Linagliptin and metformin sustained-release composition and preparation method thereof

Abstract

The invention relates to a linagliptin and metformin sustained-release composition and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, the linagliptin and metformin sustained-release composition comprises a metformin sustained-release tablet core and a linagliptin coating layer wrapping the metformin sustained-release tablet core; the linagliptin coating layer accounts for 2-3% of the total mass of the composition; the metformin sustained-release tablet core comprises a plain pellet core, a coating layer and a filling agent; wherein the plain pellet core comprises a large-particle-size pellet core of 1.10-1.25 mm, a medium-particle-size pellet core of 0.80-0.95 mm and a small-particle-size pellet core of 0.50-0.65 mm, and the mass ratio of the large-particle-size pellet core to the medium-particle-size pellet core to the small-particle-size pellet core is 15: 60: 25; through particle size grading, pore differentiation design and hydrophobic modification treatment, the drug release curve is optimized, the release uniformity is improved, and meanwhile, the production stability and the consistency of the preparation are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a linagliptin-metformin sustained-release composition and a preparation method thereof. Background Art

[0002] Linagliptin is the main ingredient in the drug marketed as Linagliptin tablets. Its chemical name is 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione. Clinically, the drug synthesized from this compound is a new, effective, selective dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes. Its use alone or in combination with other glucose-lowering drugs does not increase the risk of hypoglycemia. For example, when used in combination with metformin, it can effectively compensate for the shortcomings of each, not only controlling blood sugar but also protecting kidney function and ensuring medication safety.

[0003] However, existing linagliptin and metformin combination formulations present several challenges. Specifically, these formulations exhibit uneven drug release behavior, leading to variability in drug absorption and utilization in the body, impacting therapeutic efficacy. Furthermore, the tableting process can lead to uneven distribution of pellets within the tablet, further impacting the overall quality and efficacy of the formulation. Summary of the Invention

[0004] The present invention addresses the technical problems existing in the prior art by providing a sustained-release linagliptin and metformin composition and its preparation method. Through particle size classification, differentiated pore design, and hydrophobic modification, the composition optimizes the drug release profile, improves medication safety, and enhances production stability and formulation consistency, resolving the issues of inconsistent release behavior and uneven tablet content.

[0005] The technical solution of the present invention to solve the above technical problems is as follows: a linagliptin metformin sustained-release composition, comprising a metformin sustained-release tablet core and a linagliptin coating layer wrapped around the metformin sustained-release tablet core; the linagliptin coating layer accounts for 2%-3% of the total mass of the composition; The metformin sustained-release tablet core comprises a plain pill core, a coating layer and a filler; The cores of the vegetarian pills include large-size pills of 1.10-1.25 mm, medium-size pills of 0.80-0.95 mm and small-size pills of 0.50-0.65 mm, and the mass ratio of the large-size, medium-size and small-size pills is 15:60:25.

[0006] Furthermore, the core of the vegetarian pill is composed of 50.0 parts of metformin hydrochloride, 13.2 parts of D-trehalose and 0.8 parts of hydroxypropyl cellulose LF, calculated by weight. The coating layer consists of 20 parts of D-trehalose, 5.2 parts of ethylcellulose Surelease®174, and 0.8 parts of magnesium stearate; The filler is 10.0 parts of microcrystalline cellulose.

[0007] Furthermore, the linagliptin coating layer is composed of 14 parts of linagliptin, 55 parts of hydroxypropyl methylcellulose E5, 13 parts of polyethylene glycol 4000 and 15 parts of meglumine, based on weight.

[0008] Furthermore, the core of the vegetarian pill contains pores, wherein the porosity of the large-size pill core is 30%-50% and the pore size is 5-10 μm, and the porosity of the small-size pill core is 10%-15% and the pore size is 2-5 μm.

