Linagliptin metformin sustained release composition and preparation method thereof

Abstract

The present application relates to a kind of liglietan metformin sustained-release composition and its preparation method, it is related to pharmaceutical preparation technical field, including metformin sustained-release tablet core and liglietan coating layer wrapped on metformin sustained-release tablet core;The liglietan coating layer accounts for 2% to 3% of the total mass of composition;Metformin sustained-release tablet core includes element pill core, coating layer and filling agent;Wherein, element pill core includes large particle size pill core 1.10-1.25mm, medium particle size pill core 0.80-0.95mm and small particle size pill core 0.50-0.65mm, and the mass ratio of large particle size, medium particle size and small particle size pill core is 15:60:25;By particle size classification, pore differentiation design and hydrophobic modification treatment, the drug release curve is optimized, release uniformity is improved, and the production stability and preparation consistency are improved.

Description

TECHNICAL FIELD

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

[0002] The linagliptin compound is the main component of the drug with the trade name linagliptin tablets, and the chemical name is 8-[(3R)-3-amino-1-piperidyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione. The drug synthesized by the compound in the clinic is a new effective selective dipeptidyl peptidase-4 (DPP-4) inhibitor, which can be used for treating type 2 diabetes, and does not increase the risk of hypoglycemia when used alone or in combination with other hypoglycemic drugs. For example, when used in combination with metformin, the defects and deficiencies between them can be effectively compensated, not only the blood glucose can be controlled, but also the kidney function can be protected, and the safety of drug use can be ensured.

[0003] However, in the existing linagliptin and metformin combined drug preparation, there are some problems. Specifically, the drug release behavior of the preparation in the prior art is not uniform, which leads to differences in the absorption and utilization of the drug in the body, affecting the treatment effect. At the same time, there is a problem of uneven distribution of the content of the micro-pellets in the tablet during the tabletting process, which further affects the overall quality and efficacy of the preparation. SUMMARY

[0004] The present application provides a linagliptin metformin sustained-release composition and a preparation method thereof, aiming at the technical problems in the prior art. By particle size grading, pore differentiation design and hydrophobic modification treatment, the drug release curve is optimized, the drug safety is improved, and the production stability and consistency of the preparation are improved, solving the problems of inconsistent release behavior and uneven content in tabletting.

[0005] The technical scheme for solving 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 on the metformin sustained-release tablet core; the linagliptin coating layer accounts for 2%-3% of the total mass of the composition.

[0006] The metformin sustained-release tablet core comprises a base pellet core, a coating layer and a filler.

[0007] The base pellet core comprises a large particle size pellet core 1.10-1.25 mm, a medium particle size pellet core 0.80-0.95 mm and a small particle size pellet core 0.50-0.65 mm, and the mass ratio of the large particle size, medium particle size and small particle size pellet cores is 15:60:25.

[0008] Further, the core of the placebo pill is composed of metformin hydrochloride 50.0 parts, D-trehalose 13.2 parts and hydroxypropyl cellulose LF 0.8 parts by mass fraction;

[0009] The coating layer is composed of D-trehalose 20 parts, ethyl cellulose Surelease®174 5.2 parts and magnesium stearate 0.8 parts;

[0010] The filler is microcrystalline cellulose 10.0 parts.

[0011] Further, the linagliptin coating layer is composed of linagliptin 14 parts, hydroxypropyl methyl cellulose E5 55 parts, polyethylene glycol 4000 13 parts and meglumine 15 parts by mass fraction.

[0012] Further, the core of the placebo pill contains pores, wherein the porosity of the large particle size core is 30%-50% and the pore size is 5-10 μm, and the porosity of the small particle size core is 10%-15% and the pore size is 2-5 μm.

[0013] Further, the core of the placebo pill contains pores, which are formed by the following steps: spraying the large particle size wet core into a 15% hydroxypropyl cellulose E5 ethanol solution at a spraying rate of 2 g / min·kg core, and spraying the small particle size wet core into an 8% hydroxypropyl cellulose E5 ethanol solution at a spraying rate of 1 g / min·kg core, and drying and curing at 60°C.

