Ribonucleoside analogue spheroidal porous particles, controllable preparation method and application thereof

Abstract

The application discloses a kind of ribonucleoside analogue spheroid porous particles and its controllable preparation method and application.The ribonucleoside analogue spheroid porous particles are prepared by using counter-rotating impinging jet reactor system in combination with spray freeze-drying method.The ribonucleoside analogue spheroid porous particles are characterized by particle size, surface morphology and other physical and chemical properties, and it is found that the obtained powder has good flowability, is not easy to agglomerate, and has suitable particle size distribution for pulmonary administration. In-vitro aerodynamic experiment further proves that the spheroid porous particles have excellent in-vitro aerodynamic performance, and are suitable for pulmonary drug delivery.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a spherical porous particle of ribonucleoside analogue and its controllable preparation method and application. Background Technology

[0002] The ribonucleoside analog EIDD-2801 (MK-4482, Molnupiravir) is a ribonucleotide analog originally designed to treat influenza A virus. As a prodrug, it is hydrolyzed in vivo to its active form, EIDD-1931, which is then converted to its 5′-triphosphate. EIDD-1931-5′-triphosphate acts as a substrate for viral RNA-dependent RNA polymerase, participating in viral RNA replication and leading to catastrophic errors during replication. Ribonucleotide analogs possess broad-spectrum antiviral activity and can be used against various viruses, including influenza, Ebola, and coronaviruses.

[0003] EIDD-2801 has demonstrated good viral inhibition in various animal models of SARS-CoV-2 infection. Wahl et al. (https: / / doi.org / 10.1126 / scitranslmed.abb5883.) used immunodeficient mice implanted with real human lung tissue as a model to study the inhibitory effect of EIDD-2801 on SARS-CoV-2 virus. The results showed that treatment with therapeutic and prophylactic administration of EIDD-2801 could significantly inhibit the replication of SARS-CoV-2 in vivo. Mart et al. (https: / / doi.org / 10.1016 / j.trsl.2019.12.002) verified the efficacy of EIDD-2801 in a ferret SARS-CoV-2 infection model. Rana et al. (https: / / doi.org / 10.1016 / j.ebiom.2021.103595) constructed a hamster SARS-CoV-2 infection model and employed a combination therapy strategy of favipiravir and EIDD-2801. The results showed that the combination therapy not only significantly reduced the SARS-CoV-2 viral titer in the infected model, demonstrating a good viral suppression effect, but also prevented the spread of the virus to healthy hamsters to a certain extent. Recently, EIDD-2801 was granted emergency approval by the FDA for the treatment of clinical COVID-19 patients. Accumulated clinical research data has demonstrated that EIDD-2801 is an oral antiviral drug that can reduce patient mortality and hospitalization rates.

[0004] While oral administration is convenient and quick, it still suffers from drawbacks compared to pulmonary inhalation, such as lower bioavailability. The human lung has a unique structure, containing 300-400 million alveoli with a total absorptive surface area of ​​100m². 2 This greatly promotes drug absorption. Furthermore, the alveoli, composed of a single layer of epithelial cells and closely connected to the rich capillaries of the lungs, allow for rapid drug absorption and a quick onset of action. In addition to the advantages of rapid drug absorption and fast onset of action, pulmonary inhalation, as a non-invasive method of drug delivery, offers good patient compliance and effectively avoids the first-pass effect, making it particularly suitable for patients with chronic diseases requiring long-term treatment.

[0005] Based on their differences, inhaled medications can be broadly categorized into three types: nebulized formulations, metered-dose formulations, and spherical porous particles containing ribonucleoside analogues. Nebulized formulations use high-pressure airflow or ultrasound to atomize the drug solution for inhalation therapy. These formulations can uniformly atomize the drug solution into an appropriate inhalation size of 1-5 μm and do not require the patient's own inspiratory power, making them suitable for infants, the elderly, and other patients without spontaneous breathing ability. However, their disadvantages include high cost and bulky equipment, making them unsuitable for home treatment. Metered-dose formulations are currently the most widely used type of inhaler. They are simple to operate, convenient to use, and inexpensive. However, controlling the synchronization of inhalation and drug delivery is not easy; failure to achieve synchronized inhalation can lead to reduced effective drug deposition in the lungs. Furthermore, another serious problem lies in the environmental impact and damage caused by the use of propellants.

