Sitagliptin phosphate pharmaceutical composition as well as preparation, preparation method and application thereof

Abstract

The invention discloses a sitagliptin phosphate pharmaceutical composition as well as a preparation, a preparation method and application thereof. The pharmaceutical composition comprises sitagliptin phosphate, HP-beta-CD and mesoporous silica. According to the invention, a synergistic effect is generated by utilizing a molecular-level clathration effect of HP-beta-CD and a nano-level confinement adsorption effect of mesoporous silica, so that chemical degradation of sitagliptin phosphate, especially generation of a genotoxic impurity NTTP, is remarkably inhibited from molecular and physical double levels, and the stability of a product is greatly improved. Meanwhile, the mesoporous silica effectively solves the technical problems that HP-beta-CD is strong in hygroscopicity and not easy to directly tablet, and the content uniformity of low-dose drugs is fundamentally ensured by forming uniform composite particles. The process is simple, granulation is not needed, the tablet is suitable for industrial production, the prepared tablet is excellent in stability and high in safety, and animal experiments show that the bioavailability of the tablet is superior to that of a commercially available reference preparation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sitagliptin phosphate pharmaceutical composition, a preparation method and application thereof. BACKGROUND

[0002] Sitagliptin phosphate is a first-line drug for treating type 2 diabetes, and its efficacy is accurate. However, the inherent physicochemical properties of the raw material drug bring severe challenges to the preparation development, mainly in the following two aspects: firstly, the process feasibility faces great obstacles. The bulk density of sitagliptin phosphate raw material is small, and it is easy to be electrified. In the low-dose specification, the physical properties of sitagliptin phosphate raw material are greatly different from those of conventional excipients (such as lactose and microcrystalline cellulose), which leads to the easy occurrence of stratification and electrostatic adsorption in the mixing process, and it is difficult to guarantee the content uniformity, which becomes the primary technical bottleneck for commercial production. Secondly, the chemical stability problem is prominent, and there is a major safety hazard. Sitagliptin phosphate is prone to hydrolysis and other degradation reactions during production and storage, and may produce various degradation products including genotoxic impurity N-nitrosositagliptin (NTTP). The control of such impurities is directly related to the safety of drug use, therefore, how to effectively inhibit the generation is the core difficulty of the preparation research.

[0003] To cope with the above challenges, the existing technology adopts conventional strategies. For example, by optimizing the packaging (such as using high-barrier aluminum plastic blister) to isolate the external moisture, or using a wet granulation process to improve the content uniformity. However, the former can only provide external protection and cannot solve the problem of the existing or introduced moisture in the preparation during the production process, and the cost is high; the latter may accelerate the degradation of the active pharmaceutical ingredient (API) due to the involvement of the wet heat process, and increase the complexity and energy consumption of the production process.

[0004] Some studies attempt to use functional excipients. For example, hydroxypropyl-beta-cyclodextrin (HP-β-CD) is known to be able to encapsulate drug molecules through cavities, and theoretically can be used to improve stability. However, for water-soluble sitagliptin phosphate, the strong hygroscopicity of HP-β-CD itself becomes a fatal defect. The intermediate made of it is easy to absorb moisture and cake, and has poor flowability, which is difficult to be directly compressed, and the large amount of water introduced by it may offset the stabilizing effect of its encapsulation, even exacerbate the degradation, so that the application of this technology in this field is considered as taboo. On the other hand, as a carrier, mesoporous silica can improve the powder flowability and dissolution behavior, but its simple physical adsorption is not enough to provide sufficient protection for sitagliptin phosphate which has high stability requirements.

[0005] It is evident that existing technologies have significant limitations: conventional formulation processes struggle to simultaneously achieve uniformity of content and chemical stability; while the use of advanced excipients such as HP-β-CD or mesoporous silica alone fails to achieve ideal results due to their inherent defects, and may even be counterproductive. Currently, there is an urgent need in this field for an innovative formulation technology that can synergistically address the challenges of uniformity and stability of sitagliptin phosphate content at the molecular and physical levels, fundamentally and multidimensionally, while also possessing excellent process feasibility. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a sitagliptin phosphate pharmaceutical composition, its formulation, preparation method, and application, which can synergistically and significantly improve the chemical stability of sitagliptin phosphate, particularly by inhibiting the formation of the genotoxic impurity NTTP.