[0014] Further, the surface of the large particle size core containing pores is also subjected to hydrophobic modification treatment by perfluorodecyltriethoxysilane, specifically, perfluorodecyltriethoxysilane is mixed with ethanol at a mass ratio of 1:50, and is sprayed onto the surface of the core, the large particle size core is increased by 0.2%, and the small particle size core is increased by 0.5%, and the silane is crosslinked and cured by hot air drying at 80°C for 10 minutes.

[0015] A preparation method of a linagliptin metformin sustained-release composition, comprising the following steps:

[0016] (I) preparing a metformin sustained-release tablet core:

[0017] Disperse hydroxypropyl cellulose LF in water to prepare a 4% aqueous solution;

[0018] Mix metformin hydrochloride and D-trehalose, and add to the aqueous solution to prepare a soft material;

[0019] Extrude and round the soft material to prepare a core, and sieve and dry to a moisture content of 2%-3%;

[0020] Dissolve D-trehalose in water, add ethyl cellulose Surelease®174 and magnesium stearate to prepare a coating solution;

[0021] Coat and dry the core;

[0022] Mix the coated pellets of different particle sizes in a mass ratio, mix with microcrystalline cellulose, and then press into tablets;

[0023] (ii) Preparation of linagliptin coating layer: dissolve linagliptin, hydroxypropyl methylcellulose E5, polyethylene glycol 4000 and meglumine in water, and coat on the metformin sustained-release tablet core.

[0024] Further, in the tablet pressing step, a multi-stage hopper tablet pressing device is used, and the hoppers 1, 2 and 3 are filled with large, medium and small particle size coated pellets respectively, and the three groups of hoppers are synchronized to extrude the materials at the same flow rate, and the pellets of different particle sizes are mixed immediately at the outlet and then enter the mold for tablet pressing.

[0025] The beneficial effects of the present application are: through the particle size grading design, the interstitial space of the pellets is reduced, the tablets can improve the adhesion and tightness of the coating and the pellet core. Among them, the small particle size pellet core filling gap, its high specific surface area promotes the rapid diffusion of the drug, compensates for the lag in the initial slow release, the medium particle size pellet core serves as a transition connection, improves the stacking density, serves as a release main body, maintains a linear release rate, and the release slope of 4-8h is 8.32, and the large particle size pellet core constructs the main skeleton to provide support, and its low specific surface area and thick coating film delay the diffusion of the drug and prolong the terminal release;

[0026] On the basis of retaining the synergistic advantages of multiple particle sizes, the problems of insufficient release in the later period caused by the long diffusion path of large particle size pellet cores and the early burst caused by the large specific surface area of small particle size pellet cores are solved through the differential design of the pore size of different particle sizes, so that the release behavior of large and small particle sizes converges to the medium particle size, and further approaches zero-order release kinetics;

[0027] The drug release behavior is regulated by changing the hydrophilic and hydrophobic properties of the surface. The hydrophobic modification utilizes perfluorosilane to form a layer of superhydrophobic 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 the aqueous release medium to wet the surface, thereby preventing the drug from dissolving directly from the surface of the pellet core. At this time, the drug molecules are released through the pre-designed pore channel, realizing directional control of the drug release path. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 It is a schematic diagram of the multi-stage hopper tablet pressing device in the first embodiment of the present application. DETAILED DESCRIPTION

[0029] With reference to the drawings of the embodiments of the present application, the technical solutions in the embodiments of the present application will be clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments of the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the scope of protection of the present application.

[0030] In the description of the present application, the terms "first", "second" are used only for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. In the description of the present application, the meaning of "multiple" is two or more, unless otherwise explicitly and specifically limited.