[0009] Furthermore, the core of the plain pill contains pores, which are formed by the following steps: spraying the large-particle wet pill core into a 15% hydroxypropyl cellulose E5 ethanol solution at a spray rate of 2 g / min·kg pill core, spraying the small-particle wet pill core into an 8% hydroxypropyl cellulose E5 ethanol solution at a spray rate of 1 g / min·kg pill core, and drying and solidifying at 60°C.

[0010] Furthermore, the surface of the pellet core containing pores of different particle sizes was hydrophobically modified using perfluorodecyltriethoxysilane. Specifically, perfluorodecyltriethoxysilane was mixed with ethanol in a mass ratio of 1:50 and sprayed onto the surface of the pellet core. The large-particle pellet core gained weight by 0.2% and the small-particle pellet core gained weight by 0.5%. The pellet core was then dried with hot air at 80°C for 10 minutes to cross-link and cure the silane.

[0011] A method for preparing a linagliptin metformin sustained-release composition comprises the following steps: (1) Preparation of metformin sustained-release tablet core: Hydroxypropylcellulose LF was dispersed in water to prepare a 4% aqueous solution; Mixing metformin hydrochloride and D-trehalose, and adding the aqueous solution to prepare a soft material; The soft material is extruded and rounded into pellet cores, which are then sieved and dried to a moisture content of 2%-3%; Dissolve D-trehalose in water, add ethylcellulose Surelease®174 and magnesium stearate to prepare a coating solution; Coating and drying the pellet cores; Coated pellets of different particle sizes are mixed according to mass ratio, mixed with microcrystalline cellulose and then tableted; (2) Preparation of linagliptin coating layer: dissolving linagliptin, hydroxypropyl methylcellulose E5, polyethylene glycol 4000 and meglumine in water and coating the resulting mixture on metformin sustained-release tablet core.

[0012] Furthermore, a multi-stage hopper tableting device is used in the tableting step to extrude the pellets synchronously to the conical outlet. Hopper 1 is filled with large-size coated pellets, hopper 2 is filled with medium-size coated pellets, and hopper 3 is filled with small-size coated pellets. The three groups of hoppers extrude the materials synchronously at an equal flow rate ratio. The pellets of different sizes are immediately mixed at the outlet and then enter the mold for tableting.

[0013] The beneficial effects of the present invention are: through particle size classification design, the gaps between micropellets are reduced, achieving dense packing, and tableting can improve the adhesion between the coating and the pellet core. Among them, the small-sized pellet core fills the gaps, and its high specific surface area promotes rapid drug diffusion, compensating for the initial lag of sustained release. The medium-sized pellet core acts as a transition link, improving stacking density and serving as the main release body, maintaining a linear release rate with a 4-8h release slope of 8.32. The large-sized pellet core provides support for the main skeleton, and its low specific surface area and thickened coating delay drug diffusion and prolong terminal release. While retaining the synergistic advantages of multi-size micropellets, the differentiated pore design of different particle sizes addresses the problems of large-size pellets with a long diffusion path, which can lead to insufficient late release, and small-size pellets with a large specific surface area, which can cause early burst release. This allows the release behavior of large and small particle sizes to converge toward the medium particle size, further approaching zero-order release kinetics. Drug release behavior is regulated by changing the surface hydrophilicity and hydrophobicity. Hydrophobic modification uses perfluorosilane to form a super-hydrophobic film on the surface of the pellet core, thereby changing the path and rate of drug release. After hydrophobic modification, the surface of the pellet core becomes hydrophobic, making it difficult for aqueous release media to wet the surface, thereby preventing the drug from directly dissolving from the pellet core surface. At this time, the drug molecules are released through pre-designed pore channels, achieving directional control of the drug release path. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Schematic diagram of a multi-stage hopper tableting device in Example 1 of the present invention. DETAILED DESCRIPTION

[0015] The following will be combined with the drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without making creative efforts are within the scope of protection of this application.

