Sitaπb and metformin extended release pharmaceutical composition, and preparation method and application thereof

Abstract

The application provides a sitagliptin and metformin hydrochloride sustained-release pharmaceutical composition and a preparation method and application thereof, and relates to the technical field of sustained-release preparations. The pharmaceutical composition comprises a sustained-release tablet core and a quick-release coating layer; the sustained-release tablet core comprises active ingredients metformin hydrochloride and a sustained-release matrix material hydroxypropyl methyl cellulose, and the sustained-release tablet core does not contain microcrystalline cellulose; the quick-release coating layer comprises active ingredients sitagliptin phosphate; the weight ratio of metformin hydrochloride to hydroxypropyl methyl cellulose in the sustained-release tablet core is 50:(24-27). The composition realizes double-phase release of drugs by using a double-layer structure; by removing the microcrystalline cellulose and limiting the specific ratio of active ingredients to the matrix material, the forming property of the preparation and the ideal dissolution behavior are ensured while the tablet weight is significantly reduced to improve the swallowing compliance, and the technical problem that a high drug loading compound preparation is difficult to maintain the function of the sustained-release matrix under a large amount of weight reduction is successfully solved.

Description

Sitagliptin-Metformin Extended-Release Drug Composition, Preparation Method and Application Technical Field

[0001] This invention relates to the field of sustained-release formulation technology, and more specifically, to a sitagliptin-metformin sustained-release pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Type 2 diabetes is a common metabolic disease whose pathogenesis mainly involves complex pathophysiological processes such as insulin resistance and insufficient insulin secretion. With changes in global lifestyles, the incidence of this disease is increasing year by year. Poor blood glucose control can easily lead to serious microvascular and macrovascular complications. Therefore, the main goal of clinical treatment is to achieve and maintain stable blood glucose levels through diet control, exercise therapy, and drug intervention, thereby delaying the onset of complications and improving the patient's quality of life.

[0003] In the current drug treatment system, metformin hydrochloride is widely used as a first-line drug for treating type 2 diabetes due to its significant blood glucose-lowering effect, lack of hypoglycemia, and ability to improve insulin resistance. Sitagliptin phosphate, on the other hand, is a dipeptidyl peptidase-IV (DPP-4) inhibitor that promotes insulin release in a glucose-dependent manner by protecting incretins from degradation. Clinical studies have shown that combining these two drugs with complementary mechanisms of action can exert a synergistic effect against multiple pathological defects in diabetes. Currently, the pharmaceutical field has developed fixed-dose combined extended-release formulations containing both active ingredients, aiming to reduce the frequency of dosing through extended-release technology, thereby making it more convenient for patients to use.

[0004] However, existing sitagliptin-metformin combination extended-release formulations have certain physical limitations in clinical application. Because metformin requires a relatively large single-dose dose (typically 500mg to 1000mg), existing tablets often contain a large amount of excipients for filling or constructing the matrix to maintain their extended-release characteristics and ensure proper formulation formation, resulting in a significant increase in tablet volume and weight. For example, some commercially available products have tablets weighing over 1.15g. This excessively large tablet size causes significant swallowing difficulties for patients, especially elderly patients with impaired swallowing function, leading to decreased adherence in some patients, and even self-reduction or discontinuation of treatment, directly affecting glycemic control.

[0005] While reducing tablet weight to improve swallowing compliance is a pressing clinical need, achieving this goal in high-drug-load compound sustained-release formulations presents significant technical challenges. Simply reducing excipient amounts can easily lead to insufficient strength of the sustained-release matrix structure, resulting in poor formability and high brittleness. Simultaneously, changes in excipient ratios often cause significant deviations in drug release behavior, leading to dissimilar dissolution profiles compared to the reference formulation and compromising bioequivalence. Furthermore, ensuring the chemical stability of two active ingredients with significantly different physicochemical properties during preparation and storage while simplifying the formulation is another major challenge in this field. Summary of the Invention

[0006] The purpose of this invention is to provide a sitagliptin-metformin sustained-release pharmaceutical composition, its preparation method, and its application. The composition has a structure of sustained-release tablet core combined with immediate-release coating, and uses a specific ratio of excipients in a microcrystalline cellulose-free tablet core. This significantly reduces tablet weight to improve swallowing compliance while taking into account excellent formability and ideal dissolution behavior.

[0007] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0008] In a first aspect, the present invention provides a sitagliptin-metformin sustained-release pharmaceutical composition, the pharmaceutical composition comprising a sustained-release tablet core and an immediate-release coating layer covering the sustained-release tablet core;

[0009] The sustained-release tablet core contains the active ingredient metformin hydrochloride and the sustained-release matrix material hydroxypropyl methylcellulose, and the sustained-release tablet core does not contain microcrystalline cellulose;

[0010] The immediate-release coating layer contains the active ingredient sitagliptin phosphate;

[0011] In the sustained-release tablet core, the weight ratio of metformin hydrochloride to hydroxypropyl methylcellulose is 50:(24~27).

[0012] In some embodiments, the hydroxypropyl methylcellulose in the sustained-release tablet core is high-viscosity hydroxypropyl methylcellulose;

[0013] Preferably, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose K100M.

[0014] In some embodiments, the sustained-release tablet core further comprises an adhesive; preferably, the adhesive is povidone; and / or,

[0015] The sustained-release tablet core further comprises a flow aid; preferably, the flow aid is colloidal silica; and / or,

[0016] The sustained-release tablet core also contains a lubricant; preferably, the lubricant is sodium stearate fumarate.

[0017] In some embodiments, the sustained-release tablet core is made of components comprising the following parts by weight:

[0018] 500 portions of metformin hydrochloride;

[0019] Povidone K30 30-40 parts;

[0020] Hydroxypropyl methylcellulose K100M 240~270 parts;

[0021] 2-8 parts of colloidal silica;

[0022] Sodium stearate 15-25 parts.