[0006] Compared to nebulized solutions and metered-dose aerosols used in pulmonary inhalation, spherical porous particles containing ribonucleoside analogues provide inhalation power through the patient's own breathing, making the procedure simple and convenient without the need for a propellant. Furthermore, the solid dry powder form facilitates storage, enabling the spherical porous particles to deliver the drug stably and efficiently to the lesion, effectively reducing the dosage and improving treatment efficiency and safety.

[0007] Currently, there are few reports on the preparation and application of spherical porous particles of ribonucleoside analogue EIDD-2801. Providing a new crystallization and granulation process is of great significance for the research and development and application of spherical porous particles of ribonucleoside analogues. Summary of the Invention

[0008] Objective of this invention: The objective of this invention is to provide spherical porous particles containing ribonucleoside analogs, a controllable preparation method thereof, and their applications. The preparation method of this invention requires no other carriers or excipients to produce dry powder particles with uniform particle size distribution, good particle morphology, and stable chemical properties. The spherical porous particles prepared by this invention can be administered via pulmonary inhalation, effectively improving drug delivery efficiency.

[0009] Technical solution: The objective of this invention is achieved through the following technical solution:

[0010] This invention provides a controllable method for preparing spherical porous particles of ribonucleoside analogues, using a reverse-spinning impact jet reactor system combined with a spray freeze-drying method to prepare the spherical porous particles of ribonucleoside analogues.

[0011] The inventors disclosed a composite vortex reactor in CN2022108062180. The composite vortex reactor includes a Rankine vortex reactor and a Taylor vortex reactor. The Rankine vortex reactor includes a reaction chamber with a first inlet pipe and a second inlet pipe on its side wall. Fluid entering the reaction chamber through the first and second inlet pipes can form a swirling fluid within the reaction chamber. A swirling outlet pipe is located at the center of the top of the reaction chamber. The Taylor vortex reactor includes an inner cylinder and an outer cylinder arranged coaxially. The inner cylinder is driven to rotate by a rotary drive device, and the inner and outer cylinders form an annular reaction space. The bottom center of the annular reaction space is connected to the reaction chamber through the swirling outlet pipe. The cross-sectional area of ​​the annular reaction space gradually increases from the bottom to the top. A reaction outlet pipe connecting the upper part of the annular reaction space is located at the upper end of the outer cylinder.

[0012] This invention employs the aforementioned composite vortex reactor in a counter-swirling impact jet reactor system. The counter-swirling impact jet reactor system includes two composite vortex reactors, silicone tubing, a peristaltic pump, a T-tube, and an ultrasonic generator. For example... Figure 1 As shown, two composite vortex reactors are respectively set on both sides of the T-shaped tube. The outlet of the composite vortex reactor is connected to the outlet of the T-shaped tube through a silicone tube. The ultrasonic generator is connected to the T-shaped tube through a metal screw. The peristaltic pump is connected to the inlet of the composite vortex reactor to deliver the suspension to the composite vortex reactor.

[0013] This invention utilizes the aforementioned counter-rotating impactor jet reactor system to provide a controllable method for preparing spherical porous particles of ribonucleoside analogues, comprising the following steps:

[0014] (1) Prepare a suspension of ribonucleoside analogues;

[0015] (2) The suspension is pretreated by a reverse-spinning impact jet reactor system;

[0016] (3) At a certain feed rate, the solution is transported to the pressure nozzle of the spray freezer by a peristaltic pump; at a certain atomization pressure, the solution is atomized and dispersed into liquid nitrogen to quickly form fine ice crystals;

[0017] (4) After the liquid nitrogen evaporates, the ice crystals are transferred to a freeze dryer and freeze-dried at a pressure below 20 Pa to obtain the spherical porous particles of the ribonucleotide analogue.

[0018] This invention employs a combined strategy of spray freezing and freeze drying in its granulation method. The parameters during spray freezing are easily adjustable, allowing for the production of ideal inhalable granules by setting appropriate process parameters. Furthermore, the spray freezing method enables the rapid formation of ice crystals in the drug solution. The rapid freezing time prevents drug molecules from arranging themselves in a regular and orderly manner, resulting in amorphous granules after freeze-drying. Simultaneously, the low temperature during spray freezing maintains the stability of the drug. During freeze-drying, the loss of water from the ice crystals obtained during spray freezing allows the granules to form a unique structure: a wrinkled exterior and a loose, porous interior. The wrinkled exterior reduces the contact area between particles, decreasing interparticle forces and preventing aggregation. The loose, porous interior increases the specific surface area of ​​the particles, enabling rapid drug dissolution after delivery.

