CN113679684A

CN113679684A - Sitagliptin phosphate composition, sitagliptin phosphate tablet, preparation method and application thereof

Info

Publication number: CN113679684A
Application number: CN202110958244.0A
Authority: CN
Inventors: 王志超; 伏开强; 庞建梅; 郎福双; 戴信敏
Original assignee: Beijing Xinkaiyuan Pharmaceuticals Co Ltd
Current assignee: Beijing Xinkaiyuan Pharmaceuticals Co Ltd
Priority date: 2021-08-20
Filing date: 2021-08-20
Publication date: 2021-11-23
Anticipated expiration: 2041-08-20
Also published as: CN113679684B

Abstract

The invention belongs to the field of medicines, and particularly relates to a sitagliptin phosphate composition, a sitagliptin phosphate tablet, a preparation method and application thereof, wherein the sitagliptin phosphate composition comprises the following components in percentage by mass: 25 to 35 percent of sitagliptin phosphate monohydrate; 20 to 40 percent of anhydrous calcium hydrophosphate; 20 to 40 percent of microcrystalline cellulose; 1% -4% of croscarmellose sodium; 0.5 to 2 percent of magnesium stearate; 1 to 4 percent of sodium stearyl fumarate; the D90 particle size of the sitagliptin phosphate monohydrate is 30-90 microns, and the D90 particle size of the microcrystalline cellulose is more than or equal to 260 microns. The in vitro dissolution curve of the sitagliptin phosphate tablet provided by the invention is similar to that of the imported original preparation produced by Merck company, the possibility of biological equivalence with the original preparation is improved, and the consistency evaluation requirement is met.

Description

Sitagliptin phosphate composition, sitagliptin phosphate tablet, preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a sitagliptin phosphate composition, a sitagliptin phosphate tablet, a preparation method and application thereof.

Background

Diabetes is a metabolic disease characterized by hyperglycemia. Hyperglycemia is caused by a defect in insulin secretion or an impaired biological action, or both. The chronic hyperglycemia causes chronic injury and dysfunction of various tissues, particularly eyes, kidneys, heart, blood vessels and nerves. Research shows that in 2015, the number of adult diabetes patients in China is as high as 1.096 hundred million, the adult diabetes patients are the first in the world, and the prevalence and incidence of diabetes are gradually increased in the world.

Sitagliptin phosphate is a potent and highly selective dipeptidyl peptidase IV (DPP-IV) inhibitor that can improve glycemic control in type 2 diabetic patients by increasing the levels of the active incretin insulinotropic hormones glucagon-like polypeptide-1 (GLP-l) and glucose-dependent insulinotropic polypeptide (GIP). Meglitinide phosphate tablets were developed by merck 2006. Imported to China in 2009 at 9 months, the product is Jienowei with specifications of 25mg, 50mg and 100 mg. Can be clinically used alone or combined with other oral hypoglycemic drugs to form compound drugs (such as metformin or thiazolidinedione) for treating type 2 diabetes.

The evaluation of drug consistency requires that the quality and curative effect of the simulated drug are consistent with those of the original drug. Specifically, it is required that the impurity spectra are consistent, the stability is consistent, and the in vivo and in vitro dissolution rules are consistent. The evaluation work of the quality and the curative effect consistency of the imitation pharmacy is carried out, and the evaluation method has very important significance for improving the integral level of the pharmacy industry in China, ensuring the safety and the effectiveness of the medicine, promoting the upgrade and the structure adjustment of the pharmaceutical industry and enhancing the international competitive power.

In the prior art, when in-vitro dissolution behavior investigation is carried out on the imitation drug of sitagliptin phosphate, the obvious difference is found between the release behavior of the imitation drug and the original preparation, and the in-vitro dissolution of the imitation drug is difficult to be consistent with that of the original preparation, so that the safety and the effectiveness of the imitation drug are not guaranteed.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a sitagliptin phosphate composition, a sitagliptin phosphate tablet, a preparation method and application thereof, wherein the in vitro dissolution curve of the sitagliptin phosphate tablet is similar to that of an imported original preparation produced by Merck company, and the problem that the in vitro dissolution of the sitagliptin phosphate imitation drug and the original preparation in the prior art is inconsistent is solved.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the invention provides a sitagliptin phosphate composition, which comprises the following components in percentage by mass:

the D90 particle size of the sitagliptin phosphate monohydrate is 30-90 mu m;

the D90 particle size of the microcrystalline cellulose is more than or equal to 260 mu m.