[0007] This invention is achieved through the following technical solution:

[0008] A sitagliptin phosphate pharmaceutical composition comprising the active ingredient sitagliptin phosphate, hydroxypropyl-β-cyclodextrin, and mesoporous silica; wherein the sitagliptin phosphate is encapsulated in hydroxypropyl-β-cyclodextrin and co-loaded within the pores of the mesoporous silica; wherein the mass ratio of sitagliptin phosphate to hydroxypropyl-β-cyclodextrin is (1:0.5) to (1:2), and the mass ratio of sitagliptin phosphate to mesoporous silica is (1:1) to (1:3).

[0009] Preferably, the specific surface area of ​​the mesoporous silica is 300~800 m². 2 / g, with an average pore size of 5~20 nm.

[0010] A sitagliptin phosphate tablet comprising the above-described sitagliptin phosphate pharmaceutical composition, and pharmaceutically acceptable excipients.

[0011] Preferably, the excipients include a diluent, a disintegrant, and a lubricant; the diluent is one or more of microcrystalline cellulose and mannitol; the disintegrant is croscarmellose sodium; and the lubricant is sodium stearate fumarate.

[0012] The above-mentioned method for preparing sitagliptin phosphate tablets includes the following steps:

[0013] Step 1) Sitagliptin phosphate and hydroxypropyl-β-cyclodextrin are dissolved together in a solvent to carry out an inclusion reaction, thereby obtaining an inclusion solution;

[0014] Step 2) The inclusion solution obtained in Step 1) is added to mesoporous silica under stirring, and the mixture is thoroughly mixed to ensure complete adsorption of the solution. Then, the solution is dried and sieved to obtain ternary composite powder.

[0015] Step 3) Mix the ternary compound powder obtained in Step 2) with diluent, disintegrant and lubricant. After mixing evenly, compress directly into tablets and finally coat to obtain the final product.

[0016] Preferably, the solvent in step 1) is water, ethanol, or an aqueous solution of ethanol.

[0017] Preferably, the drying in step 2) is fluidized bed drying or vacuum drying, and the drying temperature is 40~60℃.

[0018] The use of the above-mentioned sitagliptin phosphate pharmaceutical composition, or the above-mentioned sitagliptin phosphate tablets, in the preparation of a medicament for the prevention and / or treatment of type 2 diabetes.

[0019] The above-mentioned sitagliptin phosphate pharmaceutical composition is used in the preparation of a drug, wherein the use is to improve the stability of sitagliptin phosphate in the drug.

[0020] The above-mentioned sitagliptin phosphate pharmaceutical composition is used in the preparation of a drug for inhibiting or reducing the formation of the genotoxic impurity N-nitrositagliptin during storage.

[0021] The beneficial effects of this invention are as follows:

[0022] (1) This invention utilizes nanoscale drug loading technology with mesoporous silica to firmly "fix" sitagliptin phosphate raw material, which is highly susceptible to static electricity and has a low bulk density, within its uniform pores, forming uniform composite particles with particle size and density matching those of conventional excipients. This innovation completely eliminates the potential risks of separation and electrostatic adsorption during the mixing process from a physical source, allowing the content uniformity (RSD) to be easily controlled within 2.0%, far superior to conventional processes, providing a fundamental solution for the commercial production of low-dose sitagliptin phosphate tablets.

[0023] (2) This invention combines the molecular-level inclusion of HP-β-CD with the nanoscale confined adsorption of mesoporous silica to form a dual, synergistic stabilization barrier. First, intramolecular inclusion acts as the first barrier. The cavity of HP-β-CD encapsulates sitagliptin phosphate molecules, restricting their conformational movement and vibrational energy at the molecular level and physically isolating them from the surrounding environment (especially water molecules), thereby fundamentally inhibiting the initiation of chemical degradation reactions such as hydrolysis. Second, macroscopic physical barrier forms the second barrier. The rigid framework of mesoporous silica not only provides strong adsorption capacity to fix residual moisture, but its hydrophobicity and pore confinement effect also constitute a robust "shield," effectively blocking the intrusion of external moisture and oxygen, providing a dry and inert microenvironment for the internal HP-β-CD inclusion complex. This dual protection mechanism produces an amazing synergistic effect, resulting in excellent performance of the product in accelerated stability tests. The formation of genotoxic impurity NTTP is extremely suppressed, the growth of total impurities is slowed, and the shelf-life stability is revolutionaryly improved.

