Preparation process of urinary lesion targeting medicinal adjuvant

Abstract

The application relates to the technical field of pharmaceutical auxiliary material manufacturing, and discloses a preparation process of urinary disease lesion targeting pharmaceutical auxiliary material, which comprises the following steps: dissolving a carrier polymer with pH response characteristics to prepare a carrier solution; adding a targeting ligand molecule to the carrier solution and adjusting the environmental pH value, preparing a modified polymer solution through a grafting reaction; introducing the modified polymer solution into a slit homogenization loop, synchronously injecting a polarity adjusting factor under a mechanical shear field, inducing phase separation of the carrier polymer and in-situ precipitation and solidification, and matching the time scale of substance diffusion with the time scale of fluid shear, so that the chemical phase separation process and the mechanical stretching process are synchronized, the extension conformation of the macromolecular skeleton is locked through physical pinning, the effective adhesion site is effectively prevented from shrinking and wrapping, and the auxiliary material microparticles have high-strength electrostatic attraction capacity and persistent biological adhesion stability on the surface of urinary disease lesions.

Description

Technical Field

[0001] This invention relates to a preparation process of pharmaceutical excipients for targeted urinary lesions, belonging to the field of pharmaceutical excipient manufacturing technology. Background Technology

[0002] Currently, pharmaceutical excipients serve as drug carriers in local drug delivery technology for the urinary system. They interact physically or chemically with the urinary tract mucosa through functional groups distributed on the basic macromolecular chain segments, thereby prolonging the residence time of the drug at the lesion site. In the preparation process of polymeric pharmaceutical excipients, the spatial topology of the polymer and the distribution of functional groups on the surface of microspheres directly determine the adhesion performance and drug release kinetics of the excipient. The surface of the urinary system mucosa is in a high-frequency fluid shear environment formed by the continuous production and excretion of urine. Conventional water-soluble or particulate excipients are easily physically evacuated after contacting the lesion site. Current mainstream preparation processes focus on homogeneous mixing and random cross-linking of components, resulting in a disordered distribution of adhesive functional groups inside the product. In polymer excipients generated under such processes, a large number of effective adhesion sites are embedded inside the polymer coil, producing a severe steric hindrance effect, making the effective exposure rate of adhesion sites on the particle surface insufficient to resist the scouring of physiological fluids.

[0003] To overcome the technical obstacle of uneven functional group distribution, increasing the amount of functional monomers or adjusting the catalyst concentration can lead to excessive crosslinking density and compromise the biocompatibility of the excipients. In industrial rheological processing, although attempts have been made to induce stretching of molecular chains using high shear fields to alter conformation, the deformation relaxation time of polymer chains after shear force removal is typically very short. to The timescale of heat conduction is on the order of seconds, while industrial-grade heat exchangers typically require several seconds or more for fluid cooling. This physical time difference between the rate of heat conduction and the rate of molecular chain segment deformation recovery causes conformational retraction, resulting in the exposed adhesion groups being re-encapsulated within the polymer before the temperature drops to the solidification point. Existing preparation techniques have shortcomings in controlling the timing of induced stretching and phase separation curing. For example, Chinese invention patent application CN106074392A discloses a polymer drug-loaded microsphere prepared by a coagulation bath shearing method and its formulation. The method and application utilize a rotary motor to drive a coagulation bath to generate shear force to disperse the emulsion. Essentially, it relies on the passive diffusion and penetration of the solvent in the overall coagulation bath to drive solidification. The timescale of the mass exchange process based on the chemical potential gradient is much larger than the conformational relaxation time of the polymer chain segments. During the slow diffusion of the solvent, the active groups exposed by the shear force stretching rapidly undergo conformational retraction due to the loss of stress support and are re-encapsulated into the inner layer of the microspheres. The mismatch of the underlying dynamic parameters makes it impossible for the existing technology to achieve in-situ freezing of the extended state of macromolecules at the surface level, and the adhesion strength of the product interface is difficult to meet the requirements of the urinary system flow field conditions.

[0004] Therefore, the technical problem to be solved by this invention is how to provide a pharmaceutical excipient preparation process that targets urinary lesions and solves the problem of embedding adhesion groups caused by polymer conformation relaxation by controlling the temporal correlation of energy field and material flow during the processing. Summary of the Invention

[0005] To address the problems mentioned in the background art, the technical solution of the present invention is as follows: A preparation process for pharmaceutical excipients targeting urinary lesions, comprising the following steps:

[0006] Step S101: The carrier polymer with pH response characteristics is completely dissolved in an organic solvent to obtain a carrier solution with a mass concentration of 1.5% to 5.0%. The dynamic viscosity of the carrier solution is maintained between 200 mPa·s and 800 mPa·s by adjusting the dissolution temperature and stirring rate of the carrier polymer.

[0007] In step S102, a targeting ligand molecule is added to the carrier solution, the pH of the reaction system is adjusted to 7.2 to 8.5, the mass ratio of the targeting ligand molecule to the carrier polymer is controlled to be 0.05:1 to 0.25:1, and the grafting reaction is carried out at 20℃ to 30℃ for 12h to 24h to obtain a modified polymer solution.

[0008] Step S103: The modified polymer solution is input into the external slit homogenization circuit. Under a mechanical shear force field with a rotation speed of 2800 rpm to 4000 rpm, a polarity adjustment factor is simultaneously injected into the fluid shear peak region of the external slit homogenization circuit, so that the conformational deformation time scale of the polymer chain caused by mechanical shear stretching is adjusted. Phase separation curing timescale induced by solvent polarity gradient satisfy: By utilizing the coupling effect of mechanical stretching and in-situ precipitation, the extended conformation of the carrier polymer is physically pinned to obtain an excipient suspension.

