A tenofovir prodrug tablet, preparation method and application

Abstract

This invention belongs to the field of pharmaceutical formulation technology and discloses a tenofovir prodrug tablet, its preparation method, and its application. The tablet is made from components comprising the following weight percentages: active pharmaceutical ingredient 2.0%-10.0%, non-hygroscopic backbone 60.0%-80.0%, mesoscopic buffer complex flow aid 2.0%-8.0%, in-situ water trap 3.0%-8.0%, and non-alkaline lubrication system 1.0%-3.0%. In this invention, the mesoscopic buffer complex flow aid is anchored around the active pharmaceutical ingredient to form a bound water buffer membrane with a uniform microenvironment pH. A solid-phase water activity gradient is formed between the in-situ water trap and this bound water buffer membrane. Driven by the chemical potential difference, free water in the system undergoes directional migration and is targeted and locked. This invention blocks the catalytic hydrolysis pathway of the active pharmaceutical ingredient under acidic and alkaline conditions, and simultaneously cuts off the hydrolysis mediator pathway caused by free water, thereby improving the chemical and physical stability of the tablet.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically a tenofovir prodrug tablet, its preparation method, and its application. Background Technology

[0002] Tenofovir prodrugs (such as tenofovir alafenamide and its salts) are important antiviral drugs currently used clinically to treat hepatitis B and HIV infection. The chemical structure of these drugs is highly sensitive to moisture and environmental pH, and they are prone to catalytic hydrolysis during formulation processing and long-term storage, producing corresponding degradation impurities, which leads to a decrease in the content of the active drug.

[0003] To address the stability issues of this type of drug, current conventional techniques typically employ highly barrier moisture-proof packaging materials to isolate it from external moisture. While this physical barrier method can prevent external moisture intrusion, it cannot handle bound water inherent in the excipients within the formulation or trace amounts of free water introduced during manufacturing. Under prolonged sealed storage, this residual moisture gradually migrates towards the drug molecules, creating a free water environment at the particle interface that can mediate hydrolysis, leading to drug degradation.

[0004] Meanwhile, traditional tablet formulations often require the addition of conventional lubricants such as magnesium stearate to ensure smooth tableting. These conventional lubricants are usually alkaline, and the alkaline metal ions they introduce can alter the local pH within the tablet, leading to an increase in the pH of the microenvironment surrounding the active pharmaceutical ingredient (API). This alkalization of the microenvironment can catalyze and accelerate the hydrolysis of the tenofovir prodrug. Current conventional formulations and processes struggle to simultaneously disrupt internal moisture migration pathways while maintaining a uniform and stable pH in the microenvironment. This results in inconsistent quality stability of the tablets during long-term storage, posing a risk of excessive impurities and ultimately affecting the drug's clinical efficacy. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a tenofovir prodrug tablet, its preparation method, and its application, solving the problem that the active pharmaceutical ingredient in tenofovir prodrug tablets is prone to hydrolysis and degradation and has poor long-term stability due to residual internal moisture and local microenvironment alkalization during processing and storage.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a tenofovir prodrug tablet, its preparation method, and its application.

[0007] In a first aspect, the present invention provides a tenofovir prodrug tablet, comprising components in the following weight percentages: The active pharmaceutical ingredient (API) has a molecular weight of 2.0%-10.0%. Non-hygroscopic skeleton: 60.0%-80.0%; Mesoscopic buffering compound flow aid 2.0%-8.0%; In-situ moisture traps: 3.0%-8.0%; Non-alkaline lubrication systems: 1.0%-3.0%; The mesoscopic buffer composite flow aid is anchored to the periphery of the main drug molecule through surface energy to form a bound water buffer membrane with a pH homogenized microenvironment. The in-situ water trap and the bound water buffer membrane form a solid-phase water activity gradient, which directionally locks in the free water in the system.

[0008] By employing the above technical solution, a multi-component system consisting of a specific ratio of active pharmaceutical ingredient, matrix, flow aid, water trap, and lubrication system is formed, creating a specific microenvironment and activity gradient in its spatial structure. This results in improved stability of tenofovir prodrug tablets. Specifically, this solution addresses the issue from the perspective of microenvironment control. The mesoscopic buffer composite flow aid in the system spontaneously coats the surface of the active pharmaceutical ingredient molecule using its own surface energy, forming a tightly structured buffer film. This film contains a multi-level dissociation equilibrium system. When trace amounts of water exist within the formulation, causing local ionization, this buffer system can dynamically absorb or release protons, maintaining a uniform and constant pH value in the microenvironment surrounding the active pharmaceutical ingredient. This blocks the catalytic hydrolysis pathway of the active pharmaceutical ingredient molecule under acidic or alkaline conditions. Furthermore, to handle free water within the system, this solution utilizes the water activity characteristics of the in-situ water trap to artificially construct an activity gradient from the periphery of the active pharmaceutical ingredient towards the water trap within a closed solid matrix. Driven by this chemical potential difference, internal free water molecules undergo directional migration, eventually entering the three-dimensional network of the polymer and being locked in place by hydrogen bonds. This spatially targeted water migration mechanism further disrupts the mediating conditions for the hydrolysis reaction.

[0009] Preferably, the active pharmaceutical ingredient is tenofovir alafenamide or a pharmaceutically acceptable salt of tenofovir alafenamide; the non-hygroscopic backbone is at least one of D-mannitol, isomaltitol, and low-moisture microcrystalline cellulose; the in-situ moisture trap is crospovidone or crospovidone sodium carboxymethyl cellulose; and the non-alkaline lubrication system is sodium fumarate stearate or hydrogenated castor oil.

[0010] By adopting the above technical solutions and selecting non-hygroscopic frameworks such as D-mannitol and isomaltitol, the pathway for environmental moisture to penetrate into the interior through the pores of the excipients is cut off at the source. Simultaneously, sodium fumarate stearate or hydrogenated castor oil is used as a non-alkaline lubrication system, eliminating the alkaline metal ions introduced by traditional lubricants such as magnesium stearate, thus preventing accelerated degradation of the active pharmaceutical ingredient due to microenvironment alkalization. Regarding the selection of moisture traps, polymers such as cross-linked polyvinylpyrrolidone, due to their cross-linked networks providing ample space for moisture absorption, can better complement the overall moisture-locking mechanism.

[0011] Preferably, the mesoscopic buffer composite flow aid is made from raw materials comprising the following components: a proton donor, a proton acceptor, and a high specific surface area carrier; wherein the molar ratio of the proton donor to the proton acceptor is 1:2-1:3; the weight of the high specific surface area carrier accounts for 20.0%-30.0% of the total weight of the mesoscopic buffer composite flow aid; the proton donor is anhydrous citric acid, anhydrous tartaric acid, or anhydrous malic acid; the proton acceptor is anhydrous trisodium citrate or anhydrous disodium hydrogen phosphate; and the high specific surface area carrier is hydrophilic fumed silica, wherein the BET specific surface area of ​​the hydrophilic fumed silica is 150-300 m² / g.

[0012] By employing the above technical solution, the molar ratio of proton donor to acceptor is controlled at 1:2 to 1:3, which precisely provides a buffer capacity that matches the stable pH range of the tenofovir prodrug. Furthermore, the numerous silanol groups on the surface of the hydrophilic fumed silica provide binding sites for the proton donor and acceptor, making it less prone to aggregation of the buffer salt and thus ensuring a sufficiently uniform distribution on the drug surface.

[0013] Preferably, the mesoscopic buffer composite flow aid is a supramolecular composite powder, wherein the crystal lattices of the proton donor and the proton acceptor are broken and cleaved into submicron or nanoscale fragments by mechanochemical action, and are anchored and dispersed on the three-dimensional network surface of the high specific surface area carrier through hydrogen bonding and electrostatic interaction.

[0014] By employing the above technical solution, cleavage of the crystal lattice not only increases the specific surface area of ​​the buffer material but also allows its size to better match the carrier. After these three components combine through hydrogen bonds and electrostatic interactions to form a supramolecular assembly, phase separation is less likely to occur even after subsequent mixing and tableting processes, thus ensuring the integrity and stability of the buffer film structure across different batches.