[0016] In the description of this application, the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, a feature specified as "first" or "second" may explicitly or implicitly include one or more of the described features. In the description of this application, "plurality" means two or more, unless otherwise specifically specified.

[0017] In the description of this application, the term "for example" is used to mean "used as an example, illustration or explanation". Any embodiment described as "for example" in this application is not necessarily to be construed as being more preferred or advantageous than other embodiments. The following description is given to enable any person skilled in the art to implement and use the present invention. In the following description, details are listed for the purpose of explanation. It should be understood that a person of ordinary skill in the art will recognize that the present invention can be implemented without using these specific details. In other examples, well-known structures and processes will not be elaborated in detail to avoid obscuring the description of the present invention with unnecessary details. Therefore, the present invention is not intended to be limited to the embodiments shown, but is consistent with the widest scope consistent with the principles and features disclosed in this application.

[0018] Example 1 A linagliptin metformin sustained-release composition comprising a metformin sustained-release tablet core and a linagliptin coating layer; The metformin sustained-release tablet core consists of a vegetarian pill core, a coating layer and a filler. In parts by mass, the vegetarian pill core consists of 50.0 parts of metformin hydrochloride, 13.2 parts of D-trehalose and 0.8 parts of hydroxypropyl cellulose LF. The coating layer consists of 20 parts of D-trehalose, 5.2 parts of ethylcellulose Surelease®174, and 0.8 parts of magnesium stearate; The filler consists of 10.0 parts of microcrystalline cellulose; The linagliptin layer is composed of 14 parts of linagliptin, 55 parts of hydroxypropyl methylcellulose E5, 13 parts of polyethylene glycol 4000 and 15 parts of meglumine, calculated by weight; The linagliptin layer accounts for 2%-3% of the mass of the linagliptin metformin sustained-release composition; The preparation method of the linagliptin metformin sustained-release composition specifically comprises the following steps: (1) Preparation of metformin sustained-release tablet core, Step 1. Add hydroxypropyl cellulose LF to water under stirring and disperse, stirring until completely dissolved to prepare a 4% aqueous solution; Among them, the stirring speed of the wet granulator is 450 rpm and the shear speed is 900 rpm; Step 2. Metformin hydrochloride and D-trehalose are mixed evenly, and the hydroxypropyl methylcellulose LF aqueous solution obtained in step 1 is added thereto, and a wet granulator is used to prepare a moist and uniform soft material; Step 3. The soft material obtained in step 2 is extruded in an extruder, and the extrudate is spheronized in a spheronizer to form pellet cores, which are then sieved and dried to control the moisture content to 2%-3% to obtain the pellet cores containing the drug; Among them, the pellet cores are separated by three-stage vibrating screens, the upper screen is 1.25 mm (14 mesh), which intercepts the pellet cores with large particle size; Middle screen: 0.95 mm (18 mesh), intercepting medium-sized pellets; Bottom screen: 0.65 mm (25 mesh), intercepting small particle size pellets; The pellet cores include large particle size 1.10-1.25 mm; medium particle size 0.80-0.95 mm; small particle size 0.50-0.65 mm; Step 4. Dissolve D-trehalose in water while stirring, add Surelease® 174 ethylcellulose until completely dissolved, and then add magnesium stearate and disperse evenly to prepare a coating solution; Specifically, D-trehalose was added to boiling water, stirred until completely dissolved, and cooled to room temperature. The mass ratio of D-trehalose to water was 2:1. After cooling to room temperature, Surelease was added. ® 174. Mix magnesium stearate evenly; Step 5. Place the three particle sizes of drug-containing pellet cores obtained in step 3 in a fluidized bed coater, heat the pellet cores to 37°C, spray the coating solution obtained in step 4, coat the pellets, and dry them to obtain coated pellets. The large-size, medium-size, and small-size coated pellets were mixed in a mass ratio of 15:60:25 and placed in a three-dimensional motion mixer (25 rpm, 10 min). 0.5% of the total mass of fumed silica was added to prevent electrostatic adsorption. The parameters of the fluidized bed coating equipment are as follows: atomization pressure: peristaltic pump speed 5r / min, air volume 40m3 / h, air inlet temperature 80℃, atomization pressure 1.0kg / cm2, air outlet temperature: 65℃, coating weight gain: 25%, cooling temperature: 25℃; Step 6. Mix the mixed pellets prepared in step 5 with the auxiliary material microcrystalline cellulose, as shown in FIG. Figure 1 As shown, a multi-stage hopper tableting device is used to extrude materials synchronously to a conical outlet. Hopper 1 is filled with large-size particles, hopper 2 is filled with medium-size particles, and hopper 3 is filled with small-size particles. The three groups of hoppers extrude materials synchronously at an equal flow rate ratio. Pellets with different particle sizes are immediately mixed at the outlet and then enter the mold for tableting to obtain metformin sustained-release tablets. Among them, the tableting pressure is 15-20 kN; (2) Coating of the Linagliptin Coating Layer Dissolving hydroxypropyl methylcellulose E5, polyethylene glycol 4000, meglumine, and linagliptin in water to prepare a linagliptin layer solution, and coating the linagliptin layer solution on a metformin hydrochloride sustained-release tablet core by a coating process to obtain a linagliptin-metformin sustained-release composition; The mass ratio of hydroxypropyl methylcellulose E5, polyethylene glycol 4000, meglumine, linagliptin and water is 1:50, and the immediate-release coating solution is coated on the metformin hydrochloride sustained-release tablet core using a coating pan; the coating pan parameters are: inlet temperature: 50-60°C; exhaust temperature: 30-40°C, spray pressure: 1.0-1.5 bar, spray gun distance: 15-20 cm, and the moisture content of the linagliptin metformin sustained-release composition is ≤2%.