[0009] Step S104: The excipient suspension is placed in a dialysis bag with a molecular weight cutoff of 3500 Da to 14000 Da for dialysis treatment. The dialysis time is 48 h to 72 h, and the deionized water is replaced every 6 h to 8 h to remove unreacted impurities. The conductivity of the deionized water is not greater than 2.0 μS / cm.

[0010] Step S105: The dialysis-treated excipient suspension is subjected to vacuum freeze-drying to remove moisture under conditions of vacuum pressure below 10 Pa and ambient temperature of -55°C to -80°C, and the powdered pharmaceutical excipient is collected.

[0011] Preferably, the carrier polymer is selected from one or more of chitosan, polyacrylic acid, sodium carboxymethyl cellulose, polymethacrylic acid, polyethyleneimine, and polyhistidine; the pH-responsive characteristics are manifested in that the molecular chain of the carrier polymer contains basic ionized chemical groups that can undergo protonation transformation in an environment with a pH value of 5.0 to 6.5, so as to change the surface charge state of the powdered pharmaceutical excipient in the urinary microenvironment.

[0012] Preferably, the organic solvent is selected from one or more of dimethyl sulfoxide, dichloromethane, and N,N-dimethylformamide, and the solubility parameter deviation between the organic solvent and the carrier polymer is not greater than 2.0 (J / cm³). This ensures that the carrier polymer with pH-responsive properties forms a homogeneous, monomolecularly dispersed system in step S101 and reduces the probability of conformational relaxation occurring in step S103.

[0013] Preferably, in step S102, before adding the targeting ligand molecule, an activating agent composed of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide in a mass ratio of 1:1 to 1:2 is added to the carrier solution, and the solution is stirred in the dark at 20°C to 35°C for 2 to 5 hours to improve the grafting efficiency of the targeting ligand molecule by activating the carboxyl groups on the carrier polymer molecular chain.

[0014] Preferably, in step S103, the critical shear stress τ within the homogeneous loop of the external slit follows the formula: Where τ is the critical shear stress, μ is the dynamic viscosity of the modified polymer solution, R is the rotor radius of the external slit homogeneous circuit, ω is the rotational speed, and d is the slit spacing; the critical shear stress τ is used to overcome the entropy restoring force of molecular chain curling, and the physical solidification of molecular conformation is achieved in conjunction with the polarity adjustment factor.

[0015] Preferably, in step S102, the targeting ligand molecule is selected from one or more of mannose, folic acid, arginine-glycine-aspartic acid sequence peptide and galactose; in the grafting reaction, the pH fluctuation range of the reaction system is controlled by sodium hydroxide solution or hydrochloric acid solution to be no greater than 0.05, so as to maintain the hydrodynamic diameter of the carrier polymer in solution state and ensure the consistency of the shear response in step S103.

[0016] Preferably, in step S103, the polarity regulating factor is selected from one or more of anhydrous ethanol, isopropanol, and acetone, and the volume flow ratio of the polarity regulating factor to the modified polymer solution is controlled between 1:5 and 1:10, so as to construct an instantaneous polarity transition environment in the fluid shear peak region of the external slit homogeneous circuit, thereby achieving in-situ locking of the extended state of the carrier polymer molecular chain.

[0017] Preferably, in step S105, vacuum freeze drying includes a pre-freezing stage, a sublimation drying stage, and a desorption drying stage. In the sublimation drying stage, the heating rate of the plate is controlled between 0.2℃ / min and 0.5℃ / min to prevent the skeletal collapse of the powdered pharmaceutical excipients, ensuring that the residual water content of the final powdered pharmaceutical excipients is not greater than 3.0% and that it has good resolubility.

[0018] Preferably, after step S105, step S106 is further included: dissolving the collected powdered pharmaceutical excipients in phosphate buffer solution or physiological saline to prepare a reconstituted solution, filtering the reconstituted solution using a polyethersulfone sterile filter membrane with a pore size of 0.22 μm, and dispensing it in an environment with a cleanliness level of not less than B, so as to meet the aseptic technical requirements for the clinical application of powdered pharmaceutical excipients in urology.

[0019] Preferably, the powdered pharmaceutical excipient is composed of microparticles cured in step S103. The surface of the microparticles is enriched with targeting ligand molecules and the average particle size is between 150 nm and 400 nm. The microparticles have a zeta potential of not less than 15 mV in an environment with a pH value of 5.0 to 6.5. They utilize their positive charge to generate electrostatic attraction with the negative charge on the surface of the mucosa of urinary system lesions, thereby forming a stable bioadhesive layer on the surface of the lesions.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] 1. In the preparation of pharmaceutical excipients for urinary tract lesion targeting, by physically overlapping the injection site of the polarity regulating factor with the high shear force field, the chemical phase separation process and the mechanical stretching process of the macromolecular skeleton are synchronized on a time scale. This invention, through limiting... and The matching range of this process solves the conformational shrinkage problem caused by thermal conduction or diffusion lag in traditional processes. Experimental data show that, with the same ligand feed amount, the exposure rate of effective adhesion sites on the surface of the microparticles prepared by this process is more than 40% higher than that of conventional homogeneous reactions, which significantly enhances the exfoliant's anti-peeling ability in the high-frequency fluid shear environment of the urinary system. This in-situ precipitation and solidification mechanism avoids the heat transfer lag problem of conventional thermal conduction cooling, ensuring that physical pinning is completed before conformational relaxation of polymer chain segments, thereby maintaining the enrichment state of the adhesive monomer on the surface of the exfoliant microparticles.