[0023] In some embodiments, the immediate-release coating layer further comprises an antioxidant; preferably, the antioxidant is propyl gallate; and / or,

[0024] The immediate-release coating layer further comprises a film-forming material; preferably, the film-forming material is low-viscosity hydroxypropyl methylcellulose; and / or,

[0025] The immediate-release coating layer further comprises a plasticizer; preferably, the plasticizer is polyethylene glycol; and / or,

[0026] The immediate-release coating layer further comprises an anti-adhesion agent; preferably, the anti-adhesion agent is talc; and / or,

[0027] The immediate-release coating layer accounts for 12% to 14% of the weight of the sustained-release tablet core; and / or,

[0028] The immediate-release coating contains 93.0% to 107.0% sitagliptin phosphate; and / or,

[0029] The weight ratio of propyl gallate to sitagliptin phosphate is 1:(80~100); and / or,

[0030] The pharmaceutical composition further includes a thin film coating layer covering the immediate-release coating layer; and / or,

[0031] In the immediate-release coating layer, the weight ratio of sitagliptin phosphate to the film-forming material is (2.5~3.0):1; and / or,

[0032] The immediate-release coating layer is composed of the following components in parts by weight: 60-70 parts sitagliptin phosphate, 0.5-1.0 parts propyl gallate, 20-30 parts low-viscosity hydroxypropyl methylcellulose, 4-7 parts polyethylene glycol, and 8-15 parts talc.

[0033] Secondly, the present invention also provides a method for preparing the sitagliptin-metformin sustained-release drug composition as described in the foregoing embodiments, comprising:

[0034] S1, Metformin hydrochloride is mixed with a binder and optional sustained-release matrix material, and granules are prepared by wet granulation. After drying, the granules are sized, and the resulting granules are mixed with the remaining or all of the sustained-release matrix material. A lubricant is added and the mixture is compressed into tablets to obtain a sustained-release tablet core. Microcrystalline cellulose is not added during the entire preparation process of the sustained-release tablet core.

[0035] S2, prepare a coating solution containing sitagliptin phosphate, and spray the coating solution onto the surface of the sustained-release tablet core, and dry it to form an immediate-release coating layer.

[0036] In some embodiments, during the step of forming the immediate-release coating layer after drying, the moisture content of the dried particles is controlled to be below 2.0%; and / or,

[0037] The hardness of the compressed tablet is controlled between 150N and 300N.

[0038] In some embodiments, the coating solution comprises sitagliptin phosphate and a film-forming material, and at least one of an antioxidant, a plasticizer, and an anti-adhesion agent; preferably, the film-forming material is hydroxypropyl methylcellulose; preferably, the antioxidant is propyl gallate; preferably, the plasticizer is polyethylene glycol; preferably, the anti-adhesion agent is talc; and / or,

[0039] The bed temperature during coating liquid spraying is controlled at 38℃~45℃; and / or,

[0040] In step S1, the metformin hydrochloride is pulverized and sieved before mixing, and the sieve mesh size is 20 mesh; and / or,

[0041] In step S1, the wet granulation process specifically involves: first, mixing metformin hydrochloride with a binder to prepare drug-containing granules; after drying and granulation, dry-mixing the drug-containing granules with dry powdered hydroxypropyl methylcellulose as a sustained-release matrix material; and then adding a lubricant for final mixing; and / or,

[0042] In step S2, the preparation process of the coating solution includes: heating purified water to 55°C~65°C, and sequentially dissolving or dispersing antioxidant, sitagliptin phosphate, plasticizer, film-forming material and anti-adhesion agent; preferably, the purified water is heated to a temperature of 60°C.

[0043] In some embodiments, during the wet granulation process in step S1, the amount of purified water used as a wetting agent is 30 mg / tablet to 60 mg / tablet; and / or, the sieve mesh size used for granulation is 2.0 mm; and / or,

[0044] In step S1, the median particle size D50 of the dried and granulated particles is controlled between 350 μm and 500 μm, and the bulk density of the particles is between 0.55 g / mL and 0.65 g / mL.

[0045] Thirdly, the present invention also provides the use of the sitagliptin metformin sustained-release pharmaceutical composition as described in the foregoing embodiments in the preparation of a medicament for treating type 2 diabetes.

[0046] This invention provides a sitagliptin-metformin sustained-release pharmaceutical composition, its preparation method, and its application, relating to the field of sustained-release formulation technology. The sitagliptin-metformin sustained-release pharmaceutical composition, through a structural design employing a sustained-release tablet core combined with an immediate-release coating layer, effectively synergizes the pharmacokinetic characteristics of the two active ingredients. This achieves sustained release of metformin hydrochloride to maintain basal blood glucose control, while simultaneously ensuring rapid dissolution of sitagliptin phosphate to address postprandial blood glucose fluctuations. More importantly, this composition creatively eliminates microcrystalline cellulose, a conventional and bulky filler, in the formulation design of the sustained-release tablet core. This improvement significantly reduces the weight and volume of the final formulation, effectively solving the problem of excessively large tablet size often faced by high-drug-loading combination formulations, thereby improving the patient's swallowing experience and enhancing long-term medication adherence.

[0047] Furthermore, this composition successfully solves the problem of matrix function failure that may be caused by the removal of fillers by strictly limiting the specific weight ratio of metformin hydrochloride to the sustained-release matrix material hydroxypropyl methylcellulose in the sustained-release tablet core to 50:(24~27) and combining it with a specific preparation process of "adding the matrix material after wet granulation". Experiments have shown that if only this ratio is used but the addition method is changed (such as internal addition), it will lead to particle densification and inhibit release; only the specific formulation and specific process of this application can maintain a dissolution behavior highly similar to the reference formulation (f2>90) while significantly reducing the amount of excipients.

[0048] Furthermore, the inventors unexpectedly discovered that by removing the highly hygroscopic microcrystalline cellulose, the resulting pharmaceutical composition exhibited a significantly reduced (approximately 70%) hygroscopic weight gain under high humidity conditions. This improvement not only helps maintain the physical structural stability of the sustained-release matrix during storage (preventing hygroscopic swelling) but also provides a drier microenvironment for the moisture-sensitive sitagliptin phosphate, thereby significantly enhancing the overall chemical stability of the compound formulation. Attached Figure Description

[0049] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0050] Figure 1 is a schematic cross-sectional view of the sitagliptin-metformin sustained-release drug composition of the present invention;

[0051] Figure 2 is a comparison of the in vitro dissolution curves of Example 1, Comparative Example 1, Comparative Example 4 and the reference preparation (Comparative Example 3) in pH 6.8 medium. The horizontal axis in the figure is time (h) and the vertical axis is cumulative dissolution (%). The blue curve represents Example 1 and the orange curve represents the reference preparation (Comparative Example 3), showing a high degree of overlap between the two. The gray curve represents Comparative Example 1 (burst release) and the yellow curve represents Comparative Example 4 (release inhibition).