[0024] (3) This invention ingeniously utilizes mesoporous silica to solve the core technical problem of HP-β-CD's strong hygroscopicity and difficulty in direct tableting. Mesoporous silica transforms the easily hygroscopic and agglomerated HP-β-CD inclusion complex into a dry powder with excellent flowability. Its superior compressibility enables the simplest and most efficient process of direct tableting of the powder to be successfully realized. This not only completely avoids the potential damage to API stability caused by hygrothermal stress in processes such as wet granulation, but also greatly simplifies the production process, reduces energy consumption and production costs, and has significant industrialization advantages.

[0025] (4) Through the synergistic effect of multiple mechanisms, the sitagliptin phosphate tablets prepared by this invention not only have accurate content, stable quality, and high safety (extremely low impurity level), but also show that in vivo pharmacokinetic studies in animals have shown that they have higher bioavailability than commercially available reference formulations. Attached Figure Description

[0026] Figure 1 This is a comparison chart of the 0-month leaching curves of the water medium in Test Example 2;

[0027] Figure 2 This is a comparison chart of the leaching curves of the water medium in Test Example 2 over a long-term experiment of 12 months. Detailed Implementation

[0028] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0029] Unless otherwise specified, the technical means used in the following embodiments are all conventional means well known to those skilled in the art, and the experimental methods without specific conditions are all conventional methods in the art.

[0030] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0031] A method for preparing sitagliptin phosphate tablets, the specific steps of which are as follows:

[0032] (1) Sitagliptin phosphate and hydroxypropyl-β-cyclodextrin are dissolved together in a solvent (such as water, ethanol or aqueous ethanol solution) to carry out inclusion reaction and obtain primary inclusion complex solution.

[0033] The mass ratio of sitagliptin phosphate to hydroxypropyl-β-cyclodextrin is (1:0.5) to (1:2).

[0034] (2) Under continuous stirring, the inclusion solution is added to a surface with a large specific surface area (specific surface area 300~800 m²). 2 In mesoporous silica (such as Sylysia) with an average pore size of 5-20 nm / g, the drug solution is rapidly drawn into the nanopores by the strong adsorption and high specific surface area of ​​the mesoporous silica. After thorough mixing to ensure complete adsorption, the solvent is removed under mild conditions (such as fluidized bed drying or vacuum drying at 40-60°C), and the powder is sieved to obtain a dry, loose powder. At this point, the API is highly dispersed in an amorphous or microcrystalline state within the silica framework, forming a ternary complex of sitagliptin phosphate-HP-β-CD-mesoporous silica with excellent flowability, no static electricity, and improved stability.

[0035] The mass ratio of sitagliptin phosphate to mesoporous silica is (1:1) to (1:3).

[0036] (3) Treat the ternary compound powder as a "premix" and mix it directly with a specific diluent (such as a combination of mannitol and microcrystalline cellulose, which takes into account both compressibility and dissolution) and a disintegrant (such as croscarmellose sodium). Finally, add a lubricant (preferably sodium stearate fumarate, which has a smaller effect on dissolution than magnesium stearate) and mix briefly. The mixed powder has excellent flowability and compressibility and can be directly compressed and coated.

[0037] Example 1 (Standard Prescription)

[0038] A sitagliptin phosphate tablet, the composition of which is shown in Table 1, and the specific preparation process is as follows:

[0039] (1) Preparation of the ternary composite: Sitagliptin phosphate and HP-β-CD were dissolved in purified water to prepare a 30% (w / w) solution. This solution was slowly added to mesoporous silica in a high-speed shear mixer and stirred thoroughly until a homogeneous wet material was formed. The wet material was placed in a fluidized bed dryer and dried at 50°C until the moisture content was below 2.0%. After drying, it was passed through a 30-mesh sieve to obtain free-flowing ternary composite powder.

