CN113679684B - Sitagliptin phosphate composition, sitagliptin phosphate tablet, and preparation methods and application thereof - Google Patents

Sitagliptin phosphate composition, sitagliptin phosphate tablet, and preparation methods and application thereof Download PDF

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CN113679684B
CN113679684B CN202110958244.0A CN202110958244A CN113679684B CN 113679684 B CN113679684 B CN 113679684B CN 202110958244 A CN202110958244 A CN 202110958244A CN 113679684 B CN113679684 B CN 113679684B
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sitagliptin phosphate
tablet
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sitagliptin
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王志超
伏开强
庞建梅
郎福双
戴信敏
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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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% -35% of sitagliptin phosphate monohydrate; 20-40% of anhydrous calcium hydrophosphate; 20% -40% of microcrystalline cellulose; 1 to 4 percent of crosslinked sodium carboxymethyl cellulose; 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 mu m, and the D90 particle size of the microcrystalline cellulose is more than or equal to 260 mu m. The in vitro dissolution curve of the sitagliptin phosphate tablet provided by the invention is similar to that of an imported original developer produced by merck company, the possibility of bioequivalence with the original developer is improved, and the consistency evaluation requirement is met.

Description

Sitagliptin phosphate composition, sitagliptin phosphate tablet, and preparation methods and application thereof
Technical Field
The invention belongs to the field of medicines, and in particular 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 defective insulin secretion or impaired biological action, or both. Long-standing hyperglycemia leads to chronic damage to various tissues, especially the eyes, kidneys, heart, blood vessels, nerves, and dysfunction. Studies have shown that in 2015, the number of adult-onset diabetes patients in China has reached 1.096 billion, and is the first place in the world, and the prevalence and incidence of diabetes are gradually increasing worldwide.
Sitagliptin phosphate is a potent and highly selective dipeptidyl peptidase IV (DPP-IV) inhibitor that can improve glycemic control in type 2 diabetics by increasing the levels of the active incretin glucagon-like polypeptide-1 (GLP-l) and glucose-dependent insulinotropic polypeptide (GIP). The merck company developed a sitagliptin phosphate tablet in 2006. The product is imported into China in 9 months 2009, and has the trade name of Mentha and the specification of 25mg, 50mg and 100mg. Can be clinically used singly or combined with other oral hypoglycemic drugs to form compound drugs (such as metformin or thiazolidinedione) for treating type 2 diabetes.
The drug consistency evaluation requires that the imitated drug is consistent with the quality and the curative effect of the original drug. Specifically, the impurity spectrum is required to be uniform, the stability is required to be uniform, and the dissolution rule in vivo and in vitro is required to be uniform. The method has very important significance in developing the evaluation work of imitative drug quality and curative effect consistency, improving the overall level of the pharmaceutical industry in China, guaranteeing the safety and effectiveness of drugs, promoting the upgrading and structure adjustment of the pharmaceutical industry and enhancing the international competitive capacity.
In the prior art, when the in-vitro dissolution behavior of the simulated medicine of sitagliptin phosphate is investigated, the release behavior of the simulated medicine is found to have a remarkable gap from that of the original preparation, and the release behavior of the simulated medicine is difficult to be consistent with the in-vitro dissolution of the original preparation, so that the safety and the effectiveness of the simulated medicine 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 developing agent produced by merck company, and the problem that the in vitro dissolution of the sitagliptin phosphate simulated pharmacy and the original developing agent in the prior art are inconsistent is solved.
In order to achieve the above 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:
Figure BDA0003221127720000021
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:
Figure BDA0003221127720000022
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.
The invention controls the D90 particle size of the sitagliptin phosphate monohydrate and the microcrystalline cellulose, so that the in-vitro dissolution curve of the preparation prepared from the sitagliptin phosphate composition is similar to that of an imported original developer produced by merck company, the bioequivalence possibility of the preparation with the original developer is improved, and the preparation meets the requirement of drug consistency evaluation.
In a second aspect, the present invention provides a sitagliptin phosphate tablet comprising a tablet core comprising a sitagliptin phosphate composition as described in 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, every 1000 sitagliptin phosphate tablets comprise the following components:
Figure BDA0003221127720000031
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.
The in vitro dissolution curve of the sitagliptin phosphate tablet provided by the invention is similar to that of an imported original developer produced by merck company, the possibility of bioequivalence with the original developer is improved, and the consistency evaluation requirement is met.