[0031] In the description of the present application, the term "for example" is used to indicate "as an example, illustration or description". Any embodiment described as "for example" in the present application is not necessarily interpreted as more preferred or more advantageous than other embodiments. The following description is given in order to enable any person skilled in the art to implement and use the present application. 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 can realize the present application without using these specific details. In other examples, well-known structures and processes will not be described in detail to avoid unnecessary details making the description of the present application obscure. Therefore, the present application is not intended to be limited to the shown embodiments, but is consistent with the broadest scope in accordance with the principles and characteristics disclosed in the present application.

[0032] Embodiment 1

[0033] A linagliptin metformin sustained-release composition, comprising a metformin sustained-release tablet core and a linagliptin coating layer;

[0034] The metformin sustained-release tablet core is composed of a base pellet core, a coating layer and a filler, wherein the base pellet core is composed of metformin hydrochloride 50.0 parts, D-trehalose 13.2 parts and hydroxypropyl cellulose LF 0.8 parts in terms of mass fraction;

[0035] The coating layer is composed of D-trehalose 20 parts, ethyl cellulose Surelease®174 5.2 parts and magnesium stearate 0.8 parts;

[0036] The filler is composed of microcrystalline cellulose 10.0 parts;

[0037] The linagliptin layer is composed of linagliptin 14 parts, hydroxypropyl methyl cellulose E5 55 parts, polyethylene glycol 4000 13 parts and meglumine 15 parts in terms of mass fraction;

[0038] said linagliptin layer accounts for 2%-3% of the mass of the linagliptin metformin sustained release composition;

[0039] said linagliptin metformin sustained release composition, specifically comprising the following steps:

[0040] (I) preparation of metformin sustained release tablet core,

[0041] Step 1. Disperse hydroxypropyl cellulose LF in water under stirring, stir until completely dissolved, to prepare a 4% aqueous solution;

[0042] wherein the stirring speed of the wet granulator is 450 rpm and the shear speed is 900 rpm;

[0043] Step 2. Mix metformin hydrochloride and D-trehalose uniformly, add the hydroxypropyl methyl cellulose LF aqueous solution obtained in step 1, and prepare a wet uniform soft material using a wet granulator;

[0044] Step 3. Place the soft material obtained in step 2 into an extruder for extrusion, and place the extrudate into a rounder for rounding, round the cores, sieve, dry, and control the moisture content at 2%-3%, to obtain the drug-containing cores;

[0045] wherein the cores are separated by a three-stage vibrating screen, the upper screen: 1.25 mm (14 mesh), which traps large particle size cores;

[0046] the middle screen: 0.95 mm (18 mesh), which traps medium particle size cores;

[0047] the bottom screen: 0.65 mm (25 mesh), which traps small particle size cores;

[0048] The cores include large particle size 1.10-1.25 mm; medium particle size 0.80-0.95 mm; and small particle size 0.50-0.65 mm;

[0049] Step 4. Dissolve D-trehalose in water under stirring, add ethyl cellulose Surelease® 174 until completely dissolved, and then add magnesium stearate and disperse uniformly to prepare a coating solution;

[0050] Specifically, add D-trehalose to boiling water, stir until completely dissolved, cool to room temperature, and the mass ratio of D-trehalose to water is 2:1. After cooling to room temperature, add Surelease ® 174, magnesium stearate and mix uniformly;

[0051] Step 5. Place the three kinds of drug-containing cores obtained in step 3 into a fluidized bed coater, heat the drug-containing cores to a temperature of 37°C, spray the coating solution obtained in step 4, coat, and dry, to obtain coated pellets;

[0052] The large, medium and small size coated pellets are mixed in a mass ratio of 15:60:25, placed in a three-dimensional motion mixer (25 rpm, 10 min), and 0.5% of fumed silica is added to prevent static adsorption;

[0053] The fluidized bed coating equipment parameters are: atomizing pressure: 5 r / min for peristaltic pump, air volume: 40 m3 / h, inlet air temperature: 80℃, atomizing pressure: 1.0 kg / cm2, outlet air temperature: 65℃, coating weight gain: 25%, cooling temperature: 25℃;