[0015] Secondly, the present invention provides a method for preparing tenofovir prodrug tablets, comprising the following steps: Prepare the corresponding raw materials according to the weight percentage of each component of the tablet; The in-situ moisture capture trap is subjected to deep dehydration and drying treatment, and then sealed for later use. The active pharmaceutical ingredient, non-hygroscopic framework, and mesoscopic buffer composite flow aid are introduced into a fluidized bed for gas-solid contact fluidization equilibrium to construct a water-bound buffer membrane. The fluidized powder, along with the in-situ moisture trap after dehydration and drying, was fed into a mixer for low-shear mixing to create a spatial water activity gradient. After being lubricated and mixed with a non-alkaline lubrication system, it is directly compressed into tablets and then sealed in packaging. The packaged tablets are stored naturally at room temperature, utilizing solid pores and thermodynamic gradients to achieve targeted migration and locking of moisture.

[0016] By employing the above-mentioned technical solutions and following specific procedures, orderly spatial construction can be achieved. Deep dehydration of the water traps is necessary to achieve an initial low water activity state. During the fluidized bed gas-solid equilibrium stage, the gliding agent and the drug molecules can fully contact and collide, forming a coating layer on the surface. Subsequent low-shear mixing operations can uniformly disperse the water traps into the matrix without damaging this buffer membrane. After direct tableting, the spatial positions of each component are solidified, and the three-dimensional solid pores inside the tablet become the physical channels for spontaneous water migration. The final natural storage after packaging is essentially a thermodynamic relaxation process that allows the activity gradient to truly function, thereby completing the redistribution of internal water.

[0017] Preferably, the mesoscopic buffer composite flow aid is prepared in advance by the following method: a proton donor, a proton acceptor, and a high specific surface area carrier are put into a high-shear mixing granulator with a water-cooled jacket, and the filling coefficient of the mixing container is controlled to be 25%-30% by volume; the cooling circulating water is turned on, and the material is continuously dry-state high-shear co-dispersed for 15-20 minutes at a main stirring paddle speed of 400-600 rpm and a chopping blade speed of 2500-3500 rpm, during which the maximum temperature of the material is controlled not to exceed 40°C.

[0018] By employing the above technical solution, the high shear mechanical energy generated by the synergistic action of the main stirring impeller and the shredder can effectively trigger a mechanochemical reaction to complete crystal cleavage and surface anchoring. During this process, the water-cooling jacket keeps the temperature below 40℃, preventing the organic acids from melting, bonding, or even degrading upon heating, thus maintaining the required microstructure of the powder.

[0019] Preferably, the specific process for deep dehydration and drying of the in-situ moisture trap is as follows: in a vacuum drying oven, the heating temperature is set to 55℃-65℃, the vacuum degree is controlled at -0.08MPa to -0.10MPa, and the drying is carried out continuously for 4-8 hours; and the drying weight loss of the in-situ moisture trap after treatment is controlled to be less than 0.5%, and the water activity is less than 0.10.

[0020] By adopting the above technical solution, the boiling point of water is correspondingly reduced under negative pressure and medium temperature, allowing water deep within the polymer to escape smoothly. This also avoids the skeletal aging or discoloration problems easily caused by traditional high-temperature treatment. Controlling the drying weight loss and water activity parameters within a specific range lays the foundation for building a potential energy difference for directional water migration in the later stages.

[0021] Preferably, the specific parameters for the gas-solid contact fluidization equilibrium are: the liquid spray system is shut off throughout the process, the inlet air temperature is set to 20℃-30℃, the inlet air dew point is controlled by the air conditioning unit, the relative humidity in the fluidized bed cavity is kept constant at 45%-50%, and the gas-solid contact fluidization equilibrium is continuously maintained for 15-30 minutes.

[0022] By adopting the above technical solution, the liquid spray is shut off throughout the operation, eliminating interference from the introduction of external liquid water. By maintaining a constant air intake with a specific relative humidity, the hydrophilic groups on the surface of the mesoscopic buffer composite flow aid undergo a certain degree of hydration. This moderate hydration increases its surface adhesion, allowing it to be more firmly adsorbed onto the drug surface.

[0023] Preferably, during the low-shear mixing process, the mixer speed is set to 10-20 rpm, the short-term low-shear mixing is performed for 8-12 minutes, and the relative humidity of the environment is controlled to not exceed 40%; the room temperature conditions for natural storage under the room temperature conditions are 15℃-30℃.

[0024] By employing the above technical solution, a relatively gentle rotation speed and a short mixing time are mainly considered to reduce the physical wear caused by mechanical shearing on the buffer film on the particle surface. Combined with the control of relative humidity, the penetration of external moisture during the mixing stage can be prevented. The storage environment of 15℃-30℃ after tableting provides suitable thermodynamic conditions for the spontaneous migration of moisture within the system.

[0025] Thirdly, this invention provides an application of a tenofovir prodrug tablet, employing the following technical solution: The use of a tenofovir prodrug tablet in the preparation of a drug for treating hepatitis B or HIV infection.

[0026] By employing the above-described technical solution, the tenofovir prodrug tablets prepared according to this invention exhibit good stability at both chemical and physical levels. During the drug's shelf life, the active pharmaceutical ingredient content remains relatively stable, and the levels of related degradation impurities are suppressed, which helps ensure the safety and efficacy of this type of antiviral drug in actual clinical applications.

[0027] This invention provides a tenofovir prodrug tablet, its preparation method, and its application. It possesses the following beneficial effects: 1. This invention utilizes a mesoscopic buffer composite flow aid to form a bound water buffer film on the surface of the active pharmaceutical ingredient, constructing a localized, multi-level dissociation equilibrium system around the active pharmaceutical ingredient. When trace amounts of water are present within the formulation and local ionization occurs, this buffer system can dynamically absorb or release protons, maintaining the pH value of the microenvironment around the active pharmaceutical ingredient in a uniform and stable state. This effectively blocks the catalytic hydrolysis pathway of tenofovir prodrug under acidic or alkaline conditions, thereby improving the chemical stability of the tablet.

[0028] 2. This invention introduces an in-situ moisture trap that has undergone deep dehydration pretreatment, constructing a water activity gradient pointing towards the moisture trap within a sealed solid matrix. Driven by this thermodynamic chemical potential difference, free water molecules within the formulation undergo directional migration, entering the three-dimensional network of the polymer and being locked by hydrogen bonds. This interrupts the water-mediated degradation pathway of the active pharmaceutical ingredient, solving the problem of residual moisture in excipients within the formulation, which is difficult to handle with conventional moisture-proof packaging.

[0029] 3. This invention employs a combination of a non-hygroscopic matrix and a non-alkaline lubrication system. The use of a non-hygroscopic matrix reduces the penetration of external moisture into the tablet through the pores of the excipients; simultaneously, the non-alkaline lubrication system eliminates alkaline metal ions introduced by traditional lubricants such as magnesium stearate, preventing accelerated degradation of the active pharmaceutical ingredient caused by localized microenvironment alkalization. The combination of these formulation components further ensures the quality stability of the tablets during long-term processing and storage. Attached Figure Description

[0030] Figure 1 Line graphs showing the pH value and buffering capacity test results of the solid microenvironment of each preparation example and control sample of this invention; Figure 2 The following describes the evolution trajectory of moisture state at each process stage in the embodiments and comparative examples of the present invention. Figure 1 ; Figure 3 The following describes the evolution trajectory of moisture state at each process stage in the embodiments and comparative examples of the present invention. Figure 2 ; Figure 4 The following are dynamic tracking curves of specific degradation impurities during accelerated stability studies for embodiments and some comparative examples of the present invention. Figure 1 ; Figure 5 The following are dynamic tracking curves of specific degradation impurities during accelerated stability studies for embodiments and some comparative examples of the present invention. Figure 2 ; Figure 6 This is a comprehensive evaluation of the macroscopic flowability and tableting mechanical defects of the total mixed powder in the embodiments and some comparative examples of the present invention. Figure 1 ; Figure 7 This is a comprehensive evaluation of the macroscopic flowability and tableting mechanical defects of the total mixed powder in the embodiments and some comparative examples of the present invention. Figure 2 . Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the preparation examples, comparative examples, and test examples. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications: Tenofovir alafenamide fumarate, chemically named L-alanine, N-((S)-(((1R)-2-(6-amino-9H-purine-9-yl)-1-methylethoxy)methyl)phenoxyphosphonyl)-,1-methylethyl ester,(2E)-2-butenedia salt (2:1), CAS number 1392275-56-7, is a commercially available pharmaceutical grade active pharmaceutical ingredient.