[0019] In step (1), the concentration of the suspension is 10-100 mg / mL. Preferably, the concentration of the suspension is 50 mg / mL.

[0020] In step (2), the method of pretreatment of the suspension by the reverse vortex impact jet reactor system is as follows: under the ultrasonic assistance of the ultrasonic generator, the suspension is transported to the composite vortex reactors on both sides by a peristaltic pump for impact mixing, and after further impact mixing at the T-tube, it is output through the T-tube outlet and transported to the composite vortex reactor again for circulation reaction. The suspension is continuously impacted and mixed in the reactor for 10 minutes.

[0021] The power of the ultrasound-assisted device is 50-1200W.

[0022] In step (2), the feed rate of the pretreatment peristaltic pump is 1-200 mL / min. Preferably, the feed rate is 30 mL / min.

[0023] In step (3), the atomization pressure is 0.1-0.5 MPa. Preferably, the atomization pressure is 0.3 MPa.

[0024] In step (3), the feed rate of the peristaltic pump is 6-50 mL / min.

[0025] In step (4), the freeze-drying time is 48 hours.

[0026] The present invention also provides spherical porous particles of ribonucleoside analogues prepared by the above preparation method.

[0027] Beneficial effects:

[0028] (1) This invention improves the dosage form of the ribonucleoside analog EIDD-2801 and provides for the first time a method for preparing spherical porous particles of ribonucleoside analogs. These particles can be used as dry powder inhalation formulations, reducing the dosage and improving the administration efficiency through inhalation. In industrial production, it has advantages such as simple operation, high production efficiency, and low energy consumption.

[0029] (2) The spherical porous particles of the ribonucleoside analogues of the present invention have a suitable particle size range, morphology and flowability, and good drug stability.

[0030] (3) The spherical porous particles of ribonucleoside analogues of the present invention are prepared by a composite eddy current reaction system and spray freeze-drying technology, which can obtain particles with a suitable inhalation particle size range and a good spherical morphology.

[0031] (4) The spherical porous particles of the ribonucleoside analogue of the present invention have good in vitro aerodynamic properties and can achieve effective drug delivery to the lungs. Attached Figure Description

[0032] Figure 1 Schematic diagram of a counter-rotating impact jet reactor system; Figure 1 A is a schematic diagram of the anti-rotation impact jet reaction system; Figure 1 B is a schematic diagram of the connection relationship between the internal devices of the system;

[0033] Figure 2 This is a schematic diagram of the composite vortex reactor. Figure 2 A is a three-dimensional structural diagram of the composite vortex reactor; Figure 2 B is a partial cross-sectional schematic diagram of the composite vortex reactor;

[0034] Among them, 100-composite vortex reactor, 1-Rankine vortex reactor, 11-reaction chamber, 12-first inlet pipe, 13-second inlet pipe, 14-vortex outlet pipe, 2-Taylor vortex reactor, 21-inner cylinder, 22-outer cylinder, 23-rotation drive device, 24-annular reaction space, 25-reaction outlet pipe.

[0035] Figure 3 Nucleoside analogues: spherical porous particles and particle size distribution of active pharmaceutical ingredients;

[0036] Figure 4Surface morphology images of spherical porous particles containing ribonucleotide analogs; Figure 4 A represents the particles prepared in Example 1: Figure 4 B represents the particles prepared in Example 2; Figure 4 C represents the particles prepared in Example 3;

[0037] Figure 5 FTIR spectra of ribonucleoside analogue raw materials and their spherical porous particles;

[0038] Figure 6 A comparison diagram of the crystal forms of spherical porous particles of ribonucleoside analogs and the active pharmaceutical ingredient;

[0039] Figure 7 This is a simulated lung deposition image of spherical porous particles of ribonucleoside analogs obtained in Example 1. Detailed Implementation

[0040] The technical solution of the present invention will be described in detail below through specific embodiments, but the scope of protection of the present invention is not limited to the embodiments described.