[0054] Step 6. The mixed pellets prepared in step 5 are mixed with the excipient microcrystalline cellulose, as shown in Figure 1 The multi-stage hopper tabletting device is used to simultaneously extrude the materials at the tapered outlet, hopper 1 is filled with large particles, hopper 2 is filled with medium particles, and hopper 3 is filled with small particles. The three groups of hoppers are synchronized to extrude the materials at the same flow rate, and the different particle cores are mixed immediately after entering the mold to obtain metformin sustained-release tablet cores;

[0055] The tabletting pressure is 15-20 kN;

[0056] (II) coating of the linagliptin layer

[0057] The hydroxypropyl methylcellulose E5, polyethylene glycol 4000, meglumine and linagliptin are dissolved in water to prepare a linagliptin layer solution. The linagliptin layer solution is wrapped around the metformin hydrochloride sustained-release tablet core by a coating process to obtain a linagliptin metformin sustained-release composition;

[0058] The mass ratio of hydroxypropyl methylcellulose E5, polyethylene glycol 4000, meglumine, linagliptin and water is 1:50. The immediate-release coating solution is wrapped around the metformin hydrochloride sustained-release tablet core using a coating kettle. The coating kettle parameters are: inlet air temperature: 50-60℃; exhaust air temperature: 30-40℃, 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%.

[0059] Experiments are conducted on the above technical solutions to prepare metformin sustained-release tablet cores and detect the release rate of the metformin sustained-release tablet cores. The comparative example does not use the particle size classification technical solution.

[0060] Take the metformin sustained-release tablet core, and test according to the second method of Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0931, with 1000 ml of pH 6.8 phosphate buffer as the release medium, a rotation speed of 50 rpm, and a temperature of 37 ℃±5 ℃, take 10 ml of the solution at 0 h, 2 h, 4 h, 6 h, 8 h, 10 h and 12 h respectively, filter, and immediately supplement 10 ml of pH 6.8 phosphate buffer at the same temperature in the dissolution cup; precisely take 1 ml of the filtrate, dilute to the mark in a 100 ml volumetric flask with water, shake well, and measure the absorbance at a wavelength of 233 nm by ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition Volume IV General Rules 0401). The release amount of each tablet at different times is calculated according to the absorption coefficient (E1cm100%) of C4H11N5·HCl, which is 798. The 0.5 g specification metformin hydrochloride sustained-release tablets produced by Merck Serono Ltd. are used as the reference preparation for the study.

[0061] Table 1. Dissolution measurement results of commercially available Merck Serono Ltd. 0.5 g specification metformin hydrochloride sustained-release tablets;

[0062] Table 1

[0063]

[0064] Regression equation: Y = 8.4714X + 3.3067, r = 0.9971;

[0065] According to the results of the commercially available metformin hydrochloride sustained-release tablets, the release is close to zero order.

[0066] Table 2 is the dissolution measurement results of the metformin sustained-release tablet cores prepared in this example and the comparative examples in pH 6.8 medium;

[0067] Table 2

[0068]

[0069] The technical solutions in the embodiments of the present application have at least the following technical effects or advantages:

[0070] Through particle size grading design, the gap between the pellets is reduced, the tightness of the filling is realized, and the tabletting can improve the adhesion tightness of the coating and the pellet core. Among them, the small particle size pellet core fills the gap, its high specific surface area promotes the rapid diffusion of the drug, compensates for the lag in the initial release, the medium particle size pellet core serves as a transition connection, improves the stacking density, serves as a release main body, maintains a linear release rate, and the release slope is 8.32 in 4-8 h, and the large particle size pellet core constructs the main skeleton to provide support, its low specific surface area and thick coating film delay the diffusion of the drug and prolong the terminal release;

[0071] Small particle size pellets (25%) fill the gap between large and medium particle sizes, forming a dense packing structure, and the stress is evenly distributed during tabletting. The dense packing structure allows the pressure (15-20 kN) to be evenly transmitted to each pellet, avoiding local high pressure that can cause the coating to break, with a breakage rate of <5%, compared to 15-20% for traditional single particle size. Magnesium stearate forms a lubricating barrier in the coating layer, and D-trehalose plasticizes the film to improve ductility. The combination of the two allows the film to closely adhere to the surface of the pellet core, and to deform rather than break during tabletting.

