A pharmaceutical composition containing verbascoside for intervening high altitude nephropathy

Abstract

The application relates to the technical field of medicines, and specifically discloses a medicine composition containing verbascoside for intervention of highland nephropathy. The medicine composition is composed of verbascoside and auxiliary materials, the auxiliary materials include microcrystalline cellulose, lactose, crosslinked polyvinylpyrrolidone, hydroxypropyl methyl cellulose K4M, polyvinylpyrrolidone K30 and magnesium stearate; the medicine composition is an oral solid preparation, contains fast-release medicine-containing particles and slow-release medicine-containing micro-pellets, is filled in hard capsules after mixing, and further contains enteric delayed-release micro-pellets in the hard capsules. A preparation method is as follows: the verbascoside raw material is subjected to low-temperature micronization treatment, fast-release medicine-containing particles are prepared, slow-release medicine-containing micro-pellets are prepared, the three kinds of particles are mixed with magnesium stearate, and the capsules are filled. The medicine composition can be used for intervention of highland nephropathy individuals at high risk or diagnosed as active iron death according to the 4-hydroxy nonene aldehyde / creatinine ratio screening, and has the advantages of pulse release and sustained release synergistic cooperation.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and more specifically, to a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy. Background Technology

[0002] High-altitude nephropathy is a kidney disease characterized by progressive loss of renal function that occurs in high-altitude, hypoxic environments. Its core pathological component is tubulointerstitial hypoxia and the resulting oxidative stress and inflammatory damage. Oral medication is a crucial treatment for this disease. If the drug can rapidly reach an effective blood concentration after oral administration, it can promptly respond to the cellular stress signals initiated in the early stages of hypoxic exposure. Maintaining a certain level of blood drug concentration over the following hours helps provide sustained protection against persistent hypoxic damage. Therefore, an ideal drug formulation needs to balance rapid onset of action with sustained-release properties after administration.

[0003] However, existing conventional oral solid dosage forms struggle to reconcile these two needs within a single dosing unit. Conventional immediate-release formulations release almost all of their drug within a short time after oral administration, providing rapid onset of action but failing to maintain effective blood drug concentrations for an extended period, resulting in therapeutic gaps between dosing intervals. While conventional single-dose sustained-release formulations can prolong drug release time, they lack a rapid drug release phase after initial dosing, resulting in a relatively slow onset of action and hindering timely intervention in the pathological progression of early hypoxia exposure. Therefore, achieving both rapid initial drug release to ensure a rapid onset of action and sustained drug release in subsequent periods within a single dosage form remains a technical challenge in this field. Summary of the Invention

[0004] To address the problem that conventional oral solid dosage forms in the prior art cannot easily achieve both rapid onset of action and sustained maintenance of blood drug concentration in the same dosing unit, this application provides a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy.

[0005] In a first aspect, this application provides a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy, employing the following technical solution: A pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy is disclosed, comprising verbascoside and excipients including microcrystalline cellulose, lactose, crospovidone, hydroxypropyl methylcellulose K4M, povidone K30, and magnesium stearate. The pharmaceutical composition is an oral solid dosage form comprising immediate-release drug-containing granules and sustained-release drug-containing microcapsules with a mass ratio of 1:2 to 1:5. The granules are mixed and then filled into hard capsules. The pharmaceutical composition is used to intervene in individuals identified as high-risk or diagnosed with high-altitude nephropathy with active ferroptosis after screening for urinary 4-hydroxynonenal / creatinine ratio.

[0006] By employing the above-mentioned technical solution, immediate-release drug-containing granules and sustained-release drug-containing microcapsules are combined and filled into the same hard capsule at a specific mass ratio. In the immediate-release granules, crospovidone undergoes rapid disintegration of the granule structure due to strong water absorption and swelling in gastric juice, allowing the contained verbascoside to dissolve quickly and form an initial blood drug concentration pulse, which is beneficial for timely response to the renal tubular epithelial cell stress signals initiated early in hypoxia exposure. In the sustained-release drug-containing microcapsules, hydroxypropyl methylcellulose (K4M) forms a gel barrier layer on the surface of the microcapsules upon contact with water. The drug is slowly released through a dual mechanism of diffusion through the gel layer and dissolution of the matrix, continuously replenishing the drug for several hours after the immediate-release pulse to maintain an effective blood drug concentration level. This synergistic release pattern of pulsed and sustained release allows a single dose to meet both the needs of rapid onset and sustained action, which is beneficial for matching the body's circadian rhythm requirements for drug intervention in high-altitude hypoxic environments.

[0007] Preferably, the mass percentage of verbascoside in the immediate-release drug-containing granules is 10% to 50%, and the mass percentage of verbascoside in the sustained-release matrix drug-containing microspheres is 40% to 80%. The immediate-release drug-containing granules release at least 80% of their contained verbascoside within 0.5 to 1 hour after oral administration, and the sustained-release matrix drug-containing microspheres continuously release their contained verbascoside within 2 to 6 hours after oral administration.

[0008] By employing the above technical solutions, the drug loading of verbascoside in the immediate-release drug-containing particles is controlled at a low to moderate level. The particles have ample pore space within them, allowing the disintegrant to fully absorb water and swell, facilitating rapid dissolution of the drug after sufficient contact with the disintegrant in gastric juice, thus achieving the expected pulsed release effect. In the sustained-release drug-containing microspheres, the drug loading of verbascoside is controlled at a higher level. The drug is dispersed within a gel matrix formed by hydroxypropyl methylcellulose (K4M), allowing for stable release under the regulation of the gel barrier layer. The sustained release window covers the main pathological processes during hypoxic exposure. The differentiated design of the immediate-release and sustained-release units in terms of drug loading and release time allows for a combination of high and low release rates and a sequential release timeline in vivo.

[0009] Preferably, the hard capsule further comprises enteric-coated delayed-release microspheres, wherein the enteric-coated delayed-release microspheres contain 50% to 90% verbascoside by mass and are coated with an enteric coating, wherein the enteric coating dissolves in an environment with pH ≥ 5.5, so that the enteric-coated delayed-release microspheres begin to release the verbascoside contained therein 6 to 8 hours after oral administration.