[0022] 2. By adopting a structural combination of a slit homogeneous circuit and a coaxial fluid injection port, the random turbulence in the main reaction vessel is transformed into a unidirectional controlled flow field in the external circuit. This design, combined with the pump inflow rate control of the polarity adjustment factor, eliminates the surface conformational heterogeneity caused by uneven flow field distribution in industrial-scale preparation, ensuring that pharmaceutical excipients exhibit consistent interfacial adhesion strength and physicochemical stability across different production batches.

[0023] 3. The introduction of ethanol component in polarity regulating factor reduces the overall dielectric constant of the reaction system, increases the internal repulsive force of the hydrophobic polymer backbone, reduces the critical shear stress required to induce molecular chain stretching, and improves the conversion efficiency of macromolecular conformation without increasing mechanical energy consumption. This enables the excipient microparticles to have adaptive adhesion characteristics and enhances their physical resistance to physiological flushing by urine. Attached Figure Description

[0024] Figure 1 This is a flowchart illustrating the phase separation and solidification preparation process of the targeted pharmaceutical excipients for urinary lesions according to the present invention.

[0025] Figure 2 This is a flowchart illustrating the multi-step synthesis and in-situ precipitation process of the urinary targeted pharmaceutical excipients of the present invention.

[0026] The objectives, features, and advantages of this invention will be further explained in conjunction with the embodiments and with reference to the accompanying drawings. Detailed Implementation

[0027] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0028] A process for preparing a pharmaceutical excipient for urinary lesion targeting includes the following steps:

[0029] Step S101: The carrier polymer with pH response characteristics is completely dissolved in an organic solvent to obtain a carrier solution with a mass concentration of 1.5% to 5.0%. The dynamic viscosity of the carrier solution is maintained between 200 mPa·s and 800 mPa·s by adjusting the dissolution temperature and stirring rate of the carrier polymer.

[0030] In step S102, a targeting ligand molecule is added to the carrier solution, the pH of the reaction system is adjusted to 7.2 to 8.5, the mass ratio of the targeting ligand molecule to the carrier polymer is controlled to be 0.05:1 to 0.25:1, and the grafting reaction is carried out at 20℃ to 30℃ for 12h to 24h to obtain a modified polymer solution.

[0031] Step S103: The modified polymer solution is input into the external slit homogenization circuit. Under a mechanical shear force field with a rotation speed of 2800 rpm to 4000 rpm, a polarity adjustment factor is simultaneously injected into the fluid shear peak region of the external slit homogenization circuit, so that the conformational deformation time scale of the polymer chain caused by mechanical shear stretching is adjusted. Phase separation curing timescale induced by solvent polarity gradient satisfy: By utilizing the coupling effect of mechanical stretching and in-situ precipitation, the extended conformation of the carrier polymer is physically pinned to obtain an excipient suspension.

[0032] Step S104: The excipient suspension is placed in a dialysis bag with a molecular weight cutoff of 3500 Da to 14000 Da for dialysis treatment. The dialysis time is 48 h to 72 h, and the deionized water is replaced every 6 h to 8 h to remove unreacted impurities. The conductivity of the deionized water is not greater than 2.0 μS / cm.

[0033] Step S105: The dialysis-treated excipient suspension is subjected to vacuum freeze-drying to remove moisture under conditions of vacuum pressure below 10 Pa and ambient temperature of -55°C to -80°C, and the powdered pharmaceutical excipient is collected.

[0034] Preferably, the carrier polymer is selected from one or more of chitosan, polyacrylic acid, sodium carboxymethyl cellulose, polymethacrylic acid, polyethyleneimine, and polyhistidine; the pH-responsive characteristics are manifested in that the molecular chain of the carrier polymer contains basic ionized chemical groups that can undergo protonation transformation in an environment with a pH value of 5.0 to 6.5, so as to change the surface charge state of the powdered pharmaceutical excipient in the urinary microenvironment.

[0035] Preferably, the organic solvent is selected from one or more of dimethyl sulfoxide, dichloromethane, and N,N-dimethylformamide, and the solubility parameter deviation between the organic solvent and the carrier polymer is not greater than 2.0 (J / cm³). This ensures that the carrier polymer with pH-responsive properties forms a homogeneous, monomolecularly dispersed system in step S101 and reduces the probability of conformational relaxation occurring in step S103.

[0036] Preferably, in step S102, before adding the targeting ligand molecule, an activating agent composed of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide in a mass ratio of 1:1 to 1:2 is added to the carrier solution, and the solution is stirred in the dark at 20°C to 35°C for 2 to 5 hours to improve the grafting efficiency of the targeting ligand molecule by activating the carboxyl groups on the carrier polymer molecular chain.

[0037] Preferably, in step S103, the critical shear stress τ within the homogeneous loop of the external slit follows the formula: Where τ is the critical shear stress, μ is the dynamic viscosity of the modified polymer solution, R is the rotor radius of the external slit homogeneous circuit, ω is the rotational speed, and d is the slit spacing; the critical shear stress τ is used to overcome the entropy restoring force of molecular chain curling, and the physical solidification of molecular conformation is achieved in conjunction with the polarity adjustment factor.

[0038] Preferably, in step S102, the targeting ligand molecule is selected from one or more of mannose, folic acid, arginine-glycine-aspartic acid sequence peptide and galactose; in the grafting reaction, the pH fluctuation range of the reaction system is controlled by sodium hydroxide solution or hydrochloric acid solution to be no greater than 0.05, so as to maintain the hydrodynamic diameter of the carrier polymer in solution state and ensure the consistency of the shear response in step S103.