In a third aspect, the present invention provides a method for preparing the sitagliptin phosphate tablet according to the second aspect, the method comprising the steps of: the sitagliptin phosphate composition according to the first aspect is directly tableted.
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 weight;
mixing the sitagliptin phosphate monohydrate, anhydrous calcium hydrophosphate, 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 compressing the second mixture into a tablet by a tablet press to obtain the sitagliptin phosphate tablet.
In any of the above embodiments, in the step of obtaining the first mixture, the mixing is preferably performed in a three-dimensional mixer for a period of 10 minutes to 30 minutes.
In any of the above embodiments, in the step of obtaining the second mixture, the mixing is preferably performed in a three-dimensional mixer for a period of 1 to 10 minutes.
Preferably in any of the above aspects, the tablet press is a rotary tablet press.
Preferably in any of the above embodiments, after said step of compressing said second mixture into tablets using a tablet press, the step of obtaining said sitagliptin phosphate tablet further comprises:
coating the sitagliptin phosphate tablet, and controlling the weight gain of the coating layer to be 1% -3%.
The preparation method of the sitagliptin phosphate tablet provided by the invention adopts the powder direct tabletting technology to reduce the procedures of granulating, drying and the like, has the advantages of simple preparation process, high safety and low cost, saves manpower and material resources, and is more suitable for large-scale production.
In a fourth aspect, the present invention provides a use of the sitagliptin phosphate composition according to the first aspect for the preparation of a medicament for the prevention or treatment of type 2 diabetes.
Drawings
FIG. 1 is a graph comparing dissolution curves of examples 1-3 and a raw preparation in water;
FIG. 2 is a graph comparing the dissolution curves of examples 4-6 and the original developer in water;
FIG. 3 is a graph comparing the dissolution curves of comparative example 2 and comparative example 4 with the original developer in water.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved more clear, the invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. The experimental reagents used in the following examples are all conventional biochemical reagents unless otherwise specified; the raw materials, instruments, equipment, etc. used in the following examples are all available commercially or by the existing methods, and unless otherwise specified, all refer to conventional raw materials, instruments, equipment, etc. available commercially or by the existing methods, 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, an embodiment of the present invention provides a sitagliptin phosphate composition, which includes the following components in percentage by mass:
Figure BDA0003221127720000051
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.
In the embodiment of the present invention, the D90 particle size refers to a particle size corresponding to a cumulative particle size distribution percentage of the sample reaching 90%, for example: the D90 particle size of the sample was 60. Mu.m, meaning that 90% of the particles of the sample measured had a particle size of less than 60. Mu.m.
The D90 particle size of the sitagliptin phosphate monohydrate may be controlled to be 30 to 90 μm by jet milling or mechanical milling, for example, the D90 particle size may be 30 μm, 40 μm, 50 μm, 60 μm, 80 μm or 90 μm, etc., and if the D90 particle size is too small, the in vitro dissolution rate of a formulation made of the sitagliptin phosphate composition is too fast, the difference from the dissolution curve of a reference formulation is large, and the energy consumption required for milling is large, sticky flushing is easy, and if the D90 particle size is too large, the in vitro dissolution rate of a formulation made of the sitagliptin phosphate composition is too slow, and the difference from the dissolution curve of a reference formulation is large, preferably, the D90 particle size is 40 to 80 μm.
The microcrystalline cellulose has a D90 particle size of not less than 260. Mu.m, for example, the D90 particle size may be 260. Mu.m, 280. Mu.m, 300. Mu.m, etc., and may be selected from the microcrystalline cellulose which is commercially available and which meets the D90 particle size of not less than 260. Mu.m. If the D90 particle size of microcrystalline cellulose is too small, the in vitro dissolution rate of the formulation made from the sitagliptin phosphate composition is too slow and the tablet weight difference is large, the dissolution curve difference from the reference formulation is large. Preferably, the D90 particle size is not less than 280. Mu.m.
According to the embodiment of the invention, the D90 particle size of the sitagliptin phosphate monohydrate and the microcrystalline cellulose is controlled, so that the in-vitro dissolution curve of the preparation prepared from the sitagliptin phosphate composition is similar to that of an imported original developer produced by merck company, the bioequivalence possibility of the preparation with the original developer is improved, and the consistency evaluation requirement is met.
Further, the sitagliptin phosphate composition comprises the following components in percentage by mass:
Figure BDA0003221127720000061
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.
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.
Because the prescription and the preparation process of the original preparation can be inquired, the domestic sitagliptin phosphate preparation mostly uses the same prescription and process (powder direct tabletting process) as the original preparation.