[0019] Experiments were conducted based on the above technical solution to prepare metformin sustained-release tablet cores and test the release rate of metformin sustained-release tablet cores; the comparative example did not adopt the technical solution of particle size classification; Take metformin sustained-release tablet cores and test them according to the provisions of the second method of Part IV of the Chinese Pharmacopoeia 2020 edition, 0931. Use 1000 ml of pH 6.8 phosphate buffer as the release medium, the rotation speed is 50 rpm, and the temperature is 37°C ± 5°C. Take 10 ml of the solution at 0 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours respectively, filter, and immediately add 10 ml of pH 6.8 phosphate buffer at the same temperature to the dissolution cup; accurately measure 1 ml of the filtrate respectively, place it in a 100 ml volumetric flask, dilute with water to the scale, shake well, and measure the absorbance at a wavelength of 233 nm according to the UV-visible spectrophotometry method (Part IV of the Chinese Pharmacopoeia 2020 edition 0401). The release amount of each tablet at different times is calculated based on the absorption coefficient of C4H11N5·HCl (E1cm100%) of 798. The study was conducted using 0.5g metformin hydrochloride sustained-release tablets produced by Merck Serono Ltd as the reference preparation.

[0020] Table 1. Dissolution measurement results of 0.5 g metformin hydrochloride sustained-release tablets produced by Merck Serono Ltd. Table 1

[0021] Regression equation: Y=8.4714X+3.3067, r=0.9971; The results of commercially available metformin hydrochloride sustained-release tablets show that the release is close to zero order; Table 2 shows the dissolution measurement results of metformin sustained-release tablets prepared in this example and comparative example in a pH 6.8 medium; Table 2

