Indomethacin controlled release tablets, compositions and methods of making same

Abstract

The application discloses an indometacin controlled-release tablet, a preparation composition and a preparation method thereof, and belongs to the technical field of modern pharmaceutical preparations. The preparation composition comprises a low drug loading ratio mixture and a high drug loading ratio mixture, wherein the low drug loading ratio mixture and the high drug loading ratio mixture both comprise indometacin, a filler, a hydrophilic gel skeleton material, a thickening agent and a binder, and the low drug loading ratio mixture further comprises a wetting agent; the indometacin in the low drug loading ratio mixture accounts for 1-20% of the mass of solid materials in the mixture, and the indometacin in the high drug loading ratio mixture accounts for 50-90% of the mass of solid materials in the mixture; and the preparation composition can be used to prepare the controlled-release tablet with constant drug release speed in a predetermined time period through a 3D printing process of one-time forming.

Description

Technical Field

[0001] This invention relates to the field of modern pharmaceutical formulation technology, and in particular to an indomethacin controlled-release tablet, its preparation composition, and preparation method. Background Technology

[0002] Controlled-release formulations are a class of pharmaceutical preparations with numerous advantages. They release the drug slowly and at a constant rate in a specified release medium, reducing the frequency of administration compared to conventional formulations, resulting in more stable blood drug concentrations. They also offer advantages such as longer therapeutic effects, reduced toxicity and side effects, and improved patient adherence.

[0003] Formulations prepared with hydrophilic matrices are usually in a uniform drug loading mode. As the tablet gradually dissolves, the surface area of ​​the tablet gradually decreases, the volume of the tablet that has dissolved decreases, while the drug loading ratio of the tablet remains unchanged. This results in a gradual decrease in the amount of drug released, making it impossible to achieve a zero-order or near-zero-order drug release curve. As a result, it fails to meet the constant-rate drug release requirements of controlled-release formulations and can only become sustained-release formulations.

[0004] To achieve a constant release rate of hydrophilic matrix formulations within a predetermined time period, the conventional method is to use multilayer gradient drug loading (increasing the drug loading ratio from the outside in). Researchers have prepared drug mixtures for each layer according to the required amount of drug, and then used traditional techniques such as tablet presses and fluidized beds to prepare multilayer gradient drug-loaded formulations. However, the preparation of each layer requires reintroducing the drug mixture and restarting the equipment, which is a very cumbersome process and consumes a lot of manpower. As a result, this type of formulation has remained in the laboratory research stage for two or three decades and has not achieved further development. Summary of the Invention

[0005] To address the lack of hydrophilic matrix formulations that can achieve zero-order or near-zero-order drug release in conventional technologies, this invention provides a preparation composition for indomethacin controlled-release tablets. This preparation composition can be fabricated using a one-step 3D printing process to obtain controlled-release tablets that release drugs at a constant rate within a predetermined time period.

[0006] On one hand, the present invention discloses a preparation composition for indomethacin controlled-release tablets, comprising a low drug loading ratio mixture and a high drug loading ratio mixture, wherein both the low drug loading ratio mixture and the high drug loading ratio mixture contain indomethacin, a filler, a hydrophilic gel matrix material, a thickener, and a binder, and the low drug loading ratio mixture further contains a wetting agent; in the low drug loading ratio mixture, indomethacin accounts for 1% to 20% of the solid material mass of the mixture, and in the high drug loading ratio mixture, indomethacin accounts for 50% to 90% of the solid material mass of the mixture.

[0007] During preliminary research, the inventors considered that 3D printing technology is a rapid prototyping technology that constructs objects layer by layer based on digital models. Layer-by-layer rapid prototyping and digital modeling are two characteristics of 3D printing technology, giving it unique advantages in the preparation of gradient drug-loaded formulations. Based on these characteristics, this invention utilizes the layer-by-layer stacking characteristics of 3D printing to combine a low drug-load ratio outer layer with a high drug-load ratio inner layer. This allows the tablet to maintain a higher drug density in the exposed inner layer during the dissolution process, even though the surface area and volume continuously decrease. This compensates for the decrease in drug release caused by area decay, maintaining a nearly constant drug release per unit time, ultimately obtaining a zero-order drug release curve.

[0008] In some specific embodiments, indomethacin accounts for 2% to 10% of the mass of the solid material in the low drug loading mixture, preferably 4% to 6%, and more preferably 5%.

[0009] In some specific embodiments, indomethacin accounts for 60% to 80% of the mass of the solid material in the high drug loading mixture, preferably 70% to 80%, and more preferably 75%.

[0010] In some specific embodiments, the hydrophilic gel skeleton material is selected from one or more of the HPMC class, more preferably one or both of HPMC4000 and HPMC100.

[0011] In some specific embodiments, the filler is microcrystalline cellulose.

[0012] In some specific embodiments, the thickener is sodium carboxymethyl cellulose; preferably, the thickener is 2-7% of the mass of the hydrophilic gel skeleton material, more preferably 3-5%, for example 4%.

[0013] In some specific embodiments, the wetting agent is an aqueous ethanol solution; preferably, the wetting agent is an aqueous ethanol solution with a volume percentage concentration of 60%-80%; more preferably, it is an aqueous ethanol solution with a volume percentage of 70%-80%; for example, it is an aqueous ethanol solution with a volume percentage of 70%.

[0014] Because the filler content in low-drug-load mixtures is relatively high, the material is generally dry and hard, with insufficient cohesion between powders and limited flowability. Direct 3D printing in this condition easily leads to problems such as weak interlayer bonding, poor forming accuracy, and nozzle clogging, making it difficult to meet the process requirements of 3D printing for material plasticity and extrusion stability. Therefore, an appropriate amount of wetting agent is introduced into the formulation to adjust the viscoelastic properties and processability of the material. Furthermore, after examining the formulation compatibility and 3D printing process suitability of various candidate wetting agents, the aforementioned wetting agent was finally selected. It exhibits good compatibility with other excipients in the formulation; while adjusting the material's moisture and plasticity, it can synergistically work with other excipients to improve material uniformity and extrusion molding effect, resulting in a good overall combination that can stably meet the process requirements of 3D printing.

[0015] In some specific embodiments, the ratio of the wetting agent to the solid material of the mixture in the low drug loading ratio mixture is 2-5 ml / 6.48 g, preferably 3-4 ml / 6.48 g, for example 3.2 ml / 6.48 g.

[0016] In some specific embodiments, the adhesive is polyvinylpyrrolidone; preferably, the polyvinylpyrrolidone is PVP K29; more preferably, the adhesive accounts for 5% to 10% of the mass of the solid material in the mixture, preferably 7% to 8%, for example 7.4%.

[0017] In some specific embodiments, the adhesive is added in solution form, and the ratio of adhesive solution to the solid material in the mixture is 1.0-1.5 ml / g, for example, 1.23 ml / g.

[0018] In some specific implementations of the above scheme, the adhesive solution is an ethanol solution with a concentration of 6±1wt% PVP K29, wherein the volume fraction of ethanol in the ethanol solution is 70-80%, for example, 70%.

