Construction method of polycarbophil calcium tablet enhanced anti-diarrhea release system

Abstract

The invention discloses a construction method of a polycarbophil calcium tablet enhanced anti-diarrhea self-adaptive release system. According to the method, calcium polycarbophil and an ion-exchangeable multivalent metal salt carrier are treated under controlled humidity to form a microporous structure, so that the calcium polycarbophil and the ion-exchangeable multivalent metal salt carrier can be replaced and released by monovalent cations in intestinal fluid. The obtained pretreated component and a biodegradable porous polymer matrix are mixed and pressed at low temperature, and pH responsive microcapsules are distributed in the matrix. A composite blocking layer cross-linked by hydrophilic and hydrophobic polymers is formed on the surface of the matrix, so that the expansion rate of the composite blocking layer dynamically changes along with local pH; the outer layer is provided with a controllable degradation nano-porous membrane, and the pore size distribution is reconfigured under the induction of the ion concentration gradient. After constant-temperature and constant-humidity compaction treatment, the obtained system shows a self-adaptive release curve in an in-vitro simulation experiment, and delayed effect and stable release can be realized under different individual intestinal tract conditions. According to the method, the treatment effect of the anti-diarrhea medicine is remarkably improved through a multi-response mechanism.

Description

[0001] TECHNICAL FIELD

[0002] The present application relates to the technical field of medicine, in particular to a construction method of a polycarbophil calcium tablet enhanced anti-diarrhea release system. BACKGROUND

[0003] In the prior art, polycarbophil calcium is a commonly used anti-diarrhea drug, usually in the form of tablets or granules. Its sustained or controlled release effect mainly depends on the water swelling properties of the high molecular backbone and the common hydrophilic or hydrophobic polymer coating to delay the release of the drug in the intestinal tract. Some improved preparations attempt to adjust the drug release behavior by multi-layer coating, enteric film or adding acid-base adjuvants to adapt to the environment in different parts of the gastrointestinal tract, thereby improving the sustained efficacy and patient compliance.

[0004] However, the prior art generally has a single controlled release mode and insufficient adaptability to individual differences in the intestinal tract. Specifically, the traditional sustained release system often cannot dynamically adjust according to the pH value or ion concentration in the intestinal environment of different individuals, resulting in unstable drug release rate, and in some cases, reduced efficacy or increased side effects in some patients. At the same time, the multi-layer coating structure has complexity and instability in the process, making it difficult to achieve consistent and long-acting anti-diarrhea treatment effect.

[0005] Therefore, there is a need to develop a new construction method to achieve stable release and delayed effect of polycarbophil calcium in different intestinal environments, thereby improving the treatment reliability and adaptability of anti-diarrhea preparations. SUMMARY

[0006] The present application provides a construction method of a polycarbophil calcium tablet enhanced anti-diarrhea release system to improve the therapeutic effect of anti-diarrhea drugs.

[0007] The present application provides a construction method of a polycarbophil calcium tablet enhanced anti-diarrhea release system, comprising:

[0008] The polycarbophil calcium active ingredient and the ion-exchangeable multivalent metal salt body are co-pressed under controlled humidity conditions to obtain a pre-pressed polycarbophil calcium active ingredient that forms a uniform microporous structure and forms a reversible coordination bond with the multivalent metal salt body.

[0009] The pre-pressed polycarbophil calcium active ingredient is mixed with a biodegradable porous polymer matrix and pressed into shape under low temperature conditions to obtain a biodegradable porous polymer tablet matrix containing the pre-pressed polycarbophil calcium active ingredient, and the biodegradable porous polymer tablet matrix contains uniformly distributed pH-responsive microcapsules.

[0010] A composite retardant layer is formed on the surface of the biodegradable porous polymer tablet matrix, the composite retardant layer is formed by cross-linking hydrophilic polymer and hydrophobic polymer to form a three-dimensional network structure, and the swelling rate of the three-dimensional network structure is affected by the local microenvironment pH to cause dynamic reversible change;

[0011] A controllable degradation nanoporous membrane is formed on the outer surface of the composite retardant layer, the pore size distribution of the controllable degradation nanoporous membrane is induced by the ion concentration gradient during the hydration of the composite retardant layer to cause dynamic restructuring, so that the drug release performance of the controllable degradation nanoporous membrane is dynamically coupled with the ion concentration of the intestinal fluid;

[0012] The biodegradable porous polymer tablet matrix coated with the controllable degradation nanoporous membrane is compacted under constant temperature and humidity conditions to stabilize the overall structure of the biodegradable porous polymer tablet matrix, and the adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea release system in the intestinal environment is determined by in vitro simulation of intestinal fluid release.

[0013] The beneficial effects of the technical solutions provided in the application include:

[0014] (1) By compacting the polycarbophil calcium active ingredient and the multivalent metal salt under controlled humidity, a uniform microporous structure is formed and a reversible coordination bond is established, so that the drug can be released by monovalent cation replacement in the intestinal fluid, effectively avoiding the instability of the release rate of traditional preparations, and ensuring the predictability and uniformity of the drug in different environments. (2) The introduction of pH-responsive microcapsules in the biodegradable porous polymer matrix can gradually release organic acids under alkaline conditions to adjust the local microenvironment pH, thereby offsetting the influence of differences in intestinal environment of different individuals or different parts, making the drug release process more stable and improving the consistency of treatment effect. (3) The composite retardant layer is formed by cross-linking hydrophilic and hydrophobic polymers to form a three-dimensional network structure, and the swelling rate of the three-dimensional network structure can be reversibly changed with the local pH, which is coupled with the pore size restructuring of the outer controllable degradation nanoporous membrane under the action of ion concentration gradient, and the drug release rate is dynamically coupled with the intestinal environment, providing more precise sustained release and delayed effect. (4) The tablet structure is stabilized by constant temperature and humidity compaction, and the adaptive release curve is determined by in vitro simulation, which ensures that the preparation has good physical stability and repeatability during compaction, thereby improving the clinical applicability and patient compliance of polycarbophil calcium in anti-diarrhea treatment.

[0015] The accompanying drawings illustrate

[0016] Figure 1 is a flow chart of a construction method of a polycarbophil calcium tablet enhanced anti-diarrhea release system provided in the first embodiment of the application.

[0017] Specific compression methods

[0018] In the following description, numerous specific details are set forth to provide a thorough understanding of the present application. However, the present application can be practiced without the specific details. Other variations can be used according to other realizations of the present application, and structural and functional modifications can be made without departing from the scope of the present application, and it is therefore not intended to limit the present application to the preferred embodiments set forth in the following description and claims.

[0019] The first embodiment of the present application provides a method for constructing an enhanced anti-diarrhea release system of polycarbophil calcium tablets. Please refer to Figure 1 , which is a schematic diagram of the first embodiment of the present application. The following will be described in detail with reference to Figure 1 The first embodiment of the present application provides a method for constructing an enhanced anti-diarrhea release system of polycarbophil calcium tablets. Please refer to

[0020] Step S101: jointly compressing polycarbophil calcium active ingredients and ion-exchangeable multivalent metal salt under controlled humidity conditions to obtain pre-compressed polycarbophil calcium active ingredients forming uniform microporous structures and partially forming reversible coordination bonds with the multivalent metal salt, which can be replaced by monovalent cations in intestinal fluid to release.

[0021] The compression of step S101 aims to obtain pre-compressed polycarbophil calcium active ingredients. The core is to make polycarbophil calcium active ingredients and the multivalent metal salt fully contact and mildly rearrange the surface and locally coordinate ions under a controlled humidity environment, so as to form uniform microporous structures inside and on the surface of the particles and establish reversible coordination bonds, while avoiding overall gelation or irreversible cross-linking. When compressing, the polycarbophil calcium active ingredients can be first divided and mildly crushed to obtain initial powders with narrow particle size distribution and stable geometric shape, preferably with a median particle size falling within a stable compression interval and a limited fine powder ratio to facilitate the subsequent controllable generation and repeatability of microporous structures. The multivalent metal salt is a solid particle or porous salt body composite particle that can provide polycarbophil calcium active ingredients with multivalent cations in the presence of solid phase or trace moisture, typical cases including calcium citrate, calcium lactate, calcium hydrogen phosphate or magnesium citrate, etc. with exchangeable multivalent cation sites and without macroscopic dissolution or aggregation under controlled humidity. The particle size of the multivalent metal salt is preferably matched with or slightly smaller than that of the polycarbophil calcium active ingredients, so as to increase the contact frequency and reduce the density stratification after mixing; the specific surface area and surface hydration capacity thereof should be coordinated with the target micropore size, so as to provide uniform osmotic pressure and ion strength gradient for the micro-region swelling and shrinkage of polycarbophil calcium active ingredients during trace moisture adsorption and release.

[0022] The co-pressing can be carried out in a controllable temperature and humidity roller mixer, a fluidized bed humidity adjusting device or a closed constant humidity chamber, using clean dry air as the base gas and forming a stable controlled humidity airflow through a humidifying unit, slowly introducing it into the device cavity and maintaining sufficient and gentle inter-particle friction and turning under low shear mixing. To avoid excessive one-time wetting of the salt leading to agglomeration or surface pasting of the active ingredient of polycarbophil calcium, it is appropriate to use a humidity over-progressive step and cooperate with a short-time heat preservation balance humidity adjusting program, so that the moisture first reaches quasi-equilibrium on the particle surface layer, and then gradually penetrates into the near-surface micro zone. Through the slow process of "moisture absorption-micro-expansion-re-equilibrium", the carboxyl network of the active ingredient of polycarbophil calcium produces reversible micro volume adjustment under the premise of not damaging the integrity of the skeleton, and cooperates with the multi-valent metal salt body provided by the multi-valent cation at the particle contact interface, to form a coordination bridge between the local carboxylate and the multi-valent cation, and then to be shaped into a stable micropore cavity under the coupling action of water redistribution and local stretching and contraction. After the humidity adjustment is completed, dry air can be used to reduce the relative humidity in the cavity to close to the initial level at a relatively slow rate, so that the micropores that have been formed can be solidified and retained without rapid water loss collapse, while avoiding the formation of irreversible macroscopic shrinkage cracks. The whole humidity adjusting and drying process should be kept at a moderate and stable temperature to avoid the glass transition migration caused by the change of the thermal history of the active ingredient of polycarbophil calcium or the surface hardening caused by the sharp loss of salt body crystal form.

[0023] To ensure the formation of uniform microporous structure, mixing uniformity, humidity uniformity and ion supply uniformity should be controlled as key process parameters online or offline. Mixing uniformity can be indirectly characterized by measuring the content uniformity of the multivalent metal salt in the sample, humidity uniformity can be judged by the cavity multi-point humidity probe combined with the equilibrium time curve, and ion supply uniformity can be proved by the consistent distribution of surface exchangeable multivalent cations in the representative sample. The microporous structure of the pre-pressed polycarbophil calcium active ingredient can be characterized by mercury intrusion method, nitrogen adsorption specific surface area, low-field nuclear magnetic relaxation or micro-computed tomography, preferably obtaining unimodal or narrow bimodal pore size distribution in micron to sub-micron scale, and the dynamic heterogeneity coefficient is controlled in the range conducive to subsequent tablet forming and diffusion control. To prove the existence and exchangeability of the reversible coordination bond, monovalent cation replacement test can be carried out in simulated intestinal fluid medium, and the mobility of multivalent cation binding and free in the sample before and after the test is measured, and the displacement of the asymmetric and symmetric stretching peak position difference of the carboxylate in the infrared spectrum is used to indicate the formation of coordination, and the reversibility of coordination is proved by adding complexing agent. To prevent "over coordination" from causing irreversible crosslinking and brittle fracture of the system during subsequent hydration, the addition amount of the multivalent metal salt should be limited to the range that allows the target surface coordination density of the pre-pressed polycarbophil calcium active ingredient without forming a through rigid network, if necessary, local ion overloading can be alleviated by reducing the highest relative humidity of the humidification, shortening the high humidity residence time or moderately increasing the material layer thickness.