[0022] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: Through particle size classification design, the gaps between micropellets are reduced, achieving tight packing. Tableting can improve the adhesion between the coating and the core. Among them, the small-sized core fills the gaps, and its high specific surface area promotes rapid drug diffusion, compensating for the initial lag of sustained release. The medium-sized core acts as a transition link, improving stacking density and serving as the main release body, maintaining a linear release rate with a 4-8h release slope of 8.32. The large-sized core provides support for the main skeleton. Its low specific surface area and thickened coating delay drug diffusion and prolong the final release. Small-sized micropellets (accounting for 25%) fill the gaps between large / medium-sized particles, forming a dense stacking structure. Stress is evenly distributed during tableting, and the dense filling structure allows pressure (15-20 kN) to be evenly transmitted to each micropellet, avoiding local high pressure that may cause coating rupture. The rupture rate is <5%, while the rupture rate of traditional single-size particles is 15% to 20%. Magnesium stearate forms a lubricating barrier in the coating layer, and D-trehalose plasticizes the coating to improve ductility. The two work together to make the coating fit tightly to the surface of the pill core, causing deformation rather than rupture during tableting.

[0023] The multi-stage hopper tableting device achieves particle size classification, preventing particle size sedimentation and stratification during transportation while ensuring uniformity. The multi-stage hopper particle size classification controls the release behavior consistency from the source. The three hoppers extrude micropellets at an equal speed in a ratio of 15:60:25 and are immediately mixed at the conical outlet to ensure uniformity and stability. Micropellets of different particle sizes are interlocked, and the tableting pressure (15-20 kN) is evenly transmitted, improving the integrity of the film. Through particle size classification and simultaneous particle size screening during tableting, an optimized release profile was achieved. The 6-hour release was 50.1%, with a deviation of only -0.97% and an f2 value of 82.0, demonstrating high bioequivalence to the original drug. The 2-6-hour release increment was 30.6%, avoiding the risk of burst release and thus reducing blood sugar fluctuations. Furthermore, production stability was improved, and simultaneous tableting technology ensured uniform and stable content distribution of the pellets within the tablets. The fumed silica (0.5%) eliminated electrostatic adsorption, prevented adhesion, and improved pellet flowability. Through particle size grading and control combined with synchronous tableting technology, the problems of inconsistent drug release behavior, easy rupture of the coating film, and uneven tableting content are solved. Near-zero-order release is achieved through the collaboration of multiple particle sizes, small particle filling disperses stress and combines with plasticizers to improve coating elasticity, and particle size grading and synchronous extrusion achieve uniform content distribution of microcapsules in the tablet.

[0024] Example 2 The above embodiment 1 solves the problems of inconsistent drug release behavior, easy rupture of the coating film, and uneven tablet content by combining particle size classification control with synchronous tableting technology, optimizes the release curve, and improves production stability. In order to further optimize the release curve and stability, further improvements are made on the basis of embodiment 1.

[0025] The pellet core contains pores, wherein the large particle size has a porosity of 30%-50% and a pore size of 5-10 μm, and the small particle size has a porosity of 10-15% and a pore size of 2-5 μm; Step 3: After spheronization to form pellet cores, pellet cores of different particle sizes were separated through a three-stage vibrating screen. The large-size wet pellet cores were placed in a fluidized bed and sprayed with a 15% hydroxypropyl cellulose E5 ethanol solution at a spray rate of 2 g / min·kg pellet core. Drying conditions: hot air at 60°C until the surface wet layer solidified (10 min). Place the small-size wet pellets in a fluidized bed and spray 8% hydroxypropylcellulose E5 ethanol solution at a spray rate of 1 g / min·kg pellets. Dry with hot air at 60°C until the surface wet layer solidifies (8 min). Drying, controlling the moisture content at 2%-3%, to obtain a porous pill core; When preparing the coating solution in step 4, add 1.5 parts of polyvinyl alcohol (PVA), the molecular weight of which is 30,000; During tableting in step 6, the tableting pressure is 12-15 kN.

