

[0078] 4. Surface morphology test:

[0079] The surface morphology of the pirfenidone inhalation powder in Examples 1-9 and Comparative Example 1 was observed using a scanning electron microscope (SEM). The specific operating steps are as follows: First, conductive adhesive was placed on a metal sample stage. Then, a small amount of the powder to be tested was taken, allowed to adhere to the conductive adhesive, and dispersed with a spray gun. Excess powder was removed, and gold was sprayed onto the powder surface of the conductive adhesive. The prepared sample stage was placed in the sample chamber of the SEM, and the sample morphology was observed and images were acquired under an accelerating voltage of 3.00 kV.

[0080] 5. Aerodynamic Testing:

[0081] Due to the physiological structure of the lungs and the specific nature of drug administration via the lungs, drug powders require specific aerodynamic properties to effectively deposit in the lungs. The amount of drug powder deposited in the lungs directly affects the efficacy of the drug. According to the 2020 Chinese Pharmacopoeia, this invention uses a Next Generation Pharmaceutical Impactor (NGI) to determine the aerodynamic and in vitro deposition performance of dry powder inhalers. The NGI has seven collection stages and one microporous collector (MOC). At a flow rate of 60 L / min, the airflow passes through the impactor in a zigzag pattern. The cutoff diameter (D) of the particles collected at each stage is... 50 The micrometers (μm) were 8.06, 4.46, 2.82, 1.66, 0.94, 0.55, 0.34, and 0.14 μm, respectively. In this invention, a 0.5% Tween 80 aqueous solution was uniformly coated onto the surface of each collection tray.

[0082] Take 10.00±0.03 mg of pirfenidone inhalation powder from Examples 1-9, weighing three portions for each example, and fill them into HPMC capsules. Place the capsules in a dry environment for later use. Connect the NGI body, homogeneity testing device, and vacuum pump in sequence. Connect the inhalation device containing the capsules to the NGI body via the adapter, ensuring good airtightness. Adjust the equipment parameters and enter the test program. Under the conditions of a pressure of 4 kPa, a vacuum pump flow rate of 60±2 L / min, and the homogeneity testing device controlling the pressure ratio before and after to be P3 / P2≤0.5, puncture the capsules in the inhalation device, and evacuate air. Each capsule is evacuated three times, with each evacuation lasting 4 seconds and an interval of 15 seconds between each evacuation. After the test, rinse the inhalation device, adapter, artificial throat, pre-separator, and collection tray with aqueous solution. Collect the rinsing solution in a volumetric flask, dilute to the mark, and shake well. Perform quantitative analysis using high-performance liquid chromatography (HPLC) to calculate the mass of drug on each collection tray.

[0083] The aerodynamic behavior of the pirfenidone inhalation powder prepared in Examples 1-9 was studied. In vitro deposition distribution is as follows: Figure 3 As shown, in Examples 1, 3, 4, and 5, most of the material was deposited in the collection tray, exhibiting good lung deposition performance. Aerodynamic data are shown in Table 2. The MMAD (macrophage density) ranged from 2.93 μm to 6.29 μm. Example 1 showed a higher FPF (fiber per square meter) value, indicating better powder dispersion and thus better lung deposition performance.

[0084] Table 2. Aerodynamic particle size distribution parameters of pirfenidone inhalation powder prepared in each example.

[0085]

[0086] The higher the content of hydrophobic amino acids, the stronger the hydrophobicity and the more pronounced the surface wrinkles. This may be attributed to the amphiphilicity and low water solubility of hydrophobic amino acids: they rapidly accumulate at the gas-liquid interface of atomized droplets, forming a continuous and dense hydrophobic shell in the early stages of drying. Under rapid evaporation conditions, the rate of shell solidification is much higher than the rate of solute diffusion inside. This hydrophobic shell cannot extend synchronously with the shrinkage of particle volume, eventually resulting in brittle collapse and the formation of a wrinkled, sheet-like morphology. When the content of hydrophobic amino acids is low, the solute distribution and solvent evaporation tend to be balanced, and the particles are more likely to maintain a spherical structure under the action of surface tension. However, if there are no hydrophobic amino acids or the content of hydrophobic amino acids is too low (Examples 6, 7, and Comparative Example 1), the particles are prone to aggregation, forming large, irregular aggregates that cannot be used for lung inhalation. Figure 4 ).

[0087] PFD-LEU-SD particles are irregularly aggregated with a rough, wrinkled surface and no obvious spherical structure; PFD-PHE-SD exists as aggregated lumps with multiple concave spherical particles attached to the surface; PFD-Tri7wt%-SD (Example 3) and PFD-Tri13wt%-SD (Example 4) particles are both spherical with smooth surfaces, relatively uniform particle size, and a small number of particles are slightly adhered; PFD-Tri27%-SD (Example 5) shows a significant change in morphology compared to the Tri7wt% and Tri13wt% formulations, transforming from spherical to irregular flakes and wrinkles, with a rough surface, increased angularity, and almost disappearance of the spherical structure, indicating that the higher the content of hydrophobic amino acids, the stronger the hydrophobicity and the more significant the surface wrinkles. This may be attributed to the amphiphilic nature and low water solubility of hydrophobic amino acids: they rapidly accumulate at the gas-liquid interface of atomized droplets, forming a continuous, dense, rigid hydrophobic shell in the early stages of drying. Under rapid evaporation conditions, the solidification rate of the shell is much higher than the diffusion rate of the solute inside. This hydrophobic shell cannot extend synchronously with the shrinkage of the particle volume, eventually resulting in brittle collapse and the formation of a wrinkled, sheet-like morphology. When the content of hydrophobic amino acids is low, the solute distribution and solvent evaporation tend to be balanced, and the particles are more likely to maintain a spherical structure under the action of surface tension (Examples 3 and 4). However, if the content of hydrophobic amino acids is too low or even absent (Examples 6, 7, and Comparative Example 1), the particles are prone to aggregation, forming large, irregular aggregates that cannot be used for pulmonary inhalation. The experimental results show that the dispersing effect of hydrophobic amino acids significantly reduces the intrinsic cohesiveness of each formulation. However, when the content of hydrophobic amino acids is too low or absent (Examples 6, 7, and Comparative Example 1), the drug forms large aggregates, making it unsuitable for pulmonary inhalation.