[0019] In some specific embodiments, the hydrophilic gel skeleton material in the low drug loading ratio mixture is composed of HPMC4000 and HPMC100, the hydrophilic gel skeleton material accounts for 5-15% of the mass of the solid material in the mixture, and / or the mass ratio of HPMC4000 to HPMC100 is 8:2-5:5.

[0020] In some specific embodiments of the low drug loading ratio mixture, the hydrophilic gel framework material accounts for 8-12% of the mass of the solid material in the mixture, for example, 10%.

[0021] In some specific embodiments of the low drug loading ratio mixture, the mass ratio of HPMC4000 to HPMC100 is 6-8:2-4, for example 7:3; In the high drug loading ratio mixture, the hydrophilic gel skeleton material is HPMC4000, and the hydrophilic gel skeleton material accounts for 5-15% of the mass of the solid material in the mixture, preferably 8-12%, for example 10%.

[0022] In some specific embodiments, the low drug loading ratio mixture consists of indomethacin, fillers, hydrophilic gel matrix materials, thickeners, wetting agents, and binders; The mixture contains indomethacin, comprising 2%–10% of the solid material mass; microcrystalline cellulose as the filler; and HPMC4000 and HPMC100 as the hydrophilic gel skeleton material, comprising 5%–15% of the solid material mass with a mass ratio of 8:2–5:5. The thickener is sodium carboxymethyl cellulose, comprising 2–7% of the hydrophilic gel skeleton material mass. The wetting agent is a 60%–80% (v / v) aqueous ethanol solution, with a wetting agent to solid material mass ratio of 2–5 ml / 6.48 g. The binder is PVPK29, comprising 5%–10% of the total solid material mass, added in solution form with a binder solution to solid material mass ratio of 1.0–1.5 ml / g, and the binder solution is 6 ± 1% PVP. The ethanol solution of K29 has a volume fraction of 70-80% ethanol. The high drug loading ratio mixture is composed of indomethacin, filler, hydrophilic gel matrix material, thickener and binder; In this mixture, indomethacin accounts for 60% to 80% of the solid material mass; the filler is microcrystalline cellulose; the hydrophilic gel skeleton material is HPMC4000, accounting for 5-15% of the solid material mass; the thickener is sodium carboxymethyl cellulose, accounting for 2-7% of the hydrophilic gel skeleton material mass; the binder is PVP K29, accounting for 5% to 10% of the total solid material mass, and is added in solution form. The ratio of binder solution to solid material in the mixture is 1.0-1.5 ml / g, and the binder solution is a 6±1% PVP K29 ethanol solution, wherein the volume fraction of ethanol in the ethanol solution is 70-80%.

[0023] In some specific implementation schemes of the above-mentioned scheme, indomethacin accounts for 4% to 6% of the mass of the solid material in the low drug loading mixture, the hydrophilic gel skeleton material accounts for 8% to 12% of the mass of the solid material in the mixture, and the mass ratio of HPMC4000 to HPMC100 is 7.5:2.5-5:5; the thickener accounts for 3% to 5% of the mass of the hydrophilic gel skeleton material; the wetting agent is an ethanol aqueous solution with a volume percentage concentration of 70% to 80%, and the dosage ratio of the wetting agent to the solid material in the mixture is 3-4 ml / 6.48 g; the binder accounts for 7% to 8% of the total mass of the solid material in the mixture, and the dosage ratio of the binder solution to the solid material in the mixture is 1.1-1.3 ml / g; In the high drug loading ratio mixture, indomethacin accounts for 70% to 80% of the mass of the solid material in the mixture, the hydrophilic gel skeleton material accounts for 8-12% of the mass of the solid material in the mixture, the thickener accounts for 3-5% of the mass of the hydrophilic gel skeleton material, the binder accounts for 7% to 8% of the total mass of the solid material in the mixture, and the ratio of binder solution to solid material in the mixture is 1.1-1.3 ml / g.

[0024] In some specific implementation schemes of the above-mentioned scheme, indomethacin accounts for 5% of the mass of the solid material in the low drug loading mixture, the hydrophilic gel skeleton material accounts for 10% of the mass of the solid material in the mixture, and the mass ratio of HPMC4000 to HPMC100 is 7:3; the thickener accounts for 4% of the mass of the hydrophilic gel skeleton material; the wetting agent is a 70% (v / v) aqueous ethanol solution, and the ratio of the wetting agent to the solid material in the mixture is 3.2 ml / 6.48 g; the binder accounts for 7.4% of the total mass of the solid material in the mixture, and the ratio of the binder solution to the solid material in the mixture is 1.23 ml / g, wherein the binder solution is a 6% PVP K29 ethanol solution, and the volume fraction of ethanol in the ethanol solution is 70%; In the high drug loading ratio mixture, indomethacin accounts for 75% of the mass of the solid material in the mixture, the hydrophilic gel skeleton material accounts for 10% of the mass of the solid material in the mixture; the thickener accounts for 4% of the mass of the hydrophilic gel skeleton material; the binder accounts for 7.4% of the total mass of the solid material in the mixture, the ratio of binder solution to solid material in the mixture is 1.23 ml / g, and the binder solution is a 6% PVP K29 ethanol solution, wherein the volume fraction of ethanol in the ethanol solution is 70%.

[0025] On the other hand, this invention discloses a method for preparing indomethacin controlled-release tablets, using a dual-pump semi-solid extrusion 3D printer to print the controlled-release tablets according to the following three-dimensional digital model: Define the dimensions of the three-dimensional digital model from bottom to top as printing layers, and the dimensions from outside to inside as concentric circles. Calculate the volume V of the i-th concentric circle from the outside to the inside of the controlled-release tablet according to the following formulas 1 to 3. i The volume V of the high drug loading ratio mixture in the i-th layer 75,i and its corresponding diameter d 75,i ; ] Formula 1 In Formula 1, V i Let H be the volume of the i-th layer from the outside to the inside of the controlled-release tablet, H be the tablet height, D be the diameter of the controlled-release tablet, ΔH be the height decrease between two adjacent layers, and ΔD be the diameter decrease between two adjacent layers. Formula 2 In Formula 2, V 75,i ρi is the volume of the high-drug-loading mixture in the i-th layer, ρ5 is the density of indomethacin in the low-drug-loading mixture, and ρi is the density of indomethacin in the low-drug-loading mixture. 75 M represents the density of indomethacin in a high drug loading ratio mixture, and M represents the target drug loading per layer. Formula 3 In Formula 3, d 75,i Let be the diameter of the high drug loading mixture in the i-th layer, and h represent the layer height of the printed layer; Using the above-mentioned composition as raw material for a dual-pump semi-solid extrusion 3D printer, and based on the three-dimensional digital model established above, the proportion of the high drug loading ratio mixture is increased layer by layer from the outer layer to the inner layer of the controlled-release tablet for 3D printing, thus obtaining the final product.