[0052] Explanation of reference numerals in the attached figures:

[0053] 100. Sitagliptin-metformin sustained-release drug composition; 1. Sustained-release tablet core (containing metformin hydrochloride and sustained-release matrix material, excluding microcrystalline cellulose); 2. Immediate-release coating layer (containing sitagliptin phosphate); 3. Film coating layer (outermost protective layer). Detailed Implementation

[0054] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0055] This application provides a sitagliptin-metformin sustained-release pharmaceutical composition (its structural schematic diagram is shown in Figure 1). The pharmaceutical composition includes a sustained-release tablet core and an immediate-release coating layer covering the sustained-release tablet core. The sustained-release tablet core contains the active ingredient metformin hydrochloride and the sustained-release matrix material hydroxypropyl methylcellulose, and the sustained-release tablet core does not contain microcrystalline cellulose. The immediate-release coating layer contains the active ingredient sitagliptin phosphate. In the sustained-release tablet core, the weight ratio of metformin hydrochloride to hydroxypropyl methylcellulose is 50:(24~27). For example, it can be 50:24, 50:24.5, 50:25, 50:25.5, 50:26, 50:26.5, 50:27, etc.

[0056] The "pharmaceutical composition" refers to a solid dosage form for pharmaceutical treatment, which is spatially divided into two physical parts: an inner "sustained-release tablet core" and an outer "immediate-release coating layer." This structural form means that the two active ingredients are spatially isolated and have different release kinetic characteristics. The principle lies in utilizing the spatial difference between the tablet core and the coating layer, combined with the solubility or swelling properties of different excipients, to achieve phased drug release.

[0057] The pharmaceutical composition can simultaneously achieve the slow and sustained release of one drug and the rapid release of another drug in a single formulation unit (such as a tablet), thereby meeting different therapeutic needs.

[0058] The aforementioned "sustained-release tablet core" refers to the portion that slowly releases the drug over a relatively long period after entering the body; the "immediate-release coating layer" refers to the portion that rapidly disintegrates or dissolves upon contact with body fluids to release the drug. By using a "sustained-release matrix material" in the tablet core to block drug diffusion, while no blocking material or a readily soluble material is used in the coating layer, this method synergistically regulates blood glucose: the immediate-release portion acts quickly to control postprandial blood glucose, while the sustained-release portion provides a sustained effect to maintain basal blood glucose.

[0059] Regarding the active ingredient metformin hydrochloride and the sustained-release matrix material hydroxypropyl methylcellulose (HPMC) in the sustained-release tablet core, metformin hydrochloride is the pharmacologically active substance in the core; hydroxypropyl methylcellulose (HPMC) is the carrier material that forms the sustained-release structure. Upon contact with water, hydroxypropyl methylcellulose hydrates to form a gel layer. Drug molecules must diffuse through this gel layer to be released, thereby ensuring a stable and continuous release of high doses of metformin hydrochloride and avoiding fluctuations in blood drug concentration.

[0060] The aforementioned "free of microcrystalline cellulose" designation is a negative limitation on the tablet core components, explicitly excluding microcrystalline cellulose, a commonly used filler in conventional formulations. It should be noted that microcrystalline cellulose typically occupies a significant volume and weight. Removing this component means reducing the total amount of excipients while maintaining drug loading, thereby significantly reducing the volume and weight of the sustained-release tablet core and even the final product. This solves the swallowing difficulties caused by excessive tablet weight and improves patient compliance.

[0061] The aforementioned "metformin hydrochloride to hydroxypropyl methylcellulose weight ratio of 50:(24~27)" specifies a particular mass ratio between the active ingredient and the matrix material. For example, if the metformin hydrochloride content is 500 mg, the amount of hydroxypropyl methylcellulose must be between 240 mg and 270 mg. This specific ratio is crucial for maintaining the integrity of the matrix structure when microcrystalline cellulose, a conventional filler, is removed. Hydroxypropyl methylcellulose at this ratio is sufficient to encapsulate high doses of drug into a robust gel matrix, preventing tablet collapse or burst release. Even with significant weight reduction (excluding microcrystalline cellulose), good tablet core shapeability is maintained, and ideal sustained-release dissolution behavior is preserved, achieving a balance between formulation lightweighting and release stability.

[0062] The active ingredient, sitagliptin phosphate, in the aforementioned immediate-release coating layer is located on the outermost layer. This outer layer allows it to be the first to come into contact with bodily fluids, thus facilitating the rapid onset of action of the drug.

[0063] In some embodiments, the hydroxypropyl methylcellulose in the sustained-release tablet core is high-viscosity hydroxypropyl methylcellulose; preferably, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose K100M.

[0064] The aforementioned "high viscosity" refers to the high fluid resistance exhibited by the polymer in aqueous solution; "K100M" is a specific specification of the material (usually representing a nominal viscosity of approximately 100,000 mPa·s).

[0065] It should be noted that high-viscosity hydroxypropyl methylcellulose hydrates more rapidly upon contact with bodily fluids than low-viscosity varieties, forming a denser, more resistant gel protective layer on the tablet core surface. In the absence of microcrystalline cellulose (a filler that often also acts as a dry binder), the high-viscosity polymer provides stronger physical winding forces, maintaining the integrity of the matrix. This ensures that the gel layer does not prematurely dissolve or disintegrate during the extended release process (e.g., 12 hours), thus maintaining a stable drug release rate. It also prevents the risk of drug burst release due to insufficient polymer viscosity, ensuring therapeutic stability.

[0066] In some embodiments, the sustained-release tablet core further comprises an adhesive; preferably, the adhesive is povidone.

[0067] In some embodiments, the sustained-release tablet core further comprises a flow aid; preferably, the flow aid is colloidal silica.

[0068] In some embodiments, the sustained-release tablet core further comprises a lubricant; preferably, the lubricant is sodium stearate fumarate.

[0069] The aforementioned povidone, through the binding effect of its polymer chains, aggregates drug powder and matrix materials into particles with a certain strength. Colloidal silica microparticles are distributed on the particle surface, reducing van der Waals forces and friction between particles. Sodium stearate fumarate forms a film between the mold wall and the tablet during tableting, reducing tablet pushing resistance.