[0026] The technical solution of this embodiment was tested on the basis of the technical solution of Example 1, as Example 2 (I). The difference between the technical solution of this embodiment and the technical solution of Example 1 is that the porosity of the large particle size is 30%-50%, the pore size is 5-10 μm, and the porosity of the small particle size is 10-15%, and the pore size is 2-5 μm. The performance of the samples prepared by the technical solution of this embodiment was tested, and the test results are shown in Table 3 below. Table 3

[0027] The surface of the porous and large-sized pellet cores was also hydrophobically modified by perfluorodecyltriethoxysilane (PFDS); Specifically, perfluorodecyltriethoxysilane and ethanol were mixed in a mass ratio of 1:50 and dissolved by ultrasonication; The pellets with different particle sizes were placed in a fluidized bed and sprayed with PFDS solution at a spray rate of 0.5 g / min·kg pellets. The pellets were dried to obtain the pellets. Among them, the weight gain of large particle size pellets is controlled at 0.2%, and the weight gain of small particle size pellets is controlled at 0.5%; The drying condition is 80°C hot air, and the treatment is 10 minutes to crosslink and cure the silane.

[0028] The technical solution of this embodiment was tested on the basis of the technical solution of the above-mentioned embodiment 2 (1), as embodiment 2 (2). The difference between the technical solution of this embodiment and the technical solution of embodiment 2 (1) is that the surface of the large and small particle cores containing pores is also hydrophobically modified by perfluorodecyltriethoxysilane (PFDS). The samples prepared by the technical solution of this embodiment were subjected to performance testing, and the test results are shown in Table 4 below. Table 4

[0029] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: On the basis of retaining the synergistic advantages of multi-particle size microcapsules, the differentiated design of pores with different particle sizes is used to solve the problems of large-particle size pellets with long diffusion paths that easily lead to insufficient release in the later stage and small-particle size pellets with large specific surface area that easily lead to early burst release in particle size control, so that the release behavior of large and small particle sizes converges to the medium particle size, further approaching zero-order release kinetics.

[0030] Large-particle cores have a highly porous structure. The large pore size (5-10 μm) shortens the diffusion path, shortening the distance drug molecules travel across the core. The high porosity forms an open skeleton, and the interconnected pores form a capillary network. This actively adsorbs the release medium through the capillary effect, accelerating the dissolution of the drug inside the core, thereby compensating for the diffusion disadvantage of large particles and avoiding insufficient release in the later stages. Small-particle cores have a low-porosity structure. The small pore size (2-5 μm) limits infiltration, enhancing the microporous capillary force and prolonging the medium penetration time. At the same time, hydroxypropyl cellulose E5 absorbs water and expands in the pores to form a high-viscosity gel layer, increasing the resistance to drug dissolution, thereby inhibiting the natural burst release of small-particle cores. Medium-particle cores have a non-porous structure. The dense matrix maintains the dominant controlled release effect of the ethylcellulose coating, serving as the stable base point of the release curve. Pores are created through the phase separation mechanism of hydroxypropyl cellulose E5 ethanol solution. Ethanol, acting as a good solvent, penetrates the hydration layer on the surface of the pellet core, causing in-situ gelation of the hydroxypropyl cellulose. Upon contact with the aqueous matrix, a hydrogen-bonded cross-linked gel network is formed. Hot air at 60°C evaporates the ethanol, causing the gel network to lose water and shrink, forming a rigid porous skeleton with controllable pore size. The polyvinyl alcohol (PVA) in the coating layer acts as a nanopore sealer. PVA molecules penetrate the pore edges and form a flexible sealing layer after coating and drying. This prevents the ethyl cellulose coating solution from clogging the pores and absorbs stress fluctuations during tableting, resulting in a pore collapse rate of less than 5%. The low-pressure tableting process achieves stress redistribution, with the pore structure acting as a micro-buffer unit to absorb local pressure. Through differentiated pore design for different particle sizes, the fitting degree of the release curve and production stability are further improved, the coating breakage rate is further reduced due to the pore dispersion stress, and the release uniformity is further improved. Due to the protective pore effect of PVA and the synergy of low-pressure tableting, the stability of the porosity in production is maintained; large particles use high pores to counteract the diffusion attenuation caused by geometric dimensions, solving the problem of delayed release; small particles use microporous capillary resistance to offset the burst release problem caused by high specific surface area, eliminating the risk of burst release; PVA nano-sealing and low-pressure tableting form double protection to ensure production stability.