[0041] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0042] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples are commercially available products.

[0043] The anti-vortex impact jet reactor system of the present invention includes two composite vortex reactors, silicone tubing, a peristaltic pump, a T-tube, and an ultrasonic generator. For example... Figure 1 As shown, two composite vortex reactors are respectively set on both sides of the T-shaped tube. The outlet of the composite vortex reactor is connected to the outlet of the T-shaped tube through a silicone tube. The ultrasonic generator is connected to the T-shaped tube through a metal screw. The peristaltic pump is connected to the inlet of the composite vortex reactor to deliver the suspension to the composite vortex reactor.

[0044] The composite vortex reactor of this invention is the reactor disclosed in CN2022108062180, and the schematic diagram of the reactor structure is shown below. Figure 2 , Figure 2 A is a three-dimensional structural diagram of the composite vortex reactor; Figure 2 B is a partial cross-sectional schematic diagram of the composite vortex reactor.

[0045] The composite vortex reactor 100 includes a Rankine vortex reactor 1 and a Taylor vortex reactor 2. The Rankine vortex reactor 1 includes a disc-shaped reaction chamber 11. A first inlet pipe 12 and a second inlet pipe 13 are provided on the side wall of the reaction chamber 11. The fluid entering the reaction chamber 11 through the first inlet pipe 12 and the second inlet pipe 13 can form a swirling fluid in the reaction chamber 11. A swirling outlet pipe 14 is provided at the top center of the reaction chamber 11. The Taylor vortex reactor 2 includes an inner cylinder 21 and an outer cylinder 22 arranged coaxially. The inner cylinder 21 is driven to rotate by a rotary drive device 23. The inner cylinder 21 and the outer cylinder 22 form an annular reaction space 24. The bottom center of the annular reaction space 24 is connected to the reaction chamber 11 through the swirling outlet pipe 14. The cross-sectional area of ​​the annular reaction space 24 gradually increases from the bottom to the top. A reaction outlet pipe 25 connecting the upper part of the annular reaction space 24 is provided at the upper end of the outer cylinder 22.

[0046] In operation, the two reaction fluids enter the reaction chamber 11 through the first inlet pipe 12 and the second inlet pipe 13, respectively. A swirling fluid is formed within the reaction chamber 11. This swirling fluid then enters the annular reaction space 24 of the Taylor vortex reactor 2 through the swirling outlet pipe 14. The inner cylinder 22 is rotated by the rotary drive device 23 (i.e., the drive motor), causing the swirling fluid to generate variable-size Taylor vortices within the annular reaction space 24, resulting in a more diverse flow field environment within the reactor. Because the cross-sectional area of ​​the annular reaction space 24 gradually increases from bottom to top, the local turbulent shearing and contact reaction time of the reactants within the annular reaction space 24 can be controlled, thereby significantly improving the mixing effect of the materials and increasing the interfacial mass transfer efficiency. The reacted material flows out from the reaction outlet pipe 25.

[0047] Example 1: Preparation method of spherical porous particles of ribonucleotide analogues

[0048] (1) Weigh 5g of EIDD-2801, purchased from Shandong Sihuan Pharmaceutical Co., Ltd., and prepare it into a suspension with a total volume of 100mL and a concentration of 50mg / mL using pure water.

[0049] (2) The suspension is pretreated by a reverse-spinning impact jet reactor system, specifically, such as... Figure 1 As shown, the suspension was pumped to inlet 1, inlet 2, inlet 3, and inlet 4 via peristaltic pumps under magnetic stirring, with a feed rate of 100 mL / min. After being mixed by impact in two composite vortex reactors on both sides under 600W ultrasonic assistance, the mixture converged at the T-tube and was mixed again by impact before being pumped through the T-tube outlet to a beaker containing the suspension. The peristaltic pump then pumped the suspension from this beaker back to the reactor for a circulating reaction. This reaction process was completed after 10 minutes of circulation.

[0050] (3) The pretreated suspension was subjected to spray freeze-drying. The atomization pressure of the freeze sprayer was set to 0.3 MPa and the feed rate was 30 mL / min. The suspension was sprayed into liquid nitrogen through the atomizing nozzle to form fine ice crystals. After the liquid nitrogen evaporated, the product was transferred to a freeze dryer and freeze-dried at a pressure below 20 Pa for 48 hours to obtain the product.