The auxiliary materials and coating prescription of the original grinding preparation are as follows:
123.8mg of microcrystalline cellulose, 123.8mg of uncrushed calcium hydrophosphate, 8mg of croscarmellose sodium, 4mg of magnesium stearate and 12mg of sodium stearyl fumarate;
the coating 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 present inventors have unexpectedly found during the course of the study that samples similar to the original formulations could be prepared in the original formulations without using any microcrystalline cellulose of different D90 particle sizes or sitagliptin phosphate monohydrate of different D90 particle sizes. Microcrystalline cellulose with different D90 particle sizes or sitagliptin phosphate monohydrate with different D90 particle sizes show different properties, correspondingly, show different dissolution behaviors in the preparation, and have obvious influence on the dissolution behaviors of the preparation.
The in-vitro dissolution curve of the sitagliptin phosphate tablet provided by the embodiment of the invention is similar to that of an imported original developing agent produced by merck company, the possibility of bioequivalence with the original developing agent is improved, the consistency evaluation requirement is met, the flowability and compressibility of prescription powder are good, the obtained tablet surface is smooth, the tablet weight difference is less than +/-3.0%, and the sitagliptin phosphate tablet is more suitable for large-scale production.
Further, the sitagliptin phosphate tablet also 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 the mass of the tablet core, for example, the mass of the coating layer can be 1%, 2% or 3% of the mass of the tablet core.
Further, every 1000 sitagliptin phosphate tablets comprise the following components:
Figure BDA0003221127720000071
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.
In a third aspect, an embodiment of the present invention provides a method for preparing a sitagliptin phosphate tablet according to the second aspect, the method comprising the steps of: the sitagliptin phosphate composition according to the first aspect is directly tableted.
The preparation method of the sitagliptin phosphate tablet provided by the embodiment of the invention adopts the powder direct tabletting technology to reduce the procedures of granulating, drying and the like, has the advantages of simple preparation process, high safety and low cost, saves manpower and material resources, and is more suitable for large-scale production.
Further, the preparation method comprises the following steps:
s1, weighing sitagliptin phosphate monohydrate, anhydrous calcium hydrophosphate, microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate according to the formula weight;
s2, mixing the sitagliptin phosphate monohydrate, anhydrous calcium hydrophosphate, 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;
and S4, pressing the second mixture into tablets by adopting a tablet press to obtain the sitagliptin phosphate tablets.
Further, in step S2, mixing is performed in a three-dimensional mixer for a period of 10min to 30min, for example, the mixing period may be 10min, 20min, 30min, or the like.
Further, in step S3, mixing is performed in a three-dimensional mixer for a period of 1 to 10 minutes, for example, the mixing period may be 1, 2, 5, 7, 10, or the like.
Further, the tablet press is a rotary tablet press.
Further, after step S4, the method further includes:
the sitagliptin phosphate tablet is coated, the weight gain of the coating layer is controlled to be 1% -3%, for example, the weight gain of the coating layer can be 1%, 2% or 3%.
In a fourth aspect, an embodiment of the present invention provides a use of the sitagliptin phosphate composition according to the first aspect for the preparation of a medicament for preventing or treating type 2 diabetes.
The invention has been tested several times in succession, and the invention will now be described in further detail with reference to a few test results, which are described in detail below in connection with specific examples.
In each of the following examples and comparative examples, the D90 particle size was obtained by detection on a Markov laser particle size analyzer, the apparatus model was Mastersizer 3000, the light source was a 633nm high stability helium-neon laser, and the detection method was a dry method.
In the following examples and comparative examples, the results were determined according to the following rules, compared with the dissolution profile of the original developer: according to the judgment of dissolution curve comparison in the general oral solid preparation dissolution curve comparison guiding principle, a similarity factor (f 2) method in a non-model dependent method is adopted, namely when the numerical value of the similarity factor (f 2) of two dissolution curves is not less than 50, the two dissolution curves can be considered to be similar.
Raw grinding preparation: sitagliptin phosphate tablet, trade name is benoweiv (imported from uk to china), specification is 100mg.
The coating layer in each of the following examples and comparative examples is 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).
The sitagliptin phosphate tablets provided in examples 1 to 6 include components having the mass shown in table 1 (in terms of 1000 tablets), and the sitagliptin phosphate tablets provided in comparative examples 1 to 4 include components having the mass shown in table 2 (in terms of 1000 tablets).