[0088] In summary, surface modification with hydrophobic amino acids can significantly improve the dispersibility and lung deposition properties of formulations. Utilizing the surface enrichment of hydrophobic drugs or excipients can achieve effective moisture-wicking protection. Hydrophobic amino acids such as leucine and trileucine have good stabilizing effects on highly hygroscopic spray-dried powders.

[0089] 6. Storage stability test:

[0090] Storage stability tests can examine the shelf life and storage conditions of inhaled powders. The pirfenidone cocrystal inhaled powders prepared in Examples 1-5 were stored at 25°C and 10% humidity for 0 days, 30 days, 60 days, and 90 days, respectively, and their stability was tested using the same method as the particle size test.

[0091] The 90-day storage stability test data of the pirfenidone inhalation powder prepared in Examples 1-5 are as follows: Figure 5 As shown, pirfenidone cocrystal inhalation powder exhibits good hygroscopic resistance. After 90 days of storage, pirfenidone inhalation powder D... 50 No significant changes have occurred.

Claims

1. An inhaled puffy of pirfenidone characterized in that, The pirfenidone inhalation powder includes pirfenidone and excipients; wherein the excipients are selected from any of the following: amino acid surface modifiers, mixtures of amino acid surface modifiers and sugar excipients, mixtures of amino acid surface modifiers and sugar alcohol excipients, and mixtures of amino acid surface modifiers, sugar excipients, and sugar alcohol excipients; Based on the total mass of pirfenidone inhalation powder as 100%: the amount of pirfenidone used is 1wt%-99wt% of the total mass of pirfenidone inhalation powder; the amount of the excipient used is 1wt%-99wt% of the total mass of pirfenidone inhalation powder.

2. An inhaled pirefenidone powder formulation according to claim 1, wherein The particle size D of the pirfenidone inhalation powder 50 The particle size ranges from 1.64 μm to 4.25 μm, the in vitro drug deposition rate ranges from 17.23% to 68.32%, and the aerodynamic median mass diameter ranges from 2.93 μm to 6.49 μm; the change in in vitro drug deposition rate within 90 days of storage is less than 5%.

3. An inhaled pirefenidone powder formulation according to claim 1, wherein The amino acid surface modifier is any one of valine, leucine, L-leucyl-L-leucyl-L-leucine, and phenylalanine; the sugar excipient is one or more of mannose, trehalose, lactose, hyaluronic acid, and cyclodextrin; and the sugar alcohol excipient is one or more of xylitol, sorbitol, and mannitol.

4. An inhaled pirefenidone powder formulation according to claim 3, wherein The excipient is any one of the following systems: "valine and hyaluronic acid", "phenylalanine and mannitol", "L-leucyl-L-leucyl-L-leucine, cyclodextrin and mannitol", "leucine, trehalose and mannitol", "leucine", "leucine and trehalose", "phenylalanine", "L-leucyl-L-leucyl-L-leucine", "leucine and mannitol", "leucine and xylitol", "L-leucyl-L-leucyl-L-leucine and trehalose", "L-leucyl-L-leucyl-L-leucine and mannitol".

5. An inhaled pirefenidone powder formulation according to claim 4, wherein The amount of pirfenidone used is 7wt%-90wt% of the total mass of the pirfenidone inhalation powder; the amount of excipient used is 10wt%-93wt% of the total mass of the pirfenidone inhalation powder, and the excipient is L-leucyl-L-leucyl-L-leucine.

6. An inhaled pirefenidone powder formulation according to claim 4, wherein The amount of pirfenidone used is 10wt%-90wt% of the total mass of the pirfenidone inhalation powder; the amount of excipient used is 10wt%-90wt% of the total mass of the pirfenidone inhalation powder, and the excipient is leucine.

7. An inhaled pirefenidone powder formulation according to claim 4, wherein The amount of pirfenidone used is 40wt%-90wt% of the total mass of the pirfenidone inhalation powder; the amount of excipient used is 10wt%-60wt% of the total mass of the pirfenidone inhalation powder, and the excipient is phenylalanine.

8. A method for preparing a pirfenidone inhalation powder according to any one of claims 1 to 7, characterized in that, The process includes the following: dissolving or dispersing pirfenidone and excipients in a solvent to obtain a spray-dried injection solution, followed by spray drying to obtain pirfenidone powder; The spray-drying injection solution refers to a mixture containing pirfenidone and excipients to be spray-dried, in the form of a solution, suspension, or emulsion; the solvent is an organic phase or a mixture of an organic phase and an aqueous phase; the organic phase is methanol, acetonitrile, or a mixture of methanol and acetone; the total solid concentration of pirfenidone and excipients is 2 mg / mL-90 mg / mL; the inlet temperature of the spray dryer is 50℃-150℃, and the outlet temperature is 30℃-100℃.

9. The method of claim 8, wherein the inhalation powder of pirfenidone is prepared by, The conditions for small-scale spray drying are as follows: the atomization pressure is 357 L / h-819 L / h, and the feed rate is 1 mL / min-20 mL / min.

10. The use of the pirfenidone inhalation powder according to any one of claims 1 to 7 in the preparation of a medicament for treating idiopathic pulmonary fibrosis.

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