[0024] In terms of raw material quality management, the polycarbophil calcium active ingredient should have stable neutralization value and residual monomer limit and pass heavy metal and microbial limit test; the multivalent metal salt should be of pharmaceutical or compatible grade, and the moisture, particle size, specific surface area and exchangeable site concentration should be locked within the supplier's quality agreement, and rechecked after entering the factory. The process gas for humidification and the surface of the layer should meet the requirements of pharmaceutical contact materials and cleanliness grade, and all parts in contact with the material should avoid the interference of metal ions or extractables on the coordination sites. To ensure batch consistency, a quality correlation model of process parameters and structure indicators can be established, and the controlled humidity trajectory, temperature curve, mixing energy consumption signal and final microporous structure parameters are correlated, and the judgment criteria for layer placement are placed, such as the target water activity range of the pre-pressed polycarbophil calcium active ingredient, the surface exchangeable multivalent cation density range, the porosity and average pore size range, and the initial mass gain and ion replacement kinetics in simulated intestinal fluid.

[0025] After the pre-pressing, the pre-pressed polycarbophil calcium active ingredient should be immediately stored in a sealed moisture-proof container in a low-humidity environment to avoid secondary migration of the microporous structure or deviation of the proportion of reversible coordination bonds caused by re-moisture absorption. If necessary, a compliant desiccant can be placed in the container and a humidity indicator sheet can be layered to make the process visible. To ensure that the pre-pressed polycarbophil calcium active ingredient is compatible with the subsequent process, it is advisable to review the flowability, bulk density, and compressibility of the powder during the storage period, so as to provide stable and predictable input characteristics for the subsequent mixing with biodegradable porous polymer matrix and low-temperature pressing. Through the above controlled humidity co-pressing, the pre-pressed polycarbophil calcium active ingredient obtains a uniform microporous structure and reversible coordination bonds that can be replaced by monovalent cations, which not only lays a consistent diffusion path for the connectivity of the pores of the biodegradable porous polymer tablet matrix and the hydration kinetics, but also provides a reliable chemical switch for the programmable ion-triggered drug release of the compacted in the intestinal fluid environment, thereby ensuring that the pre-pressed polycarbophil calcium active ingredient as the effective functional unit of the subsequent construction has compressibility and batch consistency.

[0026] A specific compression example is given below for compressing the pre-pressed polycarbophil calcium active ingredient obtained in step S101. The entire process is based on pharmaceutical-grade raw materials and assumed process parameters, and all weighing, environmental control, and testing are performed in accordance with the requirements of pharmaceutical production quality management. 500g of pharmaceutical-grade polycarbophil calcium active ingredient is selected, with a median particle size D50 of (120±15) μm, a water content of ≤3.0% (LOD, 105°C), and heavy metal and microbial limits meeting the requirements; 40g of the multivalent metal salt body is selected as calcium citrate-silicon dioxide composite particles, with a calcium citrate negative salt content of (15±2)% (w / w), a salt body specific surface area of (250±30) m 2 / g, and a particle size D50 of (80±10) μm, with exchangeable Ca 2 + sites on the surface. The two materials are pre-granulated through a 100-mesh sieve and then placed in a 316L stainless steel drum mixer at a mass ratio of 100:8, with a layer setting drum speed of 12 rpm, and the mixer is placed in a constant temperature and humidity chamber with closed loop control, with a chamber volume of ≥1 m 3, clean dry air as the base gas, stable humid air was formed by isothermal humidification, temperature control at (25.0 ± 0.5) ℃. The humidity trajectory of "overrun conditioning - equilibrium - slow dry back" was executed: the relative humidity linearly climbed from 20% RH to 45% RH for 20 min, maintained for 20 min; then from 45% RH to 60% RH for 20 min, and then balanced for 30 min; continue to rise to 65% RH for 10 min, and maintain 65% RH for 30 min to complete the full distribution of moisture in the particle near the surface. The whole process keeps the drum speed at 12 rpm, so that the material is pressed in a low shear tumbling motion, and the three-point temperature and humidity probe (upper, middle, and lower) is placed in the inner layer of the cavity to control uniformity, with a three-point reading deviation of less than ± 2% RH. After conditioning, switch to dry air (25℃, dew point ≤-10℃) to slowly reduce to 30% RH at a gradient of 3-4% RH / 10 min, with a total dry back time of about 60 min, continue to maintain 12 rpm tumbling during this period to avoid surface caking and pore collapse. Stop mixing when dry back is completed, and immediately transfer the material to a pre-dried aluminum plastic composite moisture-proof barrel, add pharmaceutical silica gel desiccant (indicating type) and seal; place in a (25℃ / 30% RH) condition for 12 h to eliminate the internal and external moisture and stress gradient of the particles.

[0027] The in-batch release is based on structural and functional indicators. First, the water activity aw is 0.35-0.40 (25℃), the flowability indicators are (31±2)° for the rest angle, 0.37-0.41 g / mL for the bulk density, and 1.20-1.24 for the Hausner ratio, and there are no >1 mm agglomerates by visual inspection. The mercury intrusion method is used to characterize the microporous structure, the porosity is (22±4)%, the volume distribution is unimodal, the average pore size is (0.65±0.10) μm, and the pore size coefficient of variation is <25%; the BET specific surface area is (12±3) m 2 / g, which is significantly higher than the original active ingredient, indicating the formation of new internal surface. Fourier transform infrared spectroscopy is used to verify the carboxylate coordination: the difference Δν between the asymmetric stretching and symmetric stretching peaks of the carboxylate in the sample is increased by about 15-25 cm-1 from the original (≈(1640-1650)-(1400-1410) cm-1), and the shoulder peak of the coordination characteristic is formed, indicating the formation of reversible coordination bonds on the surface and near the surface of the particles. The exchangeable Ca 2 + density is quantitatively determined by inductively coupled plasma emission spectroscopy, the sample is oscillated in simulated intestinal fluid (USP SIF, pH 6.8, containing Na+ ≈ 145 mM) at 37℃, and the free Ca 2+ release (38-45)% of the bound amount, (80-88)% in 4h, >90% in 30min upon addition of disodium EDTA (2mM), demonstrating the reversibility of the complexation with monovalent cation replacement. The hydration kinetics is evaluated by low-field NMR T2 relaxation distribution, which shows a narrower T2 distribution and lower free water fraction in the early hydration stage for the pre-pressed product compared to the un-pressed control, consistent with the characteristics of a microporous network and surface complexation restricting water migration. To avoid excessive complexation leading to subsequent irreversible crosslinking, the dosing amount of the multivalent metal salt and the residence time at 65% RH in the pre-pressing process are pre-determined as an upper limit safety range, and any deviation is downgraded if mercury intrusion test shows bimodal pore size distribution or FTIR shows significant crosslinking signature (abnormal increase in peak position difference and not reversed by Na+ / EDTA). The product yield is ≥98%, and the product is temporarily stored in a sealed moisture-proof barrel in an environment with ≤30% RH for no more than 72h before entering step S102. Through the above parameters and detection methods, the pre-pressed active ingredient of calcium polycarbophil has a uniform microporous structure and reversible complexation with monovalent cation replacement, which is used as an input material for the subsequent biodegradable porous polymer tablet matrix.

[0028] Further, the pre-pressing of the active ingredient of calcium polycarbophil and the ion-exchangeable multivalent metal salt under controlled humidity conditions comprises:

[0029] The active ingredient of calcium polycarbophil is subjected to coordinated moisture and particle size adjustment and granulation to obtain the target surface area and moisture state for subsequent pre-pressing;

[0030] The low-shear dry mixing is performed according to the ratio established between the ion exchange capacity of the ion-exchangeable multivalent metal salt and the target surface area and moisture state, to form an initial complexation nucleation distribution on the surface of the active ingredient of calcium polycarbophil for subsequent moisture-induced nucleation;

[0031] The moisture adjustment process by combining the moisture increase and the moisture equilibrium under controlled humidity conditions makes the multivalent cation complexation bridge grow along the particle surface layer and near-surface layer and be limited to a uniform microporous structure, while generating a reversible complexation group with replaceability;

[0032] The desiccation shaping trajectory is placed according to the characteristic pore size and connectivity of the uniform microporous structure, so that the density and spatial distribution of the reversible complexation reach the comprehensive goal of maintaining diffusion channels and compressibility when mixed with the biodegradable porous polymer matrix and pressed into a shape under low temperature conditions, and the pre-pressed active ingredient of calcium polycarbophil is obtained.

[0033] In a pharmaceutical clean environment, the active ingredient of pharmaceutical grade calcium polycarbophil is selected as the starting material. First, the abnormal coarse and fine classification is removed by low-energy whole-grain and gas-solid separation. Then, the moisture of the material is fine-tuned by short-range vacuum drying or dew point controlled air blowing, and the target surface area and moisture state are confirmed by water activity meter and Kulkul method micro water determination to reach the stable interval. In this process, avoid exceeding the thermal history of the material glass transition temperature, prevent irreversible agglomeration or surface coating hardening, so as to ensure that the plastic-reversible chain segment movement required for the subsequent formation of uniform microporous structure is retained. After the target surface area and moisture state are established, the active ingredient of calcium polycarbophil is transferred to a calibrated closed mixing container. According to the specific surface area and salt body exchangeable site capacity estimated by batch, the theoretical input range of the salt body containing ion-exchangeable multivalent metal salt is determined, and the feeding ratio of this batch is calculated by the function relationship established by small measurement, so that the potential coordination site density per unit surface area falls within the window that can induce pore formation without forming a rigid network. The salt body of the multivalent metal salt is preferably a fine composite particle formed by salt formation on an inert inorganic or organic porous substrate, to ensure the slow release of multivalent cations under controlled humidity conditions without macroscopic dissolution and precipitation, and its particle size and density should match the active ingredient of calcium polycarbophil to prevent stratification after mixing.

[0034] The two-phase material is dry mixed under low shear conditions, and a three-dimensional or drum mixer is used to make the particle group have uniform surface contact and mild friction through the program of slow start and stop, intermittent turning and reverse turning. If necessary, a small amount of pharmaceutical certified flow aid is added to improve spreading, but avoid affecting the exposure of ion exchange sites. During the dry mixing process, the mixing uniformity is controlled by process control through near-infrared probe or plasma emission spectroscopy trace measurement, and the attachment distribution of the multivalent metal salt body on the surface of the active ingredient of calcium polycarbophil is confirmed by microscopic image analysis, confirming that the initial coordination nucleation distribution has been formed as the basis for subsequent humidity induction; If local agglomeration or salt body enrichment is observed, the rotation speed should be reduced and the turning time should be extended to make the distribution return to the uniform interval. After completing the low-shear dry mixing and achieving the target distribution, the mixed material is transferred to a programmable temperature and humidity box or a fluidized bed humidity adjustment device with bottom ventilation under the condition of maintaining an inert atmosphere. Open the controlled humidity track, first slowly linearly increase the humidity to a medium relative humidity and keep the humidity balance, so that the water forms a stable adsorption layer on the surface layer of the particles, and then further increase the humidity to the predetermined upper limit and maintain a short platform, so that the near-surface chain segment produces limited hydration; During the whole humidity adjustment process, the uniformity is observed through multiple humidity and temperature probes, and the distribution of moisture in the pores and surface layer is judged by the online mass gain curve and low-field nuclear magnetic relaxation rapid measurement linkage to avoid local pasting or overall softening caused by rapid penetration.