[0039] Preferably, in step S103, the polarity regulating factor is selected from one or more of anhydrous ethanol, isopropanol, and acetone, and the volume flow ratio of the polarity regulating factor to the modified polymer solution is controlled between 1:5 and 1:10, so as to construct an instantaneous polarity transition environment in the fluid shear peak region of the external slit homogeneous circuit, thereby achieving in-situ locking of the extended state of the carrier polymer molecular chain.

[0040] Preferably, in step S105, vacuum freeze drying includes a pre-freezing stage, a sublimation drying stage, and a desorption drying stage. In the sublimation drying stage, the heating rate of the plate is controlled between 0.2℃ / min and 0.5℃ / min to prevent the skeletal collapse of the powdered pharmaceutical excipients, ensuring that the residual water content of the final powdered pharmaceutical excipients is not greater than 3.0% and that it has good resolubility.

[0041] Preferably, after step S105, step S106 is further included: dissolving the collected powdered pharmaceutical excipients in phosphate buffer solution or physiological saline to prepare a reconstituted solution, filtering the reconstituted solution using a polyethersulfone sterile filter membrane with a pore size of 0.22 μm, and dispensing it in an environment with a cleanliness level of not less than B, so as to meet the aseptic technical requirements for the clinical application of powdered pharmaceutical excipients in urology.

[0042] Preferably, the powdered pharmaceutical excipient is composed of microparticles cured in step S103. The surface of the microparticles is enriched with targeting ligand molecules and the average particle size is between 150 nm and 400 nm. The microparticles have a zeta potential of not less than 15 mV in an environment with a pH value of 5.0 to 6.5. They utilize their positive charge to generate electrostatic attraction with the negative charge on the surface of the mucosa of urinary system lesions, thereby forming a stable bioadhesive layer on the surface of the lesions.

[0043] Example 1: When the system faces the condition of local targeted drug delivery to the urinary tract mucosa, the surface of the urinary tract mucosa is in a high-frequency fluid shear environment of continuous urine production and discharge. Conventional water-soluble or particulate excipients will undergo physical emptying after contact with the lesion site. Existing preparation processes focus on homogeneous mixing and random cross-linking of components, resulting in a large number of effective adhesion sites being embedded inside the polymer coil. In the processing practice of applying a mechanical shear force field to induce stretching of polymer chain segments to change conformation, the deformation relaxation time of polymer chain segments after the shear force is removed is usually on the order of milliseconds, while the fluid cooling of industrial-grade heat exchangers usually requires a time scale of several seconds or more. The physical time difference between the fluid heat conduction rate and the molecular chain segment deformation recovery rate produces a conformational retraction phenomenon, causing the adhesion groups that were stretched and exposed before the temperature dropped to the solidification point to be re-encapsulated inside the polymer.

[0044] The preparation system selects a carrier polymer whose molecular chain contains basic ionized chemical groups that can undergo protonation transformation in an environment with a pH value of 5.0 to 6.5, and completely dissolves it in a solution with a solubility parameter deviation between the carrier polymer and the carrier polymer of no more than 2.0 (J / cm³). 1 / 2 In an organic solvent, a homogeneous monomolecular dispersion of 1.5% to 5.0% by mass was prepared. The dynamic viscosity of the carrier solution was maintained at 200 mPa·s to 800 mPa·s by adjusting the dissolution temperature and stirring rate. Targeting ligand molecules were added to the carrier solution, and the pH of the reaction system was adjusted to 7.2 to 8.5. The mass ratio of the targeting ligand molecules to the carrier polymer was controlled at 0.05:1 to 0.25:1, and a grafting reaction was carried out at 20°C to 30°C for 12 to 24 hours to obtain a modified polymer solution. The modified polymer solution was fed into an external slit homogenizing circuit, and a unidirectional fluid shear force was applied under a mechanical shear field with a rotation speed of 2800 rpm to 4000 rpm. The critical shear stress in the external slit homogenizing circuit follows the formula... Where τ is the critical shear stress, μ is the dynamic viscosity of the modified polymer solution, R is the rotor radius of the external slit homogeneous circuit, ω is the rotational speed, and d is the slit spacing; the system utilizes the critical shear stress to overcome the entropy restoring force of molecular chain coiling, and simultaneously injects a polarity regulating factor with a volumetric flow rate ratio of 1:5 to 1:10 with the modified polymer solution into the fluid shear peak region of the external slit homogeneous circuit, ensuring that the contact path length between the polarity regulating factor and the fluid shear peak region is no greater than 2 mm; the polarity regulating factor constructs an instantaneous polar transition environment in the fluid shear peak region, inducing phase separation and solidification of the carrier polymer within milliseconds through the solvent polarity gradient, and locking the extended state of the carrier polymer in situ using the coupling effect of mechanical stretching and in-situ precipitation, thus obtaining an excipient suspension. When executing step S103, the external slit... The alignment of the peak shear region of the homogeneous circuit fluid with the polarity adjustment factor is achieved through a rigid limiting structure of a coaxial annular micro-orifice injector. The radial distance between the injector jet outlet end face and the center line of the stator slit is set to 1.5 mm to 2.0 mm. During the static debugging phase before equipment startup, a high-sensitivity differential pressure sensor is used to monitor the fluid resistance loss at both ends of the slit. The measured pressure drop is made to reach the theoretical fluid dynamics model setting value by adjusting the displacement compensation mechanism driven by the stepper motor. During the dynamic calibration phase, a non-reaction simulation medium is injected into the circulation circuit and the online light scattering particle size monitor is turned on. The pumping phase of the polarity adjustment factor is finely adjusted according to the intensity fluctuation characteristics of the scattering signal, so that the instantaneous evolution point of the solvent polarity gradient is locked at the spatiotemporal position of the maximum value of the molecular chain mechanical stretching deformation, producing pharmaceutical excipient microparticles with an average particle size between 150 nm and 400 nm.