[0070] After removing a large amount of filler (microcrystalline cellulose), the combination of the above excipients effectively improved the compressibility and flowability of high drug-load materials, solving the process problem that it is difficult to compress qualified tablets (such as easily cracked tablets or tablets that stick together) simply by mixing drugs with matrix materials.

[0071] In some embodiments, the sustained-release tablet core is made of components comprising the following parts by weight:

[0072] 500 portions of metformin hydrochloride;

[0073] Povidone K30 30~40 parts; for example, it can be 30 parts, 32 parts, 34 parts, 35 parts, 36 parts, 38 parts, 40 parts, etc.

[0074] Hydroxypropyl methylcellulose K100M 240~270 parts; for example, it can be 240 parts, 245 parts, 250 parts, 255 parts, 260 parts, 265 parts, 270 parts, etc.

[0075] 2 to 8 parts of colloidal silica; for example, it can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, etc.

[0076] Sodium stearate, 15-25 parts. For example, it can be 15 parts, 17 parts, 19 parts, 20 parts, 21 parts, 23 parts, 25 parts, etc.

[0077] In some embodiments, the immediate-release coating layer further comprises an antioxidant; preferably, the antioxidant is propyl gallate. An antioxidant is a substance that prevents oxidation reactions.

[0078] In some embodiments, the immediate-release coating layer further comprises a film-forming material; preferably, the film-forming material is low-viscosity hydroxypropyl methylcellulose. The film-forming material is a polymer that forms the film matrix.

[0079] In some embodiments, the immediate-release coating layer further comprises a plasticizer; preferably, the plasticizer is polyethylene glycol. The plasticizer is a substance that increases the flexibility of the film.

[0080] In some embodiments, the immediate-release coating layer further comprises an anti-adhesion agent; preferably, the anti-adhesion agent is talc. The anti-adhesion agent is a substance that prevents adhesion during the coating process.

[0081] In some embodiments, the immediate-release coating layer accounts for 12% to 14% of the weight of the sustained-release tablet core. For example, it can be 12%, 12.3%, 12.5%, 13%, 13.5%, 13.8%, 14%, etc. A coating layer that is too thin may result in insufficient or uneven drug loading, while a coating layer that is too thick will increase the tablet weight and may affect the release rate.

[0082] In some embodiments, the sitagliptin phosphate content in the immediate-release coating layer is 93.0% to 107.0%. For example, it can be 93.0%, 95.0%, 98.0%, 100.0%, 102.0%, 105.0%, 107.0%, etc. These quality control indicators ensure the accuracy of sitagliptin dosing and spraying processes.

[0083] In some embodiments, the pharmaceutical composition further includes a thin film coating layer covering the immediate-release coating layer.

[0084] In some embodiments, the weight ratio of sitagliptin phosphate to the film-forming material in the immediate-release coating layer is (2.5~3.0):1. For example, it can be 2.5:1, 2.6:1, 2.7:1, 2.75:1, 2.8:1, 2.9:1, 3.0:1, etc. This is a key parameter for "high drug loading coating." The principle lies in using a high proportion of drug (with good water solubility) combined with a small amount of film-forming material, allowing the coating layer to rapidly disintegrate upon contact with water, releasing the drug.

[0085] In some embodiments, the weight ratio of propyl gallate to sitagliptin phosphate in the immediate-release coating layer is 1:(80~100); this is a key parameter for "high drug loading coating". The principle is to use a high proportion of drug (with good water solubility) combined with a small amount of film-forming material, so that the coating layer can quickly disintegrate upon contact with water, releasing the drug.

[0086] Existing technologies typically focus only on adding antioxidants, but the inventors have discovered that because this composition removes microcrystalline cellulose, the humidity of the microenvironment surrounding the coating layer changes. Under this specific humidity environment, when the proportion of antioxidants is within this range, it can both maximally inhibit the formation of oxidative impurities and prevent the yellowing of the tablet surface caused by the oxidation of propyl gallate, thus achieving a dual improvement in chemical stability and appearance quality.

[0087] It should be noted that the specific use of the antioxidant (propyl gallate) effectively inhibits the potential oxidative degradation of sitagliptin in the coating layer, reducing the generation of related substances. The use of a low-viscosity film-forming material and a limited high excipient-to-drug ratio (2.5~3.0:1) ensures that the sitagliptin layer has "immediate-release" characteristics, enabling rapid disintegration and onset of action. The specific combination of plasticizers and anti-sticking agents guarantees that the coating film will not crack or peel off during storage. Furthermore, the additional "thin film coating layer" provides further physical isolation and aesthetic enhancement.

[0088] In some embodiments, the immediate-release coating layer comprises the following components in parts by weight: 60-70 parts sitagliptin phosphate (e.g., 60, 62, 64, 65, 66, 68, 70, etc.), 0.5-1.0 parts propyl gallate (e.g., 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, etc.), 20-30 parts low-viscosity hydroxypropyl methylcellulose (e.g., 20, 22, 24, 25, 26, 28, 30, etc.), 4-7 parts polyethylene glycol (e.g., 4, 4.5, 5, 5.5, 6, 6.5, 7, etc.), and 8-15 parts talc (e.g., 8, 9, 10, 11.5, 13, 14, 15, etc.).

[0089] This application embodiment also provides a method for preparing the sitagliptin-metformin sustained-release drug composition as described in the foregoing embodiments, comprising:

[0090] S1, Metformin hydrochloride is mixed with a binder and optional sustained-release matrix material, and granules are prepared by wet granulation. After drying, the granules are sized, and the resulting granules are mixed with the remaining or all of the sustained-release matrix material. A lubricant is added and the mixture is compressed into tablets to obtain a sustained-release tablet core. Microcrystalline cellulose is not added during the entire preparation process of the sustained-release tablet core.

[0091] This step involves constructing the core structure of the drug and employs a "wet granulation-tableting" process. Specifically, it may include the following processing steps:

[0092] (1) Mixing and granulation: The active ingredient metformin hydrochloride is mixed with a binder (and optional sustained-release matrix material), and a wetting agent (such as water or binder solution) is added to prepare a soft material, which is then made into wet granules.