[0040] (2) Mixing, tableting and coating: Add the ternary compound powder, mannitol, microcrystalline cellulose and croscarmellose sodium to a double cone mixer and mix for 20 min. Then add sodium stearate fumarate and continue mixing for 3 min. Use a rotary tablet press to directly compress the powder into tablets and coat them to obtain the final product.

[0041] Table 1. Composition of Sitagliptin Phosphate Tablets (Theoretical Total Weight of Tablet Core 725 mg)

[0042]

[0043] Example 2 (High HP-β-CD Ratio Formulation)

[0044] A sitagliptin phosphate tablet, the composition of which is shown in Table 2, is prepared using the same process as in Example 1.

[0045] Table 2. Composition of Sitagliptin Phosphate Tablets (Theoretical Total Weight of Tablet Core 825 mg)

[0046]

[0047] Example 3 (Low HP-β-CD ratio formulation)

[0048] A sitagliptin phosphate tablet, the composition of which is shown in Table 3, is prepared using the same process as in Example 1.

[0049] Table 3. Composition of Sitagliptin Phosphate Tablets (Theoretical Total Weight of Tablet Core 675 mg)

[0050]

[0051] Example 4 (Formulation of high mesoporous silica ratio)

[0052] A sitagliptin phosphate tablet, the composition of which is shown in Table 4, is prepared using the same process as in Example 1.

[0053] Table 4. Composition of Sitagliptin Phosphate Tablets (Theoretical Total Weight of Tablet Core 825 mg)

[0054]

[0055] Example 5 (using different types of mesoporous silica)

[0056] A sitagliptin phosphate tablet, the composition of which is shown in Table 1, is prepared using the same process as in Example 1.

[0057] The difference is that the type of mesoporous silica has been changed from Sylysia 350 to AEROSIL 380.

[0058] Example 6 (Changing the drying method)

[0059] A sitagliptin phosphate tablet, the composition of which is shown in Table 1, and the specific preparation process is as follows:

[0060] (1) Preparation of ternary composite: The wet material was prepared in the same way as in Example 1. The wet material was spray-dried with an inlet temperature of 80°C and an outlet temperature of 45°C until the moisture content was less than 2.0%. After drying, the powder was passed through a 30-mesh sieve to obtain a finer ternary composite powder with better flowability.

[0061] (2) Mixing, tableting and coating: Same as in Example 1.

[0062] Comparative Example 1 (Mesoporous Silica Formulation)

[0063] A sitagliptin phosphate tablet, the composition of which is shown in Table 5, omits mesoporous silica, and attempts to spray dry after co-dissolving API with HP-β-CD.

[0064] Table 5. Composition of Sitagliptin Phosphate Tablets (Theoretical Total Weight of Tablet Core 525 mg)

[0065]

[0066] Comparative Example 2 (Prescription without HP-β-CD)

[0067] A sitagliptin phosphate tablet, the composition of which is shown in Table 6, omits HP-β-CD, and directly loads an API aqueous solution onto mesoporous silica, then dries and compresses it into tablets.

[0068] Table 6. Composition of Sitagliptin Phosphate Tablets (Theoretical Total Weight of Tablet Core 625 mg)

[0069]

[0070] Comparative Example 3 (Traditional powder direct compression tablets)

[0071] A sitagliptin phosphate tablet has the following components as shown in Table 1. However, none of the components are pretreated. The active pharmaceutical ingredient sitagliptin phosphate is directly mixed with all other excipients (including HP-β-CD and mesoporous silica), then compressed into tablets and coated.

[0072] Comparative Example 4 (Traditional Wet Granulation)

[0073] A sitagliptin phosphate tablet, the composition of which is shown in Table 7, is prepared by conventional wet granulation process, in which sitagliptin phosphate, all diluents and disintegrants are mixed, and granulation is carried out using an aqueous solution of povidone K30 as a binder. After drying and granulation, a lubricant is added for tableting and coating.