[0045] The excipient suspension was placed in a dialysis bag with a molecular weight cutoff of 3500 Da to 14000 Da and dialyzed for 48 to 72 hours. Deionized water with a conductivity of no more than 2.0 μS / cm was replaced every 6 to 8 hours to remove unreacted impurities. The dialyzed excipient suspension then entered a vacuum freeze-drying process to remove moisture under vacuum pressure below 10 Pa and ambient temperature of -55°C to -80°C. During the sublimation drying stage, the heating rate of the plate was controlled between 0.2°C / min and 0.5°C / min to prevent the skeleton from collapsing. The final collected powdered pharmaceutical excipient consisted of particles with an average particle size between 150 nm and 400 nm and a residual water content of no more than 3.0%. The surface of the particles was enriched with targeting ligand molecules. These particles generated a zeta potential of no less than 15 mV at a pH of 5.0 to 6.5. They relied on their positive charge to generate electrostatic attraction with the negative charge on the surface of the mucosa of urinary system lesions, forming a stable bioadhesive layer on the lesion surface.

[0046] Example 2: This example constructs a microfluidic biomimetic scouring test platform based on a parallel plate flow cavity to quantify the physical parameters of pharmaceutical excipient microparticles resisting dynamic fluid stripping. The platform is equipped with a peristaltic pump and a constant-temperature circulating water bath, using fresh decellularized porcine bladder mucosa tissue as a biological substrate, providing an adjustable volumetric flow rate from 0.1 mL / min to 5.0 mL / min. A pH fluctuation simulator is connected in series in the fluid loop, and artificial urine is used as the fluid medium. Gaussian white noise with an amplitude of 0.5 pH units is actively superimposed in the test signal source to simulate the environmental disturbance of irregular and violent fluctuations in pH value between 5.5 and 6.5 under pathological conditions.

[0047] The rotational speed parameters of the external slit homogenization loop were calibrated experimentally. These parameters needed to balance the physical contradiction between the stretching of the polymer molecular chains and the risk of mechanical breakage of the backbone covalent bonds. When the fluid shear stress provided by the homogenization rotational speed was less than the entropy restoring force of the molecular chains, the target ligand molecules did not reach the preset exposure rate. When this stress exceeded the carbon-carbon bond breaking energy threshold of the polymer backbone, the carrier polymer underwent irreversible molecular weight degradation. Based on the rheological force model, the dynamic viscosity of the modified polymer solution was set to 400 mPa·s. To overcome the conformational energy barrier of the coiled molecular chains without inducing chain breakage, the following formula was used... The critical shear stress τ was calculated, where μ is the dynamic viscosity of the modified polymer solution, R is the rotor radius of the external slit homogeneous circuit, ω is the rotational speed, and d is the slit spacing. Based on the formula and polymer physical parameters, the rotational speed boundary was derived to be 2800 rpm to 4000 rpm. 3500 rpm was selected as the calibration setting value for the sample group of this invention. When the mass ratio of the target ligand molecule to the carrier polymer was limited to 0.05:1 to 0.25:1, the shear stress τ of the grafted carrier polymer was calculated. Exhibiting conformational extension, the powdered pharmaceutical excipients produced generate a zeta potential of not less than 15 mV in an artificial urine flushing environment at pH 5.5. When this ratio is increased to 0.25:1, the introduction of targeted ligand molecules into the molecular chain increases the polymer phase separation rate in step S103 by increasing the density of intermolecular hydrogen bonds, thereby forming a dense microsphere structure with surface-enriched target sites. Adjusting the ratio and shear field to synergistically generate the surface morphology improves the adhesion persistence of pharmaceutical excipients on the surface of urinary system lesions without adding additional chemical crosslinking agents.

[0048] Four independent verification groups were set up; control group 1 was prepared by adding a polarity regulating factor dropwise in a constant temperature reactor with mechanical stirring at 500 rpm, lacking high shear stretching characteristics; control group 2 was prepared by applying a rotation speed of 1500 rpm in an external slit homogenization loop, serving as an out-of-range control group below the lower limit; control group 3 was prepared by applying a rotation speed of 6000 rpm, serving as an out-of-range control group above the upper limit; the sample group of this invention was prepared at a rotation speed of 3500 rpm; the four groups of microparticle suspensions were injected into parallel plate flow chambers with bladder mucosa tissue at constant concentrations and incubated for 15 min; the artificial urine flushing program was started, and the shear stress of the flushing tube wall was gradually increased from 2.0 dyn / cm² to 10.0 dyn / cm², and the residual fluorescence intensity of microparticles on the mucosal surface was collected in real time using a confocal microscope with a fluorescence detection module.