[0026] In terms of model design, the above preparation method uses Formula 1 to calculate the volume of each layer of the controlled-release tablet from the outside to the inside. Formula 2 calculates the volume of the high drug loading ratio mixture required in each layer under the constraint of equal target drug loading in each layer. Formula 3 then converts this volume into the diameter of the high drug loading region in each printed layer, thereby accurately constructing a gradient drug loading three-dimensional digital model with the proportion of high drug loading ratio mixture gradually increasing from the outside to the inside. In this way, even if the tablet gradually dissolves in the release medium and the surface area and dissolution volume gradually decrease, the original drug release can still be maintained due to the high drug loading ratio of the inner layer, thus compensating for the defect of the gradual decrease in drug release of uniformly loaded formulations.

[0027] Furthermore, regarding prescription formulation, the drug densities ρ5 and ρ5 on which the aforementioned model calculations rely are... 75 The specific formulation determines the printability of the semi-solid mixture, the tablet forming properties, and the dissolution-release behavior of the gel matrix, thereby achieving the effect of zero-order release. The setting of two drug loading ratios (e.g., 5% and 75%), the viscosity, proportion and amount of the hydrophilic gel matrix material, and the selection of the type of binder and solvent are all determined by the specific formulation.

[0028] In some specific embodiments, the controlled-release tablet is a cylinder with a diameter D of 8±0.8 mm and a height H of 5.88±0.588 mm; there are a total of 14±2 printed layers, with a single printed layer height h of 0.42±0.042 mm; it is divided into 7±1 concentric layers from the outside to the inside according to the dissolution sequence, with ΔH of 0.84±0.084 mm and ΔD of 1.143±0.1143 mm; M is 2.997±0.2997 mg and ρ5 is 0.0274±0.00274 mg / mm. 3 , ρ 75 It was 0.4139 ± 0.04139 mg / mm. 3 .

[0029] In some specific implementations of the above scheme, the controlled-release tablet is a cylinder with a diameter D of 8 mm and a height H of 5.88 mm; there are 14 printing layers in total, with a single printing layer height h of 0.42 mm; it is divided into 7 concentric layers from the outside to the inside according to the dissolution sequence, with ΔH of 0.84 mm and ΔD of 1.143 mm; M is 2.997 mg, ρ5 is 0.0274 mg / mm3, and ρ 75 It is 0.4139 mg / mm3.

[0030] In some specific embodiments, the 3D printing parameters are: needle aperture 410±41μm, infill pattern is linear, infill spacing is 0.3±0.03mm, and printing speed is 8±0.8mm / s; the extrusion pressure of the low drug loading ratio mixture is 0.15~0.18MPa, and the extrusion pressure of the high drug loading ratio mixture is 0.12~0.14MPa; preferably, the needle aperture is 410μm, the infill spacing is 0.3mm, and the printing speed is 8mm / s.

[0031] In some specific implementations, the 3D printing process includes a drying step, preferably a room temperature drying process.

[0032] On the other hand, the present invention discloses an indomethacin controlled-release tablet, wherein the drug loading ratio of the controlled-release tablet gradually increases from the outer layer to the inner layer in the order of dissolution, so that the amount of indomethacin loaded in each layer of the controlled-release tablet from the outside to the inside is equal.

[0033] In some specific embodiments, the indomethacin controlled-release tablets are prepared using the above-described preparation method.

[0034] In some specific embodiments, the controlled-release tablet is a cylinder with a diameter of 8±0.8 mm and a height of 5.88±0.588 mm, consisting of 14±2 printed layers with a layer height of 0.42±0.042 mm. The central region of the first 14 printed layers from bottom to top is the high drug-load ratio mixture of the above-mentioned preparation composition, while the remaining regions are the low drug-load ratio mixture. The diameters of the central regions from bottom to top are 0±0.1 mm, 1.83±0.183 mm, and 2.4 mm, respectively. The thicknesses are 7±0.247mm, 2.89±0.289mm, 3.16±0.316mm, 0±0.1mm, 0±0.1mm, 0±0.1mm, 0±0.1mm, 3.16±0.316mm, 2.89±0.289mm, 2.47±0.247mm, 1.83±0.183mm, and 0±0.1mm. The remaining printed layers and the remaining areas of each printed layer are low drug loading ratio mixtures in the above-mentioned preparation composition.

[0035] In the aforementioned controlled-release tablets, the central regions of the 1st to 5th printed layers and the 10th to 14th printed layers contain a high drug-load ratio mixture, forming a symmetrical drug-loaded core. The central region diameter of the 6th to 9th printed layers is designed to be 0±0.1 mm, meaning these four layers do not contain a high drug-load ratio mixture. This design is based on drug release kinetics considerations. When the tablet dissolves to the level of the 6th layer, the drug release time has exceeded 12 hours. At this point, the drug release behavior of the core is no longer within the timeframe that requires precise control in this formulation. Furthermore, the drug load of the 6th and 7th layers accounts for only 1.25% of the total drug load of the entire tablet; this portion of the drug is not released within 12 hours. This design does not affect the effective blood drug concentration within the dosing interval, nor does it interfere with the accuracy of subsequent dosing.

[0036] In some specific implementations of the above scheme, the controlled-release tablet is a cylinder with a diameter of 8 mm and a height of 5.88 mm, consisting of 14 printed layers with a layer height of 0.42 mm. The central region of the 1st to 14th printed layers from bottom to top is the high drug loading ratio mixture in the above-mentioned preparation composition, while the remaining regions are the low drug loading ratio mixture. The diameters of the central regions from bottom to top are 0 mm, 1.83 mm, 2.47 mm, 2.89 mm, 3.16 mm, 0 mm, 0 mm, 0 mm, 0 mm, 3.16 mm, 2.89 mm, 2.47 mm, 1.83 mm, and 0 mm, respectively.

[0037] In some specific embodiments, the in vitro release profile of the control tablet conforms to a zero-order release model.

[0038] In some specific implementation schemes of the above-mentioned scheme, the cumulative release rate of the controlled-release tablet is ≥90% over 12 hours, and / or the fitting coefficient R of the zero-order release model is... 2 ≥0.99.

[0039] The "drug loading ratio" mentioned above refers to the percentage (w / w) of the active pharmaceutical ingredient indomethacin (API) in the total mass of the solid material of the formulation. For example, a 75% drug loading ratio means that 75 g of indomethacin is contained in every 100 g of solid material.

[0040] The term "solid material" as used above refers to material in which the excipient itself is solid, that is, excluding solvents and other substances added during the preparation process to meet the requirements of the formulation. In this invention, when the excipients include fillers, hydrophilic gel skeleton materials, thickeners and binders, the solid material is the excipients themselves, excluding solvents such as water and ethanol added to prepare binders, and also excluding wetting agents and other substances that will evaporate after the formulation dries.

[0041] The aforementioned "filler" refers to an inert excipient used in controlled-release tablets to supplement the portion where the sum of the active pharmaceutical ingredient and other functional excipients is less than 100%, thereby increasing the overall volume, improving formability, and facilitating dosage and tablet preparation. These fillers typically have no pharmacological activity themselves. Examples include microcrystalline cellulose, lactose, and pregelatinized starch.