[0031] Furthermore, drug release behavior is regulated by changing the surface hydrophilicity and hydrophobicity. Hydrophobic modification uses perfluorosilane to form a super-hydrophobic film on the surface of the pellet core, thereby changing the path and rate of drug release. After hydrophobic modification, the surface of the pellet core becomes hydrophobic, making it difficult for aqueous release media to wet the surface, thereby preventing the drug from directly dissolving from the pellet core surface. At this time, the drug molecules are released through pre-designed pore channels, achieving directional control of the drug release path. The fluorinated alkyl chains of perfluorodecyltriethoxysilane have self-assembly properties, forming a close-packed molecular layer with low surface energy on the surface of the pellet core, significantly increasing the contact angle and preventing aqueous media from wetting the surface, forcing drug molecules to diffuse only through pre-set pore channels. The long-chain perfluoroalkyl group of PFDS has extremely low surface energy. When it is sprayed onto the surface of the pellet core through a fluidized bed and cured, it forms a dense fluorinated layer on the surface, significantly reducing the surface energy and increasing the contact angle, forming a superhydrophobic surface. The aqueous medium appears spherical on the surface, unable to spread, and thus unable to directly dissolve the drug from the surface. In traditional formulations, the drug can freely penetrate the hydrophilic coating and diffuse from the surface. However, after hydrophobic modification, the only exit for the drug is through the pore channels, greatly reducing the number of pathways and significantly suppressing the risk of burst release. Because the surface is covered with a hydrophobic membrane, drug molecules cannot diffuse from the entire surface and can only diffuse out from the pores. The pore size of the large-particle pellet core is 5-10μm, and the pore size of the small-particle pellet core is 2-5μm. The drug release path is confined to the inside of the pore, thereby achieving controlled drug release. The small-particle pellet core has a small pore size, and after hydrophobic modification, the capillary force of its pore is stronger, which slows down the speed at which the medium penetrates the pore, thereby delaying drug release. The large-particle pellet core has a larger pore size, relatively smaller capillary force, and a shorter diffusion path for drug molecules, resulting in relatively faster release. During the tableting process, the hydrophobic layer can also act as a lubricant, reducing friction between the pellet cores, thereby protecting the pore structure from being destroyed. Through surface hydrophobic modification, the release curve can be precisely controlled. By limiting drug release only from the pores, the drug release rate can be more accurately controlled and the release uniformity can be enhanced. Since all drug molecules must be released through the pores, the consistency of the release path is improved, so the release differences between different pellets are reduced, and the intra-batch uniformity of the release curve is improved. The tableting stability is improved: the lubricating effect of the hydrophobic layer reduces the friction and stress concentration between the pellets during the tableting process, thereby reducing the risk of film rupture during the tableting process and reducing the film breakage rate. The terminal release is improved. During the 12-hour release, the release is closer to that of commercially available formulations. The hydrophobic modification can maintain the stability of the late release. The hydrophobic modification treatment changes the hydrophilicity and hydrophobicity of the pellet core surface, limiting the drug release path to the designed pore channel. The release curve has a higher fit, reducing the risk of early burst release, improving medication safety, and further improving the production stability of the preparation and product consistency.

[0032] It should be noted that, in the above embodiments, the description of each embodiment has its own focus. For parts that are not described in detail in a certain embodiment, reference can be made to the relevant description of other embodiments.