[0049] Fluorescence signal attenuation data showed gradient differences; under an initial scouring intensity of 2.0 dyn / cm², the particle residue rate of the control sample group 1 decreased to 14.5% within 10 minutes, while the particle residue rate of the sample group of this invention remained at 92.3%; conventional mixing processes lead to the failure of adhesion site embedding due to conformational relaxation, while synchronous injection of polarity adjustment factors under high shear field utilizes the diffusion mechanism of polarity transition to replace fluid heat conduction cooling, physically pinning the high-energy extended conformation; as the shear stress of the scouring wall increases to 6.0 dyn / cm², the superimposed acid-base noise... The disturbance caused a local dynamic reversal of the charge on the mucosal surface of the mucosa. Compared with the residual rate of sample group 2, which dropped to 8.2%, the residual rate of the sample group of this invention remained at 81.6%. The densely distributed target ligand molecules on the surface and the alkaline ionized chemical groups synergistically output a high-density electrostatic attraction, which suppresses the desorption trend caused by fluid peeling force and acid-base noise. The residual rate of sample group 3 did not exceed 25.0% in the full gradient scouring stage. Excessive mechanical shear caused the polymer skeleton to break and lose its structural integrity. When the scouring intensity approached the boundary of 10.0 dyn / cm², At that time, the residual rate of the sample group of the present invention showed a nonlinear accelerated decay, and the performance degradation inflection point appeared at 9.5 dyn / cm², with the residual rate dropping to 45.2%. This nonlinear inflection point objectively calibrated the physical limit of the electrostatic adhesion mechanism in resisting overall hydrodynamic peeling, and conversely confirmed that the shear speed system of 2800 rpm to 4000 rpm is the optimal working window for balancing molecular extension and skeleton integrity. The experimental data under the dual interference of hydrodynamic peeling and pH fluctuation confirmed that the process conditions of simultaneous injection of specific slit shear force field and polarity adjustment factor locked the extended conformation of the carrier polymer in situ. The produced pharmaceutical excipient microparticles maintained the surface adhesion ability, solving the problem of physical emptying of excipients during targeted drug delivery to the urinary system. Through the surface charge distribution scanning of nanoparticles, it was found that the positively charged active groups on the surface of the microparticles of the present invention were distributed in a highly uniform radial pattern, rather than the clustered distribution of the control sample group 1. This difference in micromorphology proved that the physical pinning mechanism successfully prevented the self-coiling of the macromolecular skeleton during the solidification process, and ensured the adhesion persistence of the pharmaceutical excipients on the surface of urinary system lesions from a physical level.

[0050] Example 3: When the manufacturing system is in the large-scale production mode of pharmaceutical excipients for local targeted drug delivery to the urinary system mucosa, a cationic polymer formed by copolymerizing dimethylaminoethyl methacrylate and neutral methacrylate monomers in a 1:1 molar ratio is selected as the carrier polymer with pH-responsive properties; the tertiary amine groups arranged on the main chain of this polymer undergo a protonation reaction in a slightly acidic environment with a pH value of 5.0 to 6.5, exhibiting positive charge; 4-carboxyphenylboronic acid is selected as the targeting ligand molecule in the preparation system, and 1-ethyl-3- An activating agent composed of (3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide in a 1:1 mass ratio activates the carboxyl terminus, causing 4-carboxyphenylboronic acid to undergo dehydration condensation with the reactive functional groups of the side chain of the carrier polymer to form a covalent amide bond. This combination of substances establishes a physicochemical adhesion pathway that relies on both electrostatic attraction and borate ester bonds. The manufacturing system is configured with a feeding control valve according to the above mass ratio to maintain the dynamic viscosity of the carrier solution at 400 mPa·s and set the initial rheological parameters of the polymer chain segments under a shear field.

[0051] The phase separation and precipitation process within the slit homogenization loop relies on a coaxial annular microporous injector to achieve spatiotemporal alignment between the polarity adjustment factor and the fluid shear parameters. The manufacturing system uses deionized water as the polarity adjustment factor, mixing it with an organic solvent system containing the carrier polymer in a reverse polarity manner. The system installs the coaxial annular microporous injector at the stator-rotor gap of the external slit homogenization loop, limiting the contact path length between the polarity adjustment factor and the fluid shear peak region to a physical boundary of no more than 2.0 mm. Based on the fluid dynamics continuity equation, the volumetric flow rate ratio of the inner ring deionized water to the outer ring modified polymer solution is set to 1:8, and the base flow velocity at the slit inlet is set to 15.5 m / s. The mixed fluid generates a radial velocity gradient under a mechanical shear force field at a rotation speed of 3500 rpm. Deionized water molecules change the overall solubility parameters of the mixed solvent within a micrometer-scale radial diffusion distance, causing the mixed solvent to deviate from the good solubility thermodynamic window of the carrier polymer.

[0052] The geometry and flow rate ratio of the coaxial annular microporous injector compress the diffusion time of deionized water to the microsecond level, matching the physical residence time of the macromolecular chain segments stretched by mechanical shear force. The sudden drop in local solution polarity causes the carrier polymer molecular chains in the extended conformation to precipitate and nucleate in situ due to the decrease in solubility, blocking the conformational retraction evolution path of the fluid heat conduction cooling process. After the produced excipient suspension is dialyzed and plate sublimation drying process to remove the residual aqueous phase and organic solvent, powdered pharmaceutical excipient particles with an average particle size of 250 nm and enriched with 4-carboxyphenylboronic acid ligands are generated. The tertiary amine cations on the particle surface undergo initial electrostatic anchoring with the negatively charged mucin on the mucosal surface, and the extended exposed phenylboronic acid groups simultaneously form reversible covalent bonds with sialic acid residues on the surface of mucosal epithelial cells, maintaining the interfacial adhesion state of the powdered pharmaceutical excipient under 10.0 dyn / cm² scouring shear stress.