[0033] D-Mannitol, CAS No. 69-65-8, is a commercially available pharmaceutical-grade excipient.

[0034] Isomaltitol, CAS No. 64519-82-0, is a commercially available pharmaceutical-grade excipient.

[0035] Anhydrous citric acid, CAS number 77-92-9, is a commercially available pharmaceutical-grade excipient.

[0036] Anhydrous trisodium citrate, CAS number 68-04-2, is a commercially available pharmaceutical-grade excipient.

[0037] Hydrophilic fumed silica, CAS number 112945-52-5, Brunol-Emmett-Taylor (BET) specific surface area 200 m2 / g, commercially available pharmaceutical grade excipient.

[0038] Crosslinked polyvinylpyrrolidone, CAS number 25249-54-1, is a high molecular weight crosslinked homopolymer of 1-vinyl-2-pyrrolidone, exhibiting a three-dimensional network insoluble crosslinked structure, and is a commercially available pharmaceutical-grade excipient.

[0039] Sodium fumarate stearate, CAS number 4070-80-8, is a commercially available pharmaceutical-grade excipient.

[0040] Hydrogenated castor oil, CAS number 8001-78-3, is a commercially available pharmaceutical-grade excipient.

[0041] Preparation Example 1: This preparation example provides a method for preparing a mesoscopic buffer composite flow aid, including the following steps: Anhydrous citric acid and anhydrous trisodium citrate were weighed in a molar ratio of 1:2, along with hydrophilic fumed silica, wherein the hydrophilic fumed silica accounted for 20.0% of the total weight of the three. The weighed anhydrous citric acid, anhydrous trisodium citrate, and hydrophilic fumed silica were then added to a high-shear mixing granulator equipped with a water-cooled jacket, controlling the filling coefficient of the mixing container to be 25% (volume ratio). The water-cooling jacket was turned on, and cooling circulating water at a temperature of 10°C was introduced. The equipment was started for dry high-shear co-dispersion, with the main agitator speed set to 400 rpm and the shredder speed set to 2500 rpm, running continuously for 15 minutes. During this period, the material bed temperature was monitored, controlling the maximum material temperature to not exceed 35°C. After the operation was completed, the material was discharged, yielding a mesoscopic buffer composite flow aid.

[0042] Preparation Example 2: This preparation example provides a method for preparing a mesoscopic buffer composite flow aid, including the following steps: Anhydrous citric acid and anhydrous trisodium citrate were weighed at a molar ratio of 1:2.5, along with hydrophilic fumed silica, with the hydrophilic fumed silica accounting for 25.0% of the total weight of the three. The weighed anhydrous citric acid, anhydrous trisodium citrate, and hydrophilic fumed silica were then added to a high-shear mixing granulator equipped with a water-cooled jacket, controlling the filling coefficient of the mixing container to be 28% (volume ratio). The water-cooling jacket was turned on, and cooling circulating water at a temperature of 12°C was introduced. The equipment was started for dry high-shear co-dispersion, with the main agitator speed set to 500 rpm and the shredder speed set to 3000 rpm, running continuously for 18 minutes. During this period, the material bed temperature was monitored, controlling the maximum material temperature to not exceed 35°C. After the operation was completed, the material was discharged, yielding a mesoscopic buffer composite flow aid.

[0043] Preparation Example 3: This preparation example provides a method for preparing a mesoscopic buffer composite flow aid, including the following steps: Anhydrous citric acid and anhydrous trisodium citrate were weighed in a molar ratio of 1:3, along with hydrophilic fumed silica, wherein the hydrophilic fumed silica accounted for 30.0% of the total weight of the three. The weighed anhydrous citric acid, anhydrous trisodium citrate, and hydrophilic fumed silica were then added to a high-shear mixing granulator equipped with a water-cooled jacket, controlling the filling coefficient of the mixing container to be 30% (volume ratio). The water-cooling jacket was turned on, and cooling circulating water at a temperature of 15°C was introduced. The equipment was started for dry high-shear co-dispersion, with the main agitator speed set to 600 rpm and the shredder speed set to 3500 rpm, running continuously for 20 minutes. During this period, the material bed temperature was monitored, controlling the maximum material temperature to not exceed 40°C. After the operation was completed, the material was discharged, yielding a mesoscopic buffer composite flow aid.

[0044] Example 1:

[0045] This embodiment provides a method for preparing tenofovir prodrug tablets, including the following steps: The following components were weighed as a percentage of the total weight of the formulation: 2.0% tenofovir alafenamide fumarate, 80.0% D-mannitol, 8.0% the mesoscopic buffer complex flow aid prepared in Example 1, 8.0% crospovidone, and 2.0% sodium stearate fumarate.

[0046] Deep dehydration pretreatment of polymeric disintegrant: The prescribed amount of cross-linked povidone was spread evenly on a stainless steel tray and placed in a vacuum drying oven. The heating temperature was set to 55℃, the vacuum degree was controlled at -0.08MPa, and drying was carried out continuously for 4 hours. Sampling and analysis showed a drying loss of 0.48% and a water activity of 0.09. After discharge, the material was immediately sealed in a moisture-proof bag with built-in silica gel desiccant for later use.

[0047] Fluidized bed gas-solid two-phase humidity conditioning and equilibrium: The prescribed amounts of tenofovir alafenamide fumarate, D-mannitol, and the mesoscopic buffer composite flow aid obtained in Preparation Example 1 were added to the material tank of the fluidized bed, with the liquid spray system shut off throughout the process. The fluidizing fan was turned on, and the inlet air temperature was set to 20°C. The inlet air dew point was precisely controlled by the air conditioning unit to maintain a constant relative humidity of 45% within the fluidized bed cavity. The airflow was adjusted to achieve a uniform boiling fluidized state in the powder bed. Continuous gas-solid contact fluidization equilibrium was maintained for 15 minutes, after which the material was discharged into a closed hopper.

[0048] Low-shear short-time total mixing to build space activity gradient: Under the condition that the relative humidity of the environment does not exceed 40%, the fluidized equilibrium powder, together with the dehydrated pretreated crosslinked polyvinyl chloride, is put into a fully enclosed square cone hopper mixer, the mixer speed is set to 10 rpm, and short-time low-shear mixing is performed for 8 minutes.

[0049] Lubrication and direct compression molding: Add the prescribed amount of sodium stearate fumarate, which has passed through a 60-mesh sieve, to the square cone hopper mixer, and continue lubrication mixing at 10 rpm for 3 minutes. Transfer the total powder mixture to a rotary tablet press and perform direct tableting under ambient relative humidity not exceeding 40%. After tableting, use aluminum-aluminum cold-formed blister packs for high-barrier, airtight packaging.

[0050] In-situ moisture redistribution within the matrix: After packaging, the tablets are stored naturally at room temperature of 15°C. The solid three-dimensional pores after tableting and the preset thermodynamic gradient spontaneously complete the targeted migration and locking of moisture.

[0051] In the prepared tenofovir prodrug tablets, a mesoscopic buffer complex gliding agent forms a structurally continuous bound water buffer film on the surface of tenofovir alafenamide fumarate particles, and a water activity gradient decreasing from the active pharmaceutical ingredient to cross-linked povidone exists within the tablet. Stability studies showed that the generation of active pharmaceutical ingredient degradation impurities was inhibited when the tablets were stored under sealed conditions.

[0052] The tenofovir prodrug tablets prepared in this embodiment can be used to prepare drugs for treating hepatitis B or HIV infection.

[0053] Example 2:

[0054] This embodiment provides a method for preparing tenofovir prodrug tablets, including the following steps: The following components were weighed as a percentage of the total weight of the formulation: 5.0% tenofovir alafenamide fumarate, 80.0% D-mannitol, 5.0% the mesoscopic buffer complex flow aid prepared in Preparation Example 2, 8.0% crospovidone, and 2.0% sodium stearate fumarate.

[0055] Deep dehydration pretreatment of polymeric disintegrant: The prescribed amount of cross-linked povidone was spread evenly on a stainless steel tray and placed in a vacuum drying oven. The heating temperature was set to 60℃, the vacuum degree was controlled at -0.09MPa, and drying was carried out continuously for 6 hours. Sampling and analysis showed a drying loss of 0.15% and a water activity of 0.05. After discharge, the material was immediately sealed in a moisture-proof bag with built-in silica gel desiccant for later use.