[0010] By adopting the above technical solution, enteric-coated delayed-release microspheres are introduced into the binary system composed of immediate-release granules and sustained-release microspheres. These microspheres remain intact and do not release drug in the low pH environment of the stomach. After entering the intestines, the coating begins to dissolve as the pH of the digestive tract environment gradually rises above the threshold, initiating the third drug release phase several hours after oral administration. The dissolution pH threshold and delay time of the enteric coating are adjusted by the copolymerization ratio of methacrylic acid and ethyl acrylate in the coating material and the coating weight gain, ensuring that the release initiation point of the drug within the core can be controlled within the expected range. The mass percentage of verbascoside in the enteric-coated delayed-release microspheres is controlled within a relatively high range, which is beneficial for providing sufficient drug quantity to form an effective hysteresis pulse after the initiation of the third drug release phase. This hysteresis pulse compensates for the potential trough in blood drug concentration caused by the gradual decrease in drug release rate due to reduced drug content in the later stages of release from the sustained-release microspheres, further extending the coverage time of the effective drug concentration and forming a three-phase relay drug release mode of immediate-release pulse - sustained-release maintenance - enteric hysteresis pulse.

[0011] Preferably, the enteric coating is an aqueous dispersion of methacrylate-ethyl acrylate copolymer.

[0012] By adopting the above technical solution, the aqueous dispersion of methacrylic acid-ethyl acrylate copolymer, as an enteric coating material, exhibits excellent film-forming properties and flexibility. The coating layer is dense and uniform, and its structure remains stable under low pH conditions in gastric juice, effectively protecting the verbascoside in the pellet core from premature release. Upon entering the duodenum and posterior jejunum, the acidic groups in the copolymer's molecular structure ionize with changes in environmental pH, causing the coating layer to hydrate and gradually dissolve. The coating dissolution rate adapts to the pH changes in the digestive tract, ensuring accurate control of the drug release initiation point within the expected delay time range.

[0013] Secondly, this application provides a method for preparing a pharmaceutical composition containing verbascoside for intervening in high-altitude nephropathy, employing the following technical solution: A method for preparing a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy includes the following steps: S1. Low-temperature micronization treatment: The verbascoside raw material is pulverized under low-temperature conditions to obtain verbascoside micronized powder for later use. S2. Manufacturing of immediate-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with microcrystalline cellulose, lactose and cross-linked povidone, add an ethanol solution of povidone K30 as a binder to form a soft material, extrude and roll it into rounds, dry it to obtain immediate-release drug-containing granules. S3. Manufacturing of sustained-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with hydroxypropyl methylcellulose K4M, microcrystalline cellulose and lactose, add an ethanol solution of povidone K30 as a binder to make a soft material, extrude and roll it into spheres, and dry it to a predetermined moisture content under predetermined drying conditions to obtain sustained-release matrix drug-containing micro pellets. S4. Unit combination mixing: Mix the immediate-release drug-containing granules obtained in S2 and the sustained-release matrix drug-containing microcapsules obtained in S3 with the enteric-coated delayed-release microcapsules evenly, and add magnesium stearate to obtain the total mixed granules. S5. Filling and Packaging: The total mixed particles obtained in S4 are filled into hard capsules under isostatic pressure to obtain the pharmaceutical composition.

[0014] By adopting the above technical solution, the verbascoside raw material is first subjected to low-temperature micronization to reduce the particle size and improve the dissolution rate and mixing uniformity in subsequent formulation processes. The low-temperature environment can inhibit the thermal degradation of verbascoside during mechanical pulverization, maintaining the chemical stability of the active ingredient. Then, immediate-release drug-containing granules and sustained-release matrix drug-containing microcapsules are prepared independently. The immediate-release granules use microcrystalline cellulose and lactose as filler and diluent, crospovidone as disintegrant, and an ethanol solution of povidone K30 as binder. They are made into uniform spherical granules by extrusion and spheroidization, which facilitates rapid disintegration and drug dissolution. The sustained-release microcapsules use hydroxypropyl methylcellulose K4M as the matrix material, microcrystalline cellulose and lactose as filler and diluent, and are made into dense spherical microcapsules by the same extrusion and spheroidization process. They are then dried in a fluidized bed to a predetermined moisture content to form a stable gel matrix structure. Finally, the two types of granules are mixed in a certain proportion and magnesium stearate is added as a lubricant before being filled into capsules. The process design of independently granulating and combining immediate-release granules and sustained-release microcapsules allows the formulation composition and preparation parameters of the two drug release units to be independently controlled without interference, which is conducive to precise control of the drug release behavior of each unit and has good process controllability and batch-to-batch reproducibility.

[0015] Preferably, in step S1, the low temperature condition is -20℃ to -10℃; the air inlet pressure for pulverization is 0.6MPa to 0.8MPa, and the pulverization is performed 1 to 2 times; the particle size D of the verbascoside micro powder is... 90 The range is from 1 μm to 20 μm.

[0016] By employing the above technical solution, high-speed airflow is used to impact and pulverize verbascoside raw materials under low-temperature conditions. The heat generated by mechanical friction is effectively absorbed by the low-temperature environment, preventing thermal degradation of verbascoside due to localized instantaneous heating. By controlling the inlet pressure and the number of pulverization cycles, micro-powders within the desired particle size range can be obtained. At this particle size, the specific surface area of ​​the raw material is significantly increased, which is beneficial for improving the uniformity of dispersion of active ingredients in excipients and the dissolution rate after oral administration during subsequent granulation. Simultaneously, it avoids the problems of particle agglomeration and decreased flowability that may result from excessively fine particle sizes.

[0017] Preferably, in step S2, the total mass of the microcrystalline cellulose, lactose, and crospovidone accounts for 50% to 90% of the total mass of the immediate-release drug-containing particles, wherein the weight ratio of the microcrystalline cellulose, lactose, and crospovidone is (9-12):(4-7):(1-2); in the ethanol solution of povidone K30, the mass fraction of povidone K30 in the total mass of the solution is 5% to 15%, the solvent is a mixture of ethanol and water, and the volume ratio of ethanol to water is 50:50 to 95:5; the drying conditions are an inlet air temperature of 45°C to 55°C, and drying until the moisture content is less than 2.0%.

[0018] By employing the above technical solution, microcrystalline cellulose and lactose, as filler diluents, provide the necessary volume and appropriate hardness for the rapid-release drug-containing granules. Crosslinked povidone, as a disintegrant, rapidly disintegrates the granule structure upon contact with water through strong water absorption and swelling. The specific weight ratio of these three components ensures rapid disintegration while maintaining the mechanical strength of the granules. Povidone K30, dissolved in a mixture of ethanol and water, acts as a binder. A higher proportion of ethanol facilitates rapid wetting of the powder material during the soft material preparation stage and rapid evaporation during the drying stage after extrusion and rounding, shortening the drying time. The concentration range of povidone K30 provides adequate binding force to ensure granule formation without excessive hardening that could hinder disintegration. Controlling the drying temperature within a suitable range effectively removes moisture while preventing excessive heat from causing degradation of active ingredients or crusting on the granule surface.