[0053] Example 4: When the system faces fluctuations in the molecular weight distribution of carrier polymers from different batches or differences in the initial state of raw materials, the manufacturing system executes a standardized rheological baseline calibration procedure before starting continuous production. A rotational rheometer is used to collect the steady-state shear stress signal of the carrier solution sample at a constant shear rate and calculate the actual dynamic viscosity calibration value. The controller substitutes this calibration value into the formula τ=μ×2π×R×ωd, using the preset critical shear stress τ as the target to solve for the target rotational speed ω suitable for the current batch of raw materials. Here, μ is the actual dynamic viscosity calibration value, R is the rotor radius, and d is the slit spacing. The system generates corrected rotational speed parameters and overwrites them into the drive device of the external slit homogenization loop to maintain the physical matching of the fluid tensile force field. When the dynamic viscosity μ in the formula τ=μ×2π×R×ω / d is determined, after preparing the modified polymer solution, a portion of the sample is placed in a cone-plate rotational rheometer for rheological characteristic scanning to obtain the shear rate... Increment to During the period, the apparent viscosity data were fitted by a power-law fluid model to obtain the consistency coefficient and flow index of the batch raw materials. The actual viscosity at the target shear rate corresponding to the preset rotation speed ω was calculated and used as the input parameter for the drive controller to perform rotation speed compensation. Based on the feedback control of the raw material rheological baseline, the energy consumption deviation caused by the difference in molecular weight and distribution width of the carrier polymer in different batches was offset, and the critical shear stress τ was kept constant during the physical pinning process.

[0054] After baseline calibration is completed, the system synchronously initiates the on-site flow rate adjustment procedure for the polarity adjustment factor. The controller acquires the real-time flow rate of the modified polymer solution in the flow channel and calculates the critical demand for the polarity adjustment factor required to trigger phase separation based on the polarity transition compensation model. The servo injection pump adjusts the pumping frequency of the polarity adjustment factor according to this demand until the optical probe captures a continuous light scattering signal representing the nucleation and precipitation of polymer particles at the fluid path boundary no more than 2.0 mm from the slit inlet. The system fixes the flow rate ratio parameter of the injection pump based on the spatial position of this optical feedback signal, so that the diffusion time of the polarity adjustment factor is aligned with the physical residence time of the stretched macromolecular chain segments, establishing a production state that adapts to fluctuations in raw material parameters and continuously outputs pharmaceutical excipient suspension.

[0055] Example 5: When the manufacturing system is in the pre-verification phase before production start-up or when changing raw material batches, a feedback calibration procedure including an online optical monitoring loop is executed for parameter calibration of the flow ratio of deionized water to modified polymer solution. This procedure aims to establish a mixing ratio reference baseline for triggering phase separation in the system. A transmissivity meter is integrated into the slit channel wall outside the coaxial annular micro-injector, and its detection wavelength matches the isoabsorption point of the mixed solution. In the initial state, the servo injection pump injects deionized water at a flow ratio of 1:10, and the transmissivity meter records a stable transmittance baseline signal. The sampling frequency of the controller executing the underlying control logic is set to 1000.0Hz, and a sliding buffer with a capacity of 64 sampling points is opened in memory to sum and average the transmission voltage signal in real time to filter out electromagnetic interference caused by fluid pulsation. The polarity transition compensation model operates based on linear interpolation. The input is the volumetric flow rate ratio of deionized water to organic solvent, with a step increment set to 0.1. The output corresponds to the slope of the transmitted voltage change. When the average voltage in the sliding buffer continuously decreases from the initial 4.8V and exceeds the threshold of 3.2V, and the signal drop slope exceeds 0.5V per millisecond for 5 consecutive milliseconds, the system locks the current flow ratio parameter of the servo pump. The controller increments the flow ratio parameter in steps of 0.1 and records the transmittance signal after each step. When the flow ratio reaches 1:8, solid particles are generated in the fluid mixing area due to the precipitation of carrier polymer molecular chains. The transmittance meter detects a step decay of the transmittance signal and exceeds the set drop threshold. The flow ratio of 1:8 that triggers this drop threshold is recorded as the calibration ratio of the current batch of raw materials, and the opening configuration of the servo injection pump is locked to provide a definite material supply benchmark for the subsequent injection of the polarity adjustment factor.

[0056] After locking the flow rate ratio benchmark, the system synchronously activates an online fault-tolerant mechanism for the fluid velocity gradient within the external slit homogeneous loop. 2.0 mm downstream of the polarity adjustment factor injection port, the system is equipped with a fluid Reynolds number monitoring node integrated with a miniature differential pressure sensor. This node collects the laminar-to-turbulent transition pressure drop data at a set flow rate as the actual differential pressure value. The actual differential pressure value is compared with the theoretical pressure drop baseline derived from the formula. When the deviation between the actual differential pressure value and the theoretical pressure drop baseline exceeds 5%, the system controller outputs an adjustment command to reduce the hydraulic pressure of the coaxial annular micro-orifice injector, limiting the entry rate of deionized water and re-establishing a time-scale matching relationship between the polarity change rate of the solvent environment and the abnormally fluctuating fluid shear rate.

[0057] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention.