[0042] The aforementioned "hydrophilic gel framework material" refers to a hydrophilic polymer material that can absorb water and swell to form a gel barrier upon contact with water, thereby regulating the drug release rate by controlling drug diffusion and framework erosion. Hydroxypropyl methylcellulose (HPMC) is an example.

[0043] The aforementioned "thickener" refers to an additive that can increase the viscosity of a liquid or semi-solid system, improve its rheological properties, and thus enhance the system's stability and formability. For example, sodium carboxymethyl cellulose (CMC-Na).

[0044] The aforementioned "binder" refers to an excipient that can bind drug powder and excipient particles into granules or tablets with sufficient mechanical strength, making the material easy to form. An example is polyvinylpyrrolidone (PVP).

[0045] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0046] The reagents and raw materials used in this invention are all commercially available.

[0047] The positive and progressive effects of this invention are as follows: The present invention provides a preparation composition for an indomethacin controlled-release tablet, which can be manufactured by a one-time molding 3D printing process to obtain a controlled-release tablet that releases the drug at a constant rate within a predetermined time period. The obtained controlled-release tablet increases the proportion of the raw material composition with a high drug loading ratio from the outer layer to the inner layer. Even if the tablet volume gradually dissolves and decreases, the original drug release can still be maintained based on the higher drug loading ratio of the inner layer, thereby obtaining a drug release curve of approximately zero order.

[0048] Furthermore, in vitro release experiments showed that the cumulative release rates of the indomethacin controlled-release tablets were 9.9% and 18.3% at the initial 1h and 2h, respectively, with no significant burst release; the cumulative release rate increased steadily and linearly from 4 to 10h; and the cumulative release rate reached 99.8% at 12h, indicating complete drug release; the release curve conformed to the zero-order model (R²). 2 =0.9929) and the Ritger-Peppas equation (R 2 =0.9962, release index n=0.9507), which is consistent with the dissolution and drug release mechanism.

[0049] The preparation method of indomethacin controlled-release tablets of the present invention utilizes the characteristics of 3D printing layer-by-layer stacking and digital modeling, and prints the tablets in one step according to the proportion set by the digital model. Unlike traditional multi-layer gradient drug delivery formulations, it does not require layer-by-layer preparation and pressing, which greatly simplifies the process.

[0050] Furthermore, the model parameters are precisely calculated and determined by formulas 1 to 3, and digital modeling and printing ensure the accuracy and batch-to-batch reproducibility of the gradient drug loading structure. Attached Figure Description

[0051] Figure 1 Photographs of tablets used in screening experiments for different adhesive solvent formulations; Among them, ab represents the top and bottom surfaces of the IN75-1 tablet after it has been dried for 1 hour, c represents the IN75-1 tablet after it has been printed and dried immediately, de represents the top and bottom surfaces of the IN75-2 tablet after it has been printed and dried at room temperature, and fg represents the top and bottom surfaces of the IN75-3 tablet after it has been printed and dried at room temperature. Figure 2 Comparison of release rates in screening experiments for HPMC formulations with different viscosities; Figure 3 Comparison of release rates in screening experiments for different HPMC4000 dosage formulations; Figure 4 Comparison of release rates in screening experiments of HPMC4000 and HPMC100 with different formulation ratios; Figure 5 For controlled-release tablet model; Where: a is the mixture model with a drug loading ratio of 75%, b is the controlled-release tablet model; 100 is the mixture with a drug loading ratio of 75%, and 200 is the mixture with a drug loading ratio of 5%; Figure 6 This is a schematic diagram of a controlled-release tablet; Figure 7 The prepared indomethacin controlled-release tablets; Where a and b represent the diameter and height, respectively; Figure 8 The results of in vitro release of indomethacin controlled-release tablets and the fitting of the zero-order release model are presented. Detailed Implementation

[0052] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0053] Additional ingredients: Indomethacin: Shanghai Aladdin, batch number: I2202362; Microcrystalline cellulose: Shanghai Aladdin, batch number: G1824293; HPMC4000: Shanghai Aladdin, batch number: J2422425; HPMC100: Shanghai Aladdin, batch number: I517102; CMC-Na (Sodium Carboxymethyl Cellulose): Shanghai Aladdin, Batch No.: J2126508; Polyvinylpyrrolidone: Shanghai Aladdin, batch number: G2409401; The following methods were used to conduct the indomethacin release rate test: According to the first method (basket method) of General Chapter 0931, Part IV, of the 2025 edition of the Chinese Pharmacopoeia, dissolution and release were determined using phosphate buffer (pH 7.2) (500 mL for the 5% low-drug-load group and controlled-release tablets, and 1000 mL for the 75% high-drug-load group). The rotation speed was 100 rpm, and the medium temperature was (37±0.5)℃. 5 mL samples were taken at 1, 2, 4, 6, 8, 10, and 12 hours, and an equal volume of release medium at the same temperature was immediately added. The samples were filtered through a 0.45 μm microporous membrane, and the absorbance of the filtrate was measured at 320 nm using ultraviolet-visible spectrophotometry (General Chapter 0401). The cumulative release rate of each tablet at different times was calculated using a standard curve regression equation. Six tablets were tested in parallel, and the average value was taken.

[0054] Example 1: Preparation of Indomethacin Controlled-Release Tablets

[0055] This embodiment studies and develops indomethacin controlled-release tablets based on 3D printing.

[0056] I. Prescription Screening

[0057] Formulation screening was conducted using 3D-printed sustained-release tablets with uniform drug loading. To create the largest possible drug loading gradient within the printable process boundaries, preliminary experiments compared sustained-release tablets with different drug loading ratios. Drug loading ratios of 5% and 75% were selected as the components of the low and high drug loading gradients, respectively. The 5% low drug loading ensured a smooth initial release and avoided burst release, while the 75% high drug loading provided sufficient drug density to compensate for the release rate reduction caused by the decrease in surface area and volume during tablet dissolution. Thus, a near-zero-order constant-rate drug release was achieved through a progressively increasing gradient design.

[0058] The following method for preparing uniformly loaded sustained-release tablets in formulation screening is as follows: A predetermined amount of indomethacin and microcrystalline cellulose are mixed and dispersed evenly. Predetermined amounts of HPMC and CMC-Na are added and ground until homogeneous. Then, a polyvinylpyrrolidone solution is added and ground until homogeneous. An appropriate amount of 70% ethanol is added and ground until homogeneous, yielding a semi-solid raw material composition. Tablets are printed according to the following 3D printing model parameters and dried to obtain the final product.

[0059] The resulting 3D-printed tablet is a cylinder with a height of 5.88 mm and a diameter of 8 mm. The 3D printing parameters are: needle orifice diameter of 410 μm, infill pattern of lines, infill spacing of 0.3 mm, and printing speed of 8 mm / s.