[0019] Preferably, in step S3, the total mass of the hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose accounts for 20% to 60% of the total mass of the sustained-release drug-containing microcapsules, wherein the weight ratio of the hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose is (3-7):(1-5):(1-3); the mass fraction of povidone K30 in the ethanol solution is 5% to 15%; the predetermined drying conditions are fluidized bed drying with an inlet air temperature of 45°C to 55°C; and the predetermined moisture content is 1.5% to 2.0%.

[0020] By employing the above technical solution, hydroxypropyl methylcellulose (K4M), as a hydrophilic gel matrix material, constitutes a significant proportion of the total mass of the microcapsules. Upon contact with water, the microcapsules form a viscous gel barrier layer on their surface. The density and thickness of this gel layer are jointly regulated by the ratio of the matrix material to the diluent. The drug must diffuse through the gel layer and undergo gradual dissolution of the matrix to be released into the medium, thus achieving sustained drug release within a predetermined time range. Fluidized bed drying ensures uniform and rapid drying of the microcapsules in a suspended state. The moisture content at the drying endpoint is controlled within a suitable range. At this moisture content, the molecular chains of hydroxypropyl methylcellulose (K4M) do not excessively dehydrate and shrink. During storage, the matrix structure of the microcapsules remains stable after moisture equilibrium is achieved, and upon contact with water, it can normally hydrate to form a gel layer, thereby ensuring batch-to-batch consistency of the sustained-release performance.

[0021] Preferably, in step S4, the amount of magnesium stearate added accounts for 0.5% to 2.0% of the total mass of the mixed particles.

[0022] By adopting the above technical solution, after the immediate-release drug-containing granules and the sustained-release matrix drug-containing microcapsules are mixed evenly, an appropriate amount of magnesium stearate is added as a lubricant. The tiny particles of magnesium stearate adhere to the surface of the granules, reducing the friction between the granules and the metal mold and the inner wall of the capsule during the filling process, improving the fluidity of the granules, making the filling process smooth and the filling amount accurate and stable. At the same time, within this dosage range, the hydrophobic film formed by magnesium stearate will not hinder the disintegration of the granules and the dissolution of the drug after they come into contact with water.

[0023] Preferably, in step S5, the disintegration time of the capsule is 1 to 3 minutes.

[0024] By adopting the above technical solution, the disintegration time of hard capsules is controlled within a short time range. The capsule shell can quickly disintegrate in gastric juice to release the contents, including immediate-release drug-containing granules and sustained-release matrix drug-containing microspheres. This ensures that the immediate-release granules can quickly disintegrate and release the drug within the expected time window to form an initial pulse, providing an accurate release starting point for the sequential connection of subsequent sustained-release pulses and enteric hysteresis pulses.

[0025] In summary, this application has the following beneficial effects: 1. Because this application uses a multi-unit drug delivery system that includes immediate-release drug-containing particles and sustained-release drug-containing microspheres with a mass ratio of 1:2 to 1:5, the immediate-release portion rapidly releases after a single oral dose to form an initial blood drug concentration pulse, while the sustained-release portion continues to release in subsequent periods to maintain the blood drug concentration. This achieves a drug delivery mode that combines pulsed release and sustained release, which is beneficial for matching the body's physiological response rhythm to a hypoxic environment.

[0026] 2. In this application, hydroxypropyl methylcellulose K4M is preferably used as the matrix material of sustained-release drug-containing microspheres. Since this hydrophilic gel matrix material with a specific viscosity grade can form a stable gel barrier layer when it comes into contact with water, the drug can be released continuously and stably within 2h to 6h through a dual mechanism of diffusion and dissolution, thus achieving a sustained-release effect with a stable and controllable drug release rate and good intra-batch uniformity.

[0027] 3. The method of this application effectively suppresses the mechanical frictional heat of the raw material during the micronization process by air-jet milling of verbascoside under low temperature conditions, thereby avoiding thermal degradation of heat-sensitive verbascoside and maintaining the chemical stability of the active ingredient while improving drug dissolution.

[0028] 4. This application adopts a design that further adds enteric-coated delayed-release microspheres into hard capsules, and controls the mass percentage of verbascoside in the enteric-coated microspheres at a high level. Since the microspheres are coated with an enteric coating that dissolves in an environment of pH≥5.5, they only begin to release the drug 6 to 8 hours after oral administration. This forms a third drug release phase with sufficient drug release after the immediate-release pulse and sustained-release phases, thereby prolonging the effective drug coverage time and filling the possible drug supply gap in the later stages of drug release.

[0029] 5. The method of this application, by separately granulating immediate-release drug-containing granules and sustained-release matrix drug-containing microspheres and then mixing them in proportion, allows the formulation composition and preparation parameters of the two drug release units to be optimized independently without interference. Therefore, it achieves the effect of strong flexibility in formulation design and easy precise control of drug release behavior. Attached Figure Description

[0030] Figure 1 This is a flowchart of a method for preparing a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy, as provided in this application; Figure 2 This is a comparison chart of the in vitro cumulative release percentage determination results of the various embodiments and comparative examples provided in this application; Figure 3 This is a comparison chart of the pharmacodynamic index determination results of the various embodiments and comparative examples provided in this application for rats with high-altitude nephropathy; Figure 4 This is a comparison chart of the related substance detection results of the various embodiments and comparative examples provided in this application. Detailed Implementation

[0031] The present application will be further described in detail below with reference to embodiments and comparative examples. Unless otherwise specified, the experimental methods used below are conventional methods. Unless otherwise specified, the materials, reagents, methods and instruments used are all conventional materials, reagents, methods and instruments in the art, which can be obtained by those skilled in the art through commercial channels or prepared according to literature methods.

[0032] Technical Concept: The core pathological factor of high-altitude nephropathy is persistent tubulointerstitial hypoxia caused by hypoxia. Oral medications need to simultaneously meet two requirements: rapid onset of action in the initial stage of hypoxia exposure and sustained action over several hours thereafter. However, existing oral solid dosage forms suffer from a single drug release mode. Immediate-release formulations have a fast onset of action but a short duration of blood drug concentration, while sustained-release formulations have a long duration of action but a relatively slow onset of action. The root cause is that conventional formulations only contain a single type of drug release unit and have not constructed a multi-unit synergistic drug release system.