[0058] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A process for preparing pharmaceutical excipients for urinary tract lesion targeting, characterized in that, Includes the following steps: Step S101: The carrier polymer with pH response characteristics is completely dissolved in an organic solvent to obtain a carrier solution with a mass concentration of 1.5% to 5.0%. The dynamic viscosity of the carrier solution is maintained between 200 mPa·s and 800 mPa·s by adjusting the dissolution temperature and stirring rate of the carrier polymer. In step S102, a targeting ligand molecule is added to the carrier solution, the pH of the reaction system is adjusted to 7.2 to 8.5, the mass ratio of the targeting ligand molecule to the carrier polymer is controlled to be 0.05:1 to 0.25:1, and the grafting reaction is carried out at 20℃ to 30℃ for 12h to 24h to obtain a modified polymer solution. Step S103: The modified polymer solution is input into the external slit homogenization circuit. Under a mechanical shear force field with a rotation speed of 2800 rpm to 4000 rpm, a polarity adjustment factor is simultaneously injected into the fluid shear peak region of the external slit homogenization circuit, so that the conformational deformation time scale of the polymer chain caused by mechanical shear stretching is adjusted. Phase separation curing timescale induced by solvent polarity gradient satisfy: By utilizing the coupling effect of mechanical stretching and in-situ precipitation, the extended conformation of the carrier polymer is physically pinned to obtain an excipient suspension. Step S104: The excipient suspension is placed in a dialysis bag with a molecular weight cutoff of 3500 Da to 14000 Da for dialysis treatment. The dialysis time is 48 h to 72 h, and the deionized water is replaced every 6 h to 8 h to remove unreacted impurities. The conductivity of the deionized water is not greater than 2.0 μS / cm. Step S105: The dialysis-treated excipient suspension is subjected to vacuum freeze-drying to remove moisture under conditions of vacuum pressure below 10 Pa and ambient temperature of -55°C to -80°C, and the powdered pharmaceutical excipient is collected.

2. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, The carrier polymer is selected from one or more of chitosan, polyacrylic acid, sodium carboxymethyl cellulose, polymethacrylic acid, polyethyleneimine, and polyhistidine; the pH-responsive characteristics are manifested in that the molecular chain of the carrier polymer contains basic ionized chemical groups that can undergo protonation transformation in an environment with a pH value of 5.0 to 6.5, so as to change the surface charge state of the powdered pharmaceutical excipient in the urinary microenvironment.

3. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, The organic solvent is selected from one or more of dimethyl sulfoxide, dichloromethane, and N,N-dimethylformamide, and the solubility parameter deviation between the organic solvent and the carrier polymer is not greater than 2.0 (J / cm³). This ensures that the carrier polymer with pH-responsive properties forms a homogeneous, monomolecularly dispersed system in step S101 and reduces the probability of conformational relaxation occurring in step S103.

4. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, In step S102, before adding the targeting ligand molecule, an activating agent consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide in a mass ratio of 1:1 to 1:2 is added to the carrier solution, and the solution is stirred in the dark at 20°C to 35°C for 2 to 5 hours to improve the grafting efficiency of the targeting ligand molecule by activating the carboxyl groups on the carrier polymer molecular chain.

5. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, In step S103, the critical shear stress τ within the homogeneous loop of the external slit follows the formula: Where τ is the critical shear stress, μ is the dynamic viscosity of the modified polymer solution, R is the rotor radius of the external slit homogeneous circuit, ω is the rotational speed, and d is the slit spacing; the critical shear stress τ is used to overcome the entropy restoring force of molecular chain curling, and the physical solidification of molecular conformation is achieved in conjunction with the polarity adjustment factor.

6. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, In step S102, the targeting ligand molecule is selected from one or more of mannose, folic acid, arginine-glycine-aspartic acid sequence peptide and galactose; in the grafting reaction, the pH fluctuation range of the reaction system is controlled by sodium hydroxide solution or hydrochloric acid solution to be no greater than 0.05, so as to maintain the hydrodynamic diameter of the carrier polymer in solution state and ensure the consistency of the shear response in step S103.

7. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, In step S103, the polarity regulating factor is selected from one or more of anhydrous ethanol, isopropanol and acetone, and the volume flow ratio of the polarity regulating factor to the modified polymer solution is controlled between 1:5 and 1:10, so as to construct an instantaneous polar transition environment in the fluid shear peak region of the external slit homogeneous circuit, thereby achieving in-situ locking of the extended state of the carrier polymer molecular chain.

8. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, In step S105, vacuum freeze drying includes a pre-freezing stage, a sublimation drying stage, and a desorption drying stage. In the sublimation drying stage, the heating rate of the plate is controlled between 0.2℃ / min and 0.5℃ / min to prevent the skeleton collapse of the powdered pharmaceutical excipients, ensuring that the residual water content of the final powdered pharmaceutical excipients is not greater than 3.0% and that it has good resolubility.

9. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, The procedure following step S105 includes step S106: dissolving the collected powdered pharmaceutical excipients in phosphate buffer solution or physiological saline to prepare a reconstituted solution, filtering the reconstituted solution using a polyethersulfone sterile filter membrane with a pore size of 0.22 μm, and dispensing it in an environment with a cleanliness level of not less than B, in order to meet the aseptic technical requirements for the clinical application of powdered pharmaceutical excipients in urology.

10. The preparation process of a pharmaceutical excipient for urinary tract lesion targeting according to claim 1, characterized in that, The powdered pharmaceutical excipient is composed of microparticles solidified in step S103. The surface of the microparticles is enriched with targeting ligand molecules and the average particle size is between 150 nm and 400 nm. The microparticles have a zeta potential of not less than 15 mV in an environment with a pH value of 5.0 to 6.

5. They utilize their positive charge to generate electrostatic attraction with the negative charge on the surface of the mucosa of urinary system lesions, thereby forming a stable bioadhesive layer on the surface of the lesions.

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