Preferably, the sitagliptin phosphate composition comprises the following components in percentage by mass:

the D90 particle size of the sitagliptin phosphate monohydrate is 40-80 mu m;

the D90 particle size of the microcrystalline cellulose is more than or equal to 280 mu m.

According to the invention, by controlling the D90 particle sizes of the sitagliptin phosphate monohydrate and the microcrystalline cellulose, the in vitro dissolution curve of a preparation prepared from the sitagliptin phosphate composition is similar to that of an imported original preparation produced by Merck company, the possibility of bioequivalence to the original preparation is improved, and the requirement of drug consistency evaluation is met.

In a second aspect, the present invention provides a sitagliptin phosphate tablet comprising a tablet core comprising a sitagliptin phosphate composition according to the first aspect.

Preferably, the sitagliptin phosphate tablet further comprises a coating layer, wherein the coating layer comprises an Opadry gastric-soluble film coating premix, and the mass of the coating layer is 1% -3% of that of the tablet core.

In any of the above schemes, preferably, each 1000 sitagliptin phosphate tablets comprise the following components:

the D90 particle size of the sitagliptin phosphate monohydrate is 30-90 mu m;

The in vitro dissolution curve of the sitagliptin phosphate tablet provided by the invention is similar to that of the imported original preparation produced by Merck company, the possibility of biological equivalence with the original preparation is improved, and the consistency evaluation requirement is met.

In a third aspect, the present invention provides a preparation method of sitagliptin phosphate tablets according to the second aspect, wherein the preparation method comprises the following steps: directly compressing the sitagliptin phosphate composition of the first aspect.

Preferably, the preparation method comprises the following steps:

weighing sitagliptin phosphate monohydrate, anhydrous calcium hydrophosphate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the formula ratio;

mixing the sitagliptin phosphate monohydrate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose and croscarmellose sodium to obtain a first mixture;

adding magnesium stearate and sodium stearyl fumarate into the first mixture, and mixing to obtain a second mixture;

and pressing the second mixture into tablets by using a tablet press to obtain the sitagliptin phosphate tablets.

In any of the above embodiments, in the step of obtaining the first mixture, the mixing is performed in a three-dimensional mixer for a mixing time of 10min to 30 min.

In any of the above embodiments, in the step of obtaining the second mixture, the mixing is performed in a three-dimensional mixer for a mixing time of 1min to 10 min.

Preferably in any of the above embodiments, the tablet press is a rotary tablet press.

In any of the above embodiments, it is preferable that after the step of compressing the second mixture into tablets by using a tablet press to obtain the sitagliptin phosphate tablets, the method further comprises:

and coating the sitagliptin phosphate tablets, and controlling the weight of the coating layer to be increased by 1-3%.

According to the preparation method of the sitagliptin phosphate tablet, the processes of granulating, drying and the like are reduced by adopting a direct powder tabletting technology, the preparation process is simple, the safety is high, the cost is low, manpower and material resources are saved, and the preparation method is more suitable for large-scale production.

In a fourth aspect, the invention provides a sitagliptin phosphate composition according to the first aspect for use in the preparation of a medicament for preventing or treating type 2 diabetes.

Drawings

FIG. 1 is a graph showing the comparison of the dissolution curves of examples 1 to 3 with the original preparation in water;

FIG. 2 is a graph showing the comparison of the dissolution curves of examples 4 to 6 with the original preparation in water;

FIG. 3 is a graph comparing the dissolution curves in water of comparative example 2 and comparative example 4 with the original formulation.