[0033] This technical solution constructs a three-phase relay drug release mode—immediate-release drug-containing granules, sustained-release drug-containing microspheres, and enteric-coated delayed-release microspheres—by combining three drug release units in hard capsules: immediate-release pulse, sustained-release maintenance, and enteric-coated delayed-release pulse. The immediate-release granules use crospovidone as a disintegrant to achieve rapid drug release and form the initial pulse. The sustained-release microspheres use hydroxypropyl methylcellulose (K4M) as a matrix material to continuously release drug through a gel barrier layer, maintaining blood drug concentration. The enteric-coated microspheres are coated with a pH-sensitive coating to trigger release in the intestine, forming the delayed pulse. The three units are granulated independently and then mixed and filled in a specific ratio. The release behavior of each unit can be controlled independently without interference, achieving rapid onset of action, sustained release, and seamless follow-up after a single dose.

[0034] Preparation Example: The preparation method of enteric delayed release microspheres is as follows: Take 70 parts of verbascoside micro powder, 15 parts of microcrystalline cellulose, and 15 parts of lactose and mix them evenly. Add 35 parts of a povidone K30 ethanol solution containing 10% povidone K30 by mass as a binder to make a soft material. The volume ratio of ethanol to water in the povidone K30 ethanol solution is 70:30. The soft material is extruded through an extruder with a 0.6 mm aperture, and rolled in a spherical mill at 1000 rpm for 5 min. The wet pellets are taken out and dried in a fluidized bed with an inlet air temperature of 50℃ for 40 min until the moisture content is 1.5%. The pellet cores between 18 and 24 mesh are collected by passing them through a 24 mesh sieve.

[0035] Ten parts of methacrylic acid, eight parts of ethyl acrylate, and two parts of methyl methacrylate were added to 80 parts of deionized water under stirring. 0.5 parts of sodium dodecyl sulfate were added as an emulsifier. Under nitrogen protection, the mixture was heated to 75°C, and then 0.3 parts of potassium persulfate were added as an initiator. The polymerization reaction was carried out at a constant temperature of 75°C with stirring for 4 hours. After cooling, the pH was adjusted to 7.0 with ammonia water. The mixture was filtered through a 300-mesh sieve to obtain a methacrylic acid-ethyl acrylate copolymer aqueous dispersion with a solid content of 20%, which was used as the coating solution. One hundred parts of pellet cores were placed in a fluidized bed coating machine and bottom-sprayed with the above coating solution. The coating weight increased to 15% of the pellet core mass. During the coating process, the inlet air temperature was 30°C, the atomization pressure was 0.15 MPa, and the liquid supply rate was 2.5 g / min. After coating, the pellets were dried at 40°C for 2 hours to obtain enteric-coated delayed-release microspheres.

[0036] Example 1: This example provides a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy. The composition consists of verbascoside and excipients, including microcrystalline cellulose, lactose, crospovidone, hydroxypropyl methylcellulose K4M, povidone K30, and magnesium stearate. The pharmaceutical composition is an oral solid dosage form comprising immediate-release drug-containing granules and sustained-release drug-containing microcapsules with a mass ratio of 1:3.5. The mixture is then filled into hard capsules. This pharmaceutical composition is used to intervene in individuals identified as having active ferroptosis-type high-risk or confirmed high-altitude nephropathy after screening for urinary 4-hydroxynonenal / creatinine ratio.

[0037] The immediate-release drug-containing granules contain 30% verbascoside by mass, while the sustained-release drug-containing microcapsules contain 60% verbascoside by mass. The immediate-release drug-containing granules release at least 80% of their verbascoside content within 0.75 hours after oral administration, while the sustained-release drug-containing microcapsules continuously release their verbascoside content within 4 hours after oral administration.

[0038] The hard capsule also contains enteric-coated delayed-release microspheres, which are prepared according to the above preparation example. The enteric-coated delayed-release microspheres account for 20% of the total mass of the three drug release units: immediate-release drug-containing particles, sustained-release matrix drug-containing microspheres, and enteric-coated delayed-release microspheres. The enteric-coated delayed-release microspheres contain 70% verbascoside by mass and are coated with an enteric coating. The enteric coating dissolves in an environment with pH ≥ 5.5, so that the enteric-coated delayed-release microspheres begin to release the verbascoside they contain 7 hours after oral administration.

[0039] The enteric coating is an aqueous dispersion of methacrylate-ethyl acrylate copolymer.

[0040] The preparation method of the above-mentioned pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy includes the following steps: S1. Low-temperature micronization treatment: The verbascoside raw material is pulverized under low-temperature conditions to obtain verbascoside micronized powder for later use. The low-temperature condition was -15℃; the inlet pressure for pulverization was 0.7MPa; the pulverization was performed once; and the particle size D of the obtained verbascoside micro powder was... 90 The particle size is 10μm. Low-temperature pulverization avoids thermal degradation of verbascoside due to mechanical friction and heating, effectively ensuring the chemical stability of the active ingredient.

[0041] S2. Manufacturing of immediate-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with microcrystalline cellulose, lactose and cross-linked povidone, add an ethanol solution of povidone K30 as a binder to form a soft material, extrude and roll it into rounds, dry it to obtain immediate-release drug-containing granules. The total mass of microcrystalline cellulose, lactose, and crospovidone accounts for 70% of the total mass of the immediate-release drug-containing granules, with a weight ratio of 10.5:5.5:1.5 for microcrystalline cellulose, lactose, and crospovidone. In the ethanol solution of povidone K30, povidone K30 accounts for 10% of the total mass of the solution, and the solvent is a mixture of ethanol and water with a volume ratio of 70:30. The mass of the binder solution added is 35% of the total mass of the powder material. The stirring time for preparing the soft material is 8 minutes, and the stirring speed is 120 rpm. The extrusion orifice diameter is 0.6 mm, the spherical rotation speed is 1000 rpm, and the spherical rotation time is 5 minutes. The drying conditions are an inlet air temperature of 50℃, a drying time of 40 minutes, and drying to a moisture content of 1.0%.

[0042] S3. Manufacturing of sustained-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with hydroxypropyl methylcellulose K4M, microcrystalline cellulose and lactose, add an ethanol solution of povidone K30 as a binder to make a soft material, extrude and roll it into spheres, and dry it to a predetermined moisture content under predetermined drying conditions to obtain sustained-release matrix drug-containing micro pellets. The total mass of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose accounts for 40% of the total mass of the sustained-release drug-containing microspheres, with a weight ratio of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose of 5:3:2. The ethanol solution of povidone K30 contains 10% povidone K30 by mass, and the solvent is a mixture of ethanol and water with a volume ratio of 70:30. The binder solution accounts for 40% of the total mass of the powder material. The stirring time for preparing the soft material is 10 min, and the stirring speed is 100 rpm. The extrusion orifice diameter is 0.8 mm, the spheroidizing speed is 900 rpm, and the spheroidizing time is 6 min. The predetermined drying conditions are fluidized bed drying, an inlet air temperature of 50℃, and a drying time of 50 min. The predetermined moisture content is 1.8%. The sustained-release matrix material, hydroxypropyl methylcellulose K4M, forms a gel barrier upon contact with water, enabling the drug to be continuously released within 2 to 6 hours through a dual mechanism of diffusion and dissolution.