[0056] Fluidized bed gas-solid two-phase humidity conditioning and equilibrium: The prescribed amounts of tenofovir alafenamide fumarate, D-mannitol, and the mesoscopic buffer composite flow aid obtained in Preparation Example 2 were added to the material tank of the fluidized bed, with the liquid spray system completely shut off. The fluidizing fan was turned on, and the inlet air temperature was set to 25°C. The inlet air dew point was precisely controlled by the air conditioning unit to maintain a constant relative humidity of 48% within the fluidized bed cavity. The airflow was adjusted to achieve a uniform boiling fluidized state in the powder bed. Continuous gas-solid contact fluidization equilibrium was maintained for 20 minutes, after which the material was discharged into a closed hopper.

[0057] Low-shear short-time total mixing to build space activity gradient: Under the condition that the relative humidity of the environment does not exceed 40%, the fluidized equilibrium powder, together with the dehydrated pretreated crosslinked polyvinyl chloride, is put into a fully enclosed square cone hopper mixer, the mixer speed is set to 15 rpm, and short-time low-shear mixing is carried out for 10 minutes.

[0058] Lubrication and direct compression molding: Add the prescribed amount of sodium stearate fumarate, which has passed through a 60-mesh sieve, to the square cone hopper mixer, and continue lubrication mixing at 15 rpm for 4 minutes. Transfer the total powder mixture to a rotary tablet press and perform direct tableting under ambient relative humidity not exceeding 40%. After tableting, use high-barrier, airtight packaging in high-density polyethylene bottles with built-in silica gel desiccant.

[0059] In-situ moisture redistribution within the matrix: After packaging, the tablets are stored naturally at room temperature of 25°C. The solid three-dimensional pores after tableting and the preset thermodynamic gradient spontaneously complete the targeted migration and locking of moisture.

[0060] The prepared tenofovir prodrug tablets exhibit a physical structure consisting of a dense matrix supported by a non-hygroscopic framework, in which the active drug molecule is tightly coated by a water-bound buffer membrane, the microenvironment pH is maintained within a stable range, and free water is directionally locked within the cross-linked network of cross-linked povidone. These tablets demonstrate good chemical stability during long-term storage.

[0061] The tenofovir prodrug tablets prepared in this embodiment can be used to prepare drugs for treating hepatitis B or HIV infection.

[0062] Example 3:

[0063] This embodiment provides a method for preparing tenofovir prodrug tablets, including the following steps: The following components were weighed as a percentage of the total weight of the formulation: 10.0% tenofovir alafenamide fumarate, 75.0% D-mannitol, 8.0% the mesoscopic buffer complex flow aid prepared in Preparation Example 3, 5.0% crospovidone, and 2.0% sodium stearate fumarate.

[0064] Deep dehydration pretreatment of polymeric disintegrant: The prescribed amount of cross-linked povidone was spread evenly on a stainless steel tray and placed in a vacuum drying oven. The heating temperature was set to 65℃, the vacuum degree was controlled at -0.10MPa, and drying was carried out continuously for 8 hours. Sampling and analysis showed a drying loss of 0.32% and a water activity of 0.08. After discharge, the material was immediately sealed in a moisture-proof bag with built-in silica gel desiccant for later use.

[0065] Fluidized bed gas-solid two-phase humidity conditioning and equilibrium: The prescribed amounts of tenofovir alafenamide fumarate, D-mannitol, and the mesoscopic buffer composite flow aid obtained in Preparation Example 3 were added to the material tank of the fluidized bed, with the liquid spray system shut off throughout the process. The fluidizing fan was turned on, and the inlet air temperature was set to 30°C. The inlet air dew point was precisely controlled by the air conditioning unit to maintain a constant relative humidity of 50% within the fluidized bed chamber. The airflow was adjusted to achieve a uniform boiling fluidized state in the powder bed, and continuous gas-solid contact fluidization equilibrium was maintained for 30 minutes. After completion, the material was discharged into a closed hopper.

[0066] Low-shear short-time total mixing to build space activity gradient: Under the condition that the relative humidity of the environment does not exceed 40%, the fluidized equilibrium powder, together with the dehydrated pretreated crosslinked polyvinyl chloride, is put into a fully enclosed square cone hopper mixer, the mixer speed is set to 20 rpm, and short-time low-shear mixing is performed for 12 minutes.

[0067] Lubrication and direct compression molding: Add the prescribed amount of sodium stearate fumarate, which has passed through a 60-mesh sieve, to the square cone hopper mixer, and continue lubricating and mixing at 20 rpm for 5 minutes. Transfer the total powder mixture to a rotary tablet press and perform direct tableting under ambient relative humidity not exceeding 40%. After tableting, use aluminum-aluminum cold-formed blister packs for high-barrier, airtight packaging.

[0068] In-situ moisture redistribution within the matrix: After packaging, the tablets are stored naturally at room temperature of 30°C. The solid three-dimensional pores after tableting and the preset thermodynamic gradient spontaneously complete the targeted migration and locking of moisture.

[0069] The prepared tenofovir prodrug tablets exhibit uniform distribution of internal components. The supramolecular composite powder coating on the surface of the active pharmaceutical ingredient effectively regulates the local pH and reduces the probability of active pharmaceutical ingredient degradation through competitive absorption of free water via an in-situ water trap. The tablets demonstrate reliable stability at clinical application doses.

[0070] The tenofovir prodrug tablets prepared in this embodiment can be used to prepare drugs for treating hepatitis B or HIV infection.

[0071] Example 4:

[0072] This embodiment provides a method for preparing tenofovir prodrug tablets, including the following steps: The following components were weighed as a percentage of the total weight of the preparation: 5.0% tenofovir alafenamide fumarate, 80.0% isomaltitol, 5.0% the mesoscopic buffer complex flow aid prepared in Preparation Example 2, 8.0% crospovidone, and 2.0% hydrogenated castor oil.

[0073] Deep dehydration pretreatment of polymeric disintegrant: The prescribed amount of cross-linked povidone was spread evenly on a stainless steel tray and placed in a vacuum drying oven. The heating temperature was set to 60℃, the vacuum degree was controlled at -0.09MPa, and drying was carried out continuously for 6 hours. Sampling and analysis showed a drying loss of 0.15% and a water activity of 0.05. After discharge, the material was immediately sealed in a moisture-proof bag with built-in silica gel desiccant for later use.

[0074] Fluidized bed gas-solid two-phase humidity conditioning and equilibrium: The prescribed amounts of tenofovir alafenamide fumarate, isomaltitol, and the mesoscopic buffer composite flow aid obtained in Preparation Example 2 were added to the material tank of the fluidized bed, with the liquid spray system shut off throughout the process. The fluidizing fan was turned on, and the inlet air temperature was set to 25°C. The inlet air dew point was precisely controlled by the air conditioning unit to maintain a constant relative humidity of 48% within the fluidized bed cavity. The airflow was adjusted to achieve a uniform boiling fluidized state in the powder bed. Continuous gas-solid contact fluidization equilibrium was maintained for 20 minutes, after which the material was discharged into a closed hopper.

[0075] Low-shear short-time total mixing to build space activity gradient: Under the condition that the relative humidity of the environment does not exceed 40%, the fluidized equilibrium powder, together with the dehydrated pretreated crosslinked polyvinyl chloride, is put into a fully enclosed square cone hopper mixer, the mixer speed is set to 15 rpm, and short-time low-shear mixing is carried out for 10 minutes.

[0076] Lubrication and direct compression molding: Add the prescribed amount of hydrogenated castor oil (passed through a 60-mesh sieve) to the cone hopper mixer and continue lubrication mixing at 15 rpm for 4 minutes. Transfer the total powder mixture to a rotary tablet press and perform direct tableting under ambient relative humidity not exceeding 40%. After tableting, package the tablets in high-barrier, airtight high-density polyethylene bottles with built-in silica gel desiccant.

[0077] In-situ moisture redistribution within the matrix: After packaging, the tablets are stored naturally at room temperature of 25°C. The solid three-dimensional pores after tableting and the preset thermodynamic gradient spontaneously complete the targeted migration and locking of moisture.