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments, equipment and the like used in the following examples are commercially available or obtainable by an existing method, and if not specifically described, refer to conventional raw materials, instruments, equipment and the like commercially available or obtainable by an existing method, without particular limitation; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.

In a first aspect, the embodiment of the invention provides a sitagliptin phosphate composition, which comprises the following components in percentage by mass:

the D90 particle size of the sitagliptin phosphate monohydrate is 30-90 mu m;

In the embodiment of the present invention, the particle size D90 refers to the particle size corresponding to the cumulative percentage of particle size distribution of the sample reaching 90%, for example: the D90 particle size of the sample was 60 μm, meaning that 90% of the particles in the sample tested had a particle size of less than 60 μm.

The particle size of D90 of sitagliptin phosphate monohydrate can be controlled to be 30-90 μm by air flow crushing or mechanical crushing, for example, the particle size of D90 can be 30 μm, 40 μm, 50 μm, 60 μm, 80 μm or 90 μm, if the particle size of D90 is too small, the in vitro dissolution speed of a preparation prepared from the sitagliptin phosphate composition is too fast, the dissolution curve difference with a reference preparation is large, the energy consumption required for crushing is large, the preparation is easy to stick and dash, if the particle size of D90 is too large, the in vitro dissolution speed of the preparation prepared from the sitagliptin phosphate composition is too slow, the dissolution curve difference with the reference preparation is large, and preferably, the particle size of D90 is 40-80 μm.

The microcrystalline cellulose has a D90 particle size of 260 μm or more, for example, a D90 particle size of 260 μm, 280 μm or 300 μm, and the microcrystalline cellulose can be selected from commercially available microcrystalline cellulose with a D90 particle size of 260 μm or more. If the D90 particle size of the microcrystalline cellulose is too small, the in vitro dissolution rate of the preparation prepared from the sitagliptin phosphate composition is too slow, the difference of the tablet weight is large, and the difference of the dissolution curve of the preparation and the reference preparation is large. Preferably, the D90 particle size is more than or equal to 280 μm.

According to the embodiment of the invention, the particle size of D90 of the sitagliptin phosphate monohydrate and the microcrystalline cellulose is controlled, so that the in vitro dissolution curve of a preparation prepared from the sitagliptin phosphate composition is similar to that of an imported original preparation produced by Merck company, the possibility of biological equivalence with the original preparation is improved, and the requirement of consistency evaluation is met.

Further, the sitagliptin phosphate composition comprises the following components in percentage by mass:

the D90 particle size of the sitagliptin phosphate monohydrate is 40-80 mu m;

In a second aspect, embodiments of the present invention provide a sitagliptin phosphate tablet comprising a tablet core comprising a sitagliptin phosphate composition as described in the first aspect.

As the prescription and the preparation process of the original preparation can be inquired, most of the national sitagliptin phosphate preparations use the same prescription and process (powder direct compression process) as the original preparation.

The auxiliary materials and coating prescription of the original preparation are as follows:

123.8mg of microcrystalline cellulose, 123.8mg of uncrushed calcium hydrogen phosphate, 8mg of croscarmellose sodium, 4mg of magnesium stearate, and 12mg of sodium stearyl fumarate;

the coating comprises 85F17438 and 16mg of Opadry II beige, and comprises the following components in percentage by mass: 40% of polyvinyl alcohol, 21.56% of titanium dioxide (E171), 20.2% of polyethylene glycol 3350 (polyethylene glycol), 14.8% of talcum powder, 3.07% of iron oxide yellow (E172) and 0.37% of iron oxide red (E172).

The inventors of the present invention unexpectedly found in the course of their research that, in the formulation of the original formulation, it was not possible to prepare a sample similar to the original formulation using any microcrystalline cellulose of different D90 particle size or sitagliptin phosphate monohydrate of different D90 particle size. Microcrystalline cellulose with different D90 particle sizes or sitagliptin phosphate monohydrate with different D90 particle sizes shows different properties, correspondingly shows different dissolution behaviors in a preparation, and has obvious influence on the dissolution behaviors of the preparation.