[0043] S4. Unit combination mixing: Mix the immediate-release drug-containing granules obtained in S2 and the sustained-release matrix drug-containing microcapsules obtained in S3 with the enteric-coated delayed-release microcapsules evenly, and add magnesium stearate to obtain the total mixed granules. The mass ratio of immediate-release drug-containing granules to sustained-release drug-containing microcapsules is 1:3.5; the amount of magnesium stearate added accounts for 1.2% of the total mass of the mixed granules; the mixing is carried out using a hopper mixer at a speed of 15 rpm for a mixing time of 20 min.

[0044] S5. Filling and Packaging: Fill the total mixed particles obtained in S4 into hard capsules to obtain the drug composition. The filling process uses a fully automatic capsule filling machine with a filling speed of 800 capsules / min; the capsule disintegration time is 2 minutes; and the fill volume variation limit after filling is ±5% of the labeled amount.

[0045] Example 2: This example provides a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy. The composition consists of verbascoside and excipients, including microcrystalline cellulose, lactose, crospovidone, hydroxypropyl methylcellulose K4M, povidone K30, and magnesium stearate. The pharmaceutical composition is an oral solid dosage form comprising immediate-release drug-containing granules and sustained-release drug-containing microspheres with a mass ratio of 1:2. The mixture is then filled into hard capsules. This pharmaceutical composition is used to intervene in individuals identified as having active ferroptosis-type high-risk or confirmed high-altitude nephropathy after screening for urinary 4-hydroxynonenal / creatinine ratio.

[0046] The immediate-release drug-containing granules contain 10% verbascoside by mass, while the sustained-release drug-containing microcapsules contain 40% verbascoside by mass. The immediate-release drug-containing granules release at least 80% of their verbascoside content within 0.5 hours after oral administration, while the sustained-release drug-containing microcapsules continuously release their verbascoside content within 2 hours after oral administration.

[0047] The hard capsule also contains enteric-coated delayed-release microspheres, which are prepared using the method shown in the above preparation example. The enteric-coated delayed-release microspheres account for 10% of the total mass of the three drug release units: immediate-release drug-containing particles, sustained-release matrix drug-containing microspheres, and enteric-coated delayed-release microspheres. The enteric-coated delayed-release microspheres contain 50% verbascoside by mass and are coated with an enteric coating. The enteric coating dissolves in an environment with pH ≥ 5.5, so that the enteric-coated delayed-release microspheres begin to release the verbascoside they contain 6 hours after oral administration.

[0048] The enteric coating is an aqueous dispersion of methacrylate-ethyl acrylate copolymer.

[0049] The preparation method of the above-mentioned pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy includes the following steps: S1. Low-temperature micronization treatment: The verbascoside raw material is pulverized under low-temperature conditions to obtain verbascoside micronized powder for later use. The low-temperature condition was -20℃; the inlet air pressure for pulverization was 0.6MPa; the pulverization was performed once; and the particle size D of the obtained verbascoside micro powder was... 90 The particle size is 1μm. Low-temperature pulverization avoids thermal degradation of verbascoside due to mechanical friction and heating, effectively ensuring the chemical stability of the active ingredient.

[0050] S2. Manufacturing of immediate-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with microcrystalline cellulose, lactose and cross-linked povidone, add an ethanol solution of povidone K30 as a binder to form a soft material, extrude and roll it into rounds, dry it to obtain immediate-release drug-containing granules. The total mass of microcrystalline cellulose, lactose, and crospovidone accounts for 50% of the total mass of the immediate-release drug-containing granules, with a weight ratio of microcrystalline cellulose, lactose, and crospovidone of 9:4:1. In the ethanol solution of povidone K30, povidone K30 accounts for 5% of the total mass of the solution, and the solvent is a mixture of ethanol and water with a volume ratio of 50:50. The mass of the binder solution added is 25% of the total mass of the powder material. The stirring time for preparing the soft material is 6 minutes, and the stirring speed is 100 rpm. The extrusion orifice diameter is 0.6 mm, the spherical rotation speed is 800 rpm, and the spherical rotation time is 3 minutes. The drying conditions are an inlet air temperature of 45℃, a drying time of 35 minutes, and drying to a moisture content of 0.8%.

[0051] S3. Manufacturing of sustained-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with hydroxypropyl methylcellulose K4M, microcrystalline cellulose and lactose, add an ethanol solution of povidone K30 as a binder to make a soft material, extrude and roll it into spheres, and dry it to a predetermined moisture content under predetermined drying conditions to obtain sustained-release matrix drug-containing micro pellets. The total mass of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose accounts for 20% of the total mass of the sustained-release matrix drug-containing microcapsules, with a weight ratio of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose of 3:1:1. The ethanol solution of povidone K30 contains 5% povidone K30 by mass, and the solvent is a mixture of ethanol and water at a volume ratio of 50:50. The binder solution accounts for 30% of the total mass of the powder material. The stirring time for preparing the soft material is 8 min, and the stirring speed is 80 rpm. The extrusion orifice diameter is 0.6 mm, the spheroidizing speed is 800 rpm, and the spheroidizing time is 4 min. The predetermined drying conditions are fluidized bed drying, an inlet air temperature of 45℃, and a drying time of 40 min. The predetermined moisture content is 1.5%. The sustained-release matrix material hydroxypropyl methylcellulose K4M forms a gel barrier upon contact with water, enabling the drug to be continuously released within 2 to 6 hours through a dual mechanism of diffusion and dissolution.

[0052] S4. Unit combination mixing: Mix the immediate-release drug-containing granules obtained in S2 and the sustained-release matrix drug-containing microcapsules obtained in S3 with the enteric-coated delayed-release microcapsules evenly, and add magnesium stearate to obtain the total mixed granules. The mass ratio of immediate-release drug-containing granules to sustained-release drug-containing microcapsules is 1:2; the amount of magnesium stearate added accounts for 0.5% of the total mass of the mixed granules; the mixing is carried out using a hopper mixer at a speed of 10 rpm for a mixing time of 15 min.

[0053] S5. Filling and Packaging: Fill the total mixed particles obtained in S4 into hard capsules to obtain the drug composition. The filling process uses a fully automatic capsule filling machine with a filling speed of 600 capsules / min; the capsule disintegration time is 1 minute; and the fill volume variation limit after filling is ±5% of the labeled amount.