[0035] Under the above-mentioned humidity control process combining excessive humidity rise with isohydric equilibrium, the coordination bridge of polyvalent cations starts to grow along the surface layer and near-surface layer of the particles with the initial coordination nucleation distribution as the starting point. The carboxylate salt groups of the active ingredient of polycarbophil calcium undergo reversible crosslinking under the combined action of local ionic strength and osmotic pressure gradient and induce slight expansion and contraction of the microzone volume. The stress relaxation and water redistribution in the microzone are coupled with each other, and gradually limit to a continuous and uniform microporous structure; to prevent the coordination bridge from excessive expansion leading to a rigid through network, the weak bridging should be dispersed with a slight pulse ventilation or light turning at the platform stage, while the temperature difference in the box is minimized to ensure that the pore formation is mainly in the surface layer-near surface layer and does not excessively penetrate the main particles. At the end of the humidity control, the relative humidity is reduced at a slow rate and the steps should be matched with the characteristic pore size and connectivity of the above-mentioned uniform microporous structure, so that the pore wall completes the setting without brittle shrinkage under the condition that the chain segment still has reversible motion; at this stage, the isothermal mass loss rate is one of the process end criteria, and the pore size distribution of the representative test product is quickly released for judgment by mercury intrusion method or gas adsorption, to confirm that the characteristic pore size and distribution fall into the compromise interval of channel connectivity-mechanical strength of the pre-layer.

[0036] After the slow and slow humidity setting trajectory ends and reaches room temperature equilibrium, the obtained pre-pressed polycarbophil calcium active ingredient is temporarily stored in a low humidity environment in a sealed container, and its structure and function are confirmed. In terms of structure, the connectivity and uniformity of the uniform microporous structure are comprehensively evaluated by mercury intrusion method, nitrogen adsorption specific surface area and layer scanning electron micrograph observation; in terms of function, monovalent cation replacement test is carried out in simulated intestinal fluid medium, the release kinetics of polyvalent cations is measured by inductively coupled plasma emission spectroscopy or complexometric titration line, and the reversible migration of the asymmetric and symmetric stretching peak difference of the carboxylate salt is tracked by Fourier transform infrared spectroscopy to verify that the reversible coordination bond group with replaceability has been generated. If the replacement rate is too fast, it indicates that the coordination density is too low, and the salt input can be adjusted or the medium humidity equilibrium time can be extended in the next batch; if the replacement is not obvious, it indicates that the coordination density is too high, and the highest humidity platform should be lowered or the platform time should be shortened to ensure that when mixed with biodegradable porous polymer matrix and pressed into shape under low temperature conditions, the diffusion channel can provide a stable water entry-drug release path, and the compressibility of the powder and the mechanical consistency after tabletting are not weakened.

[0037] Throughout the whole co-pressing process, the target surface area and moisture movement, initial coordination nucleation distribution, uniform microporous structure and reversible coordination bond group are always taken as the process control points. The output of the previous control point is collected and taken as the layer input of the next control point during pressing. The traceable process batch record and quality control measurement are used to establish the batch-comparable parameter-structure-function correlation model. Only when the target surface area and moisture movement reach the stable interval, the initial coordination nucleation distribution is uniform and the visualized simulation test passes, the characteristic pore size and connectivity of the uniform microporous structure meet the established window, and the reversible coordination bond group shows the kinetic characteristics of real displacement without burst release in the simulated intestinal fluid, it is determined that the pre-pressed polycarbophil calcium active ingredient is obtained, and enters the subsequent step of mixing with the biodegradable porous polymer matrix and pressing under low temperature conditions.

[0038] Step S102: mixing the pre-pressed polycarbophil calcium active ingredient with the biodegradable porous polymer matrix and pressing under low temperature conditions to obtain a biodegradable porous polymer tablet matrix containing the pre-pressed polycarbophil calcium active ingredient, the biodegradable porous polymer tablet matrix containing uniformly distributed pH-responsive microcapsules, the pH-responsive microcapsules gradually disintegrating and releasing organic acid to adjust the local microenvironment pH in the alkaline environment of the intestinal fluid.

[0039] When the step S102 is pressed, the pre-pressed propolis calcium active ingredient is used as the main salt body of the functional skeleton, and the powder pre-pressing is first completed in a controlled workshop environment (temperature 20-25℃, relative humidity ≤35%) to make the particle size distribution and flowability meet the direct tabletting requirements. The biodegradable porous polymer matrix is preferably obtained by compounding polymers that can be orally degraded and tabletted, such as polylactic acid-glycolic acid copolymer compounded with polycaprolactone at a mass ratio of 7:3, or gelatin compounded with pregelatinized starch at a mass ratio of 6:4, and 5-15% of a water-soluble porogen (such as mannitol or sodium chloride) is added to form connected pores during the hydration stage after taking. To ensure that the "uniformly distributed pH-responsive microcapsules" are compacted in the tablet core, the pH-responsive microcapsules are preferably pre-made dry powder, the core salt is organic acid (such as citric acid or succinic acid, the core salt content is 50-70%), and the shell is an intestinal pH-responsive material that disintegrates under alkaline conditions (such as Eudragit S-grade acrylic resin or alginate / chitosan composite shell layer cross-linked and densified by pressing). The particle size is controlled to have a median particle size of 60-150μm and 90% of the particles fall within the range of 45-200μm to balance the flowability and uniform dispersion; the water content of the microcapsules should be ≤3.0% to avoid premature softening of the shell during mixing and tabletting. In the total amount of the formulation, the pre-pressed propolis calcium active ingredient usually accounts for 40-65% (mass fraction), the biodegradable porous polymer matrix accounts for 20-45%, the pH-responsive microcapsules account for 5-20%, and the rest is process aid, including 0.2-1.0% of magnesium stearate as a lubricant and 0.3-1.5% of silicon dioxide as a flow aid; to avoid early osmotic pressure impact on the shell, no free organic acid or alkaline buffer salt is added as a matrix component. The mixing operation uses a closed barrel mixer or a three-dimensional dynamic mixer, the biodegradable porous polymer matrix and water-soluble porogen, flow aid are first pre-mixed for 6-8min to make the matrix porogen fully dispersed, then the pre-pressed propolis calcium active ingredient is added for low-shear mixing for 6-8min to form a uniform skeleton mixture; the pH-responsive microcapsules are finally added after removing the oversized particles, and are mixed at a speed of 10-12rpm for 3-5min to make them uniformly embedded in the interstitial space of the skeleton powder through van der Waals force and electrostatic weak adsorption, then the lubricant is immediately added and mixed at a low speed for not more than 2min to avoid the lubricant covering the shell and causing subsequent disintegration release delay. Uniformity is determined by dynamic sampling (taking representative samples from the upper, middle and lower layers of the barrel), content determination and microscopic statistics, the relative standard deviation of the number of particles per unit mass of the pH-responsive microcapsules should not be higher than 10%, and the content uniformity of the pre-pressed propolis calcium active ingredient should be within the range of 85-115% and RSD ≤6%; the flowability is qualified when the angle of repose is ≤34° and the Carr index is ≤22% to ensure repeatable filling.

[0040] The compression molding is performed under "low temperature conditions" to limit frictional heat generation and shell stress rupture, using a rotary tablet press with a cooling jacket or a single punch tablet press with a pre-cooled punch die, with the mold temperature controlled at 15-22°C, the outer wall of the hopper and the discharge tube can be supplemented with a cooling jacket to keep the temperature below 20°C, and the relative humidity in the compression chamber is maintained at ≤35% to prevent powder deliquescence. To further reduce the endogenous heat, a moderate pre-pressing-main pressing two-stage tabletting curve is selected, the pre-pressing is applied at 20-40 MPa to exhaust and form, the main pressing is applied at 80-150 MPa to obtain the required mechanical strength, and the main pressing residence time is not less than 30 ms to reduce the instantaneous peak stress; the turntable speed is controlled within the range of 20-40 rpm to balance the production capacity and temperature rise. The punch die size is based on the target dose layer, for example, a round tablet with a diameter of 8-10 mm, a tablet weight of 300-600 mg, and a thickness of 3.5-5.5 mm; the target hardness is generally controlled in the range of 70-120 N, the friability is ≤1.0%, the thickness-diameter difference is ≤3%, and the tablet surface roughness is preferably Ra≤3μm to facilitate the formation of a composite barrier layer. To simulate the "biodegradable porous polymer tablet matrix containing the pre-pressed calcium polycarbophil active ingredient" that has been compacted and the "pH-responsive microcapsules" that have not been pressed, the tablet core microstructure can be observed by freeze-fracture layer drawing electron microscopy, the intact capsule shell rate should be ≥90%, and the three-dimensional distribution in the tablet core can be reconstructed by micro-CT to investigate the isotropy of the capsule space distribution; the toluidine blue or neutral red indicator dyeing of the capsule shell exosmosis acid is used for rapid screening to confirm that there is no significant leakage during mixing and tabletting. The formability of the biodegradable porous structure is compared before and after tabletting by mercury intrusion method and specific surface area measurement, when the pore-forming phase ratio is 5-15%, the actual porosity after tabletting should be maintained at 18-28%, the average pore size is 0.4-0.9μm, and the pore size distribution is unimodal or narrow bimodal to ensure the connectivity and stability of the subsequent hydration channels. To reduce batch-to-batch variability, a correlation model of process parameters and structure endpoints is established, and the mixing energy consumption curve, tablet temperature, main pressing peak value, and cross-sectional porosity parameters are related and analyzed; when the tablet temperature exceeds 25°C or the intact capsule shell rate is less than 90%, it is determined that the speed or pressure needs to be reduced for correction. After completion of the compression, a "biodegradable porous polymer tablet matrix containing the pre-pressed calcium polycarbophil active ingredient" is obtained, the "uniformly distributed pH-responsive microcapsules" are uniformly embedded in the space by particle size control and terminal light mixing, and the water-soluble pore-forming agent gives the ability to generate pores during the hydration stage after taking, and the low temperature, low shear, and pre-pressing-main pressing forming strategy ensures the integrity of the capsule shell structure and the pre-pressed calcium polycarbophil active ingredient microporous skeleton. Before the subsequent formation of a composite barrier layer and a controllable degradation nano-porous membrane, the tablet core should be sealed and buffered in an environment with ≤30% relative humidity for 2-12h to redistribute the stress and stabilize the physical structure, so as to ensure that it has a stable, input-like state when entering the next process.

[0041] Further, the mixing of the pre-pressed propolis calcium active ingredient with the biodegradable porous polymer matrix and the compression molding under low temperature conditions to obtain the biodegradable porous polymer tablet matrix containing the pre-pressed propolis calcium active ingredient, comprising:

[0042] The pre-mixing of the biodegradable porous polymer matrix with the pharmaceutical porogenic excipient for forming the interconnected pores and the pharmaceutical adjuvant for improving the powder spreading and filling, so that the resulting material reaches the target state of the salt-containing pre-pressed propolis calcium active ingredient in terms of fluidity and surface energy;

[0043] The addition of the pre-pressed propolis calcium active ingredient to the pre-mixture and the mixing under low shear conditions to obtain the biodegradable porous polymer matrix mixture containing the pre-pressed propolis calcium active ingredient;

[0044] The introduction of the pH-responsive microcapsule end under static shielding and surface energy matching conditions into the biodegradable porous polymer matrix mixture containing the pre-pressed propolis calcium active ingredient, so that the pH-responsive microcapsule is embedded in a uniform distribution and forms a protective interface compatible with the pre-pressed propolis calcium active ingredient under dry conditions, thereby obtaining a pre-compression composition for compression molding under low temperature conditions, and the embedding density and interlayer contact state of the pre-compression composition are input as parameters for low temperature molding;

[0045] The compression molding of the pre-compression composition under low temperature conditions, using the sequence control of pre-pressing and main pressing to complete the exhaust and molding, so that the resulting product is a biodegradable porous polymer tablet matrix containing the pre-pressed propolis calcium active ingredient, and the biodegradable porous polymer tablet matrix contains uniformly distributed pH-responsive microcapsules.

[0046] The pre-pressed biodegradable porous polymer matrix is pre-processed in a clean pharmaceutical area, and is put into a closed mixing container with a predetermined ratio of a pharmaceutical porogenic excipient for forming interconnected pores and a pharmaceutical aid for improving powder spreading and packing. The pre-processed biodegradable porous polymer matrix can be selected from one or more of an orally degradable polymer system, such as polylactic-co-glycolic acid, polycaprolactone, gelatin or pregelatinized starch. The pharmaceutical porogenic excipient for forming interconnected pores can be selected from mannitol, lactose or sodium chloride. The pharmaceutical aid for improving powder spreading and packing can be selected from a pharmaceutically approved silicon dioxide or micronized starch. Local overheating and local static electricity accumulation should be avoided during the pre-processing to prevent subsequent introduction of the pre-pressed propiverine calcium active ingredient from causing stratification or agglomeration. The resulting material has reached a target state of flow and surface energy that is conducive to the subsequent introduction of the pre-processed propiverine calcium active ingredient, and this state is used as the process level input for the subsequent mixing step.