The in-vitro dissolution curve of the sitagliptin phosphate tablets provided by the embodiment of the invention is similar to that of the imported original grinding agent produced by Merck company, the possibility of biological equivalence with the original grinding agent is improved, the consistency evaluation requirement is met, the flowability and compressibility of the prescription powder are good, the obtained tablets are smooth and clean, the weight difference of the tablets is less than +/-3.0%, and the tablet is more suitable for large-scale production.

Further, the sitagliptin phosphate tablet further comprises a coating layer, wherein the coating layer comprises an Opadry gastric-soluble film coating premix, the mass of the coating layer is 1% -3% of that of the tablet core, for example, the mass of the coating layer can be 1%, 2% or 3% of that of the tablet core, and the like.

Further, each 1000 sitagliptin phosphate tablets comprise the following components:

the D90 particle size of the sitagliptin phosphate monohydrate is 30-90 mu m;

In a third aspect, the embodiment of the present invention provides a preparation method of sitagliptin phosphate tablets according to the second aspect, and the preparation method includes the following steps: directly compressing the sitagliptin phosphate composition of the first aspect.

According to the preparation method of sitagliptin phosphate tablets, provided by the embodiment of the invention, the processes of granulation, drying and the like are reduced by adopting a direct powder tabletting technology, the preparation process is simple, the safety is high, the cost is low, the manpower and material resources are saved, and the preparation method is more suitable for large-scale production.

Further, the preparation method comprises the following steps:

s1, weighing sitagliptin phosphate monohydrate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the formula;

s2, mixing the sitagliptin phosphate monohydrate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose and croscarmellose sodium to obtain a first mixture;

s3, adding magnesium stearate and sodium stearyl fumarate into the first mixture, and mixing to obtain a second mixture;

s4, pressing the second mixture into tablets by using a tablet press to obtain the sitagliptin phosphate tablets.

Further, in step S2, the mixing is performed in a three-dimensional mixer for a mixing time of 10 to 30min, for example, the mixing time may be 10min, 20min, or 30 min.

Further, in step S3, the mixing is performed in a three-dimensional mixer for a mixing time of 1min to 10min, for example, the mixing time may be 1min, 2min, 5min, 7min, or 10 min.

Further, the tablet press is a rotary tablet press.

Further, after step S4, the method further includes:

the sitagliptin phosphate tablets are coated, and the weight of a coating layer is controlled to be increased by 1-3%, for example, the weight of the coating layer can be increased by 1%, 2% or 3%.

In a fourth aspect, the present invention provides a sitagliptin phosphate composition according to the first aspect for use in the preparation of a medicament for the prevention or treatment of type 2 diabetes.

The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.

In each of the following examples and comparative examples, the particle size of D90 was measured on a Malvern laser particle size Analyzer using a Mastersizer 3000 as the equipment model, a 633nm high stability He-Ne laser as the light source, and dry method as the measurement procedure.

In the following examples and comparative examples, the dissolution curves were compared with those of the original preparation, and the results were judged according to the following criteria: according to the judgment of comparison of dissolution curves in the 'guide principle of comparison of dissolution curves of common oral solid preparations', a similarity factor (f2) method in an independent model method is adopted, namely when the numerical value of the similarity factor (f2) of the two dissolution curves is not less than 50, the two dissolution curves are considered to be similar.

The original preparation: the sitagliptin phosphate tablet is sold as Jienowei (imported from England to China) and has the specification of 100 mg.

In each of the following examples and comparative examples, the coating layer was an opadry gastric-soluble film coating premix: the opadry II beige 85F17438 comprises the following components in percentage by mass: 40% of polyvinyl alcohol, 21.56% of titanium dioxide (E171), 20.2% of polyethylene glycol 3350 (polyethylene glycol), 14.8% of talcum powder, 3.07% of iron oxide yellow (E172) and 0.37% of iron oxide red (E172).

Examples 1 to 6 provide sitagliptin phosphate tablets comprising the components in the mass shown in table 1 (in terms of 1000 tablets), and comparative examples 1 to 4 provide sitagliptin phosphate tablets comprising the components in the mass shown in table 2 (in terms of 1000 tablets).