[0054] Example 3: This example provides a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy. The composition consists of verbascoside and excipients, including microcrystalline cellulose, lactose, crospovidone, hydroxypropyl methylcellulose K4M, povidone K30, and magnesium stearate. The pharmaceutical composition is an oral solid dosage form comprising immediate-release drug-containing granules and sustained-release drug-containing microspheres with a mass ratio of 1:5. The mixture is then filled into hard capsules. This pharmaceutical composition is used to intervene in individuals identified as having active ferroptosis-prone high-risk or confirmed high-altitude nephropathy after screening for urinary 4-hydroxynonenal / creatinine ratio.

[0055] The immediate-release drug-containing granules contain 50% verbascoside by mass, while the sustained-release drug-containing microcapsules contain 80% verbascoside by mass. The immediate-release drug-containing granules release at least 80% of their verbascoside content within 1 hour after oral administration, while the sustained-release drug-containing microcapsules continuously release their verbascoside content within 6 hours after oral administration.

[0056] The hard capsule also contains enteric-coated delayed-release microspheres, which are prepared using the method shown in the above preparation example. The enteric-coated delayed-release microspheres account for 30% of the total mass of the three drug release units: immediate-release drug-containing particles, sustained-release matrix drug-containing microspheres, and enteric-coated delayed-release microspheres. The enteric-coated delayed-release microspheres contain 90% verbascoside by mass and are coated with an enteric coating. The enteric coating dissolves in an environment with pH ≥ 5.5, so that the enteric-coated delayed-release microspheres begin to release the verbascoside they contain 8 hours after oral administration.

[0057] The enteric coating is an aqueous dispersion of methacrylate-ethyl acrylate copolymer.

[0058] The preparation method of the above-mentioned pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy includes the following steps: S1. Low-temperature micronization treatment: The verbascoside raw material is pulverized under low-temperature conditions to obtain verbascoside micronized powder for later use. The low-temperature condition was -10℃; the inlet pressure for pulverization was 0.8MPa; the pulverization was performed twice; and the particle size D of the resulting verbascoside micro powder was... 90 The particle size is 20μm. Low-temperature pulverization avoids thermal degradation of verbascoside due to mechanical friction and heating, effectively ensuring the chemical stability of the active ingredient.

[0059] S2. Manufacturing of immediate-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with microcrystalline cellulose, lactose and cross-linked povidone, add an ethanol solution of povidone K30 as a binder to form a soft material, extrude and roll it into rounds, dry it to obtain immediate-release drug-containing granules. The total mass of microcrystalline cellulose, lactose, and crospovidone accounts for 90% of the total mass of the immediate-release drug-containing granules, with a weight ratio of microcrystalline cellulose, lactose, and crospovidone of 12:7:2. In the ethanol solution of povidone K30, povidone K30 accounts for 15% of the total mass of the solution, and the solvent is a mixture of ethanol and water with a volume ratio of 95:5. The mass of the binder solution added is 45% of the total mass of the powder material. The stirring time for preparing the soft material is 12 min, and the stirring speed is 150 rpm. The extrusion orifice diameter is 0.8 mm, the spherical rotation speed is 1200 rpm, and the spherical rotation time is 8 min. The drying conditions are an inlet air temperature of 55℃, a drying time of 50 min, and drying to a moisture content of 1.5%.

[0060] S3. Manufacturing of sustained-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with hydroxypropyl methylcellulose K4M, microcrystalline cellulose and lactose, add an ethanol solution of povidone K30 as a binder to make a soft material, extrude and roll it into spheres, and dry it to a predetermined moisture content under predetermined drying conditions to obtain sustained-release matrix drug-containing micro pellets. The total mass of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose accounts for 60% of the total mass of the sustained-release matrix drug-containing microspheres, with a weight ratio of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose of 7:5:3. The ethanol solution of povidone K30 contains 15% povidone K30 by mass, and the solvent is a mixture of ethanol and water with a volume ratio of 95:5. The binder solution accounts for 50% of the total mass of the powder material. The stirring time for preparing the soft material is 15 min, and the stirring speed is 120 rpm. The extrusion orifice diameter is 1.0 mm, the spheroidizing speed is 1000 rpm, and the spheroidizing time is 8 min. The predetermined drying conditions are fluidized bed drying, an inlet air temperature of 55℃, and a drying time of 60 min. The predetermined moisture content is 2.0%. The sustained-release matrix material hydroxypropyl methylcellulose K4M forms a gel barrier upon contact with water, enabling the drug to be continuously released within 2 to 6 hours through a dual mechanism of diffusion and dissolution.

[0061] S4. Unit combination mixing: Mix the immediate-release drug-containing granules obtained in S2 and the sustained-release matrix drug-containing microcapsules obtained in S3 with the enteric-coated delayed-release microcapsules evenly, and add magnesium stearate to obtain the total mixed granules. The mass ratio of immediate-release drug-containing granules to sustained-release drug-containing microcapsules is 1:5; the amount of magnesium stearate added accounts for 2.0% of the total mass of the mixed granules; the mixing is carried out using a hopper mixer at a speed of 20 rpm for a mixing time of 30 min.

[0062] S5. Filling and Packaging: Fill the total mixed particles obtained in S4 into hard capsules to obtain the drug composition. The filling process uses a fully automatic capsule filling machine with a filling speed of 1000 capsules / min; the capsule disintegration time is 3 minutes; and the fill volume variation limit after filling is ±5% of the labeled amount.

[0063] Comparative Example 1: The only difference between this comparative example and Example 1 is that the sustained-release matrix containing drug-containing microspheres has been removed, and the contents of the capsule are all immediate-release drug-containing granules. Otherwise, it is the same as Example 1.

[0064] Comparative Example 2: The only difference between this comparative example and Example 1 is that the hydroxypropyl methylcellulose K4M in the sustained-release drug-containing microcapsules is deleted and replaced with an equal amount of microcrystalline cellulose. The rest is the same as Example 1.

[0065] Comparative Example 3: The only difference between this comparative example and Example 1 is that the immediate-release drug-containing granules are removed, and the contents of the capsule are all sustained-release drug-containing microspheres. The rest is the same as Example 1.

[0066] Comparative Example 4: The only difference between this comparative example and Example 1 is that the enteric-coated delayed-release microspheres have been removed, and the hard capsules contain only immediate-release drug-containing particles and sustained-release matrix drug-containing microspheres. The rest is the same as Example 1.

[0067] Comparative Example 5: The only difference between this comparative example and Example 1 is that in step S1, the low temperature condition of -15°C is replaced with the normal temperature condition of 25°C, and the rest is the same as Example 1.