[0047] After the above pre-processing is completed, the pre-processed propiverine calcium active ingredient is slowly and evenly spread onto the moving material surface of the pre-mixture, and low-shear stirring is maintained to form an initial distribution of the pre-processed propiverine calcium active ingredient between the biodegradable porous polymer matrix particles in a bridging-embedding manner. High-energy shearing or high-speed impact should not be used during this process to avoid damaging the uniform microporous structure and reversible coordination bonds of the pre-processed propiverine calcium active ingredient. After mixing is completed, content uniformity determination and microscopic image statistics are performed to confirm that the pre-processed propiverine calcium active ingredient is uniformly dispersed in the resulting material and does not form visible agglomerates. Thus, a biodegradable porous polymer matrix mixture containing the pre-processed propiverine calcium active ingredient is obtained, and the flowability and compressibility of this mixture are used as the process level input for the subsequent introduction of the pH-responsive microcapsules.

[0048] To form the target structure of "pH-responsive microcapsules uniformly distributed in the biodegradable porous polymer tablet matrix", the pH-responsive microcapsules should be introduced in the end of the light mixing stage under the condition of matching electrostatic shielding and surface energy. For this purpose, an ion wind rod or a conductive grounding device can be placed in the mixing layer and the ambient relative humidity can be controlled in a low humidity range that does not cause hygroscopicity. By spraying a small amount of polar diluent in advance or adding a very low proportion of surface modifier, the average surface energy difference between the outer surface of the pH-responsive microcapsules and the biodegradable porous polymer matrix mixture is reduced. Subsequently, the pH-responsive microcapsules are gently mixed in a low-speed, short-time, and batched manner, so that the pH-responsive microcapsules are gently embedded in the powder gap and form a compatible protective interface with the active ingredient of the pre-pressed polycarbophil calcium to avoid the microcapsule shell from being ground or broken during dry mixing. A small amount of pharmaceutical lubricant is added immediately after mixing to improve subsequent filling and demolding. The content uniformity, particle size distribution, and capsule shell integrity are tested by dynamic measurement of the upper, middle, and lower layers of the hopper. It is confirmed that the pH-responsive microcapsules are uniformly embedded and there is no abnormal leakage, so as to obtain a pre-compression composition for low-temperature compression molding. The embedding density of the pre-compression composition and the interlayer contact state are input as parameters for low-temperature molding.

[0049] When compression molding is performed under low temperature conditions, a tabletting equipment with die cooling or compression cavity temperature control should be used to maintain the punch, feeder and tabletting chamber in a low temperature range to limit frictional heat generation and protect the structural integrity of the pH-responsive microcapsules and the pre-processed calcium polycarbophil active ingredient. Preferably, the order of pre-pressing and main pressing is controlled by a curve, which first pre-presses at a lower pressure for a short time to remove entrained air and initially shape, and then completes densification at a higher pressure, while controlling the main pressing residence time and salt addition-removal rate to stably establish mechanical interlocking and adhesion between particles under conditions that do not cause capsule shell rupture. To prevent structure destruction due to tablet temperature rise, the turntable speed can be reduced or intermittent tabletting is performed, and the tablets are placed in a low humidity, room temperature environment after tabletting to allow natural stress decay. The finished product is subjected to physical preliminary inspection of appearance, tablet weight, thickness, hardness and friability, and the tablet core is observed by freeze-fracture layer tracing electron microscopy or microcomputer tomography to confirm that the uniform microporous structure of the pre-processed calcium polycarbophil active ingredient remains connected after compression, and that the pH-responsive microcapsules are intact, uniformly distributed, and have no obvious crushing or migration; at the same time, the porosity and pore size distribution of representative test products are compared by mercury intrusion or gas adsorption method to prove that the pharmaceutical pore-forming adjuvant used to form connected channels still forms continuous channels after compression. If necessary, rapid medium permeation test is carried out on a small number of tablets to confirm that the liquid uptake rate and diffusion front advance of the tablet core in the early hydration stage are consistent with the pre-layer range. After meeting the above structure and performance release standards, a biodegradable porous polymer tablet matrix containing the pre-processed calcium polycarbophil active ingredient is obtained, which contains uniformly distributed pH-responsive microcapsules, and the overall strength, channel connectivity and tablet surface motion of the product are input as process layers into the process layer of the surface composite retardant layer forming process to ensure stable and controllable adhesion and boundary conditions during subsequent film formation.

[0050] Step S103: Forming a composite retardant layer on the surface of the biodegradable porous polymer tablet matrix, the composite retardant layer being formed by cross-linking a hydrophilic polymer and a hydrophobic polymer to form a three-dimensional network structure, the swelling rate of the three-dimensional network structure being affected by the local microenvironment pH to cause dynamic reversible changes.

[0051] When performing step S103, the biodegradable porous polymer tablet matrix containing the pre-processed calcium polycarbophil active ingredient is used as the coated core, and the film formation of the composite retardant layer is performed in a clean, temperature 20-25°C, relative humidity not higher than 35% environment.

[0052] The composite retardant layer is constructed in situ by using water-based system to form a three-dimensional network structure, so that the hydrophilic polymer sub-network and the hydrophobic polymer penetrate each other and are compacted and crosslinked by physical-ion complexation. The hydrophilic polymer can be selected from a combination of chitosan and a polymer containing carboxyl groups to form a reversible polyelectrolyte complex network. Specifically, chitosan is dissolved in a lactic acid aqueous solution to prepare a solution with a mass fraction of about 0.8% (pH about 3.0), and a partially neutralized carbomer aqueous dispersion is prepared separately, with a solid content of about 0.4% and a pH adjusted to 6.0-6.5 to ensure that the carboxylate groups are in an ionized state; the hydrophobic polymer is preferably a water-based ethyl cellulose latex, such as an ethyl cellulose 30% solid content aqueous dispersion, with 20%-25% triethyl citrate added as a plasticizer based on the polymer solids, and 5%-10% talc or silicon dioxide added as an anti-sticking agent based on the ethyl cellulose solids.

[0053] To avoid a large amount of complexation of the hydrophilic component before spraying, which can cause the spray to coagulate, the hydrophilic two-phase components are stored separately and delivered to the static mixer at the front end of the spray by two separate peristaltic pumps for immediate mixing, and then mixed with the hydrophobic ethyl cellulose latex in a three-stream mixing mode at the nozzle, with the mixing ratio of ethyl cellulose to (chitosan + carbomer) controlled at about 6:4 based on the solid mass, so that after drying, a composite retardant layer is formed with ethyl cellulose as the continuous phase and a polyelectrolyte complex as the interpenetrating sub-network. The coating layer is preferably a bottom-spraying fluidized bed (Wurster structure) to ensure that a thin layer with closed pores and uniform thickness is formed on the surface of the biodegradable porous polymer tablet matrix; the inlet air temperature is controlled at 35-42°C, the outlet product temperature is stabilized at 28-32°C, the atomization pressure is 1.2-1.6 bar, the spray rate is converted to 2.0-3.0 grams of solid per kilogram of core tablet mass per minute, the spray shape is a moderately atomized, slightly flattened spray to balance coverage and drying rate, and the distribution plate gap and lifting air speed are adjusted to just compact and smoothly rise-fall without actual entrainment or dead zones.

[0054] To prevent the pH-responsive microcapsules in the biodegradable porous polymer tablet matrix from breaking prematurely due to heat or moisture, the product temperature during coating should not exceed 32°C, and the weight gain of the composite retardant layer is measured by online weighing or offline sampling, and when the weight gain reaches 6%-8% of the core tablet mass, the spraying is stopped and the drying and shaping are entered. The drying and shaping is carried out at 40°C for 12-24 hours, with the relative humidity maintained at 45%-55%, so that the ethyl cellulose continuous phase is fully condensed and the chitosan and carbomer complete ion complexation within the film, forming a stable three-dimensional network structure; this process does not require the use of organic solvent gas neutralization, but it is necessary to avoid high humidity causing the film surface to stick or the core to return to moisture.

[0055] The film layer uniformity can be preliminarily determined by weighing the weight gain dynamic coefficient not higher than 3%, and the cross-sectional thickness and phase distribution are observed by frozen cross-section layer scanning electron microscopy. The thickness is generally 20-60 μm, and the ethyl cellulose phase and the polyelectrolyte complex phase are in continuous-discrete interpenetrating distribution; the glass transition temperature of the plasticized ethyl cellulose is reduced to the target interval by differential scanning calorimetry or dynamic kinetics analysis, and it is shown that the continuous phase has been sufficiently densified.

[0056] To confirm that the swelling rate of the composite retardation layer reversibly changes with the local microenvironment pH, the same casting film strip as the coating ratio is subjected to cyclic immersion in pH 5.5 acetic acid buffer and pH 6.8 phosphate buffer at 37°C, and the water absorption rate per unit time and thickness increase are recorded; in a typical case, the water absorption rate at pH 6.8 can reach 80%-120% (mass / dry film) in 60 minutes, and the thickness increases by 20%-35%; at pH 5.5, the water absorption rate decreases to 30%-60%, and the thickness increases by 8%-18%; both have no irreversible drift after three cycles, indicating that the swelling behavior of the three-dimensional network structure is reversible. After three cycles, there is no irreversible drift, indicating that the swelling behavior of the three-dimensional network structure is reversible.

[0057] For film densification and flux control, water vapor permeability and solute (such as acetaminophen as a probe) diffusion coefficient determination can be used to ensure that the permeability difference in the target pH interval is consistent with the above swelling difference, thereby providing a stable and predictable inner boundary condition for the subsequent controllable degradation of the nanoporous film. Throughout the process, the liquid spray solid content and ratio should be continuously controlled, and the immediate mixing pH of chitosan and carbomer should be maintained at 4.5-5.5 to complete ion complexation in the film without premature gelation in the nozzle; if the nozzle back pressure rises or atomization is unstable, the instantaneous concentration of the amphiphilic water phase can be appropriately reduced or the ethyl cellulose latex ratio can be increased, so that the composite retardation layer forms a film from the hydrophobic continuous phase first, and the hydrophilic sub-network is subsequently solidified in the film. The adhesion of the formed composite retardation layer is measured (crosshatch or bending method) and the wear resistance is measured (rotary drum method), and the adhesion is not detached, and the surface is not significantly powdered, which can be released into the next step. Through the above process, the composite retardation layer forms a three-dimensional network structure on the surface of the biodegradable porous polymer tablet matrix, which is crosslinked by hydrophilic polymers and hydrophobic polymers. The structure utilizes reversible charge pairing and hydrogen bonding and other physical crosslinking mechanisms of carboxylate-ammonium salt to produce a repeatable swelling-deswelling response under different local microenvironment pH, thereby providing a controllable and verifiable structural basis for the self-adaptive drug release of the system.

[0058] Further, the composite retardation layer formed on the surface of the biodegradable porous polymer tablet matrix comprises:

[0059] The surface energy and pore connectivity of the biodegradable porous polymer tablet matrix are pre-layered to obtain the surface energy and pore connectivity for deposition of the composite barrier layer;

[0060] Under the condition that the hydrophilic polymer and the hydrophobic polymer are separately supplied and mixed in situ at the deposition end, an initial deposition layer formed by crosslinking the hydrophilic polymer and the hydrophobic polymer to form a three-dimensional network structure is deposited in situ on the surface of the biodegradable porous polymer tablet matrix, and the crosslinking and deposition distribution of the surface energy and pore connectivity layer are fixed, so that the structure parameters of the initial deposition layer are taken as fixed shape inputs;

[0061] The fixed shape is completed during controlled drying and post-maturation, the composite barrier layer is formed by crosslinking the hydrophilic polymer and the hydrophobic polymer to form a three-dimensional network structure, and the swelling rate of the three-dimensional network structure is reversibly changed under the influence of the local microenvironment pH, and the thickness, surface roughness and swelling-deswelling characteristics of the composite barrier layer are taken as process fixed inputs for forming a controllable degradation nanoporous membrane on the outer surface of the composite barrier layer.