[0093] (2) Drying and granulation: Remove moisture from wet granules and make the dried granules uniform in size by physical methods (such as sieving).

[0094] (3) Final mixing: The dried and granulated granules are finally mixed with the remaining (or all) slow-release skeleton material and lubricant to ensure uniformity of materials.

[0095] (4) Tableting: The mixed materials are compressed and formed in a tablet press.

[0096] It should be noted that in conventional sustained-release tablets (especially those containing high-dose drugs like metformin), microcrystalline cellulose (MCC) is typically used as the main filler and dry binder, and its usage is substantial (often accounting for 20%-40% of the tablet weight). This method, by optimizing the particle size distribution and selecting high-viscosity HPMC, successfully eliminated this large "excipient space occupier." This directly resulted in a significant reduction in the total weight and volume of the tablet (e.g., from 1.2g to 0.95g), thus addressing the clinical challenge of "difficulty swallowing" for patients.

[0097] Furthermore, MCC has a sponge-like porous structure, which may adsorb some of the drug or affect the channels for water to enter the matrix. After removing MCC, drug release is mainly controlled by the gel matrix (HPMC), eliminating the potential interference of MCC on release behavior. This makes the release curve easier to precisely control by adjusting the amount of HPMC, thus obtaining tablets (tablet cores) with sustained-release function. Wet granulation improves the flowability and compressibility of the material, solving the problem that it is difficult to form tablets by directly compressing the powder after removing microcrystalline cellulose (a commonly used dry binder and filler).

[0098] S2, prepare a coating solution containing sitagliptin phosphate, and spray the coating solution onto the surface of the sustained-release tablet core, and dry it to form an immediate-release coating layer.

[0099] This step involves constructing a second layer of active drug structure on the outside of the tablet core, which is part of the "active drug loading coating" process.

[0100] The specific processing procedure can be as follows: Sitagliptin phosphate is dissolved or dispersed in a solvent to prepare a coating solution, which is then atomized and sprayed onto the surface of the sustained-release tablet core obtained in step S1 using a coating device, and the solvent is removed by drying at the same time, thereby forming a solid film containing sitagliptin phosphate on the outside of the sustained-release tablet core.

[0101] This step achieves a biphasic release structure, where the outer drug layer forms an immediate-release layer after drying, allowing for rapid dissolution without disintegrating the tablet core.

[0102] In some embodiments, during the step of forming the immediate-release coating layer after drying, the moisture content of the dried particles is controlled to be below 2.0%. For example, it can be 0.5%, 0.8%, 1.0%, 1.2%, 1.5%, 1.8%, 2.0%, etc.

[0103] This step controls the quality parameters for the final drying endpoint of the particles in step S1. Specifically, when drying wet particles in a fluidized bed or oven, the moisture content can be monitored in real time or at regular intervals using a moisture analyzer until the moisture content of the particles decreases to the range of 0-2.0%, at which point drying can be stopped.

[0104] By controlling moisture, we can prevent the granules from becoming too wet, which could cause them to stick to the mold during tableting. In addition, reducing the free water content in the system not only helps stabilize metformin but also prevents the subsequently added water-absorbing matrix material (hydroxypropyl methylcellulose) from absorbing moisture and clumping prematurely.

[0105] In some embodiments, the hardness of the compressed tablets is controlled between 150 N and 300 N. For example, it can be 150 N, 175 N, 200 N, 225 N, 250 N, 275 N, 300 N, etc. This is a control parameter for the mechanical strength of the tablets during the tableting process. The hardness of the compressed tablets can be maintained between 150 Newtons and 300 Newtons by adjusting the filling depth and main pressure of the tablet press.

[0106] This high hardness range ensures that the microcrystalline cellulose-free tablet core has sufficient physical strength to withstand the tumbling and friction of the coating machine rollers in subsequent step S2, preventing the tablet core from breaking or its edges from wearing down. It also avoids excessive hardness leading to too low porosity, which would hinder moisture penetration into the tablet core and thus affect the formation of the sustained-release matrix and drug release.

[0107] In some embodiments, the coating solution comprises sitagliptin phosphate and a film-forming material, as well as at least one of an antioxidant, a plasticizer, and an anti-adhesion agent; preferably, the film-forming material is hydroxypropyl methylcellulose; preferably, the antioxidant is propyl gallate; preferably, the plasticizer is polyethylene glycol; preferably, the anti-adhesion agent is talc.

[0108] In some embodiments, the bed temperature during coating liquid spraying is controlled at 38°C to 45°C. For example, it can be 38°C, 39°C, 40°C, 41.5°C, 43°C, 44°C, 45°C, etc.

[0109] These are the thermodynamic parameters during the coating process. The temperature of the tablets tumbling inside the coating pan can be maintained between 38°C and 45°C by adjusting the inlet air temperature and flow rate. This is the balance point between solvent evaporation rate and drug stability. Too low a temperature will cause tablets to stick together, while too high a temperature may lead to sitagliptin degradation or a rough coating film (spray drying effect).

[0110] In some embodiments, in step S1, the metformin hydrochloride is pulverized and sieved before mixing, and the sieve mesh size is 20 mesh.

[0111] The raw materials are controlled to be in a coarser particle state (rather than an ultrafine powder). Without the use of microcrystalline cellulose, coarser drug particles have better flowability, which helps to reduce tablet weight variation during compression.

[0112] In some embodiments, in step S1, the wet granulation process specifically involves: first, mixing metformin hydrochloride with a binder to prepare drug-containing granules; after drying and granulation, the drug-containing granules are then dry-mixed with dry powdered hydroxypropyl methylcellulose as a sustained-release matrix material; and finally, a lubricant is added and the mixture is finalized.

[0113] The above method is an "external addition" process. In this method, hydroxypropyl methylcellulose (HMC) does not participate in the wet granulation process (it does not come into contact with water). Instead, it is added in dry powder form after the granules are prepared and dried, allowing the matrix material to distribute within the gaps between the drug particles. When the tablet comes into contact with body fluids, the HMC rapidly absorbs water and swells between the particles, forming a continuous gel network that encapsulates the drug particles. This structure is more effective than the "internal addition" method in controlling drug release, especially when the amount of excipients used is small.