[0051] Example 2: Preparation method of spherical porous particles of ribonucleotide analogues

[0052] (1) Weigh 10g of EIDD-2801 and prepare a suspension with a total volume of 100mL and a concentration of 100mg / mL using pure water.

[0053] (2) The suspension is pretreated by a reverse-spinning impact jet reactor system, specifically, such as... Figure 1 As shown, the suspension was magnetically stirred and then pumped to inlet 1, inlet 2, inlet 3, and inlet 4 via peristaltic pumps at a feed rate of 50 mL / min. After being mixed by impact in two composite vortex reactors on both sides under 800W ultrasonic assistance, the mixture converged at the T-tube for further impact mixing before being pumped out to a beaker containing the suspension. The peristaltic pump then pumped the suspension from this beaker back to the reactor for a cyclic reaction. This reaction cycle lasted 10 minutes, after which the pretreatment was complete.

[0054] (3) The pretreated suspension was subjected to spray freeze-drying. The atomization pressure of the freeze sprayer was set to 0.5 MPa and the feed rate was 50 mL / min. The suspension was sprayed into liquid nitrogen through the atomizing nozzle to form fine ice crystals. After the liquid nitrogen evaporated, the product was transferred to a freeze dryer and freeze-dried at a pressure below 20 Pa for 48 hours to obtain the product.

[0055] Example 3: Preparation method of spherical porous particles of ribonucleotide analogues

[0056] (1) Weigh 1g of EIDD-2801 and prepare a suspension with a total volume of 100mL and a concentration of 10mg / mL using pure water.

[0057] (2) The suspension is pretreated by a reverse-spinning impact jet reactor system, specifically, such as... Figure 1 As shown, the suspension was magnetically stirred and then pumped to inlet 1, inlet 2, inlet 3, and inlet 4 via peristaltic pumps at a feed rate of 150 mL / min. After being mixed by impact in two composite vortex reactors on both sides under 1000W ultrasonic assistance, the mixture converged at the T-tube for further impact mixing before being pumped out to a beaker containing the suspension. The peristaltic pump then pumped the suspension from this beaker back to the reactor for a cyclic reaction. This reaction cycle lasted 10 minutes, after which the pretreatment was complete.

[0058] (3) The pretreated suspension was subjected to spray freeze-drying. The atomization pressure of the freeze sprayer was set to 0.1 MPa and the feed rate was 6 mL / min. The suspension was sprayed into liquid nitrogen through the atomizing nozzle to form fine ice crystals. After the liquid nitrogen evaporated, the product was transferred to a freeze dryer and freeze-dried at a pressure below 20 Pa for 48 hours to obtain the product.

[0059] Example 4: Determination of the physicochemical properties of spherical porous particles containing ribonucleotide analogs

[0060] (1) Determination of loose density and tapped density: The drug powder is evenly transferred to a graduated cylinder, and the powder is thoroughly tapped more than 100 times. The powder weight m and the drug volumes V1 and V2 before and after tapping are recorded. Calculate the following parameters: the loose density ρ of the powder. a =m / V1, tap density ρ b =m / V2, Cartesian exponent C = ((ρ b -ρ a ) / ρ b )×100%, aerodynamic particle size Where ρ0(1g / cm 3 ) represents the unit density, and x is the shape factor, which is taken as x = 1 for quasi-spherical particles.

[0061] (2) Powder particle size determination: The particle size of the drug powder was measured using a laser particle size analyzer. The particle size distribution of spherical porous particles of ribonucleoside analogues and the active pharmaceutical ingredient is shown in [reference needed]. Figure 3 .

[0062] The basic properties of spherical porous particles containing ribonucleotide analogues are shown in Table 1:

[0063] Table 1. Basic properties of spherical porous particles containing ribonucleotide analogues

[0064]

[0065] From Table 1 and Figure 3 It can be seen that the spherical porous particles of the ribonucleoside analogue (EIDD-2801) prepared in this invention have a narrow particle size distribution range, good flowability, and suitable inhalation particle size. The Karl criterion is a common indicator for measuring powder flowability; a Karl criterion of less than 25% indicates good powder flowability. For dry powder inhalation formulations, a particle size range of 1-5 μm is considered suitable for inhalation administration, achieving good pulmonary deposition. However, the active pharmaceutical ingredient (API) has a wider particle size distribution, and its particle size is unsuitable for inhalation.