[0062] To form a composite barrier layer on the surface of the biodegradable porous polymer tablet matrix, first, the surface polarity and water content of the biodegradable porous polymer tablet matrix are pre-layered in a pharmaceutical clean environment, so that the surface energy is in a range conducive to wet spreading without causing early hydration of the tablet core. The tablet can be placed in a constant temperature and humidity chamber for a short time, so that the surface of the tablet reaches a uniform and reproducible water content, and a volatile diluent with isotonic and low ionic strength is used to perform thin misting on the surface of the tablet, so that the surface energy is gently increased; then the free liquid film is carried away by a gentle air flow to avoid forming visible liquid bridges at the pores of the biodegradable porous polymer tablet matrix. The surface energy and pore connectivity of this pre-layering serve as boundary conditions for film formation, and participate in determining the wetting radius, droplet spreading angle and primary condensation position of the subsequent deposition, thereby providing a reproducible interface for forming a dense and pinhole-free film body formed by crosslinking the hydrophilic polymer and the hydrophobic polymer to form a three-dimensional network structure.

[0063] Under this boundary condition, the initial deposition layer is generated in situ by the way of instant mixing of the deposition end with the branch supply: the hydrophilic polymer adopts the hydrosol system which can form ionic complex in the weak acid-near neutral interval, for example, chitosan is configured as an acidic solution with low concentration and low viscosity, so that the degree of cationization is stable, and then the water dispersion containing carboxyl (such as carbomer partially neutralized) is configured as a dispersion with weak acid to near neutral, so that the proportion of carboxylate is moderate; the hydrophobic polymer adopts the aqueous emulsion system (such as ethyl cellulose latex) and adds a plasticizer compatible with drugs to reduce the glass transition temperature. The above two routes of hydrophilic polymer sol are independently delivered to the static-dynamic mixer at the front end of the nozzle for instant mixing, ensuring that chitosan and carbomer only have initial contact in the nozzle without premature gelation; the hydrophobic polymer emulsion is supplied as a third route independently, and a fine mist is formed by the three-flow convergence of the nozzle pressure and the hydrophilic system, so that the hydrophilic polymer and the hydrophobic polymer start to coagulate in the same space-time window falling on the biodegradable porous polymer tablet substrate surface. In order to ensure that the initial deposition layer is formed by cross-linking of the hydrophilic polymer and the hydrophobic polymer to form a three-dimensional network structure, the bottom spraying fluidized bed (Wurster structure) is preferably selected, and the atomization pressure, the solid content of the sprayed liquid and the bed air speed are adjusted, so that the single tablet receives thin layer deposition and instant drying multiple times in the rising-descending cycle to form multiple superimposed nano-micron level layers. During the deposition process, the surface energy and pore connectivity are used as layer quantification, and the flow ratio and liquid pH of the three routes are adjusted in real time, so that the hydrophilic polymer forms a "point-network" support of ionic complex network on the tablet surface in advance, and the hydrophobic polymer then fills the gaps and solidifies as a continuous phase, thereby obtaining an initial deposition layer with mechanical support and diffusion resistance. The solid content superposition, ionic complex degree and surface roughness of the initial deposition layer are recorded as structure parameters as the input of subsequent shaping.

[0064] After in-situ deposition, the composite retardant layer is finally formed by cross-linking the hydrophilic polymer and the hydrophobic polymer to form a three-dimensional network structure through controlled drying and post-aging. In the setting stage, the continuous phase of the hydrophobic polymer is first compacted by mild drying to migrate and densify the chain segments, and then aged at medium humidity to further rearrange the free ions and counter ions remaining in the hydrophilic polymer within the membrane, so that the cationic sites of chitosan and the carboxylate sites of carbomer form reversible ion pairs, and the network is strengthened through hydrogen bonding and physical entanglement. Throughout the process, avoid sudden changes in temperature and humidity to prevent stress accumulation in the membrane, which may cause micro-cracks or delamination. The set composite retardant layer is released for confirmation of thickness, surface roughness and swelling-deswelling characteristics: thickness is measured by freezing cross-section layer tracing or non-contact thickness measurement at multiple points, which should be narrow and different; surface roughness is characterized by parameters measured by a profilometer to ensure stable wetting and anchoring when forming a controllable degradation nanoporous membrane on the outer surface of the composite retardant layer; the swelling-deswelling characteristics are measured in a simulated intestinal fluid pH window, recording the water absorption rate, thickness increase and rebound per unit time, which should not be irreversibly shifted after multiple pH changes, indicating that the swelling rate of the three-dimensional network structure is affected by the local microenvironment pH and is dynamically reversible. To further ensure the synergy with the tablet core, the grid or bending method is used to confirm that the composite retardant layer does not delaminate from the biodegradable porous polymer tablet matrix, and the micro-CT layer tracing confirms that the membrane partially covers the tablet core orifice uniformly without blocking the main communication channel. The above thickness, surface roughness and swelling-deswelling characteristics are used as quantitative process inputs to directly control the spraying solid content, droplet energy, drying heat history and aging humidity when forming a controllable degradation nanoporous membrane on the outer surface of the composite retardant layer, so that the nucleation, phase separation and pore anchoring of the subsequent membrane-membrane interface can be predictable and reproducible. Through the process of linking and closing the loop of the three stages of boundary conditions-initial deposition layer-setting, a composite retardant layer can be stably obtained on the surface of a biodegradable porous polymer tablet matrix, providing a controlled interface for subsequent construction of an outer layer coupled with the ion concentration of the intestinal fluid.

[0065] Step S104: Forming a controllable degradation nanoporous membrane on the outer surface of the composite retardant layer, the pore size distribution of the controllable degradation nanoporous membrane is dynamically reconstructed by the ion concentration gradient of the composite retardant layer during hydration, so that the drug release performance of the controllable degradation nanoporous membrane is coupled with the ion concentration of the intestinal fluid.

[0066] When the step S104 is pressed, the tablet with the composite retardation layer formed is used as the coated core, and the controllable degradation nano-porous membrane is formed in situ under the conditions of low temperature, low humidity and low shear throughout. Preferably, the aqueous emulsion-nanoparticle and phase technology is used to avoid the swelling and stress cracking of the composite retardation layer caused by organic solvents: first, a water dispersion of polylactic acid-glycolic acid copolymer as the main system is prepared, lactone biodegradable polymer is dissolved in ethyl acetate to form an organic phase with a mass fraction of 10%, and the organic phase is added dropwise and emulsified in the water phase containing 1.0% polyvinyl alcohol and 0.2% sodium alginate by high-speed homogenization, and the organic phase is removed by constant pressure and pressure reduction to obtain a polylactic acid-glycolic acid copolymer nanodispersion with an average particle size of 120-180 nm and a solid content of 8%-12%.

[0067] In addition, a calcium alginate nanogel with a diameter of 80-150 nm is prepared by an internal gel method, a sodium alginate solution is mixed with a fine calcium carbonate solution under stirring, and the gel is uniformly nucleated by releasing calcium ions with gluconolactone, and the gel yield is concentrated by centrifugation to a solid content of 2%-4%.

[0068] The two dispersions are slowly mixed at a polymer solid mass ratio of 9:1-8:2, 10%-15% of triethyl citrate is used as a plasticizer based on the polymer solid, 3%-5% of polyethylene glycol 2000 is used as a pore-forming regulator based on the polymer solid, and the shear rate is controlled within a range that avoids the rupture of the nanogel, so that the calcium alginate nanogel is uniformly embedded in the interstices of the polylactic acid-glycolic acid copolymer nanoparticles as an ion-responsive micro-region to form a primary composite dispersion. The dispersion is removed through a 0.45 μm and 0.2 μm series connection to remove large particles and bubbles, so as to ensure that the atomization is stable and the film layer density is not affected by defects during the spraying process; the solid content is finally adjusted to 10%-12%, and the viscosity at 25°C is kept within the range of 80-150 mPa·s, which is beneficial to atomization and spreading.

[0069] The coating uses a bottom-spraying fluidized bed structure, the tablet with the composite retardation layer is put into a layer prepared with a Wurster cylinder, the inlet air temperature is controlled at 30-36°C, the outlet air temperature is stably controlled at 27-30°C, the relative humidity is not higher than 35%, the atomization pressure is 1.0-1.4 bar, and the spraying distance is the height of the material layer to obtain a stable particle circulation of rising and falling. The solid mass flux of the spraying liquid is converted to 1.5-2.5 g solid / min per kg of core tablet mass, so that the controllable degradation nano-porous membrane is deposited layer by layer and is preliminarily fused by water phase-polymer interphase compaction between nanoparticles. In order to prevent the composite retardation layer from being damp and causing adhesion, the fluidization air speed and the bed voidage need to be adjusted to a range that can drive the tablets without entrainment, and the spraying shape is preferably moderate atomization and slightly flat mist spraying, which is suitable for the coverage and drying rate.

[0070] Spraying to the weight gain of 3% ~ 6% of the core tablet quality can enter the film layer shaping stage, at this time stop spraying and continue to maintain 8 ~ 12 min at 35 DEG C drying air, so that the surface segment migration of nanoparticles occurs preliminary and not completely eliminate the nano gap. Subsequently, the tablet is transferred to 35 ~ 40 DEG C, relative humidity 50% ~ 60% static dynamic conditions for 8 ~ 16 h, during which the continuous phase of polylactic acid-glycolic acid copolymer is further densified under the action of plasticizer, while the calcium alginate nanogel and polyethylene glycol 2000 phase position inhibits complete coalescence, thereby retaining the average pore size of 50 ~ 200 nm, distribution dynamic coefficient not more than 30% of the nanometer pore network in dry dynamic. Dry dynamic pore structure can be confirmed by liquid permeation method or gas adsorption method, at the same time, the cross section of the film layer should be observed by freeze fracture layer description electron microscope, which should be the intercalation structure of the continuous polyester phase and discrete nanogel phase, and the thickness is generally controlled at 8 ~ 25 μm to balance mechanical strength and mass transfer control.

[0071] In order to compact the "ion concentration gradient induced dynamic restructuring of the composite barrier layer during hydration", it is necessary to preposition exchangeable divalent cation microzone in the near outer surface layer of the controllable degradation nanoporous membrane, while maintaining a slight gradient of nanogel content in the thickness direction of the membrane. After spraying, a small amount of atomized calcium chloride solution can be used to pulse press the bed layer for a short time, so that the crosslinking degree of the calcium alginate nanogel on the outer surface layer is slightly higher than that on the side close to the composite barrier layer, and the surface free ions are removed immediately after pressing by blowing dry air. When entering the intestinal fluid, the outside is first exposed to a higher concentration of sodium ions, and the calcium alginate nanogel is exchanged to Na+ to swell and locally enlarge the pore size; as the water advances from the outside to the inside, the side close to the composite barrier layer is simultaneously affected by the hydrogen ions and calcium ions released from the core, and the relative swelling and slow crosslinking relaxation are small, finally forming a pore size gradient in the thickness direction of the membrane for a period of time. 2

[0072] The pore size gradient and the ion strength, sodium sodium ratio of the intestinal fluid together determine the instantaneous flux of the controllable degradation nanoporous membrane, so that its drug release performance is coupled with the ion concentration of the intestinal fluid; when the external ion strength increases, the outer nanogel swells faster and promotes the increase of the connectivity of the nanopores, and vice versa. At the same time, the hydrolysis of polylactic acid-glycolic acid copolymer is slightly faster on the inside than on the outside in the low pH microenvironment, and the nanoscale erosion on the inside surface further superimposes the ion-induced pore dynamic shape, forming a reversible-irreversible coupled dynamic restructuring path, which ensures that similar overall mass transfer resistance is obtained under different individual intestinal conditions.