[0114] In some embodiments, in step S2, the preparation process of the coating solution includes: heating purified water to 55°C~65°C (for example, 55°C, 57°C, 58°C, 60°C, 62°C, 63°C, 65°C, etc.) to sequentially dissolve or disperse antioxidants, sitagliptin phosphate, plasticizers, film-forming materials, and anti-adhesion agents; preferably, the purified water is heated to a temperature of 60°C.

[0115] Water, which can be used as a solvent, can be heated to a specified temperature (preferably 60°C) before adding solid materials. This can improve the dissolution rate and solubility of poorly soluble excipients (such as certain antioxidants), while also helping to disperse and wet polymer film-forming materials, ensuring that the coating solution is uniform and clear, and preventing spray gun clogging or spots on the coating film.

[0116] In some embodiments, during the wet granulation process in step S1, the amount of purified water used as a wetting agent is 30 mg / tablet to 60 mg / tablet (e.g., 30 mg / tablet, 40 mg / tablet, 50 mg / tablet, 60 mg / tablet, etc.); and / or, the sieve aperture used for granulation is 2.0 mm.

[0117] The purified water dosage mentioned above is a key liquid-to-solid ratio parameter in the wet granulation process. In the soft material preparation step, the total water consumption can be calculated based on the number of tablets fed, and the total amount of purified water sprayed or added should be strictly controlled within the range of 30mg to 60mg per tablet. This is the process equilibrium point under a microcrystalline cellulose-free formulation. Insufficient water will result in more fine powder particles and poor compressibility (unacceptable hardness). Excessive water will cause metformin (extremely water-soluble) to dissolve excessively, forming a "dough" or lumps, leading to granulation failure or drying difficulties.

[0118] The aforementioned screen aperture is a hardware parameter setting for granulation equipment (such as a gyratory pellet mill or wet pellet mill). It forces soft materials through a 2.0mm aperture to form wet granules, controlling the initial size of the wet granules. The 2.0mm aperture is suitable for producing granules with a uniform particle size distribution. After drying and granulation, it ensures good flowability and facilitates uniform mixing with subsequent dry powder additives.

[0119] In some embodiments, in step S1, the median particle size D50 of the dried and granulated particles is controlled at 350 μm to 500 μm, and the bulk density of the particles is 0.55 g / mL to 0.65 g / mL.

[0120] As a preferred technical solution, in order to compensate for the potential loss of material flowability after removing microcrystalline cellulose, the present invention strictly controls the physical properties of the dry granules obtained after wet granulation. Specifically, the median particle size (D50) of the dry granules is controlled between 300 μm and 600 μm, and the angle of repose is ≤30°.

[0121] Studies have found that when the particle size is controlled within this range, even without the addition of microcrystalline cellulose, the uniformity of particle filling in the die pores remains excellent (sheet weight difference <2%). Unlike traditional technologies that tend to use fine powder (D90 < 80 μm), this embodiment adopts a 'coarse particle' strategy, which improves flowability and reduces the specific surface area of ​​the particles, further reducing the moisture absorption rate.

[0122] This embodiment provides the use of the sitagliptin-metformin sustained-release pharmaceutical composition as described in the foregoing embodiments in the preparation of a medicament for treating type 2 diabetes.

[0123] The present invention will be further illustrated below with specific embodiments. However, it should be understood that these embodiments are merely for the purpose of more detailed illustration and should not be construed as limiting the present invention in any way.

[0124] General preparation process:

[0125] Unless otherwise stated, Examples 1-3 and Comparative Examples 1-2 were prepared using the following process:

[0126] (1) Pretreatment: Metformin hydrochloride raw material was pulverized by a high-efficiency pulverizer and passed through a 20-mesh sieve; colloidal silica and sodium stearate were granulated by passing through a φ0.8mm sieve.

[0127] (2) Wet granulation (excluding microcrystalline cellulose): Add the prescribed amount of povidone K30 and pulverized metformin hydrochloride to a wet granulator and mix for 5 minutes; use purified water as a wetting agent (approximately 30-60 mg / tablet) to spray into the soft material and granulate through a 2.0 mm sieve.

[0128] (3) Drying and granulation: Dry at 70℃ until the moisture content is ≤2.0%, and granulate using a φ1.2mm sieve.

[0129] (4) Total Mixing (HPMC Addition): The dried granules and the prescribed amount of sustained-release matrix material (hydroxypropyl methylcellulose K100M) are added to a mixer. In this step, a low-shear mixing device (such as a three-dimensional motion mixer) is preferred, and the mixing time is strictly controlled to 10-20 minutes (speed controlled at approximately 10 rpm). Experiments show that this mixing window is crucial: if the mixing time is less than 10 minutes, uneven distribution of the matrix material leads to burst release in some tablets; if the mixing time exceeds 20 minutes, the high-viscosity HPMC fine powder will be excessively embedded in the pores of the drug particles, resulting in a 'lock-in' effect, causing a decrease in dissolution rate in the later stages (similar to the trend in Comparative Example 4). Therefore, 'addition method + specific mixing window' is a necessary process condition for achieving the ideal release curve of this invention. Subsequently, pretreated colloidal silica and sodium stearate fumarate are added, and the mixture is mixed for 5-10 minutes.

[0130] (5) Tableting: Control the tablet weight and hardness (150N-300N) and compress it into a sustained-release tablet core.

[0131] (6) Sitagliptin coating: Purified water was heated to 60°C, and propyl gallate, sitagliptin phosphate, polyethylene glycol 3350, hydroxypropyl methylcellulose E6, and talc were added sequentially to prepare a coating solution. The tablet cores were coated at a tablet bed temperature of 38-45°C, resulting in a weight gain of approximately 12%-14%.

[0132] (7) Film coating: The immediate-release layer is coated with a gastrointestinal-soluble film coating premix, which increases the weight by about 2%-4%.

[0133] Example 1

[0134] This embodiment provides a sitagliptin-metformin extended-release tablet, which uses a general method, and its formulation composition is shown in the table below:

[0135]

[0136] Example 2

[0137] The only difference between this embodiment and Example 1 is that the amount of hydroxypropyl methylcellulose K100M in the sustained-release tablet core is 240mg (the lower limit of the scope of protection of this application), while the proportion of other excipients and the coating layer in the tablet core remain unchanged, and the total tablet weight is adjusted accordingly.