[0060] 1. 75% drug loading ratio component formulation screening

[0061] (1) Screening of adhesive solvents

[0062] The total amount of fixed solid material is 6.48g, with indomethacin accounting for 75% of the solid material. The amounts of microcrystalline cellulose, HPMC4000, and CMC-Na are fixed. Equal amounts of different solvent binders, namely 6% polyvinylpyrrolidone aqueous solution, 6% polyvinylpyrrolidone ethanol solution (70% ethanol volume fraction), and 6% polyvinylpyrrolidone ethanol solution (80% ethanol volume fraction), are added according to the table below. The formula is shown in the table below. Grind evenly and mix to form the raw material composition.

[0063] Table 1. Formulation screening of different adhesive solvents

[0064] "-" indicates that it has not been added.

[0065] The adhesive polyvinylpyrrolidone (PVPK29) was dissolved using 100% purified water, 70% ethanol, and 80% ethanol as solvents.

[0066] The results are as follows Figure 1As shown in the figure, ab represents the top and bottom surfaces of the IN75-1 tablet after it has been dried for 1 hour, c represents the IN75-1 tablet after it has been printed and dried immediately, de represents the top and bottom surfaces of the IN75-2 tablet after it has been printed and dried at room temperature, and f represents the top and bottom surfaces of the IN75-3 tablet after it has been printed and dried at room temperature.

[0067] The results showed that all three binders could form a uniform paste. The paste formed by the binder using 100% purified water as a solvent was easy to extrude and produced tablets with good formability; however, after printing and leaving it for 1 hour, drying it in a 60°C oven resulted in deformation and dents; even after immediate drying at 60°C after printing, dents still appeared. Formulations using 70% ethanol and 80% ethanol as the binder solvent both successfully printed sustained-release tablets, which dried naturally at room temperature without collapse or dents. However, the lower the ethanol concentration, the less likely the paste was to dry and solidify, which is beneficial for filling and printing; therefore, 70% ethanol was selected as the binder solvent.

[0068] (2) Selection of adhesive type

[0069] The total amount of fixed solids is 6.48g. Indomethacin accounts for 75% of the solids. The amounts of microcrystalline cellulose, HPMC4000, and CMC-Na are fixed. Equal amounts of different types of binders are added according to the table below: 6% ethanol solution of PVP K13, 6% ethanol solution of PVP K29, and 6% ethanol solution of PVP K88 (formulas are shown in the table below). The mixture is ground and mixed to form the raw material composition.

[0070] Table 2. Formulations for different types of adhesives

[0071] PVP with three molecular weights—K13, K29, and K88—was used as binders. The results showed that all the binders could form a uniform paste. However, the filaments extruded from the formulation using PVP K13 as the binder broke, making it difficult to print complete tablets. The formulations using PVP K29 and PVP K88 were easy to extrude and had good tablet formability, but the PVP K88 formulation experienced internal pore collapse during drying. Therefore, PVP K29 was selected as the binder.

[0072] (3) Screening of HPMC viscosity

[0073] The total amount of fixed solid materials is 6.48g. Indomethacin accounts for 75% of the solid materials. The amounts of fixed microcrystalline cellulose and CMC-Na are added separately according to the table below. Equal amounts of HPMC with viscosities of 4000mPa·s and 15000mPa·s are added respectively. A 6% polyvinylpyrrolidone ethanol solution is added as a binder, and the mixture is stirred evenly to form the raw material composition.

[0074] Table 3. Formulations for different HPMC viscosities

[0075] HPMC with viscosities of 4000 mPa·s and 15000 mPa·s was used as an excipient, and its release was compared. The results are as follows: Figure 2 As shown, Figure 2 The effect of HPMC viscosity on indomethacin release (n=6).

[0076] The results showed that both excipients of different viscosities could form a uniform paste, which was easy to extrude and produced good tablet formability. However, in vitro release experiments showed that the tablets using HPMC 15000 mPa·s as excipients had a release rate of only 78.8% at 12 hours, while the tablets using HPMC 4000 as excipients had a release rate of 91.5% at 12 hours. Based on the 12-hour sustained-release design target, HPMC 4000 met the drug release requirements, therefore HPMC 4000 with a viscosity of 4000 mPa·s was selected.

[0077] (4) Screening of HPMC 4000 dosage

[0078] The total amount of fixed solids is 6.48g. Indomethacin accounts for 75% of the solids, and HPMC 4000, accounting for 5%, 10%, and 15% of the solids, is added respectively. The amount of CMC-Na is 4% of HPMC 4000, and 8ml of 6% polyvinylpyrrolidone ethanol solution is added. The remaining components are microcrystalline cellulose (formulation as shown in the table below). Grind and mix to form the raw material composition.

[0079] Table 4. Prescriptions for different dosages of HPMC4000

[0080] HPMC4000 was used as an excipient at concentrations of 5%, 10%, and 15% to compare its release characteristics. The results are as follows: Figure 3 As shown, Figure 3 The effect of different HPMC4000 dosages on indomethacin release (n=6).

[0081] The results showed that all three formulations formed a uniform paste, were easy to extrude, and exhibited good tablet formation. In vitro release assays revealed that as the HPMC4000 dosage increased from 5% to 15%, the gel matrix strength gradually increased, while drug release gradually slowed. The 5% HPMC group showed the fastest release rate, with a cumulative release of 95.3% at 12 hours, meeting the design requirements for a 12-hour sustained-release formulation, but the cumulative release at 2 hours was only 32.8%, indicating a rapid initial release. The 10% HPMC group showed a cumulative release of 23.5% at 2 hours, with a more gradual initial release, and a 12-hour release of 91.5%, also meeting the design requirements for a 12-hour sustained-release formulation. The 15% HPMC group showed a cumulative release of 88.4% at 12 hours, which did not meet the 90% requirement of the Chinese Pharmacopoeia (2025 edition). Based on a comprehensive comparison of the effects of different HPMC4000 dosages on drug release behavior, the 10% HPMC4000 formulation was selected for further research.

[0082] 2.5% drug loading ratio component formulation screening

[0083] The total amount of fixed solids was 6.48g. Indomethacin accounted for 5% of the solids. Based on the preliminary experimental results, HPMC4000 and HPMC100 were selected to account for 10% in total. The ratio of HPMC4000 to HPMC100 was adjusted to 10:0, 7:3, and 5:5. The amount of CMC-Na was 4% of the total amount of the two HPMCs. 8ml of 6% polyvinylpyrrolidone ethanol solution was used as the binder. The remaining components were all microcrystalline cellulose (accounting for approximately 77.2%). The mixture was ground evenly, and 70% ethanol was added to adjust the humidity (the formula is shown in the table below). The mixture was then used as the raw material composition.

[0084] Table 5. Prescriptions with different HPMC4000 to HPMC100 ratios

[0085] The results are as follows Figure 4 As shown, Figure 4 The effect of the ratio of HPMC4000 to HPMC100 on the release rate of indomethacin (n=6).

[0086] The results showed that the 10:0, 7:3, and 5:5 formulations all formed a uniform paste, were easy to extrude, and had good tablet formability. In vitro release tests showed that the 12-hour cumulative release rate of the 10:0 formulation was only 83.5%, failing to meet the requirement of over 90% as stipulated in the Chinese Pharmacopoeia (2025 edition); the 12-hour cumulative release rate of the 7:3 formulation was 98.1%, and that of the 5:5 formulation was 100.2%. Based on the 12-hour sustained-release design target, both met the requirement of over 90% cumulative release rate stipulated in the Chinese Pharmacopoeia.