[0066] (3) Powder morphology: The surface morphology of the powder was determined using a scanning electron microscope. Before the determination, the powder was dispersed onto a conductive adhesive and sputtered with gold.

[0067] See the surface morphology images of spherical porous particles of ribonucleotide analogs. Figure 4 SEM images show that the preparation method of this invention can produce spherical porous ribonucleoside analogs with a complete spherical structure. The particle size is within the suitable inhalation particle size of 1-5 μm. The particles have good uniformity and exhibit an overall microstructure of external wrinkling and internal loose and porous structure. This structure has the characteristics of high specific surface area, which can achieve rapid drug dissolution after administration.

[0068] (4) Powder chemical stability: The infrared spectrum of the prepared spherical porous particles of ribonucleotide analog was measured on an infrared spectrometer and compared with the infrared spectrum of its active pharmaceutical ingredient.

[0069] FTIR spectra of ribonucleoside analog raw materials and spherical porous particles of ribonucleoside analogs are shown below. Figure 5 The FTIR spectra show that the spherical porous particles of the ribonucleoside analogue have the same infrared characteristic peaks as the raw material, indicating that no changes to the molecular chemical structure of EIDD-2801 occurred during the preparation process of this invention, and the entire preparation process maintained the stability of EIDD-2801 well.

[0070] (5) Particle crystal form: The crystallinity of the powder was determined by X-ray diffraction system. The target was Cu target, the scanning starting angle was 5°2θ, the scanning range was 5°-90°, and the scanning speed was 10° / min.

[0071] XRD comparison of spherical porous particles of ribonucleoside analogues and their active pharmaceutical ingredients is shown in Figure 1. Figure 6 XRD patterns showed that the active pharmaceutical ingredient (API) exhibited clear and sharp diffraction peaks in the 0° to 90° scanning range, indicating that the API has a distinct crystalline form and a high degree of crystallinity. In contrast, the spherical porous particles of ribonucleoside analogs did not show obvious diffraction peaks across the entire scanning range, indicating that they are in an amorphous state. In actual drug delivery, amorphous drugs have higher apparent solubility than crystalline drugs, enabling higher bioavailability.

[0072] Example 5: Determination of the air displacement rate and in vitro aerodynamic performance of spherical porous particles containing ribonucleotide analogs.

[0073] 1. Determination of venting rate

[0074] The emptying rate of the spherical porous particles of ribonucleoside analogues prepared in Example 1 was determined using a Next Generation Impactor (NGI). The emptying rate of the spherical porous particles of ribonucleoside analogues was determined according to the powder atomization method in Appendix 1 of the 2010 edition of the Chinese Pharmacopoeia. Specifically, an appropriate amount of spherical porous particles of ribonucleoside analogues was filled into capsules. Ten capsules were taken, accurately weighed, and placed one capsule at a time into the NGI device. The capsules were aspirated four times with an airflow of 60 L ± 1 L per minute, each time for 1.5 seconds. The weight was recorded, and any remaining contents were wiped clean with a small brush or suitable tool. The weight of the capsule shell was then recorded again, and the emptying rate of each capsule was calculated.

[0075] The cavitation rate of spherical porous particles containing ribonucleotide analogs is shown in Table 2:

[0076] Table 2. Emptying rate data of spherical porous particles of ribonucleoside analogues obtained in Example 1.

[0077] Test number Emptying rate 1 87.80％ 2 95.65％ 3 84.21％ 4 95.65％ 5 92.11％ 6 97.50％ 7 97.22％ 8 100.00％ 9 89.19％ 10 92.86％ average value 93.22％±4.69％

[0078] The cavitation rate experiment demonstrated that the spherical porous particles of ribonucleoside analogs prepared in this invention have a good cavitation effect, which meets the requirement of the 2010 edition of the Chinese Pharmacopoeia for a cavitation rate greater than 90% for powder aerosols. The cavitation rates of experiments numbered 1, 3, and 9 in the table are less than 90%, which may be due to the particles agglomerating due to electrostatic effects, resulting in slight obstruction of cavitation.