[0074] Table 7. Composition of Sitagliptin Phosphate Tablets (Theoretical Total Weight of Tablet Core 395 mg)

[0075]

[0076] Test Example 1: Experimental Design Optimization of Key Process Parameters

[0077] 1. Experimental Design

[0078] Using an optimal experimental design, the effects of three key process parameters—the ratio of HP-β-CD to API (A), the type of mesoporous silica (B), and the drying method (C)—on the key quality attributes of tablets (Y1: NTTP content after accelerated testing; Y2: dissolution rate in aqueous medium at 15 min; Y3: content uniformity RSD) were systematically studied. The specific design is shown in Table 8.

[0079] Table 8 Experimental Screening Design Table

[0080]

[0081] 2. Experimental Results and Analysis

[0082] Table 9 Summary of Screening Results

[0083]

[0084] As shown in Table 9, firstly, the ratio of HP-β-CD to API (A) is the most significant "lever" parameter affecting all critical quality attributes (CQAs). Secondly, the type of mesoporous silica (B) has a significant impact on stability and uniformity. Finally, the drying method (C) mainly affects dissolution behavior, with a relatively small direct impact on stability.

[0085] Based on these screening results, more refined optimization experiments (such as response surface methodology) can be conducted, focusing on the two key parameters A and B, and finding the optimal operating window near their best levels, while factor C can be selected at a fixed level based on factors such as cost.

[0086] Test Example 2: Comparison of In Vitro Mass Attributes

[0087] The tablets prepared in Examples 1-6 and Comparative Examples 1-4 were tested, and the experimental design and results are summarized in Table 10.

[0088] Accelerated experimental conditions: 40℃, 75% RH.

[0089] Long-term experimental conditions: 25℃, 60% RH.

[0090] Dissolution test medium: water.

[0091] Table 10 Summary of In Vitro Quality Attribute Test Results

[0092]

[0093] Table 10 Note: * indicates that tablets cannot be compressed.

[0094] From Table 10 and Figure 1 , 2 It can be seen that the NTTP and total impurity moisture content of the tablets prepared in Examples 1-6 were significantly lower than those in Comparative Examples 2-4 and commercially available products (standard), demonstrating the universality and superiority of the synergistic effect of HP-β-CD and mesoporous silica dual technology. The tablets prepared in Comparative Example 3 (physical mixing) showed extremely poor content uniformity and stability, proving that "co-dissolution-adsorption" is an indispensable key process step for achieving the effects of this invention. The moisture gain of the tablets prepared in Examples 1-6 was much lower than that of pure HP-β-CD (typically >10%), proving that mesoporous silica successfully overcomes the moisture absorption defects of HP-β-CD. Among them, Comparative Example 1 could not be successfully tableted, so all items could not be tested.

[0095] Test Example 3: Study of the genotoxic impurity NTTP

[0096] This test case specifically examines and compares the growth of genotoxic impurity NTTP under accelerated storage and forced degradation conditions using the process of this invention (Example 1), the traditional wet granulation process (Comparative Example 4), and a commercially available reference formulation, to evaluate the absolute advantage of this invention in controlling high-risk impurities.

[0097] 1. Experimental Design

[0098] (1) Sample

[0099] The tablets prepared in Example 1, the tablets prepared in Comparative Example 4 (conventional wet granulation), and the commercially available reference formulation (Jenova) ® ).

[0100] (2) Conditions

[0101] Accelerated stability test: 40℃, 75% RH, samples were taken at the end of 0, 3 and 6 months.

[0102] Forced degradation test: Place the sample under more severe conditions (60℃ / 75% RH) for 4 weeks, and take the sample at the end of the experiment.

[0103] (3) Detection method

[0104] The content of NTTP was specifically detected using a validated, highly sensitive LC-MS / MS method, with a detection limit (LOD) of 0.5 ppm.

[0105] 2. Experimental Results and Analysis

[0106] Table 11 NTTP content under accelerated stability conditions

[0107]

[0108] Table 12 NTTP content after forced degradation test

[0109]

[0110] The growth of the genotoxic impurity NTTP is shown in Tables 11 and 12, and the specific analysis is as follows:

[0111] (1) Accelerated stability results: In the 6-month accelerated test, the tablets prepared in Example 1 showed the slowest rate of NTTP growth, and their content was significantly lower than that of the tablets prepared in Comparative Example 4 and the commercially available reference formulation (approximately 40% of the reference formulation). This indicates that the product of the present invention has a lower safety risk during routine storage.