[0072] The multi-stage hopper tabletting device is used to classify the particle size, block the particle size settlement and stratification during the conveying process, and ensure uniformity. The particle size classification by multi-stage hopper controls the release behavior consistency from the source. The three hoppers extrude the pellets at a ratio of 15:60:25, and the pellets are mixed immediately at the conical outlet to ensure uniformity and stability. Different particle size pellets are embedded in each other, and the tabletting pressure (15-20 kN) is evenly transmitted to improve the integrity of the film.

[0073] The particle size classification design and simultaneous particle size screening during tabletting are used to optimize the release curve. The 6h release amount is 50.1%, with a deviation of only -0.97% and an f2 value of 82.0, which proves high bioequivalence with the original drug. The 2-6h release increment is 30.6%, which avoids the risk of burst release and reduces blood glucose fluctuations. In addition, the production stability is improved, and the simultaneous tabletting technology makes the content uniform and stable in the tablet. Aerosol silica (0.5%) eliminates static adsorption and prevents adhesion, and the pellet flowability is improved.

[0074] The particle size classification and simultaneous tabletting technology solve the problems of inconsistent drug release behavior, easy breakage of the coating film, and uneven tablet content. The multi-particle size synergy achieves near-zero release, small particle size fills and disperses stress, and plasticizers improve the elasticity of the coating.

[0075] Example 2

[0076] The above example one uses particle size classification and simultaneous tabletting technology to solve the problems of inconsistent drug release behavior, easy breakage of the coating film, and uneven tablet content. It achieves release curve optimization and improves production stability. To further optimize the release curve and stability, the example one is further improved.

[0077] The pellet core contains pores, with a porosity of 30-50% for large particle size and a pore size of 5-10μm, and a porosity of 10-15% for small particle size and a pore size of 2-5μm.

[0078] After the core is rounded in step 3, the core of different particle sizes is separated by a three-stage vibration screen, and the wet core of large particle size is placed in a fluidized bed, and 15% hydroxypropyl cellulose E5 ethanol solution is sprayed at a spraying rate of 2 g / min·kg core; the drying condition is 60℃ hot air until the surface wet layer is solidified (10 min);

[0079] The wet core of small particle size is placed in a fluidized bed, and 8% hydroxypropyl cellulose E5 ethanol solution is sprayed at a spraying rate of 1 g / min·kg core, and the drying condition is 60℃ hot air until the surface wet layer is solidified (8 min);

[0080] Drying, moisture control at 2%-3%, and the obtained porous drug-containing core;

[0081] In step 4, when preparing the coating solution, 1.5 parts of polyvinyl alcohol (PVA) are added, and the molecular weight of the polyvinyl alcohol is 30,000;

[0082] In step 6, the tabletting pressure is 12-15 kN.

[0083] The technical scheme of the present embodiment is based on the technical scheme of embodiment one, and is used as embodiment two (one), wherein the difference between the technical scheme of the present embodiment and the technical scheme of embodiment one is that the porosity of the large particle size is 30%-50%, and 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 sample prepared by the technical scheme of the present embodiment is subjected to performance detection, and the detection results are shown in Table 3.