[0079] 2. Measurement of lung deposition rate

[0080] The lung deposition rate of spherical porous particles of ribonucleotide analogues prepared in Example 1 was determined using the aerodynamic properties determination method for fine particles in inhaled preparations, as per the General Chapter 0951 of the 2020 edition of the Chinese Pharmacopoeia. Specifically, a Next Generation Impactor (NGI) was used for the lung deposition rate experiment. The collection cups were placed in the tray, which was then mounted on the bottom support, ensuring each collection cup corresponded to its respective position on the bottom support. The lid was closed, and the handle was pulled down to seal the instrument. The pre-separator insert was assembled into the pre-separator base, which was then installed at the impactor inlet. 15 mL of pure water was added to the collection cup at the center of the pre-separator insert. The pre-separator body was then installed and secured. An L-shaped connecting tube was inserted into either the impactor inlet or the pre-separator inlet, and a suitable nozzle adapter was installed at the other end of the L-shaped connecting tube. After inserting the powder aerosol nozzle, the nozzle end of the driver should be on the horizontal axis of the L-shaped connecting tube, and the nozzle port should be flush with the L-shaped connecting tube opening. The device was then connected to the flow system. Adjust the P3 / P2 ratio to < 0.5, the airflow rate to 60.0 ± 1 L / min, and the aspiration time to 4 s. Fill 10 No. 3 gelatin capsules with 30 ± 1 mg of spherical porous ribonucleoside analogue particles. Puncture the capsules in the inhaler, start the pump, and aspirate for 4 s. After aspiration, remove the impactor, disconnect the L-shaped connecting tube and mouthpiece adapter, and collect the powder from the collection cups, L-shaped connecting tube, and inhalation device at each stage using 10 mL of pure water. Quantitatively dilute to 25 mL, remove the pre-separator, transfer the solution from the pre-separator to a 50 mL volumetric flask, wash the pre-separator with 10 mL of pure water, combine the washings, and bring the volume to 50 mL. A total of 10 capsules were aspirated in each experiment, and the measurements were performed in triplicate. The concentration of the collected solutions was determined by high-performance liquid chromatography (HPLC). The fine particle fraction (FPF), mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD) were calculated based on the mass of deposited particles at each stage. The fine particle fraction is the proportion of particles smaller than 5 μm in the total particle count. The mass median aerodynamic diameter is the aerodynamic diameter corresponding to 50% of the total particle mass when particles smaller than this aerodynamic diameter account for 50% of the total particle mass. The lung deposition rate of ribonucleoside analogue spherical porous particles is shown in [reference needed]. Figure 7 The aerodynamic parameters of spherical porous particles of ribonucleoside analogues are shown in Table 3.

[0081] Table 3. Aerodynamic parameters of the spherical porous particles of ribonucleoside analogues obtained in Example 1

[0082]

[0083] Analysis of the lung deposition distribution map showed that spherical porous particles of ribonucleoside analogues exhibited abundant deposition in subsequent stages such as Stage 3-MOC, achieving excellent deposition results. However, particle deposition was less in the early stages of the trachea and pre-separator, with deposition rates all below 5%. Furthermore, the fine particle fraction was as high as 64.04%, and the median aerodynamic particle size was within the 1-5 μm particle size requirement range for pulmonary administration. These characteristics demonstrate the excellent in vitro aerodynamic performance of the spherical porous particles of ribonucleoside analogues.