[0112] (2) Forced degradation results: Under severe stress conditions, the differences in the inhibitory ability of different processes on NTTP formation were amplified. The tablets prepared in Example 1 had the lowest NTTP formation, which was only 36% of that in the tablets prepared in Comparative Example 4 and 49% of that in the commercially available reference formulation. This strongly demonstrates that the process and formulation of the present invention have a fundamental inhibitory effect on the formation of the genotoxic impurity NTTP.

[0113] (3) Mechanism analysis

[0114] ①Stereohindrance effect: The cyclic structure of HP-β-CD is like a "molecular capsule" that encapsulates the active reaction sites (easily hydrolyzed functional groups) of sitagliptin phosphate, forming steric hindrance that greatly hinders water molecules from approaching and attacking these sensitive sites.

[0115] ② Restriction of molecular motion: Drug molecules are "fixed" in the cavity of HP-β-CD or in the rigid amorphous matrix formed therewith, and their molecular mobility (vibration and rotation) is significantly restricted. Molecules require a certain amount of energy and degrees of freedom to undergo chemical reactions (such as bond breaking). This restriction increases the activation energy barrier required for hydrolysis reactions and significantly reduces the reaction rate constant (k).

[0116] ③ Mesoporous silica has extremely strong hygroscopic properties. It preferentially adsorbs moisture from the environment and the system, creating a localized low-humidity microenvironment around the API, essentially acting as a built-in "desiccant." This fundamentally reduces the number of water molecules participating in the hydrolysis reaction.

[0117] ④ The rigid pore walls of mesoporous silica create a long diffusion path. Even if external moisture attempts to penetrate the tablet, it must first pass through the complex channels of mesoporous silica to reach the drug. This greatly slows down the rate of moisture penetration, providing a buffer time for the drug.

[0118] ⑤ Isolation effect: Mesoporous silica isolates each drug / cyclodextrin complex unit in an independent "nanoreactor", preventing cross-catalytic reactions of degradation products.

[0119] The experimental results of this test case demonstrate that the core innovation of this invention lies in the synergistic effect of HP-β-CD and mesoporous silica, rather than a simple additive effect. Firstly, HP-β-CD overcomes the shortcomings of mesoporous silica: simple mesoporous silica loading is a form of physical adsorption with relatively weak binding force. The molecular-level inclusion of HP-β-CD with API provides stronger and more precise primary protection. Secondly, mesoporous silica compensates for the deficiencies of HP-β-CD: HP-β-CD itself is hygroscopic, and its protective ability weakens in high humidity environments. Mesoporous silica, acting as a powerful "external guardian," effectively blocks most of the moisture, providing a stable and dry "working environment" for the internal HP-β-CD inclusion, allowing its protective efficacy to be sustained.

[0120] Test Example 4: Pharmacokinetic Study in Animals

[0121] This test case compares the tablets prepared according to the present invention (Example 1) with a commercially available reference formulation (Genevitro). ® Bioavailability of 100 mg in beagle dogs.

[0122] 1. Experimental Design

[0123] (1) Animals: Healthy adult beagle dogs, weighing 10-12 kg, fasted for 12 h before the experiment, with free access to water. They were randomly divided into two groups (n=6).

[0124] (2) Administration: After fasting for 12 hours, the tablets prepared in Example 1 or the reference preparation were administered orally once (the dose was 10 mg / kg sitagliptin).

[0125] (3) Sampling: Blood samples were collected from the forelimb veins before administration (0 h) and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 h after administration.

[0126] (4) Analysis: The concentration of sitagliptin in plasma was determined using a validated LC-MS / MS method.

[0127] (5) Data processing: Pharmacokinetic parameters were calculated using WinNonlin software.

[0128] 2. Experimental Results and Analysis

[0129] Table 13 Summary of pharmacokinetic parameters in beagle dogs (mean ± SD)

[0130]

[0131] The main pharmacokinetic parameters are shown in Table 13, and the specific analysis is as follows:

[0132] (1) Significantly improved bioavailability: The relative bioavailability (F) of the tablets prepared in Example 1 reached approximately 150%, indicating that its absorption was superior to that of the commercially available reference formulation. This may be due to the HP-β-CD-mesoporous silica carrier promoting drug dissolution and absorption.