[0138] Example 3

[0139] The only difference between this embodiment and Example 1 is that the amount of hydroxypropyl methylcellulose K100M in the sustained-release tablet core is 270mg (the upper limit of the scope of protection of this application), while the proportion of other excipients and the coating layer in the tablet core remain unchanged, and the total tablet weight is adjusted accordingly.

[0140] Comparative Example 1

[0141] This comparative example aims to examine the effect when the amount of matrix material used is lower than that in this application. The only difference from Example 1 is that the amount of hydroxypropyl methylcellulose K100M in the sustained-release tablet core is adjusted to 230 mg.

[0142] Comparative Example 2

[0143] This comparative example aims to examine the effect when the amount of matrix material used is higher than that in this application. The only difference from Example 1 is that the amount of hydroxypropyl methylcellulose K100M in the sustained-release tablet core is adjusted to 280 mg.

[0144] Comparative Example 3

[0145] A commercially available sitagliptin metformin extended-release tablet (trade name: Genoda XR, reference preparation) was selected as a control. Its tablet weight is approximately 1156 mg and it contains microcrystalline cellulose as a filler.

[0146] Comparative Example 4

[0147] This comparative study aims to investigate the effect of the method of adding sustained-release matrix materials on formulation performance.

[0148] The only difference from Example 1 is the preparation process. Specifically, in step S1, all the sustained-release matrix material (hydroxypropyl methylcellulose K100M) is mixed with metformin hydrochloride and povidone K30 simultaneously for wet granulation (i.e., using the "internal addition" process). The remaining steps (drying, granulation, adding lubricant and mixing, tableting and coating) are the same as in Example 1.

[0149] Test Experiment

[0150] 1. Experimental Method:

[0151] The physical properties (tablet weight) and in vitro dissolution of the tablets prepared in Examples 1-3 and Comparative Examples 1-3 were investigated. The dissolution test was conducted using the method specified in the pharmacopoeia, with pH 6.8 buffer solution as the medium, and the similarity factor (f2) with the original reference formulation (Comparative Example 3) was calculated.

[0152] 2. Experimental Results:

[0153] 2.1 Comparison of physical properties:

[0154] To visually evaluate the effectiveness of this invention in improving swallowing compliance and to verify the formability after removing microcrystalline cellulose, detailed tests were conducted on the weight, three-dimensional dimensions (length × width × thickness), hardness, and friability of the tablets in each group. The results are shown in Table 2.

[0155]

[0156] 2.2 In vitro dissolution in pH 6.8 medium (single-medium study):

[0157] The cumulative dissolution rate and similarity factor results at different time points in pH 6.8 medium are shown in Table 3 (for dissolution curve comparison, see Figure 2):

[0158]

[0159] 2.3 Multi-media dissolution curve analysis:

[0160] To comprehensively evaluate the robustness of the release behavior of the formulation of the present invention, the dissolution behavior of Example 1 and the reference formulation (Comparative Example 3) in different pH media (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, and water) was further investigated. The results showed that the formulation of the present invention exhibited good sustained-release characteristics in all physiologically relevant media, with no risk of dose evaporation, and remained highly similar to the reference formulation. The results are summarized in Table 4.

[0161]

[0162] 2.4 Investigation of process parameters for the slow-release skeleton blending process (verification of the "lock-in effect"):

[0163] To verify the theory mentioned in the instruction manual that "excessive mixing time will lead to excessive embedding of high-viscosity HPMC and hinder its release", a comparative sample (referred to as "process comparative example A") with a mixing time of "30 minutes" was prepared based on the formulation of Example 1, only changing the total mixing time of the dried particles and HPMC in step S1, and its dissolution behavior was investigated.

[0164]

[0165] Results Analysis: The experiment confirmed that the mixing window must be strictly controlled when using the "addition method". If the mixing time is too long (e.g., 30 minutes), the surface of the soft drug particles will be densely coated with HPMC fine powder, causing blockage of the water permeation channels and thus failing to achieve the expected release effect.

[0166] 2.5 Investigation into the influence of particle size on formability:

[0167] To verify the necessity of the "coarse particle strategy" in the present invention in a microcrystalline cellulose-free system, particles were prepared according to the method of Example 1 (simulating the particle size range of the prior art CN116327769A, denoted as "process comparison example B"). However, by adjusting the crushing particle size and the sieve aperture, fine powder particles with a median particle size (D50) of about 50 μm were prepared, and their flowability and the difference in tablet weight after compression were examined.

[0168]

[0169] Results Analysis: The data shows that in the formulation system where the excellent flow aid microcrystalline cellulose has been removed, the material flowability is extremely poor when using conventional fine powder processing (process comparison example B), which cannot meet the requirements of high-speed tableting. This invention successfully solves this process problem by controlling D50 within a specific coarse particle range of 350-500 μm.

[0170] 2.6 Effect of antioxidant ratio on appearance and impurities:

[0171] To verify the criticality of the amount of propyl gallate (PG) in the immediate-release coating layer, based on the coating solution formulation of Example 1, only the amount of PG was adjusted to prepare samples with PG:sitagliptin = 1:40 (high PG, denoted as "Formulation Comparative Example C") and PG:sitagliptin = 1:200 (low PG, denoted as "Formulation Comparative Example D"), and they were placed under accelerated conditions (40°C / 75%RH) for 1 month.

[0172]

[0173] 3. Experimental conclusions:

[0174] (1) Weight reduction and improved compliance: Data (Table 2) show that after removing microcrystalline cellulose, Examples 1-3 not only reduced tablet weight by approximately 18%, but more importantly, reduced tablet volume by more than 20% (from 21.5 mm to approximately 19 mm), significantly improving the patient's swallowing experience. Meanwhile, without using microcrystalline cellulose, the friability of the formulation of this invention was still controlled below 0.15% (far exceeding the pharmacopoeia requirement of <1.0%), demonstrating that the specific formulation ratio effectively ensured the mechanical strength of the formulation.

[0175] (2) Synergistic effect of formulation and process: Comparing Example 1 and Comparative Example 4, it can be seen that even if the formulation is exactly the same, if the "internal addition method" granulation is used (Comparative Example 4), the resulting particles are too dense, resulting in excessive drug encapsulation (as shown by the curve of Comparative Example 4 in Figure 2). The cumulative release rate after 10 hours is only 63.7%, which cannot meet the bioavailability requirements. This fully demonstrates that the specific process route of "wet granulation to prepare drug core + dry powder with HPMC to construct framework" adopted in this application is the key technical means to achieve ideal release (f2=95) in conjunction with this low excipient formulation.