TABLE 1

TABLE 2

Example 1

The content of the sitagliptin phosphate tablet components provided in this example is shown in table 1.

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 30 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription in sequence;

s2, mixing the sitagliptin phosphate monohydrate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer for 20min to obtain a first mixture;

s3, adding magnesium stearate and sodium stearyl fumarate into the first mixture, and continuously mixing in a three-dimensional mixer for 5min to obtain a second mixture;

s4, pressing the second mixture into tablets by using a rotary tablet press, preparing 1000 tablets to obtain plain tablets, coating the plain tablets with a film, and increasing the weight of the coating layer by 2% to obtain the sitagliptin phosphate tablets.

Example 2

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 40 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Example 3

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 80 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Example 4

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 90 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Example 5

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 30 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 280 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the formula amount in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Example 6

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 40 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 280 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the formula amount in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Comparative example 1

The content of the sitagliptin phosphate tablet components provided by the comparative example is shown in table 2.

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 30 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 150 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the formula amount in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Comparative example 2

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 30 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 200 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Comparative example 3

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 15 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Comparative example 4

The preparation method comprises the following steps:

s1, sieving anhydrous calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Weighing sitagliptin phosphate monohydrate (D90 particle size is 120 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size is 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription in sequence;

s2 to S4 are completely the same as S2 to S4 in example 1.

Effect example 1

Effect example 1 in order to measure the angle of repose of the materials after mixing before tableting in examples 1 to 6 and comparative examples 1 to 4, the appearance of the prepared plain tablets was observed, and the difference in tablet weight of the plain tablets was examined.

Slice weight difference checking method: taking 20 sitagliptin phosphate tablets, precisely weighing the total weight to obtain the average tablet weight, precisely weighing the weight of each tablet, calculating the weight difference of each tablet according to the weight of each tablet-the average tablet weight)/the average tablet weight multiplied by 100 percent, and obtaining the tablet weight difference range of 20 tablets.

The measurement results are shown in tables 3 and 4.

TABLE 3

TABLE 4

The weight difference of the sitagliptin phosphate tablets prepared in the embodiments 1-6 is less than 3%, the surfaces of the sitagliptin phosphate tablets are smooth and accord with relevant regulations, the weight difference of the sitagliptin phosphate tablets prepared in the comparative examples 1-2 is larger and is more than 3%, even more than 5%, and the surface of the sitagliptin phosphate tablets prepared in the comparative example 3 is uneven and sticky

Effect example 2

Effect example 2 is a study of the dissolution curves of the sitagliptin phosphate tablets prepared in examples 1 to 6 and comparative examples 2 and 4 and the original triturate.

Firstly, experimental samples:

test preparations: sitagliptin phosphate tablets and original formulations prepared in examples 1 to 6 and comparative examples 2 and 4.

Secondly, experimental contents:

the dissolution rate of the test preparation in water was measured using water as a dissolution medium.

Third, Experimental methods

1. Dissolution determination

Taking the test preparations respectively, according to the first method of 2020 edition of Chinese pharmacopoeia, adopting a dissolution method (appendix XC first method (basket method)) device, taking water as a dissolution medium, taking a volume of the dissolution medium of 900mL, rotating at a speed of 50r/min, operating according to the method, sampling 1.5mL as test solution at 5min, 10min, 15min, 20min, 30min, 45min and 60min respectively, and simultaneously adding an equivalent isothermal release medium. And detecting the test solution at each time point by adopting a high performance liquid chromatography. The dissolution rates of sitagliptin phosphate in water in the sitagliptin phosphate tablets prepared in examples 1 to 6 and comparative examples 2 and 4 and the original triturate were compared, respectively, and the results are shown in tables 5 and 6. The graphs comparing the dissolution curves of examples 1 to 6 and the original preparation in water are shown in fig. 1 and 2, and the graphs comparing comparative examples 2 and 4 and the dissolution curves of the original preparation in water are shown in fig. 3.