[0073] ​The entire film-forming and maturation process needs to be strictly controlled in terms of thermal history and moisture history to avoid nanopore collapse or excessive growth of connected pores: if the air outlet temperature exceeds 32℃ or the relative humidity is less than 40% for a long time, the nanoparticles may completely and mutually cause the pores to disappear, and vice versa, excessive humidity may cause the film surface to be sticky and the pore connection to be out of control, so it is appropriate to combine short-time drying and shaping with medium-humidity maturation.

[0074] The controllable degradability of the membrane layer is confirmed by in vitro degradation simulation. The film sample is placed in a pH 6.8 phosphate buffer at 37℃, and the mass loss and molecular weight decrease show a predictable first-order or autocatalytic characteristic. Under the target conditions, the molecular weight decreases by 20% to 40% within 24 hours, and the flux slowly increases over time without a sharp release. The ion coupling performance is constructed with a standard NaCl solution as the external solution and a low ionic strength buffer on the inside. The transmembrane flux of the fluorescent tracer molecule responds to the change in the external ionic strength of 0.05 to 0.15 mol·L-1, and the response curve should show a real and reversible flux-increasing effect. When the external solution is changed to an isotonic glucose solution, the flux-increasing effect is significantly weakened, proving that it is the ionic strength rather than the osmotic pressure alone. To ensure adhesion and synergy with the composite barrier layer, the tablet surface is lightly misted with an isotonic solution with a lower ionic strength before coating to activate the polar groups on the surface of the composite barrier layer. After film formation, the adhesion level is confirmed to be qualified and there is no delamination under cyclic soaking through grid and bending tests. All key intermediates and finished products need to establish release standards, including the weight gain range, thickness, dry average pore size and pore size distribution, wet flux response slope to ionic strength, degradation half-life interval of the controllable degradable nanoporous membrane, and the peel strength with the composite barrier layer. Only when all these indicators meet the pre-layer interval at the same time, can it enter the subsequent constant temperature and humidity compression and in vitro simulated intestinal fluid release simulation.

[0075] Through the above specific material system, dispersion preparation, spraying, shaping, maturation process window layering and quantifiable structure-function correlation measurement, the controllable degradable nanoporous membrane can be stably and repeatedly formed on the outer surface of the composite barrier layer, and its pore size distribution can be dynamically reconstructed under the induction of the ion concentration gradient during hydration, thereby ensuring reliable dynamic coupling with the ion concentration of the intestinal fluid.

[0076] Furthermore, the formation of the controllable degradable nanoporous membrane on the outer surface of the composite barrier layer includes:

[0077] The interface polarity and water content of the outer surface of the composite barrier layer are pre-layered to obtain a wet boundary and an anchoring site distribution for depositing the controllable degradable nanoporous membrane;

[0078] The biodegradable polymer nano-dispersion is fed separately from the ion-responsive nanogel dispersion and combined at the deposition end, and the initially wet film of the controllably degradable nanoporous membrane is deposited in situ on the outer surface of the composite barrier layer, and the wetting boundary and the distribution of anchoring sites are distributed in the volume fraction of the deposited phase and the film thickness direction;

[0079] The setting is completed under controlled drying and intermediate humidity curing conditions, so that the controllably degradable nanoporous membrane forms a nanopore network under dry conditions, and the nanopore network is used as the input of the ion exchange pre-pressing;

[0080] The outer surface of the controllably degradable nanoporous membrane is subjected to selective ion exchange pre-pressing, and a divalent cation micro-region gradient is established near the outer surface, so that the pore size distribution of the controllably degradable nanoporous membrane is dynamically reconstructed by the ion concentration gradient of the composite barrier layer during hydration, so that the drug release performance of the controllably degradable nanoporous membrane is dynamically coupled with the ion concentration of the intestinal fluid.

[0081] To form a controllably degradable nanoporous membrane on the outer surface of the composite barrier layer, the interfacial polarity and water content of the outer surface of the composite barrier layer are pre-layered in a pharmaceutical clean environment, so that the stable boundary is beneficial to the spreading of the mist droplets and does not trigger early hydration of the tablet core. The tablet can be placed in a constant temperature and humidity box for a short time to make the surface reach a uniform and reproducible water content level, and a polar diluent with isotonic, low ionic strength and easy evaporation is used for thin misting. After a small amount of wetting, the free liquid film is carried away by a gentle air flow, so that the surface energy is increased and the polar sites available for anchoring are exposed without forming a pore bridge. The contact angle and surface free energy (such as Owens-Wendt method) are used as release criteria, and the wetting boundary and the distribution of anchoring sites are used as process inputs for deposition.

[0082] After the above boundary conditions are established, the initial wet film of incomplete co-phase is deposited in situ by adopting the way of branch supply and co-phase at the deposition end. The biodegradable polymer nanodispersion is preferably prepared by solvent replacement or emulsification-solvent evaporation method, taking polylactic acid-glycolic acid copolymer as the main polymer, forming a water dispersion with an average particle size of about 100 nanometers, stable solid content, and moderate viscosity in the presence of a water-based stabilizer such as polyvinyl alcohol; the ion-responsive nanogel dispersion can be selected from a calcium alginate internal gel system, using sodium alginate and fine calcium carbonate as precursors, and using gluconolactone to release calcium ions to compact and nucleate uniformly, obtaining a dispersion with a particle size of about 100 nanometers and a narrow distribution. The two dispersions are independently metered, and large particles and bubbles are removed through online defoaming and double-stage membrane connection. At the nozzle end, the coaxial instantaneous co-phase and atomization of "biodegradable polymer nanodispersion-ion responsive nanogel dispersion-atomizing gas" are realized through a three-flow meeting structure and a low-residence static and dynamic mixer, so that the droplets maintain the dual-phase microscopic state during flight and fall onto the outer surface of the composite barrier layer. Preferably, a bottom-spraying fluidized bed (Wurster structure) is used as the deposition layer, the inlet air temperature and air volume are adjusted to support only the tablet stable up-down cycle, the atomization pressure and the solid content of the sprayed liquid are at a moderate level to form a "thin layer multiple superposition" deposition adjustment, ensuring that the surface is solidified immediately after each deposition without overall backflow. The online weighing and infrared temperature measurement control the film weight and tablet surface temperature, and the solid content superposition curve and tablet surface temperature rise together limit the co-phase degree and water history of the initial wet film, which is used as the structure input for subsequent shaping. In order to obtain a controllable nanophase volume fraction distribution along the film thickness direction, a slight gradient can be applied to the spray formula or the three-flow flow ratio, so that the area close to the outer surface contains a slightly higher proportion of ion-responsive nanogel microzone, and the side close to the composite barrier layer is mainly biodegradable polymer continuous phase, thereby providing spatial sites for the subsequent "divalent cation microzone gradient close to the outer surface".

[0083] After in-situ deposition, the controlled degradation nanoporous membrane is subjected to a controlled drying and intermediate humidity curing process to stabilize the nanopore network formed during the dry-down. A mild drying process is first applied to induce limited mobility of the biodegradable polymer segments and form a continuous phase, followed by an intermediate humidity curing process to maintain the volume fraction and microdomain integrity of the ion-responsive nanogel while avoiding complete coalescence of the nanopores leading to pore disappearance. Sudden changes in temperature and humidity should be avoided during the shaping process to suppress internal stress accumulation. The thickness of the membrane is measured at multiple points by non-contact thickness measurement or freeze-fracture layering to ensure that the target thickness is maintained at the order of tens of micrometers with a narrow variation. The average pore size of the dry-down nanopore network is confirmed to be in the sub-100 to several hundred nanometer range with a unimodal or narrow bimodal distribution by gas or liquid permeation measurement, nitrogen adsorption / mercury intrusion, etc. The adhesion strength of the controlled degradation nanoporous membrane to the composite barrier layer is verified by the grid or bending method to ensure that the membrane-membrane interface has no delamination tendency during subsequent hydration-drying cycles. After the shaping process is completed, the thickness, pore size distribution, and surface roughness of the "dry-down nanopore network" are archived as the structural input for ion exchange pre-pressing.

[0084] Under the conditions of the above-mentioned dry dynamic nanopore network and the ion concentration release characteristics of the composite barrier layer during hydration, the outer surface layer of the controllable degradation nanoporous membrane is selectively ion-exchanged pre-pressed to establish a divalent cation micro-zone gradient near the outer surface. The tablet can be exposed to a short pulse of atomized low-concentration calcium chloride or magnesium chloride solution, and the time and dose are determined according to the ion concentration release characteristics of the composite barrier layer during hydration, so that the divalent cations are preferentially combined with the outer surface layer of the nanogel micro-zone, and the inner layer is basically not affected; immediately after pressing, dry clean air is blown to remove free salt and fix the gradient. The existence of the gradient can be confirmed by energy spectrum line profiling or X-ray photoelectron spectroscopy depth profiling on the cross section, requiring that the outer layer divalent cation signal be higher than the inner layer and the mobilization be smooth without real peaks. After completing the pre-pressing, different ion concentrations of the in vitro environment are constructed with standard electrolyte solutions, the reversible response curve of the transmembrane flux of the tracer molecule or the probe drug under isothermal conditions is determined, and the comparison with the control test without pre-pressing is performed, and the dynamic coupling behavior of the increased flux under higher ion concentration of the intestinal fluid and the decreased flux under lower ion concentration of the intestinal fluid without burst release should be observed; at the same time, the degradation rate of the biodegradable polymer is measured by gel permeation chromatography or mass spectrometry, and it is confirmed that the flux increase caused by degradation is superimposed with ion-induced pore reconstruction rather than out of control. The above thickness, pore size distribution, divalent cation micro-zone gradient, and ion strength-flux response slope are used as release parameters, and are used as inputs into the process layer of "compacting and pressing the biodegradable porous polymer tablet matrix coated with the controllable degradation nanoporous membrane under constant temperature and humidity conditions", so as to stabilize the interface, balance the internal stress, and lock the ion concentration gradient-induced dynamic reconstruction ability of the controllable degradation nanoporous membrane during hydration, thereby making the drug release performance of the controllable degradation nanoporous membrane and the ion concentration of the intestinal fluid reliable dynamic coupling.

[0085] Step S105: compacting and pressing the biodegradable porous polymer tablet matrix coated with the controllable degradation nanoporous membrane under constant temperature and humidity conditions to stabilize the overall structure of the biodegradable porous polymer tablet matrix, and determine the adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system in the intestinal environment through in vitro simulated intestinal fluid release to ensure that the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system has delayed onset and stable release under different intestinal conditions of different individuals.

[0086] When the step S105 is applied, the tablet with the composite retardation layer formed and coated with the controllable degradation nanoporous membrane is taken as the object of compression, and mild compression and post-curing are carried out in a constant temperature and humidity environment, so that the film-film and film-core interfaces are fully adhered, the internal stress is balanced, and the micro-pore structure is solidified. Preferably, the compression is carried out in a flat plate compression device with closed-loop temperature and humidity control and precise pressure control, the environmental temperature is controlled at 25-28°C, the relative humidity is maintained at 45%±5%, the compression contact surface is covered with a silicon rubber buffer pad with a thickness of about 2-3 mm and a Shore A hardness of 50-60, so as to avoid local point salt load from causing shear cracking of the controllable degradation nanoporous membrane.

[0087] The tablet single layer is laid on the PTFE anti-sticking liner of the lower compression plate, the parallelism of the upper and lower compression plates is adjusted to within 0.02 mm, the salt load is slowly increased to 0.6-1.0 MPa and maintained for 15-25 s, so that the controllable degradation nanoporous membrane and the composite retardation layer below complete interface re-adhesion and pore wall micro-yield shaping under the condition that no plastic damage occurs; then the salt is unloaded at a rate of 0.1 MPa / s, the tablet is taken out and placed on a clean tray under the same temperature and humidity conditions for 2-4 h, so that the internal plasticizer and moisture of the membrane layer are redistributed, and the residual stress is naturally attenuated. After compression, the surface should be immediately observed under 10x magnification for no cracking, peeling and compression marks, the thickness change after compression should be not more than 3%, the single tablet mass difference should be not more than ±2%, and the adhesion should have no visible peeling by grid method.