[0133] (2) Faster absorption: The T of the tablets prepared in Example 1 max Slightly earlier than the reference formulation, C max A higher value indicates that the drug is released and absorbed from the formulation more quickly.

[0134] (3) Better in vivo exposure: The key exposure parameter AUC 0-t and AUC 0-∞ The tablets prepared in Example 1 were significantly better than the reference formulation (P < 0.05, indicating a statistically significant difference), demonstrating the significant progress of the present invention in improving in vivo performance.

[0135] The above experimental results demonstrate that this invention, through innovative carrier technology and a mild process, not only solves the industry-wide problem of uniform mixing of low-dose drugs in vitro, but also exhibits an absolute advantage in controlling the key safety indicator of drugs—the genotoxic impurity NTTP. Furthermore, in vivo animal studies have confirmed that it provides higher and more stable bioavailability. This fully proves that the technical solution of this invention surpasses existing technologies in terms of quality, safety, and efficacy.

[0136] The embodiments described above are only some, not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. The scope of protection of the present invention is determined by the scope claimed in the claims. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition of sitagliptin phosphate, characterized by, The active ingredient is sitagliptin phosphate, hydroxypropyl-beta-cyclodextrin and mesoporous silica; the sitagliptin phosphate is included in the hydroxypropyl-beta-cyclodextrin, and is co-loaded in the pore channel of the mesoporous silica; wherein the mass ratio of the sitagliptin phosphate to the hydroxypropyl-beta-cyclodextrin is (1:0.5)~(1:2), and the mass ratio of the sitagliptin phosphate to the mesoporous silica is (1:1)~(1:3).

2. The pharmaceutical composition of sitagliptin phosphate according to claim 1, wherein The specific surface area of the mesoporous silica is 300 to 800 m 2 / g, and the average pore diameter is 5 to 20 nm.

3. A tablet of siglitarin phosphate, characterized by, The application relates to a sitagliptin phosphate pharmaceutical composition as claimed in claim 1 or 2, and a pharmaceutically acceptable excipient.

4. A sitagliptin phosphate tablet according to claim 3, wherein The excipient comprises a diluent, a disintegrant and a lubricant; the diluent is one or more of microcrystalline cellulose and mannitol; the disintegrant is cross-linked sodium carboxymethyl cellulose; and the lubricant is sodium stearyl fumarate.

5. A process for the preparation of a tablet of sitagliptin phosphate according to claim 3 or 4, characterized in that, The application relates to a preparation method of the sitagliptin phosphate pharmaceutical composition, and comprises the following steps: Step 1) sitagliptin phosphate and hydroxypropyl-beta-cyclodextrin are co-dissolved in a solvent to carry out an inclusion reaction, and an inclusion solution is obtained; Step 2) the inclusion solution obtained in step 1) is added to mesoporous silica under stirring, is fully mixed to make the solution be completely adsorbed, and then is dried and sieved to obtain a ternary complex powder; Step 3) the ternary complex powder obtained in step 2) is mixed with a diluent, a disintegrant and a lubricant, is uniformly mixed, is directly compressed into a tablet, and is finally coated, and the sitagliptin phosphate tablet is obtained.

6. The production method according to claim 5, characterized by, Step 1) the solvent is water, ethanol or an ethanol aqueous solution.

7. The preparation method according to claim 5, characterized in that, Step 2) the drying is fluidized bed drying or vacuum drying, and the drying temperature is 40-60 DEG C.

8. The application of the sitagliptin phosphate pharmaceutical composition as claimed in claim 1 or 2, or the sitagliptin phosphate tablet as claimed in claim 3 or 4 in the preparation of a drug for preventing and / or treating type 2 diabetes.

9. Use of the seipiogliptin phosphate pharmaceutical composition according to claim 1 or 2 in the manufacture of a medicament, characterized in that, The application is used for improving the stability of sitagliptin phosphate in the drug.

10. Use of the sitagliptin phosphate pharmaceutical composition according to claim 1 or 2 in the manufacture of a medicament, characterized in that, The application is used for inhibiting or reducing the generation of genotoxic impurity N-nitrosositagliptin during the storage of the drug.

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