[0084] Table 3

[0085]

[0086] The surface of the porous core of different particle sizes is also subjected to hydrophobic modification treatment by perfluorodecyltriethoxysilane (PFDS);

[0087] Specifically, perfluorodecyltriethoxysilane and ethanol are mixed in a mass ratio of 1:50, and are ultrasonically dissolved;

[0088] The core of different particle sizes is placed in a fluidized bed, and PFDS solution is sprayed at a spraying rate of 0.5 g / min·kg core; and after drying, it is obtained;

[0089] The weight gain of the large particle size core is controlled at 0.2%, and the weight gain of the small particle size core is controlled at 0.5%;

[0090] The drying condition is 80℃ hot air, and the treatment time is 10 minutes to crosslink and solidify the silane.

[0091] The technical scheme of the present embodiment is based on the technical scheme of the above-mentioned embodiment two (I) and is taken as embodiment two (II), wherein the difference between the technical scheme of the present embodiment and the technical scheme of embodiment two (I) is that the surface of the porous size granule core is further subjected to hydrophobic modification treatment by perfluorodecyltriethoxysilane (PFDS); the sample prepared by the technical scheme of the present embodiment is subjected to performance detection, and the detection results are shown in Table 4.

[0092] Table 4

[0093]

[0094] The technical scheme of the present embodiment has at least the following technical effects or advantages:

[0095] On the basis of retaining the synergistic advantages of multiple sizes of granules, the problems of insufficient release in the later period caused by the long diffusion path of large-size granule cores and the early burst caused by the large specific surface area of small-size granule cores are solved by the differential design of different sizes of pores, so that the release behavior of large and small sizes of granule cores converges to medium size, and further approaches zero-order release kinetics.

[0096] The large-size granule core has a high-porosity structure, a large pore size (5-10 μm) shortens the diffusion path, the distance of drug molecules across the granule core is shortened, the high porosity forms an open skeleton, the pores are interconnected to form a capillary network, the capillary effect actively adsorbs the release medium, and the dissolution of the drug inside the granule core is accelerated, thereby compensating for the diffusion disadvantage of large size and avoiding insufficient release in the later period; the small-size granule core has a low-porosity structure, a small pore size (2-5 μm) limits infiltration, the micropore capillary force is enhanced, and the medium penetration time is prolonged, at the same time, hydroxypropyl cellulose E5 swells to form a high-viscosity gel layer in the pore, increasing the drug dissolution resistance, thereby inhibiting the natural burst of small-size granule cores; the medium-size granule core has a non-porosity structure, and the dense matrix maintains the dominant controlled release effect of the ethyl cellulose coating film, serving as a stable base point of the release curve;

[0097] The pores are formed by the phase separation mechanism of the hydroxypropyl cellulose E5 ethanol solution, ethanol as a good solvent penetrates the hydration layer on the surface of the granule core, hydroxypropyl cellulose is gelled in situ, forms a hydrogen-bonded gel network after contacting with the aqueous medium, and the ethanol volatilizes under the action of hot air at 60 ℃, so that the gel network shrinks to form a rigid pore skeleton with controllable pore size; polyvinyl alcohol (PVA) in the coating layer has a nano-pore sealing effect, PVA molecules penetrate to the edge of the pores, and a flexible sealing layer is formed after coating and drying, preventing the pores from being blocked by the ethyl cellulose coating liquid and the absorption stress from fluctuating during tabletting, so that the pore collapse rate is less than 5%; the low-pressure tabletting process realizes stress redistribution, and the pore structure acts as a micro-buffering unit to absorb local stress;

[0098] By differentiating the design of pores of different particle sizes, the fitting degree of the release curve and the production stability are further improved, the coating breakage rate is further reduced due to the dispersion stress of the pores, and the release uniformity is further improved. Due to the synergistic effect of the protective pore effect of PVA and low-pressure tabletting, the stability of the porosity in production is maintained; the high porosity of the large particle size counteracts the diffusion attenuation caused by the geometric size, solving the problem of delayed release; the small particle size uses the micropore capillary resistance to offset the burst problem caused by the high specific surface area, eliminating the risk of burst; the double protection of PVA nano-sealing and low-pressure tabletting ensures the production stability.