[0087] However, further comparison of the drug release curves revealed that although the release behavior of the two formulations was similar in the initial stage of drug release (0-2h), the release rate of the 5:5 formulation was significantly accelerated after 4h. Therefore, the formulation with a more stable release ratio of HPMC4000:HPMC100 (7:3) was selected for subsequent research.

[0088] II. Printed Model Design

[0089] The controlled-release tablet model is cylindrical. The dimensions from bottom to top are defined as printing layers, and the dimensions from outside to inside are defined as concentric layers. The model design is based on the assumption of proportional dissolution, dividing the cylindrical tablet into multiple concentric layers from the outside in. The volume of each layer is calculated using a formula, and a constant target drug loading is set. Based on the densities of two formulations (5% and 75%), the precise volume and diameter of the mixture requiring a high drug loading ratio in each printing layer are deduced. Figure 5 As shown, a is the 75% prescription model and b is the controlled-release tablet model. Finally, the models were imported into Blender software to construct a three-dimensional model.

[0090] Specifically, the model design formula for this indomethacin 3D printed controlled-release tablet is as follows: ] Formula 1 In the formula, V i Let H be the volume of the i-th layer of the tablet from the outside to the inside, H be the height of the tablet (mm), D be the diameter of the tablet (mm), ΔH be the height decrease between two adjacent layers (mm), and ΔD be the diameter decrease between two adjacent layers (mm).

[0091] Formula 2

[0092] In the formula, V 75,i ρ is the volume of the mixture with 75% drug loading in the i-th layer, ρ5 is the density of the active pharmaceutical ingredient in the 5% drug loading formulation, and ρ 75 M represents the drug density of a 75% drug loading ratio formulation, and M represents the target drug loading per layer.

[0093] Formula 3

[0094] In the formula, d 75,i denoted as the diameter of the mixture with 75% drug loading in the i-th layer, and h represents the layer height of the printed layer.

[0095] By importing the parameters calculated by the formula into Blender software, the 3D model of the indomethacin 3D printed controlled-release tablets can be completed.

[0096] The controlled-release tablet model in this embodiment is cylindrical, such as... Figure 6As shown, the total diameter D is 8 mm, and the total height H is 5.88 mm. The model is printed with 14 layers from bottom to top, with a single layer height of 0.42 mm. In the release experiment, the tablet dissolves from the outside in, which can be divided into 7 concentric layers. Based on the assumption of proportional dissolution, given that the height decrease ΔH between two adjacent layers is 0.84 mm, the diameter decrease ΔD between two adjacent layers is calculated to be 1.143 mm.

[0097] First, calculate the volume V of the i-th layer of the tablet from the outside to the inside using Formula 1. i (Table 6); secondly, based on the experimentally determined prescription density (ρ5 = 0.0274 mg / mm³), 3 , ρ 75 =0.4139mg / mm 3 Given that the target drug loading M for each layer is set to 2.997 mg, the volume V of the mixture with a 75% drug loading ratio in the i-th layer is calculated using Formula 2. 75,i (Table 6); then, the corresponding diameter d of the 75% drug loading mixture is further calculated using Formula 3. 75,i (Table 6) thus determines the precise dimensions of the high-drug-loaded region in each printed layer of the tablet model (Table 7); finally, the above geometric parameters are imported into Blender software to complete the three-dimensional digital modeling of the controlled-release tablet. Figure 5 , Figure 6 ).

[0098] Table 6. Diameter of the mixture with 75% drug loading in each layer

[0099] Note: The 6th and 7th layers are located in the center of the tablet. When the tablet dissolves to this point, the drug release time has exceeded 12 hours. This design does not affect the effective blood drug concentration within the dosing interval, nor does it interfere with the accuracy of subsequent dosing.

[0100] Table 7. Dimensions of each layer in the 3D printed controlled-release tablet model of indomethacin

[0101] III. Preparation of Indomethacin Controlled-Release Tablets

[0102] 1. Raw material preparation

[0103] Prepare the raw material mixture according to the prescription in the table below.

[0104] Table 8. Formulations for mixtures with 5% (IN5) and 75% (IN75) drug loading ratios

[0105] To prepare a 5% drug loading ratio mixture: HPMC4000, HPMC100 and CMC-Na are mixed evenly; indomethacin and microcrystalline cellulose are mixed evenly; after the two are mixed evenly, 6% polyvinylpyrrolidone ethanol solution is added, and the mixture is ground evenly. 70% ethanol is added to adjust the humidity, and the mixture is obtained.

[0106] To prepare a 75% drug loading ratio mixture: HPMC4000 and CMC-Na were mixed evenly; indomethacin and microcrystalline cellulose were mixed evenly; after the two were mixed evenly, 6% polyvinylpyrrolidone ethanol solution was added and ground evenly to obtain the final product.

[0107] The two semi-solid compositions were loaded into syringes and printed into tablets according to the digital model in a dual-pump semi-solid extrusion 3D printer. After drying at room temperature, indomethacin 3D printed controlled-release tablets were obtained.

[0108] The printing parameters are as follows: needle orifice diameter 410μm, filling pattern is linear, filling spacing 0.3mm, speed 8mm / s, pressure of 5% drug loading mixture 0.15~0.18MPa, pressure of 75% drug loading mixture 0.12~0.14MPa.

[0109] The prepared indomethacin controlled-release tablets are as follows Figure 7 As shown, Figure 7 In the figures, a and b represent the diameter and height of the controlled-release tablet, respectively, and the results show that the tablet has good formability.

[0110] Example 2: Drug release test of indomethacin controlled-release tablets

[0111] 1. In vitro release rate test

[0112] The indomethacin controlled-release tablets prepared in Example 1 were subjected to an in vitro release rate experiment, and the results are as follows: Figure 8 As shown in the figure. The experimental results show that the cumulative release rates of the formulation in the initial 1h and 2h were 9.9% and 18.3%, respectively, with no obvious burst release; in the 4-10h range, the cumulative release rate showed a steady linear upward trend; by 12h, the cumulative release rate reached 99.8%, indicating that the drug had been completely released.

[0113] 2. Drug release model fitting

[0114] Five commonly used drug release models were used to fit the in vitro drug release data from six parallel assays. The model equations are as follows: Zero-order model: Q = kt; First-order model: Q = 1 - e －kt ; Higuchi model: Q = kt 1 / 2 ; Ritger-Peppas model: Q = kt n ; Hixson-Crowell dissolution equation: (1-Q) 1 / 3 =kt + k0; Where Q is the cumulative release rate (%), t is the release time (h), k and k0 are release rate constants, and n is the release index.