[0078] The resulting tenofovir prodrug tablets exhibit excellent moisture and alkalization resistance due to the use of isomaltitol as a non-hygroscopic matrix and hydrogenated castor oil as a non-alkaline lubricating system, combined with the buffering protection of the active pharmaceutical ingredient surface and a moisture-targeting migration mechanism. The tablet's appearance and active ingredient content remain stable throughout its shelf life.

[0079] The tenofovir prodrug tablets prepared in this embodiment can be used to prepare drugs for treating hepatitis B or HIV infection.

[0080] Comparative Example 1: Compared to Example 2, the differences are: the separate preparation of the mesoscopic buffer complex glidant, the deep dehydration pretreatment of the polymeric disintegrant, and the fluidized bed gas-solid two-phase humidity conditioning equilibrium step are not performed. All raw and excipient materials (including undehydrated cross-linked povidone, anhydrous citric acid without high shear, anhydrous trisodium citrate, fumed silica, active pharmaceutical ingredient, and other excipients) in the prescribed amounts are directly mixed in a conventional mixer and then tableted; all other aspects are the same.

[0081] Comparative Example 2: Compared with Example 2, the difference is that in the preparation process of the mesoscopic buffer composite flow aid, a conventional low-speed trough mixer is used instead of a high-shear mixing granulator for physical mixing, and no high-shear mechanical energy is applied; otherwise, they are the same.

[0082] Comparative Example 3: Compared with Example 2, the difference is that the fluidized bed gas-solid two-phase humidity conditioning and equilibrium step is omitted. The composite flow aid obtained in Example 2 is directly mixed with the main drug and the non-hygroscopic skeleton in a dry state without undergoing exposure equilibrium at a specific relative humidity (RH48%). All other aspects are the same.

[0083] Comparative Example 4: Compared with Example 2, the difference is that the timing of material addition was changed. Deeply dehydrated cross-linked polyvinyl ketone was added to the fluidized bed along with other materials during the fluidized bed gas-solid two-phase humidity conditioning and equilibrium stage, so that it could absorb environmental moisture in advance. All other aspects are the same.

[0084] Comparative Example 5: Compared with Example 2, the difference is that in the preparation steps of the mesoscopic buffer composite flow aid (i.e., corresponding to Preparation Example 2), the high specific surface area hydrophilic fumed silica is replaced by an equal amount of conventional microcrystalline cellulose for high-shear mixing, and the rest are the same.

[0085] Test Example 1: The mesoscopic buffer composite flow aids obtained in Examples 1 to 3 of this invention were selected as experimental subjects, and the physically mixed powder prepared by the low-speed trough mixing process in Comparative Example 2 was extracted as a control sample.

[0086] Accurately weigh 2.0 g of each of the above sample powders and place them in a 50 mL polypropylene centrifuge tube. Add 20.0 mL of degassed ultrapure water. Seal the centrifuge tube and place it in a 25°C constant temperature water bath shaker. Set the shaking frequency to 150 rpm and process continuously for 10 minutes to establish the distribution equilibrium between the free components on the powder surface and the aqueous phase, thus preparing a suspension for simulating microenvironment extraction.

[0087] A high-precision pH meter calibrated with multi-point standard buffer solution was selected. The composite glass electrode was inserted into the middle of the suspension. The initial pH value was recorded after the potential reading drift rate was lower than 0.1 mV / min. This process was performed independently and in parallel three times for each group of samples, and the arithmetic mean was taken.

[0088] Add 1.0 mL of 0.01 mol / L hydrochloric acid standard solution to each group of suspensions in equilibrium, and stir at a constant speed for 3 minutes on a magnetic stirrer. Record the pH value of the system when it reaches a steady state again. Then, take another initial suspension sample from the same batch, add 1.0 mL of 0.01 mol / L sodium hydroxide standard solution, and repeat the above stirring and measurement operations. Calculate the pH range of each sample under acid-base disturbance.

[0089] Table 1: Results of microenvironmental pH and buffering capacity determination for various mesoscopic buffering compound flow aids and control samples Sample source Initial pH measurement pH value after adding acid pH value after adding alkali pH range of the system (ΔpH) Preparation Example 1 4.53 4.41 4.68 0.27 Preparation Example 2 4.78 4.65 4.91 0.26 Preparation Example 3 4.95 4.82 5.11 0.29 control sample 3.14 2.06 5.82 3.76 Reference Appendix Figure 1 The curve distributions of Preparation Example 1, Preparation Example 2 and Preparation Example 3 in the figure reflect the pH response of the composite powder after high shear treatment under acid-base disturbance, while the control sample curve shows the pH drift of conventional physical mixed powder without mechanical and chemical action under the same test conditions.

[0090] According to the data in Table 1, the initial pH values ​​of the extracts in Preparation Examples 1 to 3 were stable at 4.53, 4.78, and 4.95, respectively, all falling strictly within the 4.5 to 5.0 microenvironment range where tenofovir alafenamide fumarate prodrug is most stable. In contrast, the control sample prepared by the conventional tank mixing process had an initial pH value of only 3.14, exhibiting strong local acidity. This deviation stems from the unconstrained rapid dissociation of large anhydrous citric acid crystals in the aqueous phase of the physical mixing system, directly exposing high concentrations of hydrogen ions to the free phase. Conventional operations are insufficient to eliminate such drastic concentration changes at the mesoscale. After perturbation with acid and alkali reagents, the preparation examples exhibited strong resilience, with the pH range compressed to a narrow range of 0.26 to 0.29. In contrast, the control sample showed a dramatic pH fluctuation spanning as high as 3.76 after the addition of trace amounts of acid and alkali, indicating that its internal environment was not only destructively acidic but also completely lacked self-sustaining buffering capacity. The chemical insensitivity exhibited by the prepared powder verifies the effective disruption of the crystal lattice by high shear mechanical energy. When anhydrous citric acid and sodium citrate are cleaved into nanoscale fragments, the high specific surface area of ​​the hydrophilic fumed silica, with its dense network of silanol groups, firmly anchors these buffer pairs through electrostatic and hydrogen bonding interactions. This spatial assembly restricts the disordered release of proton donors and acceptors. When exogenous water attempts to invade as a degradation medium, the buffer pairs attached to the silica framework can rapidly capture protons or hydroxyl groups at the interface, spontaneously forming a bound water film with a high-capacity buffer barrier around the drug molecules. The macroscopic physicochemical differences reflected in the experiment demonstrate that the homogenization of the solid-phase microenvironment does not simply depend on mathematical calculations of formulation ratios. Forcibly constructing a supramolecular anchoring structure by altering the energy input method during powder forming is a necessary technical path to prevent the breakage of phosphoramide bonds due to localized extremely acidic environments.

[0091] Test Example 2: The experiment selected materials generated at three key process nodes in the preparation process of Example 2 as the main research objects: the discharge at the end of fluidized bed gas-solid two-phase humidity equilibrium (Stage I), the discharge at the end of low-shear mixing in a square cone hopper (Stage II), and the tablets after being packaged in high-density polyethylene bottles and stored at 25°C for 30 days (Stage III). Materials and tablets from the corresponding process nodes of Comparative Example 4 were extracted simultaneously as controls.

[0092] The experiment was conducted in a sterile, isolated operating room where the relative humidity was strictly controlled to be below 30%. After each stage of material acquisition, it was quickly transferred to a sealed sampling tube. Molded tablets were rapidly ground in an agate mortar until they were powdery enough to pass through a 60-mesh sieve.

[0093] Absolute water content was determined using a Karl Fischer volumetric titrator. Approximately 1.0 g of the powder sample was accurately weighed and rapidly injected into a titration cell containing anhydrous methanol working solution for water extraction and titration until the instrument's potential indication reached the endpoint drift threshold. The volume of titrating reagent consumed was recorded to calculate the total water mass fraction. This procedure was repeated three times independently for each group of samples, and the arithmetic mean was taken.

[0094] The water activity inside the powder was determined using a cold mirror dew point water activity meter. Approximately 3.0 g of powder sample was weighed and spread evenly over the bottom of a dedicated PTFE sample dish, which was then placed inside and sealed within the instrument's measuring chamber. The ambient temperature was set to a constant 25°C, and the process was allowed until gas-liquid thermodynamic equilibrium was reached and the relative humidity inside the chamber ceased to change. The equilibrium water activity value displayed by the instrument was recorded. Each sample was measured in triplicate to obtain the average value.