[0033] Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0034] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. A linagliptin metformin sustained-release composition, characterized in that: The invention comprises a metformin sustained-release tablet core and a linagliptin coating layer wrapped on the metformin sustained-release tablet core; the linagliptin coating layer accounts for 2%-3% of the total mass of the composition; The metformin sustained-release tablet core comprises a plain pill core, a coating layer and a filler; The cores of the vegetarian pills include large-size pills of 1.10-1.25 mm, medium-size pills of 0.80-0.95 mm and small-size pills of 0.50-0.65 mm, and the mass ratio of the large-size, medium-size and small-size pills is 15:60:

25.

2. The linagliptin metformin sustained-release composition according to claim 1, wherein The core of the vegetarian pill is composed of 50.0 parts of metformin hydrochloride, 13.2 parts of D-trehalose and 0.8 parts of hydroxypropyl cellulose LF in parts by mass; The coating layer consists of 20 parts of D-trehalose, 5.2 parts of ethylcellulose Surelease®174, and 0.8 parts of magnesium stearate; The filler is 10.0 parts of microcrystalline cellulose.

3. The linagliptin metformin sustained-release composition according to claim 1, wherein The linagliptin coating layer is composed of 14 parts of linagliptin, 55 parts of hydroxypropyl methylcellulose E5, 13 parts of polyethylene glycol 4000 and 15 parts of meglumine, calculated by weight.

4. The linagliptin metformin sustained-release composition according to claim 1, wherein The core of the vegetarian pill contains pores, wherein the porosity of the large-size pill core is 30%-50% and the pore size is 5-10 μm, and the porosity of the small-size pill core is 10%-15% and the pore size is 2-5 μm.

5. The linagliptin metformin sustained-release composition according to claim 4, wherein The core of the plain pill contains pores, which are formed by the following steps: spraying the large-particle wet pill core into a 15% hydroxypropyl cellulose E5 ethanol solution at a spray rate of 2 g / min·kg pill core, spraying the small-particle wet pill core into an 8% hydroxypropyl cellulose E5 ethanol solution at a spray rate of 1 g / min·kg pill core, and drying and solidifying at 60°C.

6. The linagliptin metformin sustained-release composition according to claim 4, wherein The surface of the pellet core containing pores was also hydrophobically modified using perfluorodecyltriethoxysilane. Specifically, perfluorodecyltriethoxysilane was mixed with ethanol in a mass ratio of 1:50 and sprayed onto the surface of the pellet core. The large-size pellet core gained weight by 0.2% and the small-size pellet core gained weight by 0.5%. The pellet core was then dried with hot air at 80°C for 10 minutes to cross-link and cure the silane.

7. A method for preparing the linagliptin metformin sustained-release composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) Preparation of metformin sustained-release tablet core: Hydroxypropylcellulose LF was dispersed in water to prepare a 4% aqueous solution; Mixing metformin hydrochloride and D-trehalose, and adding the aqueous solution to prepare a soft material; The soft material is extruded and rounded into pellet cores, which are then sieved and dried to a moisture content of 2%-3%; Dissolve D-trehalose in water, add ethylcellulose Surelease®174 and magnesium stearate to prepare a coating solution; Coating and drying the pellet cores; Coated pellets of different particle sizes are mixed according to mass ratio, mixed with microcrystalline cellulose and then tableted; (2) Preparation of linagliptin coating layer: dissolving linagliptin, hydroxypropyl methylcellulose E5, polyethylene glycol 4000 and meglumine in water and coating the resulting mixture on the metformin sustained-release tablet core.

8. The method for preparing the linagliptin metformin sustained-release composition according to claim 7, wherein: In the tableting step, a multi-stage hopper tableting device is used to extrude materials synchronously to the conical outlet. Hopper 1 is filled with large-size coated micropellets, hopper 2 is filled with medium-size coated micropellets, and hopper 3 is filled with small-size coated micropellets. The three groups of hoppers extrude materials synchronously at an equal flow rate ratio. The pellets of different particle sizes are immediately mixed at the outlet and then enter the mold for tableting.

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