[0099] Further, the drug release behavior is regulated by changing the hydrophilic and hydrophobic properties of the surface. The hydrophobic modification utilizes perfluorosilane to form a layer of 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 medium to wet the surface, thereby preventing the drug from dissolving directly from the surface of the pellet core. At this time, the drug molecules are released through the pre-designed pore channel, realizing directional control of the drug release path.

[0100] The fluorine-containing alkyl chain of perfluorodecyltriethoxysilane has self-assembly characteristics, forming a close-packed molecular layer with low surface energy on the surface of the pellet core, significantly increasing the contact angle, making it difficult for aqueous medium to wet the surface, forcing the drug molecules to diffuse only from the pre-designed pore channel; the long-chain perfluoroalkyl group of PFDS has extremely low surface energy. When it is sprayed onto the surface of the pellet core through the fluidized bed and solidified, it forms a dense fluorinated layer on the surface, significantly reducing the surface energy, resulting in an increase in the contact angle, forming a super-hydrophobic surface, making the aqueous medium appear spherical on the surface and unable to spread, thereby preventing the drug from dissolving directly from the surface. In traditional formulations, the drug can freely penetrate the hydrophilic film and diffuse from the surface, but after hydrophobic modification, the only outlet for the drug is the pore channel, the number of paths is greatly reduced, and the risk of burst is significantly inhibited.

[0101] Due to the coverage of the surface by the hydrophobic film, drug molecules cannot diffuse from the entire surface but only from the pores. Among them, the pore size of the large particle size pellet core is 5-10 μm, and the pore size of the small particle size pellet core is 2-5 μm. The path of drug release is limited to the inside of the pores, thereby achieving control of drug release. The pore size of the small particle size pellet core is small, and after hydrophobic modification, the capillary force of the pores is stronger, making the speed of medium penetration into the pores slower, thereby delaying drug release. The pore size of the large particle size pellet core is larger, the capillary force is relatively smaller, and the diffusion path of the drug molecules is shorter, so the release is relatively faster. During tabletting, the hydrophobic layer also plays a lubricating role, reducing the friction between the pellet cores, thereby protecting the pore structure from being damaged.

[0102] By surface hydrophobic modification, precise control of release curve, by limiting the release of drugs only from the pores, can more accurately control the release rate of drugs, enhance the release uniformity: due to all drug molecules need to be released through the pores, the consistency of the release path is improved, so the release difference between different pellet cores is reduced, the batch uniformity of the release curve is improved; Improve the stability of tabletting: the lubrication effect of the hydrophobic layer reduces the friction and stress concentration between the pellet cores during tabletting, thereby reducing the risk of film rupture during tabletting, and the film breakage rate is reduced; Improve the terminal release, in the release of 12 hours, more close to the hydrophobic modification of the marketed preparation can maintain the stability of the late release;

[0103] Hydrophobic modification treatment changes the hydrophilic and hydrophobic properties of the surface of the pellet core, limits the drug release path in the designed pore channel, the fitting degree of the release curve is higher, reduces the risk of early burst release, improves the safety of drug use, and further improves the production stability of the preparation and the consistency of the product.

[0104] It should be noted that in the above embodiments, the description of each embodiment has its own emphasis, and the parts not described in detail in a certain embodiment can be referred to the related description of other embodiments.

[0105] Although the preferred embodiments of the present application have been described, those skilled in the art can make further changes and modifications to these embodiments once they know the basic inventive concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications falling within the scope of the present application.

[0106] Obviously, those skilled in the art can make various modifications and variations to the present application without departing from the spirit and scope of the present application. Thus, if these modifications and variations of the present application fall within the scope of the claims of the present application and their equivalents, the present application also intends to include these modifications and variations.