[0095] Table 2: Dynamic tracking data of total moisture and water activity of materials at each process stage in the examples and comparative examples Group Process Stage Total moisture / LOD (%) water activity Example 2 Stage I: Fluidized bed discharge 1.31 0.468 Example 2 Phase II: Total Mixed Output 1.34 0.231 Example 2 Phase III: Tableting and storage for 30 days 1.32 0.114 Comparative Example 4 Stage I: Fluidized bed discharge 1.28 0.203 Comparative Example 4 Phase II: Total Mixed Output 1.35 0.224 Comparative Example 4 Phase III: Tableting and storage for 30 days 1.31 0.267 Reference Appendix Figure 2 and attached Figure 3 ,in Figure 2 The macroscopic fluctuations in the total moisture content of the system during the process sequence were recorded. Figure 3 The corresponding thermodynamic water activity evolution is illustrated. Example 2 in the figure reflects the dynamic process of converting free water to bound water and deep anchored water under specific process timings. Comparative Example 4 reveals the blocking effect of disrupting the timing of adding cross-linked polyvinyl ketone on the establishment of the water chemical potential of the entire system.

[0096] According to the data in Table 2, the total absolute water content of Example 2 and Comparative Example 4 remained within a narrow fluctuation range of 1.28% to 1.35% in all three process stages. This phenomenon excludes the interference of excessive external moisture absorption during processing, but it also reveals that simply measuring the total water content cannot reflect the true changes in the internal microenvironment of the solid-phase formulation. In the long-term stability studies of routine formulation development, the hydrolysis of drug molecules is often triggered by a small amount of free water with high migration capacity. In Example 2, the water activity after fluidized bed conditioning and discharge reached as high as 0.468. The ambient gas phase moisture underwent capillary condensation on the surface of the mesoscopic composite flow aid, forming a layer of bound water film containing dissolved buffer salts. When this batch of material carrying the surface water film encountered cross-linked polyvinylpyrrolidone in a deeply dehydrated state during the final mixing process, a strong thermodynamic potential difference was generated within the system. The water activity plummeted to 0.231 in a short period of time, and further bottomed out to a low level of 0.114 after 30 days of molding and storage in packaging. This spontaneous evolution, unaffected by external forces, confirms the effectiveness of the spatial activity gradient design. Free water distributed in the matrix gaps and not strongly bound to the silica carrier overcomes the mass transfer resistance within the solid lattice driven by osmotic pressure, migrates directionally, and is ultimately locked deep within the three-dimensional polymer network of cross-linked polyvinylpyrrolidone. Whether altering this specific spatial and temporal competitive hygroscopic mechanism would lead to a reversal of moisture distribution is the core logic of Comparative Example 4. Because cross-linked polyvinylpyrrolidone was pre-mixed into the fluidized bed for humidification, this highly absorbent polymer excessively absorbed ambient moisture in the initial stage of gas-liquid equilibrium, losing its chemical potential as a subsequent moisture trap. In Comparative Example 4, the water activity had already reversed to 0.224 during the total mixing stage. The subsequent mechanical tableting process, with its immense extrusion force, forced a small portion of the water adsorbed inside the saturated cross-linked polyvinylpyrrolidone to seep out, causing the water activity to rise to 0.267 during the sealed storage period instead of decreasing. The system lost its ability to automatically regulate its internal microenvironment. The free water trapped around the active pharmaceutical ingredient particles not only failed to be stripped away but also penetrated and damaged the original buffer membrane. These divergences in physicochemical parameters confirm that the timing of the feed process plays a decisive and dominant role in the directional redistribution of moisture within the solid-phase system.

[0097] Test Example 3: The experiment selected the final high-barrier sealed packaging tablets prepared in Examples 1 to 4 and Comparative Examples 1, 3 and 4 as the research objects. These packaging samples were neatly arranged in a verified and calibrated constant temperature and humidity chamber, and the operating parameters were set as temperature 40°C and relative humidity 75% to establish an accelerated destructive storage environment.

[0098] According to the stability verification schedule, on day 0 (the initial node) of the test, and at four sampling periods of 1 month, 3 months and 6 months after the test, a sufficient amount of packaged tablets were randomly selected from each test group. After removing the high-density polyethylene bottle or aluminum blister pack, the tablets were placed in a desiccator to be restored to room temperature for later use.

[0099] Each group of independent samples was ground into powder. Approximately 10 mg of the fine powder containing the active drug tenofovir alafenamide fumarate was accurately weighed and placed in a 50 mL brown volumetric flask. A mixed solvent of acetonitrile and pure water in a volume ratio of 60:40 was added, and the flask was placed in an ultrasonic water bath for 20 minutes to extract the active ingredients and potential degradation products. After cooling, the flask was diluted to the mark with the same proportion of solvent and filtered through a 0.45 μm polytetrafluoroethylene microporous membrane. The filtrate was collected for subsequent sample injection analysis.

[0100] The test solution was analyzed using a high-performance liquid chromatograph equipped with a UV detector. Chromatographic separation was performed using a C18 reversed-phase column (250 mm × 4.6 mm, 5 μm) at a constant temperature of 30 °C. The mobile phase consisted of a 0.02 mol / L potassium dihydrogen phosphate aqueous solution adjusted to pH 3.0 and chromatographic grade acetonitrile, executed using a preset gradient elution program. The detection wavelength was locked at 260 nm, and the flow rate was maintained at 1.0 mL / min. After obtaining the chromatogram, the peaks representing alkaline hydrolysis (phenol cleavage) and acidic degradation (phosphamide breakage) were identified based on relative retention times. The mass fractions of each specific impurity were calculated using the principal component self-comparison method combined with a relative correction factor. All data were derived from the arithmetic mean of three independent injections.

[0101] Table 3: Dynamic tracking data of specific degradation impurity content during accelerated stability studies for examples and comparative examples Group Inspection time Monophenol cleavage impurities Phosphamide breakage impurities Example 1 0 days 0.01 0.02 Example 1 1 month 0.03 0.05 Example 1 3 months 0.08 0.11 Example 1 6 months 0.16 0.19 Example 2 0 days 0.02 0.03 Example 2 1 month 0.04 0.05 Example 2 3 months 0.09 0.10 Example 2 6 months 0.14 0.16 Example 3 0 days 0.03 0.04 Example 3 1 month 0.06 0.06 Example 3 3 months 0.11 0.13 Example 3 6 months 0.20 0.23 Example 4 0 days 0.02 0.03 Example 4 1 month 0.04 0.06 Example 4 3 months 0.08 0.11 Example 4 6 months 0.13 0.17 Comparative Example 1 0 days 0.03 0.09 Comparative Example 1 1 month 0.11 0.38 Comparative Example 1 3 months 0.32 0.85 Comparative Example 1 6 months 0.65 1.63 Comparative Example 3 0 days 0.03 0.03 Comparative Example 3 1 month 0.15 0.12 Comparative Example 3 3 months 0.48 0.42 Comparative Example 3 6 months 1.15 1.06 Comparative Example 4 0 days 0.04 0.03 Comparative Example 4 1 month 0.29 0.08 Comparative Example 4 3 months 0.87 0.25 Comparative Example 4 6 months 2.12 0.61 Reference Appendix Figure 4 and attached Figure 5 , Figure 4 This reflects the accumulation trend of monophenol cleavage impurities over time, mediated by free water and a slightly alkaline microenvironment. Figure 5 The formation trajectory of phosphoramide fracture impurities catalyzed by localized extreme acidity was revealed during a six-month observation period. The figure shows the comparison between the typical preferred formulation Example 2 and three sets of comparative samples: those validating the conventional process, those lacking the conditioning step, and those disrupting the water competition sequence.