TABLE 1
Figure BDA0003221127720000091
TABLE 2
Figure BDA0003221127720000092
Figure BDA0003221127720000101
Example 1
The content of the sitagliptin phosphate tablet component provided in the present example is shown in table 1.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size of 30 mu m), anhydrous calcium hydrophosphate, microcrystalline cellulose (D90 particle size of 260 mu m), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2, mixing the sitagliptin phosphate monohydrate, anhydrous calcium hydrophosphate, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer for 20 minutes 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 adopting a rotary tablet press, preparing 1000 tablets to obtain plain tablets, and then coating the plain tablets with a film coating, wherein the weight of the coating layer is increased by 2%, so as to obtain the sitagliptin phosphate tablets.
Example 2
The content of the sitagliptin phosphate tablet component provided in the present example is shown in table 1.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size 40 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Example 3
The content of the sitagliptin phosphate tablet component provided in the present example is shown in table 1.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size 80 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size 260 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Example 4
The content of the sitagliptin phosphate tablet component provided in the present example is shown in table 1.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size of 90 mu m), anhydrous calcium hydrophosphate, microcrystalline cellulose (D90 particle size of 260 mu m), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Example 5
The content of the sitagliptin phosphate tablet component provided in the present example is shown in table 1.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size of 30 mu m), anhydrous calcium hydrophosphate, microcrystalline cellulose (D90 particle size of 280 mu m), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Example 6
The content of the sitagliptin phosphate tablet component provided in the present example is shown in table 1.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size 40 μm), anhydrous calcium hydrogen phosphate, microcrystalline cellulose (D90 particle size 280 μm), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Comparative example 1
The sitagliptin phosphate tablet component content provided in this comparative example is shown in table 2.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size of 30 mu m), anhydrous calcium hydrophosphate, microcrystalline cellulose (D90 particle size of 150 mu m), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Comparative example 2
The sitagliptin phosphate tablet component content provided in this comparative example is shown in table 2.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size of 30 mu m), anhydrous calcium hydrophosphate, microcrystalline cellulose (D90 particle size of 200 mu m), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Comparative example 3
The sitagliptin phosphate tablet component content provided in this comparative example is shown in table 2.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size of 15 mu m), anhydrous calcium hydrophosphate, microcrystalline cellulose (D90 particle size of 260 mu m), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Comparative example 4
The sitagliptin phosphate tablet component content provided in this comparative example is shown in table 2.
The preparation method comprises the following steps:
s1, sieving anhydrous calcium hydrophosphate, crosslinked sodium carboxymethyl cellulose, magnesium stearate and sodium stearyl fumarate with a 40-mesh sieve for later use. Sequentially weighing sitagliptin phosphate monohydrate (D90 particle size of 120 mu m), anhydrous calcium hydrophosphate, microcrystalline cellulose (D90 particle size of 260 mu m), croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the prescription amount;
s2 to S4 are identical to S2 to S4 in example 1.
Effect example 1
Effect example 1 in order to measure the repose angles of the materials before and after the mixture was tabletted in examples 1 to 6 and comparative examples 1 to 4, the appearance of the prepared tablet was observed, and the tablet weight difference of the tablet was examined.
Sheet weight difference checking method: and taking 20 pieces of sitagliptin phosphate, precisely weighing the total weight, precisely weighing each piece after the average piece weight is obtained, calculating the weight difference of each piece according to the weight-average piece weight/average piece weight multiplied by 100%, and obtaining the piece weight difference range of 20 pieces.
The measurement results are shown in tables 3 and 4.
TABLE 3 Table 3
Figure BDA0003221127720000131
Figure BDA0003221127720000141
TABLE 4 Table 4
Figure BDA0003221127720000142
The weight difference of the sitagliptin phosphate tablets prepared in examples 1 to 6 is below 3%, the surface is smooth, the relevant regulations are met, the weight difference of the sitagliptin phosphate tablets prepared in comparative examples 1 to 2 is large, the weight difference is above 3%, even exceeds 5%, and the surface of the sitagliptin phosphate tablets prepared in comparative example 3 is uneven and sticky
Effect example 2
Effect example 2 is an examination of dissolution curves of sitagliptin phosphate tablets and original formulations prepared in examples 1 to 6, comparative examples 2 and 4.
1. Experimental samples:
test formulation: sitagliptin phosphate tablets and raw preparation prepared in examples 1 to 6 and comparative examples 2 and 4.