Claims

1. A linagliptin-metformin sustained-release composition, characterized in that, The composition includes a metformin extended-release tablet core and a linagliptin coating layer encapsulated on the metformin extended-release tablet core; the linagliptin coating layer accounts for 2%-3% of the total mass of the composition. Metformin sustained-release tablet core includes a core pellet, a coating layer, and a filler; The core of the vegetarian pill includes: Large-diameter pellets, with a particle size of 1.10-1.25mm, are used to construct the main framework and provide support; Medium-sized pellets, with a particle size of 0.80-0.95mm, serve as transitional connections and release components, improving stack density. Small-diameter pellets, with a particle size of 0.50-0.65mm, are used to fill the gaps between large-diameter and medium-diameter pellets. The mass ratio of large-diameter, medium-diameter, and small-diameter pellet cores is 15:60:

25.

2. The linagliptin-metformin sustained-release composition as described in claim 1, characterized in that, By weight, the core of the vegetarian pill 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 D-trehalose, 5.2 parts ethyl cellulose Surelease® 174, and 0.8 parts magnesium stearate; The filler is 10.0 parts of microcrystalline cellulose.

3. The linagliptin-metformin sustained-release composition as described in claim 1, characterized in that, The linagliptin coating layer, by weight, consists of 14 parts linagliptin, 55 parts hydroxypropyl methylcellulose E5, 13 parts polyethylene glycol 4000, and 15 parts meglumine.

4. The linagliptin-metformin sustained-release composition as described in claim 1, characterized in that, The pellet core contains pores, wherein the porosity of the large-diameter pellet core is 30%-50% and the pore size is 5-10μm, and the porosity of the small-diameter pellet core is 10%-15% and the pore size is 2-5μm.

5. The linagliptin-metformin sustained-release composition as described in claim 4, characterized in that, The core of the pellet contains pores and is formed by the following steps: spraying large-diameter wet pellet cores into a 15% hydroxypropyl cellulose E5 ethanol solution at a spraying rate of 2 g / min·kg pellet core, spraying small-diameter wet pellet cores into an 8% hydroxypropyl cellulose E5 ethanol solution at a spraying rate of 1 g / min·kg pellet core, and drying and curing at 60°C.

6. The linagliptin-metformin sustained-release composition as described in claim 4, characterized in that, Furthermore, the surface of the pellet cores containing pores of varying sizes was hydrophobically modified using perfluorodecyltriethoxysilane. Specifically, perfluorodecyltriethoxysilane and ethanol were mixed at a mass ratio of 1:50 and sprayed onto the surface of the pellet cores. The weight gain of large-diameter pellet cores was 0.2%, and the weight gain of small-diameter pellet cores was 0.5%. The pellets were then dried with hot air at 80°C for 10 minutes to allow the silane to crosslink and solidify.

7. A method for preparing a linagliptin-metformin sustained-release composition according to any one of claims 1-6, characterized in that, Includes the following steps: (I) Preparation of metformin sustained-release tablet core: Hydroxypropyl cellulose LF was dispersed in water to prepare a 4% aqueous solution; Metformin hydrochloride and D-trehalose were mixed and added to the aqueous solution to prepare a soft material; The soft material is extruded, rounded to form pellet cores, sieved, and then dried to a moisture content of 2%-3%. Dissolve D-trehalose in water, add ethyl cellulose Surelease® 174 and magnesium stearate to prepare a coating solution; The pellet core was coated and dried to obtain coated micro pellets of different sizes; Large, medium, and small coated microspheres were mixed in a mass ratio of 15:60:25 and then mixed with microcrystalline cellulose. The mixture was then extruded simultaneously into a conical outlet using a multi-stage hopper tableting device. Hopper 1 was filled with large-diameter coated microspheres, hopper 2 with medium-diameter coated microspheres, and hopper 3 with small-diameter coated microspheres. The three hoppers extruded the material simultaneously at the same flow rate ratio. The microspheres of different sizes were mixed at the outlet and then pressed into a mold to obtain metformin sustained-release tablet cores. (II) Preparation of linagliptin coating layer: Linagliptin, hydroxypropyl methylcellulose E5, polyethylene glycol 4000 and meglumine are dissolved in water and coated on metformin sustained-release tablet core.

Images