[0084] As described above, although the invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the invention itself. Various changes in form and detail may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A spherical porous particle resembling a ribonucleoside analog, characterized in that, It is prepared by the following method: (1) Prepare a suspension of EIDD-2801, a ribonucleoside analogue, with a concentration of 10-100 mg / mL by mixing EIDD-2801 with pure water; (2) The suspension is pretreated by a reverse-spinning impact jet reactor system; (3) At a feed rate of 6-50 mL / min, the solution is delivered to the pressure nozzle of the spray freezer by a peristaltic pump; at an atomization pressure of 0.1-0.5 MPa, the solution is atomized and dispersed into liquid nitrogen to quickly form fine ice crystals; (4) After the liquid nitrogen evaporates, the ice crystals are transferred to a freeze dryer and freeze-dried at a pressure below 20 Pa to obtain the spherical porous particles of the ribonucleoside analogue. The reverse-vortex impact jet reactor system includes two composite vortex reactors, silicone tubing, a peristaltic pump, a T-tube, and an ultrasonic generator. The two composite vortex reactors are respectively positioned on either side of the T-tube, and their outlets are connected to the T-tube outlet via silicone tubing. The ultrasonic generator is connected to the T-tube via a metal threaded connection. The peristaltic pump is connected to the inlet of the composite vortex reactor, supplying the suspension to it. The composite vortex reactor includes a Rankine vortex reactor and a Taylor vortex reactor. The Rankine vortex reactor includes a disc-shaped reaction chamber. The reaction chamber is provided with a first inlet pipe and a second inlet pipe on its side wall. The fluid entering the reaction chamber through the first inlet pipe and the second inlet pipe can form a swirling fluid in the reaction chamber. A swirling outlet pipe 14 is provided in the middle of the top of the reaction chamber. The Taylor vortex reactor includes an inner cylinder and an outer cylinder arranged coaxially. The inner cylinder is driven to rotate by a rotary drive device. The inner cylinder and the outer cylinder form an annular reaction space. The bottom middle of the annular reaction space is connected to the reaction chamber through the swirling outlet pipe 14. The cross-sectional area of ​​the annular reaction space gradually increases from the bottom to the top. A reaction outlet pipe connecting the upper part of the annular reaction space is provided at the upper end of the outer cylinder.

2. The method for preparing spherical porous particles of ribonucleoside analogues according to claim 1, characterized in that, Includes the following steps: (1) Prepare a suspension of EIDD-2801, a ribonucleoside analogue, with a concentration of 10-100 mg / mL by mixing EIDD-2801 with pure water; (2) The suspension is pretreated by a reverse-spinning impact jet reactor system; (3) At a feed rate of 6-50 mL / min, the solution is delivered to the pressure nozzle of the spray freezer by a peristaltic pump; at an atomization pressure of 0.1-0.5 MPa, the solution is atomized and dispersed into liquid nitrogen to quickly form fine ice crystals; (4) After the liquid nitrogen evaporates, the ice crystals are transferred to a freeze dryer and freeze-dried at a pressure below 20 Pa to obtain the spherical porous particles of the ribonucleoside analogue. The reverse-vortex impact jet reactor system includes two composite vortex reactors, silicone tubing, a peristaltic pump, a T-tube, and an ultrasonic generator. The two composite vortex reactors are respectively positioned on either side of the T-tube, and their outlets are connected to the T-tube outlet via silicone tubing. The ultrasonic generator is connected to the T-tube via a metal threaded connection. The peristaltic pump is connected to the inlet of the composite vortex reactor, supplying the suspension to it. The composite vortex reactor includes a Rankine vortex reactor and a Taylor vortex reactor. The Rankine vortex reactor includes a disc-shaped reaction chamber. The reaction chamber is provided with a first inlet pipe and a second inlet pipe on its side wall. The fluid entering the reaction chamber through the first inlet pipe and the second inlet pipe can form a swirling fluid in the reaction chamber. A swirling outlet pipe 14 is provided in the middle of the top of the reaction chamber. The Taylor vortex reactor includes an inner cylinder and an outer cylinder arranged coaxially. The inner cylinder is driven to rotate by a rotary drive device. The inner cylinder and the outer cylinder form an annular reaction space. The bottom middle of the annular reaction space is connected to the reaction chamber through the swirling outlet pipe 14. The cross-sectional area of ​​the annular reaction space gradually increases from the bottom to the top. A reaction outlet pipe connecting the upper part of the annular reaction space is provided at the upper end of the outer cylinder.

3. The preparation method according to claim 2, characterized in that, In step (2), the method of pretreatment of the suspension by the reverse vortex impact jet reactor system is as follows: under the ultrasonic assistance of the ultrasonic generator, the suspension is transported to the composite vortex reactors on both sides by a peristaltic pump for impact mixing, and after further impact mixing at the T-tube, it is output through the T-tube outlet and transported to the composite vortex reactor again for circulation reaction. The suspension is continuously impacted and mixed in the reactor for 10 minutes.

4. The preparation method according to claim 3, characterized in that, The power of the ultrasound-assisted treatment is 50-1200W.

5. The preparation method according to claim 2, characterized in that, In step (2), the feed rate of the pretreatment peristaltic pump is 1-200 mL / min.

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