[0115] Table 9. Fitting results of the drug release model for indomethacin 3D printed controlled-release tablets

[0116] The fitting results show that the release curve of the indomethacin controlled-release tablets prepared in Example 1 conforms to the zero-order model (R²). 2 =0.9929) and Peppas equation (R 2 =0.9962). The fitting equation for the zero-order model is Q = 0.0855t + 0.0076, with an intercept of 0.0076, which approaches 0, indicating no significant burst release. The release index n = 0.9507 obtained through the Peppas equation indicates that the drug release conforms to the leaching release mechanism.

[0117] The above results show that, through the formulaic printing model design and the close coordination of the selection of active pharmaceutical ingredient and excipients, the indomethacin controlled-release tablets prepared by this invention achieve constant-rate and complete zero-order drug release within 12 hours.

Claims

1. A composition for preparing indomethacin controlled-release tablets, characterized in that, The mixture includes a low drug loading ratio mixture and a high drug loading ratio mixture. Both the low drug loading ratio mixture and the high drug loading ratio mixture contain indomethacin, a filler, a hydrophilic gel matrix material, a thickener, and a binder. The low drug loading ratio mixture also contains a wetting agent. In the low drug loading ratio mixture, indomethacin accounts for 1% to 20% of the solid material mass of the mixture, and in the high drug loading ratio mixture, indomethacin accounts for 50% to 90% of the solid material mass of the mixture.

2. The preparation composition for indomethacin controlled-release tablets as described in claim 1, characterized in that, Meets one or more of the following conditions: (1) In the low drug loading ratio mixture, indomethacin accounts for 2% to 10% of the mass of the solid material in the mixture, preferably 4% to 6%, and more preferably 5%; (2) In the high drug loading ratio mixture, indomethacin accounts for 60% to 80% of the mass of the solid material in the mixture, preferably 70% to 80%, and more preferably 75%; (3) The hydrophilic gel skeleton material is selected from one or more of the HPMC class, more preferably one or two of HPMC 4000 and HPMC100; (4) The filler is microcrystalline cellulose; (5) The thickener is sodium carboxymethyl cellulose; preferably, the thickener is 2-7% of the mass of the hydrophilic gel skeleton material, more preferably 3-5%, for example 4%; (6) The wetting agent is an aqueous ethanol solution; preferably, the wetting agent is an aqueous ethanol solution with a volume percentage concentration of 60%-80%; more preferably, it is an aqueous ethanol solution with a volume percentage of 70%-80%; for example, it is an aqueous ethanol solution with a volume percentage of 70%. (7) In the low drug loading ratio mixture, the ratio of the wetting agent to the solid material of the mixture is 2-5 ml / 6.48 g, preferably 3-4 ml / 6.48 g, for example 3.2 ml / 6.48 g; (8) The adhesive is polyvinylpyrrolidone; preferably, the polyvinylpyrrolidone is PVP K29; more preferably, the adhesive accounts for 5% to 10% of the mass of the solid material in the mixture, preferably 7% to 8%, for example 7.4%; (9) The adhesive is added in solution form, and the ratio of adhesive solution to solid material in the mixture is 1.0-1.5 ml / g, for example 1.23 ml / g; Preferably, the adhesive solution is an ethanol solution with a concentration of 6±1wt% PVP K29, wherein the volume fraction of ethanol in the ethanol solution is 70-80%, for example, 70%.

3. The preparation composition for indomethacin controlled-release tablets as described in claim 1 or 2, characterized in that, In the low drug loading ratio mixture, the hydrophilic gel skeleton material is composed of HPMC4000 and HPMC100, and the hydrophilic gel skeleton material accounts for 5-15% of the mass of the solid material in the mixture, and / or, the mass ratio of HPMC4000 to HPMC100 is 8:2-5:5; preferably, the hydrophilic gel skeleton material accounts for 8-12% of the mass of the solid material in the mixture, for example, 10%; more preferably, the mass ratio of HPMC4000 to HPMC100 is 6-8:2-4, for example, 7:3; In the high drug loading ratio mixture, the hydrophilic gel skeleton material is HPMC4000, and the hydrophilic gel skeleton material accounts for 5-15% of the mass of the solid material in the mixture, preferably 8-12%, for example 10%.

4. The preparation composition for indomethacin controlled-release tablets as described in claim 1, characterized in that, The low drug loading ratio mixture consists of indomethacin, filler, hydrophilic gel matrix material, thickener, wetting agent and binder; The mixture contains indomethacin, comprising 2%–10% of the solid material mass; microcrystalline cellulose as the filler; and HPMC4000 and HPMC100 as the hydrophilic gel skeleton material, comprising 5%–15% of the solid material mass with a mass ratio of 8:2–5:

5. The thickener is sodium carboxymethyl cellulose, comprising 2–7% of the hydrophilic gel skeleton material mass. The wetting agent is a 60%–80% (v / v) aqueous ethanol solution, with a wetting agent to solid material mass ratio of 2–5 ml / 6.48 g. The binder is PVP K29, comprising 5%–10% of the total solid material mass, added in solution form with a binder solution to solid material mass ratio of 1.0–1.5 ml / g, and the binder solution is 6 ± 1% PVP. The ethanol solution of K29, wherein the volume fraction of ethanol in the ethanol solution is 70-80%; The high drug loading ratio mixture is composed of indomethacin, filler, hydrophilic gel matrix material, thickener and binder; In this mixture, indomethacin accounts for 60% to 80% of the solid material mass; the filler is microcrystalline cellulose; the hydrophilic gel skeleton material is HPMC4000, accounting for 5-15% of the solid material mass; the thickener is sodium carboxymethyl cellulose, accounting for 2-7% of the hydrophilic gel skeleton material mass; the binder is PVP K29, accounting for 5% to 10% of the total solid material mass, and is added in solution form. The ratio of binder solution to solid material in the mixture is 1.0-1.5 ml / g, and the binder solution is a 6±1% PVPK29 ethanol solution, wherein the volume fraction of ethanol in the ethanol solution is 70-80%. Preferred, In the low drug loading ratio mixture, indomethacin accounts for 4% to 6% of the mass of the solid material in the mixture, the hydrophilic gel skeleton material accounts for 8% to 12% of the mass of the solid material in the mixture, and the mass ratio of HPMC4000 to HPMC100 is 7.5:2.5-5:5; the thickener accounts for 3-5% of the mass of the hydrophilic gel skeleton material; the wetting agent is an ethanol aqueous solution with a volume percentage concentration of 70% to 80%, and the dosage ratio of the wetting agent to the solid material in the mixture is 3-4 ml / 6.48 g; the binder accounts for 7% to 8% of the total mass of the solid material in the mixture, and the dosage ratio of the binder solution to the solid material in the mixture is 1.1-1.3 ml / g; In the high drug loading ratio mixture, indomethacin accounts for 70% to 80% of the mass of the solid material in the mixture, the hydrophilic gel skeleton material accounts for 8-12% of the mass of the solid material in the mixture; the thickener accounts for 3-5% of the mass of the hydrophilic gel skeleton material; the binder accounts for 7% to 8% of the total mass of the solid material in the mixture, and the ratio of binder solution to solid material in the mixture is 1.1-1.3 ml / g; More preferably, In the low drug loading ratio mixture, indomethacin accounts for 5% of the mass of the solid material in the mixture, the hydrophilic gel skeleton material accounts for 10% of the mass of the solid material in the mixture, and the mass ratio of HPMC4000 to HPMC100 is 7:3; the thickener accounts for 4% of the mass of the hydrophilic gel skeleton material; the wetting agent is a 70% (v / v) aqueous ethanol solution, and the ratio of the wetting agent to the solid material in the mixture is 3.2 ml / 6.48 g; the binder accounts for 7.4% of the total mass of the solid material in the mixture, and the ratio of the binder solution to the solid material in the mixture is 1.23 ml / g, and the binder solution is a 6% PVP K29 ethanol solution, wherein the volume fraction of ethanol in the ethanol solution is 70%. In the high drug loading ratio mixture, indomethacin accounts for 75% of the mass of the solid material in the mixture, the hydrophilic gel skeleton material accounts for 10% of the mass of the solid material in the mixture; the thickener accounts for 4% of the mass of the hydrophilic gel skeleton material; the binder accounts for 7.4% of the total mass of the solid material in the mixture, the ratio of binder solution to solid material in the mixture is 1.23 ml / g, and the binder solution is a 6% PVP K29 ethanol solution, wherein the volume fraction of ethanol in the ethanol solution is 70%.