[0088] To further stabilize the structure, the tablet is transferred into a constant temperature and humidity chamber at 30-35°C and a relative humidity of 50%-55% for 8-16 h, during which the tablet should not be stacked and should not be directly contacted with strong airflow, so as to prevent the nanopores from collapsing or the composite interface from cracking due to rapid water loss of the membrane layer; after the tablet surface temperature returns to 25-28°C, the tablet can be taken out of the chamber. The tablet is immediately stored in a sealed manner in an environment with a relative humidity of ≤30%, and the in-vitro evaluation is completed within 24 h, so as to avoid changes in the initial pore size distribution of the controllable degradation nanoporous membrane caused by changes in the environmental moisture.

[0089] In vitro simulated intestinal fluid release pressure to simulate the "adaptive drug release profile" recommended to use USP device IV flow cell or USP device II paddle method in parallel to obtain consistent data under the two boundary conditions of mass transfer limited and stirring limited. 37.0±0.5℃ as the water bath temperature, simulated intestinal fluid using pH 6.8 phosphate buffer, layered different ionic strength gradient to characterize the response of the controllable degradation of nanoporous membrane to the ion environment, for example, in 0.05 mol·L-1 and 0.15 mol·L-1 NaCl two conditions respectively, each condition at least 6 pieces, device IV flow rate layering 8 mL·min-1, device II speed layering 50 rpm, medium volume 900 mL. Because the active ingredient is calcium polycarbophil, direct photometric quantification is not sensitive, it is appropriate to use free calcium ions as a release surrogate indicator: according to the specified time points (such as 5, 10, 15, 30, 45, 60, 90, 120, 180, 240 min) online or offline, after removing the microparticles with 0.45 μm membrane, EDTA complex titration or inductively coupled plasma emission spectrometry was used to determine the Ca

[0090] EDTA complex titration or inductively coupled plasma emission spectrometry was used to determine the Ca 2 concentration in the solution, if necessary, the measured product was slightly acidified to stabilize the calcium ion and correct the matrix interference; at the same time, the medium pH and conductivity were recorded, and the local pH was positioned with a micro pH probe in the near field of the tablet surface to capture the microenvironment adjustment caused by the release of organic acid by the pH-responsive microcapsule. To avoid the interference of membrane fragments or microparticles in calcium quantification, low shear pre-deposition or disposable syringe gentle filtration can be performed before sampling, and blank control and recovery rate simulation are performed.

[0091] Convert the calcium release amount to the release fraction per unit time to obtain the time-release curve under two ionic strength conditions, and calculate three key parameters: the lag time Tlag (the time when the release fraction reaches 10%), the half-release time t50, and the approximate zero-order release rate k in the 60-120 min interval. The determination of the "adaptive" feature is mainly evidenced by the reversible increase of k under high ionic strength conditions relative to k under low ionic strength conditions, while Tlag and t50 remain within the pre-layer bioequivalence window (e.g. Tlag difference ≤ 15 min, t50 difference ≤ 25 min under two ionic strengths), indicating that the pores of the controllable degradation nanoporous membrane undergo dynamic reconstruction under the action of ionic concentration gradient, while the swelling-deswelling response of the composite barrier layer and the local acidity adjustment of the pH-responsive microcapsule jointly limit the burst release. To ensure methodological reliability, linear, precision, recovery, and detection limit should be established for titration or spectroscopy, the linear correlation coefficient should be ≥0.999, and the RSD of 6 parallel pieces should be ≤10%; the curve shape between Device IV and Device II should remain consistent, allowing for minor differences. If necessary, a third set of ionic strength (e.g. 0.10 mol·L-1) can be added to confirm the continuity of the response, or the stirring shear can be changed under the same ionic strength to confirm that the boundary layer disturbance does not change the adaptive trend.

[0092] After completing the release test, the tablets before and after compression are characterized to close the loop and confirm the structure-function relationship: observe the difference in pore openness of the controllable degradation nanoporous membrane after 2h hydration under different ionic strengths by freeze-fracture transmission electron microscopy; assess the molecular weight decrease of polylactic acid-glycolic acid copolymer by differential scanning calorimetry or gel permeation chromatography to confirm that the degradation rate within the target interval does not cause the overall rupture of the membrane; retest the adhesion by crosshatch and bend methods to exclude interface weakening caused by hydration-drying cycles. If Tlag is significantly shortened or the early release rate abnormally increases, first check whether the compression load and aging humidity exceed the window and cause excessive connectivity of nanopores; if k under high ionic strength does not increase as expected, recheck whether the content gradient of calcium alginate nanogel in the controllable degradation nanoporous membrane is established sufficiently, or recheck whether the outer layer of micro CaCl2 pulse compression is in place.

[0093] When compression, aging, and in vitro evaluation all meet the release standards, package in a ≤30% relative humidity environment, with a built-in pharmaceutical desiccant and humidity indicator card, and store at a temperature not higher than 25°C, and track the drift of the key parameters of the adaptive drug release curve in the stability study to ensure that the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system maintains consistent delayed onset and stable release throughout its life cycle.

[0094] Further, the biodegradable porous polymer tablet substrate coated with the controllably degradable nanoporous membrane is compacted and pressed under constant temperature and humidity conditions to stabilize the overall structure of the biodegradable porous polymer tablet substrate, and the adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea self-adaptive release system in the intestinal environment is determined by in vitro simulated intestinal fluid release compression, comprising:

[0095] The tablet surface contact interface of the biodegradable porous polymer tablet substrate coated with the controllably degradable nanoporous membrane is pre-layered under constant temperature and humidity conditions, so that the membrane-membrane and membrane-core contact areas, surface energy and pore connectivity are established as the starting boundary of compaction and pressing, and the interface fit represented by the starting boundary and the dry dynamic pore connectivity are used as the input of the compaction and pressing path;

[0096] The compaction and pressing path is subjected to segmented salt addition, pressure maintenance and controlled salt removal under constant temperature and humidity conditions, so that the controllably degradable nanoporous membrane and the composite barrier layer undergo reversible deformation and form stable fit with the biodegradable porous polymer tablet substrate, obtaining a compaction and pressing intermediate, and the interface fit, thickness uniformity and dry dynamic pore size distribution of the compaction and pressing intermediate are used as the input of isothermal standing and maturation;

[0097] The compaction and pressing intermediate is subjected to isothermal standing and humid maturation under constant temperature and humidity conditions, so that the residual stress is attenuated and the overall structure of the biodegradable porous polymer tablet substrate and the membrane-membrane interface strength are locked, obtaining a test specimen for in vitro simulated intestinal fluid release compression, and the adhesion, surface roughness and dry-wet cycle stability of the test specimen are used as the determination input of in vitro simulated intestinal fluid release compression;

[0098] The adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea self-adaptive release system in the intestinal environment is determined by in vitro simulated intestinal fluid release compression, and the key parameters such as the onset lag, half-release time and steady flux of the adaptive drug release curve are used as the process layer input of compaction and pressing under constant temperature and humidity conditions, which are used for closed-loop calibration of the aforementioned starting boundary, compaction and pressing path and isothermal standing and humid maturation conditions, so that the overall structure of the biodegradable porous polymer tablet substrate is stabilized, the pore size distribution of the controllably degradable nanoporous membrane is induced by the ion concentration gradient of the composite barrier layer during hydration to undergo dynamic reconstruction, and the drug release performance of the controllably degradable nanoporous membrane is coupled with the ion concentration of the intestinal fluid.

[0099] First, the film-membrane interface of the biodegradable porous polymer tablet matrix coated with the controllable degradation nanoporous membrane is pre-layered under constant temperature and humidity conditions, so that the contact area between the membrane-membrane and the membrane-core, the surface energy and the pore connectivity are pressed into a stable and measurable dynamic. The tablet can be placed in a constant temperature and humidity box for a short time to make the tablet surface reach a uniform water content level, and then a very thin misting liquid with isotonic, low ionic strength and easy evaporation is used to slightly wet the tablet surface to increase the surface energy, and then a gentle airflow is used to carry away the free liquid film to avoid forming a liquid bridge at the pore. After the pre-layering is completed, the contact angle and surface free energy are measured, the charge density and roughness of the near-surface layer of the tablet are used as release indicators, the interface represented by the initial boundary is used as the input of the compression path, and the dry pore connectivity is used as the input of the compression path. The medium layer with buffering and anti-sticking properties is laid on the surface of the compression table to make the pressure evenly transmitted to the controllable degradation nanoporous membrane in a surface contact manner without causing scratches.

[0100] Under constant temperature and humidity conditions, the compression path of segmented salt addition, pressure maintenance and controlled salt removal is used to make the controllable degradation nanoporous membrane and the composite barrier layer reversibly deform and form a stable fit with the biodegradable porous polymer tablet matrix. The salt addition stage establishes uniform contact at a slow rate and discharges the interface retained air and a small amount of water vapor, the pressure maintenance stage maintains constant surface pressure and constant tablet surface temperature, so that the continuous phase of the controllable degradation nanoporous membrane produces limited chain segment migration, micro-wrinkle flattening and geometric interlocking with the micro-concave-convex of the composite barrier layer, while avoiding plastic compression of the nanopore network. The whole process is measured by displacement-salt load curve, online infrared temperature measurement and acoustic emission signal line to measure the uniformity and structural integrity of the compression pressure; when the curve shows that it has entered the linear viscoelastic region and the residual rebound is within the pre-layering window, it can be determined that an effective compression cycle is completed. The compression intermediate is obtained immediately after compression, and its quality and microstructure are quickly confirmed: the thickness uniformity and tablet weight fluctuation are evaluated by non-contact thickness measurement and multi-point weighing, whether the membrane-membrane interface is actually cracked or delaminated is observed by freeze-fracture electron microscopy or micro-computed tomography, and the roughness is measured by a surface profilometer. The above results are used as the input for isothermal standing and aging.

[0101] The pressure-pressed intermediate is subjected to isothermal standing and intermediate humidity curing under constant temperature and humidity conditions to attenuate residual stress and lock the overall structure and film-film interface strength of the biodegradable porous polymer tablet matrix. The standing phase maintains the process temperature and humidity under low wind speed conditions, allowing the internal stress generated by pressure pressing to be slowly released through molecular relaxation and water redistribution; the curing phase maintains moderate relative humidity to promote secondary densification of the controllably degradable nanoporous film continuous phase and rearrangement of interfacial hydrogen bonds, van der Waals forces, and ion pairs, while inhibiting complete and excessive connectivity of nanopores. After curing, the film-film adhesion is tested by grid or bending methods to determine whether there is delamination, and the dry-wet cycle stability is tested within the predetermined layer window using dry-wet cycles, and a sample of the dry pore size distribution is tested to confirm that the nanopore network has not collapsed or abnormally enlarged. After meeting the above criteria, the test sample is obtained for in vitro simulated intestinal fluid release testing.

[0102] The adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system in the intestinal environment is determined by in vitro simulated intestinal fluid release testing. Preferably, the device IV flow cell and the device II paddle method are used in parallel to test the simulated intestinal fluid with different ionic strengths under isothermal conditions to compare the dynamic coupling behavior of the controllably degradable nanoporous film under different intestinal fluid ionic concentrations; online or offline methods are used in combination with appropriate quantitative methods to record the time-release fraction curve, calculate the three key parameters of onset lag, half-release time, and steady flux, and calculate the relative standard deviation of more than six parallel samples to evaluate batch consistency. At the same time, the medium pH, conductivity, and tablet near-field pH dynamics are measured, the swelling-deswelling of the composite barrier layer and the adjustment effect of the pH-responsive microcapsules on the local microenvironment are correlated to ensure that there is no burst release or early release. If the steady flux under high ionic strength medium is reversibly increased compared to that under low ionic strength medium, and the onset lag and half-release time are still within the bioequivalence window, it indicates that the pore size distribution of the controllably degradable nanoporous film is dynamically reconstructed by the ion concentration gradient during hydration of the composite barrier layer, and the drug release performance of the controllably degradable nanoporous film is dynamically coupled with the ionic concentration of the intestinal fluid.