[0176] (3) Stability and hygroscopicity test:

[0177] Hygroscopicity comparison: Example 1 and Comparative Example 3 (containing MCC) were placed under high humidity conditions (25°C, RH 92.5%) for 10 days. The results showed that Comparative Example 3 had a hygroscopic weight gain rate as high as 4.5%, and the tablets showed visible swelling; while Example 1 had a hygroscopic weight gain rate of only 1.2%, with no change in appearance. This confirms that removing microcrystalline cellulose significantly reduces the sensitivity of the formulation to environmental humidity.

[0178] Accelerated stability comparison: To verify the chemical stability advantage brought about by the improved hygroscopicity, the changes in key indicators of Example 1 and Comparative Example 3 during the accelerated test (40℃ / 75%RH, 3 months) were compared, and the results are shown in Table 8.

[0179]

[0180] (4) Verification of key process parameters:

[0181] Supplementary experiments (Tables 5-7) further confirmed the technical effects of the detailed control of the present invention: the coarse particle strategy (D50>350μm) compensates for the flowability defects of the absence of MCC; the strictly limited mixing time (10-20min) avoids the "lock-in effect" of HPMC; and the specific antioxidant ratio (1:80~100) achieves dual protection of the appearance and purity of the formulation.

[0182] In summary, the results show that after removing the hygroscopic excipient microcrystalline cellulose, the formulation of this application not only reduces the tablet weight but also significantly reduces the hygroscopicity of the formulation, thereby giving the product superior physical and chemical stability under high temperature and high humidity conditions.

[0183] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A sitagliptin-metformin sustained-release pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a sustained-release tablet core and an immediate-release coating layer covering the sustained-release tablet core; the sustained-release tablet core contains the active ingredient metformin hydrochloride and the sustained-release matrix material hydroxypropyl methylcellulose, and the sustained-release tablet core does not contain microcrystalline cellulose; the immediate-release coating layer contains the active ingredient sitagliptin phosphate; wherein, in the sustained-release tablet core, the weight ratio of metformin hydrochloride to hydroxypropyl methylcellulose is 50:(24~27); the sustained-release tablet core is made from the following components in parts by weight: 500 parts metformin hydrochloride; 30~40 parts povidone K30; hydroxypropyl methylcellulose K100M 240-270 parts; colloidal silica 2-8 parts; sodium stearate fumarate 15-25 parts; the immediate-release coating layer further comprises a film-forming material; in the immediate-release coating layer, the weight ratio of sitagliptin phosphate to the film-forming material is (2.5-3.0):1; wherein, the sustained-release tablet core is prepared by the following method: first, metformin hydrochloride is mixed with a binder to prepare drug-containing granules, dried and granulated, then the drug-containing granules are dry-mixed with dry powdered hydroxypropyl methylcellulose as a sustained-release matrix material, then a lubricant is added and mixed, and tableted to obtain the sustained-release tablet core; wherein, microcrystalline cellulose is not added during the entire preparation process of the sustained-release tablet core.

2. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 1, characterized in that, The immediate-release coating also contains antioxidants.

3. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 2, characterized in that, The antioxidant is propyl gallate; the weight ratio of propyl gallate to sitagliptin phosphate is 1:(80~100).

4. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 1, characterized in that, The immediate-release coating layer also contains a plasticizer.

5. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 1, characterized in that, The immediate-release coating layer also contains an anti-sticking agent.

6. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 1, characterized in that, The weight of the immediate-release coating layer accounts for 12% to 14% of the weight of the sustained-release tablet core.

7. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 1, characterized in that, The immediate-release coating contains 93.0% to 107.0% sitagliptin phosphate.

8. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 1, characterized in that, The pharmaceutical composition further includes a thin film coating layer covering the immediate-release coating layer.

9. The sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 1, characterized in that, The immediate-release coating layer is composed of the following components in parts by weight: 60-70 parts sitagliptin phosphate, 0.5-1.0 parts propyl gallate, 20-30 parts hydroxypropyl methylcellulose, 4-7 parts polyethylene glycol, and 8-15 parts talc.

10. A method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition according to any one of claims 1-9, characterized in that, include: S1, Metformin hydrochloride is first mixed with a binder to prepare drug-containing granules. After drying and granulation, the drug-containing granules are then dry-mixed with dry powdered hydroxypropyl methylcellulose as a sustained-release matrix material. Lubricant is then added and the mixture is compressed into tablets to obtain a sustained-release tablet core. Microcrystalline cellulose is not added during the entire preparation process of the sustained-release tablet core. S2, A coating solution containing sitagliptin phosphate is prepared and sprayed onto the surface of the sustained-release tablet core. After drying, an immediate-release coating layer is formed.

11. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, In the step of forming an immediate-release coating layer after drying, the moisture content of the dried particles is controlled to be below 2.0%.

12. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, The hardness of the compressed tablet is controlled between 150N and 300N.

13. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, The coating solution contains sitagliptin phosphate and a film-forming material, as well as at least one of an antioxidant, a plasticizer, and an anti-adhesion agent.

14. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, The temperature of the film bed during coating liquid spraying is controlled at 38℃~45℃.

15. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, In step S1, the metformin hydrochloride is pulverized and sieved before mixing, and the sieve mesh size is 20 mesh.

16. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, In step S2, the preparation process of the coating solution includes: heating purified water to 55°C~65°C, and sequentially dissolving or dispersing antioxidant, sitagliptin phosphate, plasticizer, film-forming material and anti-adhesion agent.

17. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, In the wet granulation process of step S1, the amount of purified water used as a wetting agent is 30 mg / tablet to 60 mg / tablet; and / or, the sieve aperture used for granulation is 2.0 mm.

18. The method for preparing the sitagliptin-metformin sustained-release pharmaceutical composition as described in claim 10, characterized in that, In step S1, the median particle size D50 of the dried and granulated particles is controlled between 350 μm and 500 μm, and the bulk density of the particles is between 0.55 g / mL and 0.65 g / mL.

19. Use of a sitagliptin-metformin extended-release pharmaceutical composition as described in any one of claims 1-9 in the preparation of a medicament for treating type 2 diabetes.

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