[0068] I. In vitro release rate determination: The determination was performed according to the second method (paddle method) of Dissolution and Release Determination Method 0931, Part IV, General Chapter of the 2020 Chinese Pharmacopoeia. 900 mL of degassed pH 1.2 hydrochloric acid solution was used as the release medium, the rotation speed was 50 rpm, and the medium temperature was 37℃ ± 0.5℃. Six capsules each from Examples 1 to 3 and Comparative Examples 1 to 5 were added to a dissolution vessel. 5 mL samples were taken at preset time points of 0.25 h, 0.5 h, 0.75 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 10 h, and fresh medium of equal volume and temperature was added simultaneously. The samples were filtered through a 0.45 μm microporous membrane. The peak area of ​​verbascoside in the filtrate was determined by high performance liquid chromatography at a wavelength of 330 nm. The cumulative release percentage at each time point was calculated using the external standard method based on the peak area, and a release curve was plotted.

[0069] II. Pharmacodynamic Experiment of High-Altitude Nephropathy Rats: The experiment was conducted in accordance with the Technical Guidelines for Pharmacological and Efficacy Studies, Section IV, General Chapter 9022 of the 2020 Edition of the Chinese Pharmacopoeia. Male SD rats weighing 180g to 220g were randomly divided into 8 groups of 10 rats each: sham-operated group, model group, Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group, Comparative Example 2 group, and Comparative Example 5 group. The sham-operated group was housed in a normoxic environment, while the rats in the other groups were placed in a hypobaric chamber to simulate the hypoxic environment at an altitude of 5000m. The oxygen partial pressure in the chamber was maintained at 8.5kPa, and the rats were continuously exposed for 23 hours daily for 4 consecutive weeks to establish the high-altitude nephropathy model. From day 1 of modeling, all groups were administered medication by gavage. Groups 1, 2, and 5 of Example 1 were given an equivalent dose of 100 mg / kg / day based on verbascoside. Groups 2 and 3 of Example 2 were given an equivalent dose of 100 mg / kg / day based on their respective formulation specifications. The model group and sham-operated group were administered an equal volume of 0.5% sodium carboxymethyl cellulose solution by gavage. The administration volume was 10 mL / kg, once daily for 4 consecutive weeks. After the last administration, the rats were fasted for 12 hours but allowed free access to water. 24-hour urine was collected in metabolic cages to determine the urinary microalbumin to creatinine ratio (UACR). Blood was collected from the orbital venous plexus and centrifuged to separate serum. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured using an automated biochemical analyzer. After euthanasia, both kidneys were harvested, weighed, and the kidney coefficient (the ratio of kidney weight to body weight) was calculated.

[0070] III. Detection of Related Substances of Active Ingredients: The determination was performed according to the General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia, Part IV, using High Performance Liquid Chromatography (HPLC). An appropriate amount of the contents of the capsules prepared in Example 1 and Comparative Example 5 was accurately weighed, dissolved in methanol, and diluted to prepare a test solution containing approximately 0.5 mg of verbascoside per mL. The chromatographic conditions were as follows: octadecylsilane-bonded silica gel as the stationary phase, gradient elution with acetonitrile-0.1% phosphoric acid aqueous solution as the mobile phase, detection wavelength of 330 nm, column temperature of 30 °C, and injection volume of 20 μL. The test solution was injected into the HPLC system, and the chromatogram was recorded up to three times the retention time of the main component peak. The percentage of each impurity peak area to the total peak area was calculated using the area normalization method. The largest single impurity should not exceed 1.0%, and the total impurities should not exceed 2.0%.

[0071] Table 1: Results of in vitro cumulative release percentage determination

[0072] Note: The data in the table represent the average cumulative release percentage of 6 capsules in each group at each time point, in units of %.

[0073] Table 2: Results of Pharmacodynamic Indicators in Rats with High-Altitude Nephropathy

[0074] Note: The data in the table are the mean ± standard deviation of 10 rats in each group. UACR is the ratio of urinary microalbumin to creatinine, Scr is serum creatinine, BUN is blood urea nitrogen, and the kidney coefficient is the ratio of bilateral kidney weight to body weight.

[0075] Table 3: Results of Related Substance Detection

[0076] Note: The data in the table are calculated using the area normalization method.

[0077] Based on Examples 1 to 3 and Comparative Example 1, and in conjunction with Tables 1 and 2, it can be seen that removing the sustained-release matrix drug-containing microgranules causes the formulation to lose the sustained-release portion in the multi-unit pulsatile drug release system. The drug is only released rapidly in the initial stage without subsequent sustained release capability, and the blood drug concentration cannot be maintained, resulting in a short-lasting renal protective effect. All efficacy indicators are inferior to those of the examples, demonstrating that the pulsatile plus sustained-release drug release mode constructed by the synergy of the immediate-release unit and the sustained-release unit plays an indispensable role in the efficacy.

[0078] Based on Examples 1 to 3 and Comparative Example 2, and in conjunction with Tables 1 and 2, it can be seen that after replacing hydroxypropyl methylcellulose K4M with microcrystalline cellulose, the sustained-release pellets lost their skeletal sustained-release function. The drug was almost completely released in a short time, and the drug release behavior was close to that of an immediate-release formulation. It could not provide a sustained blood drug concentration maintenance phase, and the efficacy was significantly inferior to that of the examples. This indicates that selecting hydroxypropyl methylcellulose K4M with a specific viscosity grade as the hydrophilic gel skeletal material is a key technical feature for constructing sustained-release units.

[0079] As can be seen from Examples 1 to 3 and Comparative Example 3, and in conjunction with Tables 1 and 2, the formulation completely lacks the initial pulsating drug release phase after the removal of the immediate-release drug-containing particles. The drug release is slow and there is no rapid onset peak. The initial blood drug concentration cannot reach the effective level. The various efficacy indicators are the worst among all dosing groups, which proves that the initial pulse provided by the immediate-release unit has an irreplaceable role in rapid onset of action and triggering the body's hypoxia adaptation response.

[0080] Based on Examples 1 to 3 and Comparative Example 4, and in conjunction with Tables 1 and 2, it can be seen that the drug release process of the formulation after removing the enteric-coated delayed-release pellets lacks a third-phase hysteresis pulse. A drug delivery window appears in the middle and late stages of drug release, which cannot meet the needs of long-term continuous intervention in high-altitude hypoxic environments. The efficacy is not as comprehensive as in the examples, indicating that the enteric-coated delayed pulse unit in the ternary drug release system plays an important supplementary role in improving the drug release time course coverage.