[0102] According to the data in Table 3, under the harsh accelerated conditions of 40℃ / 75%RH for up to 6 months in Examples 1 to 4, both monophenol cleavage impurities and phosphoramide cleavage impurities were strictly suppressed below the safety threshold of 0.23%. This gentle, bidirectional inhibition effect confirms that the multi-load gradient and non-hygroscopic skeleton replacement did not weaken the universality of the core mechanism. In early formulation development, tenofovir prodrugs are often observed to exhibit a U-shaped pH-rate curve in the liquid phase. Mapping this pattern to solid-phase systems often faces the challenge of microscopic mass transfer inhomogeneity. Comparative Example 1, which lacks the mesoscopic complex assembly step, reveals significant limitations. Because the acid regulator directly participates in mixing in macroscopic crystalline form, a high-concentration proton aggregation region inevitably forms around the drug particles, causing the phosphoramide cleavage impurity, which reflects acid catalysis, to surge to 1.63% after 6 months. This locally hyperacidic microenvironment completely destroys the structural integrity of the prodrug molecule. Comparative Example 3, which omitted the fluidized bed gas-solid conditioning and humidification process, exhibited a different degradation pathway. The tablets prepared in this example failed to form a bound water buffer film encapsulating the drug particles. Scattered water within the system remained in a free state and acted as a hydrolysis reaction medium driven by temperature, with both types of impurities increasing simultaneously by more than 1.0%. Further examination of Comparative Example 4, which disrupted the feeding sequence, revealed that the cross-linked polyvinylpyrrolidone, having absorbed water in advance, lost its ability to establish an activity gradient during the total mixing and tableting stage. The free water retained in the system continuously triggered phenol-ester bond hydrolysis on the surface lacking a bound water film, leading to an uncontrolled 2.12% increase in monophenol cleavage impurities. The disordered distribution and migration of free water on the microscopic surface of drug particles are the core trigger for multi-pathway degradation. Precise gas-solid conditioning to induce a bound water phase transition and utilizing the time difference to construct a water-trapping potential well can forcibly reshape the thermodynamic environment within the solid matrix, providing a reliable physical and chemical dual barrier for sensitive prodrug molecules at the bottom of the U-shaped stability curve.

[0103] Test Example 4: The experiment selected the dry powder discharged after the total mixing process in the square cone hopper mixer of Examples 1 to 4 and Comparative Examples 2 and 5, as well as the product of the continuous tableting process after transferring it to the hopper of an industrial-grade rotary tablet press, as the subjects of the study.

[0104] The extracted total mixed powder samples were placed in a constant temperature and humidity chamber for equilibration, with the environmental conditions set at 25℃ and 35% relative humidity. Approximately 100.0g of the equilibrated powder was weighed and poured into the vibration-free funnel of the powder comprehensive property tester. The test program was started, allowing the powder to flow out naturally and accumulate into a cone on a horizontal receiving plate. The angle of repose of the powder was directly read and recorded using the built-in laser scanning angle measurement system. This process was repeated five times for each batch of samples to obtain the arithmetic mean.

[0105] Take another 50.0g of powder and slowly fill it into a 100mL graduated glass cylinder through a stainless steel powder funnel. Record the initial volume after natural settling to calculate the loose density. Then, fix the cylinder on the platform of a tapped density meter, set the vertical drop to 14mm, and tap it 1250 times. Record the compacted volume to calculate the tapped density. Combine the measured loose density and tapped density values ​​with the standard empirical formula to calculate the Karl Fischer index, which represents the compressibility of the powder.

[0106] The remaining total powder mixture was transferred in batches to a high-speed rotary tablet press equipped with a 30-die dies for simulated commercial continuous tableting. The tablet press speed was set to 40 rpm, and the main pressure was maintained at around 15 kN. During the continuous production of 200,000 tablets, a calibrated number of formed tablets were randomly sampled every 30 minutes for online weighing, and the relative standard deviation of the weight difference of the entire batch was calculated. At the same time, through a photoelectric online detection system combined with manual verification, the number of defective tablets with adhesion, punch stringing, or peeling defects on the surface of the formed tablets was counted and converted into the defective product rate per thousand tablets.

[0107] Table 4: Statistical data on flowability and direct compression machining defects of the total mixed powder in the examples and some comparative examples Group Angle of repose (°) Carr's index (%) Tablet weight difference RSD (%) Defect rate due to sticking and punching (‰) Example 1 28.4 12.3 0.96 0.05 Example 2 27.1 11.5 0.82 0.00 Example 3 29.3 13.1 1.15 0.12 Example 4 28.8 12.7 1.03 0.08 Comparative Example 2 37.6 23.4 3.84 3.16 Comparative Example 5 42.1 28.5 5.27 9.83 Reference Appendix Figure 6 and attached Figure 7 ,in Figure 6 The angle of repose, which determines the free flow properties of powder, and the Karl Fischer index, which reflects compressibility, are simultaneously displayed using a dual Y-axis approach. Figure 7 The results recorded the powder's flake weight stability and its ability to resist adhesion to the punch within a real high-speed rotating die. The figure shows a parallel lateral comparison between the four formulation examples and Comparative Example 2 (which did not undergo high-shear treatment) and Comparative Example 5 (which replaced the carrier material).

[0108] According to the data in Table 4, Examples 1 to 4 exhibited excellent engineering material properties, with the angle of repose strictly controlled within the optimal flow range below 30 degrees, and the Karl Fischer index, representing compressibility, maintained between 11.5% and 13.1%. Reflected in high-speed, continuously operating direct compression presses, the relative standard deviation of tablet weight variation was compressed to a negligible 0.82% to 1.15%, and the sticking defect rate was almost zero. In traditional formulation processes, when handling acid modifiers, macroscopic physical mixing easily leads to extremely poor bulk density between components, often resulting in uneven feeding and powder stratification. Comparative Example 2 confirmed this; in the absence of high-shear mechanochemical intervention, the angle of repose of simply mixed materials sharply increased to 37.6 degrees, directly resulting in a tablet weight RSD as high as 3.84% in simulated commercial tableting. Turning our attention to the verification of the carrier surface energy mechanism, the engineering defects exposed in Comparative Example 5 were even more fatal. When fumed silica is replaced by an equal amount of conventional microcrystalline cellulose, the original supramolecular composite flow aid degenerates into a common powder mixture, the angle of repose worsens to 42.1 degrees, which is completely unsuitable for direct compression, and the defective product rate soars to an unacceptable level of 9.83‰. Although microcrystalline cellulose has certain water absorption and formability, its specific surface area is low, and it cannot establish a strong surface energy potential trap through high-density free silanol groups like fumed silica. This invention uses high shear force to force the cleavage of buffer salt lattices and uniformly coats and anchors them around the silica nanoparticle network. This not only homogenizes the local pH at the microscopic level, but also, from a macroscopic powder science perspective, utilizes the excellent ball-bearing effect and pore arrangement of the modified silica itself to eliminate electrostatic adsorption and agglomeration between the main and auxiliary material particles. This composite modification improves the shear rheological behavior and mold wall lubrication of the powder, proving that powder engineering assembly across the mesoscale is the key to completely solving the sticking problem of high specific surface area excipients. It paves the way for low-cost, continuous dry direct compression production of prodrug molecules that are sensitive to moisture and heat.

[0109] Test Example 5: The tenofovir prodrug tablets prepared in Examples 1 to 4, the tablets in Comparative Example 4 whose polymeric disintegrants were prematurely hygroscopic due to disruption of the feeding sequence, and the original commercially available control formulation at the same dose were selected as parallel dissolution test subjects.

[0110] The experiment was conducted according to the paddle method in the dissolution test specified in the pharmacopoeia. 900 mL of degassed dissolution medium was injected into each operating vessel of the dissolution apparatus. The constant temperature water bath circulation system was turned on to stabilize the medium temperature at 37 ± 0.5 °C, and the paddle speed was set to 50 rpm. To comprehensively evaluate the release behavior of the formulation under different gastrointestinal physiological environments, hydrochloric acid solution with pH 1.2 and phosphate buffer solution with pH 6.8 were selected as parallel evaluation media.

[0111] Each group of test tablets was placed into its corresponding dissolution vessel. At the set time points of 5, 10, 15, 20, 30, and 45 minutes, 5.0 mL of dissolution solution was extracted using an automated sampling station, and an equal volume of fresh medium at the same temperature was immediately added to the vessel. The extracted sample solution was then rapidly passed through a 0.45 μm microporous membrane to trap any insoluble excipients, and the filtrate was collected for analysis.

[0112] High-performance liquid chromatography (HPLC) was used to quantitatively analyze the concentration of free active pharmaceutical ingredient (API) in the sample solution. The mobile phase system and detection wavelength parameters were consistent with those of the related substances determination method. The absolute cumulative dissolution percentage of the drug at each time point was calculated using the external standard method. Six independent parallel determinations were performed for each formulation and each medium, and the arithmetic mean of the results was taken as the baseline data for plotting the dissolution curve.