5. A method for preparing indomethacin controlled-release tablets, characterized in that, The controlled-release tablets were printed using a dual-pump semi-solid extrusion 3D printer according to the following three-dimensional digital model: The three-dimensional digital model is defined with the bottom-to-top dimension as the printing layer and the outside-to-inside dimension as the concentric rings. The volume Vi of the i-th concentric ring and the volume V of the high drug loading ratio mixture in the i-th concentric ring are calculated according to the following formulas 1 to 3. 75,i and its corresponding diameter d 75,i ; Official 1 In Formula 1, V i Let H be the volume of the i-th layer from the outside to the inside of the controlled-release tablet, H be the tablet height, D be the diameter of the controlled-release tablet, ΔH be the height decrease between two adjacent layers, and ΔD be the diameter decrease between two adjacent layers. Official 2 In Formula 2, V 75,i ρi is the volume of the high-drug-loading mixture in the i-th layer, ρ5 is the density of indomethacin in the low-drug-loading mixture, and ρi is the density of indomethacin in the low-drug-loading mixture. 75 M represents the density of indomethacin in a high drug loading ratio mixture, and M represents the target drug loading per layer. Official 3 In Formula 3, d 75,i Let be the diameter of the high drug loading mixture in the i-th layer, and h represent the layer height of the printed layer; Using the preparation composition according to any one of claims 1-4 as the raw material for a dual-pump semi-solid extrusion 3D printer, and based on the three-dimensional digital model established above, the proportion of the high drug loading ratio mixture is increased layer by layer from the outer layer to the inner layer of the controlled-release tablet for 3D printing, thus obtaining the product.

6. The method for preparing indomethacin controlled-release tablets as described in claim 5, characterized in that, Meets one or more of the following conditions: (1) The controlled-release tablet is a cylinder with a diameter D of 8±0.8 mm and a height H of 5.88±0.588 mm; there are a total of 14±2 printed layers, and the height of a single printed layer h is 0.42±0.042 mm; it is divided into 7±1 concentric layers from the outside to the inside according to the dissolution order, with ΔH of 0.84±0.084 mm and ΔD of 1.143±0.1143 mm; M is 2.997±0.2997 mg and ρ5 is 0.0274±0.00274 mg / mm 3 , ρ 75 It was 0.4139 ± 0.04139 mg / mm. 3 ; Preferably, the controlled-release tablet is a cylinder with a diameter D of 8 mm and a height H of 5.88 mm; it has 14 printed layers, with a single printed layer height h of 0.42 mm; it is divided into 7 concentric layers from the outside to the inside according to the dissolution sequence, with ΔH of 0.84 mm and ΔD of 1.143 mm; M is 2.997 mg and ρ5 is 0.0274 mg / mm. 3 , ρ 75 It is 0.4139 mg / mm 3 ; (2) The parameters of the 3D printing are: needle aperture 410±41μm, filling pattern is linear, filling spacing 0.3±0.03mm, printing speed 8±0.8mm / s; extrusion pressure of low drug loading ratio mixture is 0.15~0.18MPa, and extrusion pressure of high drug loading ratio mixture is 0.12~0.14MPa; Preferably, the needle orifice diameter is 410μm, the fill spacing is 0.3mm, and the printing speed is 8mm / s; (3) After the 3D printing, a drying step is also included. Preferably, the drying is done at room temperature.

7. An indomethacin controlled-release tablet, characterized in that, The drug loading ratio of the controlled-release tablet gradually increases from the outer layer to the inner layer in the dissolution order, so that the amount of indomethacin loaded in each layer of the controlled-release tablet from the outside to the inside is equal.

8. The indomethacin controlled-release tablet as described in claim 7, characterized in that, It is prepared using the preparation method described in claim 5 or 6.

9. The indomethacin controlled-release tablet as described in claim 7, characterized in that, The controlled-release tablet is a cylinder with a diameter of 8±0.8 mm and a height of 5.88±0.588 mm, consisting of 14±2 printed layers with a layer height of 0.42±0.042 mm. The central region of the first 14 printed layers from bottom to top is a high drug-load ratio mixture of the preparation composition according to any one of claims 1-4, while the remaining regions are low drug-load ratio mixtures. The diameters of the central regions from bottom to top are 0±0.1 mm, 1.83±0.183 mm, and 2.47±0.24 mm, respectively. 7mm, 2.89±0.289mm, 3.16±0.316mm, 0±0.1mm, 0±0.1mm, 0±0.1mm, 0±0.1mm, 3.16±0.316mm, 2.89±0.289mm, 2.47±0.247mm, 1.83±0.183mm, 0±0.1mm, the remaining printed layers and the remaining areas of each printed layer are low drug loading ratio mixtures in the preparation composition according to any one of claims 1-4; Preferably, the controlled-release tablet is a cylinder with a diameter of 8 mm and a height of 5.88 mm, consisting of 14 printed layers with a layer height of 0.42 mm. The central region of the first to 14th printed layers from bottom to top is a high drug loading ratio mixture in the preparation composition according to any one of claims 1-4, and the remaining regions are low drug loading ratio mixtures. The diameters of the central regions from bottom to top are 0 mm, 1.83 mm, 2.47 mm, 2.89 mm, 3.16 mm, 0 mm, 0 mm, 0 mm, 0 mm, 3.16 mm, 2.89 mm, 2.47 mm, 1.83 mm, and 0 mm, respectively.

10. The indomethacin controlled-release tablet as described in claim 7, characterized in that, The in vitro release curve of the control tablet conforms to the zero-order release model; Preferably, the cumulative release rate of the controlled-release tablet is ≥90% over 12 hours, and / or the fitting coefficient R of the zero-order release model is... 2 ≥0.99.

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