TABLE 5 (dissolution medium water)

TABLE 6 (dissolution medium water)

Since comparative example 1 has a large difference in sheet weight and does not meet the relevant regulations, comparative example 3 has a sticking phenomenon, and thus the dissolution curve of comparative example 1 and comparative example 3 is not examined. The similar factors of the dissolution curves of the sitagliptin phosphate tablets prepared in the examples 1 to 6 and the original preparation are both larger than 50, the dissolution behaviors are similar, the consistency evaluation requirements are met, and the similarity of the sitagliptin phosphate tablets prepared in the example 2 and the original preparation is obviously higher than that of the sitagliptin phosphate tablets prepared in the examples 1 and 3 to 6.

Effect example 3

Effect example 3 was conducted to examine the dissolution curves of the sitagliptin phosphate tablets prepared in examples 1 to 6 and comparative examples 2 and 4 and the original troche, using a hydrochloric acid solution having a pH of 1.2, an acetate buffer having a pH of 4.5 and a phosphate buffer having a pH of 6.8 as dissolution media.

The examination method was substantially the same as in effect example 2, except that the dissolution medium was changed to a hydrochloric acid solution having a pH of 1.2, an acetate buffer having a pH of 4.5, and a phosphate buffer having a pH of 6.8. The dissolution curves of sitagliptin phosphate in different pH media in the tablets prepared in examples 1-6 and comparative examples 2 and 4 and the original preparation are respectively compared. The comparative graphs of the dissolution curves of the examples 1 to 6 and the original preparation under the three dissolution media are similar to those of the graphs in figures 1 and 2, and the comparative graphs of the comparative examples 2 and 4 and the original preparation under the three dissolution media are similar to those of the graph in figure 3.

The similar factors of the dissolution curves of the sitagliptin phosphate tablets prepared in the examples 1-6 and the original preparation in three different dissolution media are both larger than 50, the dissolution behaviors are all similar, the similar factors of the dissolution curves of the sitagliptin phosphate tablets prepared in the comparative examples 2 and the original preparation in the three different dissolution media are both smaller than 50, and the difference of the dissolution behaviors is large.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims

1. The sitagliptin phosphate composition is characterized by comprising the following components in percentage by mass:

the D90 particle size of the sitagliptin phosphate monohydrate is 30-90 mu m;

2. The sitagliptin phosphate composition according to claim 1, which comprises the following components in percentage by mass:

the D90 particle size of the sitagliptin phosphate monohydrate is 40-80 mu m;

3. Sitagliptin phosphate tablet, characterized in that it comprises a tablet core comprising a sitagliptin phosphate composition according to claim 1 or 2.

4. The sitagliptin phosphate tablet as claimed in claim 3, wherein the sitagliptin phosphate tablet further comprises a coating layer, the coating layer comprises an Opadry gastric soluble film coating premix, and the mass of the coating layer is 1% -3% of that of the tablet core.

5. The sitagliptin phosphate tablet as claimed in claim 3, wherein the following components are included in every 1000 tablets of the sitagliptin phosphate tablet:

the D90 particle size of the sitagliptin phosphate monohydrate is 30-90 mu m;

6. A method for preparing sitagliptin phosphate tablets as claimed in claim 3, characterized in that the preparation method comprises the following steps: directly compressing the sitagliptin phosphate composition of claim 1 or 2.

7. The preparation method of sitagliptin phosphate tablets as claimed in claim 6, characterized in that the preparation method comprises the following steps:

8. The method for preparing sitagliptin phosphate tablets according to claim 7, wherein,

in the step of obtaining the first mixture, mixing in a three-dimensional mixer for 10-30 min;

and/or in the step of obtaining the second mixture, mixing in a three-dimensional mixer for 1-10 min;

and/or, the tablet press is a rotary tablet press.

9. The method for preparing sitagliptin phosphate tablets according to claim 7, further comprising, after the step of compressing the second mixture into tablets by using a tablet press to obtain the sitagliptin phosphate tablets:

10. Use of the sitagliptin phosphate composition according to claim 1 or 2 in the preparation of a medicament for preventing or treating type 2 diabetes.