[0103] For the compaction process closed loop, the key parameters of the onset lag of adaptive drug release profile, half-release time and steady flux are taken as the process layer input for compaction and curing under constant temperature and humidity conditions. The sequence of "initial boundary- compaction path- isothermal standing and humidity curing" is written back to the process database and calibrated for the next batch of temperature and humidity trajectory, salting- pressure- unloading program and curing conditions. When the deviation of the onset lag shortening or the steady flux abnormally rising, the surface energy of the initial boundary and the orifice connectivity are reviewed whether they deviate from the window; when the flux under high ionic strength is not significantly improved, whether the compaction path leads to local compaction of the nanopore network or insufficient adhesion of the membrane-membrane interface is reviewed. After the above closed loop calibration, while stabilizing the overall structure of the biodegradable porous polymer tablet matrix, the reversible response ability of the controllable degradable nanoporous membrane to the ionic environment and the dynamic reconstruction ability of the pore size distribution in the hydration process are continuously maintained, ensuring that the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system obtains predictable delayed onset and stable release under different individual intestinal conditions. Finally, the in vitro simulated intestinal fluid release simulation judgment record, compaction batch record and curing record will be archived together as the basis for subsequent release and process continuous improvement.

[0104] The preferred embodiments of the present application are disclosed above, but they are not intended to limit the present application. Any person skilled in the art can make possible changes and modifications without departing from the spirit and scope of the present application. Therefore, the protection scope of the present application should be subject to the scope defined by the claims of the present application.

Claims

1. A method for constructing an enhanced anti-diarrhea release system of polycarbophil calcium tablets, characterized in that: include: The calcium polycarbophil active ingredient is co-treated with a multivalent metal salt carrier containing ion exchange under controlled humidity conditions to obtain a pre-treated calcium polycarbophil active ingredient that forms a uniform microporous structure and forms a reversible coordination bond with the multivalent metal salt carrier portion; The pretreated calcium polycarbophil active ingredient is mixed with a biodegradable porous polymer matrix and pressed under low temperature conditions to obtain a biodegradable porous polymer tablet matrix containing the pretreated calcium polycarbophil active ingredient, wherein the biodegradable porous polymer tablet matrix contains evenly distributed pH-responsive microcapsules; A composite blocking layer is formed on the surface of the biodegradable porous polymer tablet matrix, wherein the composite blocking layer is formed by cross-linking a hydrophilic polymer and a hydrophobic polymer to form a three-dimensional network structure, and the expansion rate of the three-dimensional network structure undergoes a dynamic and reversible change under the influence of the pH of the local microenvironment; A controllably degradable nanoporous membrane is formed on the outer surface of the composite barrier layer, and the pore size distribution of the controllably degradable nanoporous membrane is dynamically reconstructed by the ion concentration gradient of the composite barrier layer during hydration, thereby dynamically coupling the drug release performance of the controllably degradable nanoporous membrane with the ion concentration of the intestinal fluid; The biodegradable porous polymer tablet matrix coated with the controllable degradable nanoporous membrane is compacted under constant temperature and humidity conditions to stabilize the overall structure of the biodegradable porous polymer tablet matrix, and the adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system in the intestinal environment is determined through an in vitro simulated intestinal fluid release experiment.

2. The method for constructing the enhanced anti-diarrhea release system of polycarbophil calcium tablets according to claim 1, characterized in that: The method comprises co-treating the active ingredient of calcium polycarbophil and a carrier containing an ion-exchangeable multivalent metal salt under controlled humidity conditions, comprising: Coordinated moisture and particle size adjustment and granulation of the active ingredient calcium polycarbophil to achieve the target surface area and moisture state for subsequent processing; Low shear dry mixing is performed based on a ratio relationship established between the ion exchange capacity of the ion-exchangeable multivalent metal salt carrier and the target surface area and moisture state, so as to form an initial coordination nucleation distribution on the surface of the polycarbophil calcium active ingredient for subsequent moisture conditioning induction; Under controlled humidity conditions, through a humidity control process combining gradual humidity increase with isotropic equilibrium, the multivalent cation coordination bridges starting from the initial coordination nucleation distribution grow along the surface and near-surface of the particles and are confined to a uniform microporous structure, while simultaneously generating a reversible coordination bond group with displaceability; A slow dehumidification shaping trajectory is set based on the characteristic pore size and connectivity of the uniform microporous structure, so that the density and spatial distribution of the reversible coordination bonds can achieve the comprehensive goal of maintaining diffusion channels and compressibility during subsequent mixing with a biodegradable porous polymer matrix and compression molding under low temperature conditions, and the pretreated polycarbophil calcium active ingredient is obtained.

3. The method for constructing the polycarbophil calcium tablet enhanced anti-diarrhea release system according to claim 1, characterized in that: The method comprises mixing the pretreated calcium polycarbophil active ingredient with a biodegradable porous polymer matrix and compressing the mixture under low temperature conditions to obtain a biodegradable porous polymer tablet matrix containing the pretreated calcium polycarbophil active ingredient, comprising: The biodegradable porous polymer matrix is ​​premixed with a pharmaceutical pore-forming excipient for forming interconnected pores and a pharmaceutical excipient for improving powder spreading and filling, so that the resulting material achieves a target state in terms of fluidity and surface energy that is conducive to carrying the pretreated polycarbophil calcium active ingredient; adding the pretreated calcium polycarbophil active ingredient to the premix and mixing under low shear conditions to obtain a biodegradable porous polymer matrix mixture containing the pretreated calcium polycarbophil active ingredient; The pH-responsive microcapsules are lightly mixed into a biodegradable porous polymer matrix mixture containing a pre-treated polycarbophil calcium active ingredient under conditions of electrostatic shielding and surface energy matching, so that the pH-responsive microcapsules are embedded in a uniformly distributed manner and form a protective interface compatible with the pre-treated polycarbophil calcium active ingredient in a dry state, thereby obtaining a pre-tabletting composition for compression molding under low-temperature conditions, and the embedding density and interlayer contact state of the pre-tabletting composition are used as parameter inputs for low-temperature molding; The pre-tabletting composition is compressed and formed under low temperature conditions, and degassing and forming are completed by sequentially controlling pre-compression and main compression to obtain a biodegradable porous polymer tablet matrix containing the pretreated polycarbophil calcium active ingredient, wherein the biodegradable porous polymer tablet matrix contains evenly distributed pH-responsive microcapsules.

4. The method for constructing the enhanced anti-diarrhea release system of calcium polycarbophil tablets according to claim 1, characterized in that: The method of forming a composite barrier layer on the surface of the biodegradable porous polymer tablet matrix comprises: Presetting the surface polarity and water content of the biodegradable porous polymer tablet matrix to obtain the surface energy and pore connectivity for depositing the composite barrier layer; Under the condition that the hydrophilic polymer and the hydrophobic polymer are supplied in separate channels and mixed immediately at the deposition end, an initial deposition layer of a three-dimensional network structure formed by cross-linking the hydrophilic polymer and the hydrophobic polymer is in situ deposited on the surface of the biodegradable porous polymer tablet matrix, and the cross-linking and deposition distribution is set according to the surface energy and pore connectivity, so that the structural parameters of the initial deposition layer serve as the shaping input; The shaping is completed during the controlled drying and post-curing process, so that the composite barrier layer is cross-linked by hydrophilic polymers and hydrophobic polymers to form a three-dimensional network structure, and the expansion rate of the three-dimensional network structure undergoes dynamic reversible changes under the influence of the pH of the local microenvironment, and the thickness, surface roughness and swelling-de-swelling characteristics of the composite barrier layer are used as process setting inputs for forming a controllable degradable nanoporous membrane on the outer surface of the composite barrier layer.

5. The method for constructing the enhanced anti-diarrhea release system of calcium polycarbophil tablets according to claim 1, characterized in that: The step of forming a controllably degradable nanoporous membrane on the outer surface of the composite blocking layer comprises: Presetting the interfacial polarity and water content of the outer surface of the composite barrier layer to obtain the wetting boundary and anchor point distribution for depositing the controllably degradable nanoporous membrane; The biodegradable polymer nanodispersion and the ion-responsive nanogel dispersion are supplied in separate channels and immediately merged at the deposition end, and the initial wet film of the controllable degradable nanoporous membrane that is not completely merged is in situ deposited on the outer surface of the composite barrier layer, and the volume fraction of the nanophase and the distribution in the film thickness direction are set according to the wetting boundary and the anchor point distribution; The shaping is completed under controlled drying and medium-humidity aging conditions, so that the controllably degradable nanoporous membrane forms a nanoporous network in a dry state, and the nanoporous network is used as an input for ion exchange pretreatment; Taking the ion concentration release characteristics of the nanopore network and the composite barrier layer during the hydration process as input, selective ion exchange pretreatment is performed on the outer layer of the controllable degradable nanoporous membrane to establish a divalent cation micro-region gradient near the outer surface, so that the pore size distribution of the controllable degradable nanoporous membrane is dynamically reconstructed induced by the ion concentration gradient of the composite barrier layer during the hydration process, thereby achieving dynamic coupling between the drug release performance of the controllable degradable nanoporous membrane and the ion concentration of the intestinal fluid.

6. The method for constructing the enhanced anti-diarrhea release system of calcium polycarbophil tablets according to claim 1, characterized in that: The biodegradable porous polymer tablet matrix coated with the controllable degradable nanoporous membrane is compacted under constant temperature and humidity conditions to stabilize the overall structure of the biodegradable porous polymer tablet matrix, and the adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system in the intestinal environment is determined by an in vitro simulated intestinal fluid release experiment, including: Under constant temperature and humidity conditions, the contact interface of the biodegradable porous polymer tablet matrix coated with a controllable degradable nanoporous membrane is preset so that the membrane-membrane and membrane-core contact areas, surface energy, and pore connectivity are established as the starting boundaries of the compaction process, and the interfacial adhesion and dry-state pore connectivity represented by the starting boundaries are used as inputs to the compaction path; A compaction path of segmented loading, pressure holding, and controlled unloading is implemented under constant temperature and humidity conditions, so that the controllably degradable nanoporous membrane and the composite barrier layer undergo reversible deformation and form a stable bond with the biodegradable porous polymer tablet matrix to obtain a compacted intermediate, and the interfacial adhesion, thickness uniformity, and dry pore size distribution of the compacted intermediate are used as inputs for isothermal standing and aging; The compacted intermediate is subjected to isothermal standing and medium-humidity aging under constant temperature and humidity conditions to attenuate residual stress and lock the overall structure and membrane-membrane interface strength of the biodegradable porous polymer tablet matrix, thereby obtaining a test sample for an in vitro simulated intestinal fluid release experiment, and using the adhesion, surface roughness, and dry-wet cycle stability of the test sample as judgment inputs for the in vitro simulated intestinal fluid release experiment; The adaptive drug release curve of the polycarbophil calcium tablet enhanced anti-diarrhea adaptive release system in the intestinal environment is determined through an in vitro simulated intestinal fluid release experiment, and the key parameters of the adaptive drug release curve, including the onset lag, half-release time and steady-state flux, are used as process setting inputs for compaction treatment under constant temperature and humidity conditions, for closed-loop calibration of the aforementioned starting boundary, compaction path, isothermal standing and medium-humidity maturation conditions, thereby stabilizing the overall structure of the biodegradable porous polymer tablet matrix while maintaining the pore size distribution of the controllable degradable nanoporous membrane, which is dynamically reconstructed by the ion concentration gradient of the composite barrier layer during the hydration process, and dynamically coupling the drug release performance of the controllable degradable nanoporous membrane with the intestinal fluid ion concentration.

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