[0113] Table 5: Dynamic tracking data of cumulative dissolution in dual-pH media for examples, comparative examples, and original control formulations. Group Media type 5 minutes 10 minutes 15 minutes 20 minutes 30 minutes 45 minutes Example 2 pH 1.2 38.6 72.4 88.1 94.7 98.3 99.1 Example 3 pH 1.2 36.2 68.9 85.3 92.4 97.6 98.8 Comparative Example 4 pH 1.2 21.4 45.7 62.1 74.3 85.2 91.6 Original control pH 1.2 40.1 75.3 89.6 95.2 98.8 99.4 Example 2 pH 6.8 33.7 67.5 84.8 91.9 97.2 98.5 Example 3 pH 6.8 31.5 64.2 81.6 90.3 96.1 97.9 Comparative Example 4 pH 6.8 18.2 41.5 57.8 70.1 82.7 89.4 Original control pH 6.8 35.2 69.8 86.4 92.7 98.0 98.7 According to the data in Table 5, Examples 2 and 3 both exhibited excellent rapid-release characteristics in two extreme physiological pH media, with release exceeding 80% at the 15-minute mark and steadily climbing to over 95% within 30 minutes. The overall dissolution trajectory was highly consistent with the original control formulation. In the formulation engineering development stage, using relatively dry excipients often leads to the potential for slow dissolution. This is because excessively dehydrated polymeric disintegrants exhibit severe gelation inhibition upon contact with the external liquid phase, or the hydrophobic / buffered membrane layer encapsulating the drug substance surface repels water permeation. The test results of this invention dispel this engineering concern; the layer encapsulating the TAF is not a rigid barrier composed of polymers, but rather a water-bound buffer membrane induced by mesoscopic complex assembly. This trace aqueous film not only acts as an anchoring buffer and stabilizer to isolate free water during dry storage, but also, when the tablet enters the macroscopic, large-volume dissolution medium, this water film, rich in hydrophilic hydroxyl groups and dissociated salts, becomes an excellent wetting channel, reducing the contact angle at the solid-liquid interface and guiding water molecules to rapidly flush the active pharmaceutical ingredient particles. In stark contrast is Comparative Example 4, which disrupts the hygroscopic sequence. Because cross-linked povidone was pre-mixed during the fluidized bed gas-solid equilibrium stage, its polymer network absorbed a large amount of environmental free water and underwent partial swelling in the early stages of processing. This premature hydration during manufacturing essentially consumes the osmotic pressure and swelling capacity that the povidone three-dimensional network should possess after ingestion. When the tablet is finally placed in the dissolution vessel, the already fatigued polymeric disintegrant cannot generate sufficient capillary water absorption and mechanical disintegration force within the matrix, resulting in a dissolution rate of only 85.2% and 82.7% after 30 minutes in pH 1.2 and pH 6.8 media, respectively, exhibiting a significant release lag. The construction of the spatial water activity gradient is not simply for the purpose of removing residual water from the pressing system. Deep dehydration pretreatment and strict control of the mixing sequence not only remove free water to ensure the long-term chemical stability of the prodrug, but also perfectly preserve the thermodynamic burst potential energy of the disintegrant at the end application, achieving a balance between high stability and degradation prevention and rapid release bioequivalence.

Claims

1. A tenofovir prodrug tablet, characterized in that, The tablets are made from components comprising the following weight percentages: The active pharmaceutical ingredient (API) has a molecular weight of 2.0%-10.0%. Non-hygroscopic skeleton: 60.0%-80.0%; Mesoscopic buffering compound flow aid 2.0%-8.0%; In-situ moisture traps: 3.0%-8.0%; Non-alkaline lubrication systems: 1.0%-3.0%; The mesoscopic buffer composite flow aid is anchored to the periphery of the main drug molecule by surface energy to form a bound water buffer membrane with a pH homogenized microenvironment. A solid-phase water activity gradient is formed between the in-situ water trap and the bound water buffer membrane.

2. The tenofovir prodrug tablet according to claim 1, characterized in that, The active pharmaceutical molecule is tenofovir alafenamide or a pharmaceutically acceptable salt of tenofovir alafenamide; The non-hygroscopic skeleton is at least one of D-mannitol, isomaltitol, and low-moisture microcrystalline cellulose; The in-situ moisture trap is cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose. The non-alkaline lubrication system is sodium fumarate stearate or hydrogenated castor oil.

3. A tenofovir prodrug tablet according to claim 1, characterized in that, The mesoscopic buffer composite flow aid is made from raw materials containing the following components: a proton donor, a proton acceptor, and a high specific surface area carrier. The molar ratio of the proton donor to the proton acceptor is 1:2 to 1:3; the weight of the high specific surface area carrier accounts for 20.0% to 30.0% of the total weight of the mesoscopic buffer composite flow aid. The proton donor is anhydrous citric acid, anhydrous tartaric acid, or anhydrous malic acid; the proton acceptor is anhydrous trisodium citrate or anhydrous disodium hydrogen phosphate; the high specific surface area carrier is hydrophilic fumed silica, and the BET specific surface area of ​​the hydrophilic fumed silica is 150-300 m² / g.

4. A tenofovir prodrug tablet according to claim 3, characterized in that, The mesoscopic buffer composite flow aid is a supramolecular composite powder, wherein the crystal lattices of the proton donor and the proton acceptor are broken and cleaved into submicron or nanoscale fragments by mechanochemical action, and are anchored and dispersed on the three-dimensional network surface of the high specific surface area carrier through hydrogen bonding and electrostatic interaction.

5. A method for preparing a tenofovir prodrug tablet according to any one of claims 1-4, characterized in that, Includes the following steps: Prepare the corresponding raw materials according to the weight percentage of each component of the tablet; The in-situ moisture capture trap is subjected to deep dehydration and drying treatment, and then sealed for later use. The active pharmaceutical ingredient, non-hygroscopic framework, and mesoscopic buffer composite flow aid are introduced into a fluidized bed for gas-solid contact fluidization equilibrium to construct a water-bound buffer membrane. The fluidized powder, along with the in-situ moisture trap after dehydration and drying, was fed into a mixer for low-shear mixing to create a spatial water activity gradient. After being lubricated and mixed with a non-alkaline lubrication system, it is directly compressed into tablets and then sealed in packaging. The packaged tablets are stored naturally at room temperature, utilizing solid pores and thermodynamic gradients to achieve targeted migration and locking of moisture.

6. The method for preparing a tenofovir prodrug tablet according to claim 5, characterized in that, The mesoscopic buffer composite flow aid is prepared in advance by the following method: The proton donor, proton acceptor, and high specific surface area carrier are fed into a high-shear mixing granulator with a water-cooled jacket. The filling coefficient of the mixing container is controlled at a volume ratio of 25%-30%. The cooling circulating water is turned on, and the material is continuously dry-state high-shear co-dispersed for 15-20 minutes at a main stirring paddle speed of 400-600 rpm and a chopping blade speed of 2500-3500 rpm. During this period, the maximum temperature of the material is controlled not to exceed 40℃.

7. The method for preparing a tenofovir prodrug tablet according to claim 5, characterized in that, The specific process for deep dehydration and drying of the in-situ moisture trap is as follows: in a vacuum drying oven, the heating temperature is set to 55℃-65℃, the vacuum degree is controlled at -0.08MPa to -0.10MPa, and the drying is carried out continuously for 4-8 hours; and the drying weight loss of the in-situ moisture trap after treatment is controlled to be less than 0.5%, and the water activity is less than 0.

10.

8. The method for preparing a tenofovir prodrug tablet according to claim 5, characterized in that, The specific parameters for the gas-solid contact fluidization equilibrium are as follows: the liquid spray system is shut off throughout the process, the inlet air temperature is set to 20℃-30℃, the inlet air dew point is controlled by the air conditioning unit, the relative humidity in the fluidized bed cavity is kept constant at 45%-50%, and the gas-solid contact fluidization equilibrium is continuously maintained for 15-30 minutes.

9. The method for preparing a tenofovir prodrug tablet according to claim 5, characterized in that, During the low-shear mixing process, the mixer speed is set to 10-20 rpm, the short-term low-shear mixing is carried out for 8-12 minutes, and the relative humidity of the environment is controlled to not exceed 40%; the room temperature conditions for natural storage under the room temperature conditions are 15℃-30℃.

10. The use of a tenofovir prodrug tablet according to any one of claims 1-4 in the preparation of a medicament for treating hepatitis B or HIV infection.

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