[0081] Combined with Examples 1 to 3 and Comparative Example 5, and referring to Tables 1 to 3, it can be seen that after replacing low-temperature pulverization with room-temperature pulverization, the content of related substances of the active ingredient increased significantly, and the purity of the main peak decreased significantly. This indicates that the thermosensitive verbascoside undergoes thermal degradation during room-temperature mechanical pulverization, resulting in a reduction in the amount of effective drug and an increase in impurities. The release rate and efficacy are inferior to those of the examples, demonstrating the technical significance of low-temperature micronization pretreatment in ensuring the chemical stability of thermosensitive active ingredients.

[0082] Referring to the preparation methods of Examples 1 to 3, the mass ratio of immediate-release drug-containing granules to sustained-release drug-containing microcapsules was adjusted to 1:2 and 1:5, respectively. Simultaneously, the mass percentage of verbascoside in the enteric-coated delayed-release microcapsules was adjusted to 50% and 90%, respectively, and the proportion of enteric-coated delayed-release microcapsules in the total mass of the three drug release units was adjusted to 5% and 30%, respectively. The remaining process parameters remained consistent with Example 1. In vitro release rate determination showed that all the above-mentioned combinations of endpoint values ​​could achieve the drug release characteristics of at least 80% release of immediate-release granules within 0.5 to 1 hour, continuous release of sustained-release microcapsules within 2 to 6 hours, and initiation of third-phase pulsed release of enteric-coated microcapsules within 6 to 8 hours.

[0083] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy, characterized in that: The pharmaceutical composition comprises verbascoside and excipients, including microcrystalline cellulose, lactose, crospovidone, hydroxypropyl methylcellulose K4M, povidone K30, and magnesium stearate. It is an oral solid dosage form containing immediate-release drug-containing granules and sustained-release drug-containing microcapsules with a mass ratio of 1:2 to 1:

5. The granules are mixed and then filled into hard capsules. This pharmaceutical composition is used for intervention in individuals identified as having active ferroptosis-prone high-risk or confirmed high-altitude nephropathy after screening for urinary 4-hydroxynonenal / creatinine ratio.

2. The pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy according to claim 1, characterized in that: The immediate-release drug-containing granules contain 10% to 50% verbascoside by mass, and the sustained-release drug-containing microcapsules contain 40% to 80% verbascoside by mass. The immediate-release drug-containing granules release at least 80% of their verbascoside content within 0.5 to 1 hour after oral administration, and the sustained-release drug-containing microcapsules continuously release their verbascoside content within 2 to 6 hours after oral administration.

3. The pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy according to claim 1, characterized in that: The hard capsule also contains enteric-coated delayed-release microspheres, wherein the enteric-coated delayed-release microspheres contain 50% to 90% verbascoside by mass and are coated with an enteric coating. The enteric coating dissolves in an environment with pH ≥ 5.5, so that the enteric-coated delayed-release microspheres begin to release the verbascoside they contain 6 to 8 hours after oral administration.

4. A pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy according to claim 3, characterized in that: The enteric coating is an aqueous dispersion of methacrylate-ethyl acrylate copolymer.

5. A method for preparing a pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy, characterized in that, A pharmaceutical composition containing verbascoside for the intervention of high-altitude nephropathy as described in any one of claims 1-4, comprising the following steps: S1. Low-temperature micronization treatment: The verbascoside raw material is pulverized under low-temperature conditions to obtain verbascoside micronized powder for later use. S2. Manufacturing of immediate-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with microcrystalline cellulose, lactose and cross-linked povidone, add an ethanol solution of povidone K30 as a binder to form a soft material, extrude and roll it into rounds, dry it to obtain immediate-release drug-containing granules. S3. Manufacturing of sustained-release granules: Take a portion of the micro powder obtained in S1, mix it evenly with hydroxypropyl methylcellulose K4M, microcrystalline cellulose and lactose, add an ethanol solution of povidone K30 as a binder to make a soft material, extrude and roll it into spheres, and dry it to a predetermined moisture content under predetermined drying conditions to obtain sustained-release matrix drug-containing micro pellets. S4. Unit combination mixing: Mix the immediate-release drug-containing granules obtained in S2 and the sustained-release matrix drug-containing microcapsules obtained in S3 with the enteric-coated delayed-release microcapsules evenly, and add magnesium stearate to obtain the total mixed granules. S5. Filling and Packaging: The total mixed particles obtained in S4 are filled into hard capsules under isostatic pressure to obtain the pharmaceutical composition.

6. A method for preparing a pharmaceutical composition containing verbascoside for intervening in high-altitude nephropathy according to claim 5, characterized in that: In step S1, the low temperature condition is -20℃ to -10℃; the inlet pressure for pulverization is 0.6MPa to 0.8MPa, and the pulverization is performed 1 to 2 times; the particle size D of the verbascoside micro powder is... 90 The range is from 1 μm to 20 μm.

7. A method for preparing a pharmaceutical composition containing verbascoside for intervening in high-altitude nephropathy according to claim 5, characterized in that: In step S2, the total mass of the microcrystalline cellulose, lactose, and crospovidone accounts for 50% to 90% of the total mass of the immediate-release drug-containing particles, wherein the weight ratio of the microcrystalline cellulose, lactose, and crospovidone is (9-12):(4-7):(1-2); in the ethanol solution of povidone K30, the mass fraction of povidone K30 in the total mass of the solution is 5% to 15%, the solvent is a mixture of ethanol and water, and the volume ratio of ethanol to water is 50:50 to 95:5; the drying conditions are an inlet air temperature of 45°C to 55°C, and drying until the moisture content is less than 2.0%.

8. A method for preparing a pharmaceutical composition containing verbascoside for intervening in high-altitude nephropathy according to claim 5, characterized in that: In step S3, the total mass of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose accounts for 20% to 60% of the total mass of the sustained-release drug-containing microcapsules, wherein the weight ratio of hydroxypropyl methylcellulose K4M, microcrystalline cellulose, and lactose is (3-7):(1-5):(1-3); the mass fraction of povidone K30 in the ethanol solution is 5% to 15%; the predetermined drying conditions are fluidized bed drying with an inlet air temperature of 45°C to 55°C; and the predetermined moisture content is 1.5% to 2.0%.

9. A method for preparing a pharmaceutical composition containing verbascoside for intervening in high-altitude nephropathy according to claim 5, characterized in that: In step S4, the amount of magnesium stearate added accounts for 0.5% to 2.0% of the total mass of the mixed particles.

10. A method for preparing a pharmaceutical composition containing verbascoside for intervening in high-altitude nephropathy according to claim 5, characterized in that: In step S5, the disintegration time of the capsule is 1 to 3 minutes.

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