2. The experimental contents are as follows:
the dissolution rate of the test formulation in water was measured using water as the dissolution medium.
3. Experimental method
1. Dissolution measurement
Taking test preparations respectively, taking 1.5mL of the test preparation as a solution of the test preparation according to the first method of the 2020 edition of Chinese pharmacopoeia, taking water as a dissolution medium by a device of a dissolution rate measurement method (appendix XC first method (basket method)), wherein the volume of the dissolution medium is 900mL, the rotating speed is 50r/min, and taking 1.5mL of the sample solution as 5min, 10min, 15min, 20min, 30min, 45min and 60min according to the normal operation, and simultaneously supplementing the same amount of the release medium at the same temperature. The test solutions at each time point are all detected by high performance liquid chromatography. The dissolution rates of sitagliptin phosphate in water in the sitagliptin phosphate tablets and the as-ground formulations prepared in examples 1 to 6 and comparative examples 2 and 4, respectively, were compared, and the results are shown in tables 5 and 6. Comparative examples 1 to 6 and dissolution curves of the original formulations in water are shown in FIGS. 1 and 2, and comparative examples 2 and 4 and dissolution curves of the original formulations in water are shown in FIG. 3.
Table 5 (dissolution medium is water)
Figure BDA0003221127720000151
Table 6 (dissolution medium is water)
Figure BDA0003221127720000161
Since comparative example 1 has a large difference in weight, does not meet the relevant regulations, comparative example 3 has a sticking phenomenon, and thus comparative examples 1 and 3 were not examined for dissolution curves. The dissolution curves of the sitagliptin phosphate tablets prepared in examples 1-6 and the original preparation are all greater than 50, the dissolution behaviors are similar, the consistency evaluation requirement is met, and the similarity between the sitagliptin phosphate tablets prepared in example 2 and the original preparation is obviously higher than that of the sitagliptin phosphate tablets prepared in examples 1 and 3-6.
Effect example 3
Effect example 3 is an examination of dissolution curves of sitagliptin phosphate tablets and the original formulations prepared in examples 1 to 6, comparative examples 2 and 4, using ph=1.2 hydrochloric acid solution, ph=4.5 acetate buffer and ph=6.8 phosphate buffer as dissolution media.
The method of investigation was substantially the same as in effect example 2, except that the dissolution medium was changed to ph=1.2 hydrochloric acid solution, ph=4.5 acetate buffer and ph=6.8 phosphate buffer, respectively. The dissolution profiles of sitagliptin phosphate in different pH media in the sitagliptin phosphate tablets and the as-ground formulations prepared in examples 1 to 6 and comparative examples 2 and 4, respectively, were compared. Comparison of dissolution profiles of examples 1-6 with the as-ground formulation in the three dissolution media is similar to that of fig. 1 and 2, and comparison of dissolution profiles of examples 2 and 4 with the as-ground formulation in the three dissolution media is similar to that of fig. 3.
The dissolution curves of the sitagliptin phosphate tablets prepared in examples 1 to 6 and the original preparation in three different dissolution media are all larger than 50 in similarity factor, the dissolution behaviors are similar, the dissolution curves of the sitagliptin phosphate tablets prepared in comparative example 2 and comparative example 4 and the original preparation in three different dissolution media are all smaller than 50 in similarity factor, and the dissolution behaviors are large in difference.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims (8)

1. The sitagliptin phosphate composition is characterized by comprising the following components in percentage by mass:
Figure FDA0004040812410000011
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.
2. The sitagliptin phosphate composition according to claim 1, characterized in that the sitagliptin phosphate composition comprises the following components in percentage by mass:
Figure FDA0004040812410000012
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.
3. A sitagliptin phosphate tablet, characterized in that it comprises a tablet core comprising the sitagliptin phosphate composition according to claim 1 or 2.
4. A sitagliptin phosphate tablet according to claim 3, further comprising a coating layer comprising an opadry gastric soluble film coating premix, the coating layer being 1-3% of the tablet core mass.
5. A sitagliptin phosphate tablet according to claim 3, wherein every 1000 sitagliptin phosphate tablets comprises the following components:
Figure FDA0004040812410000021
6. a process for the preparation of sitagliptin phosphate tablets according to claim 3, characterized in that the process comprises the steps of:
weighing sitagliptin phosphate monohydrate, anhydrous calcium hydrophosphate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate and sodium stearyl fumarate according to the formula weight;
mixing the sitagliptin phosphate monohydrate, anhydrous calcium hydrophosphate, microcrystalline cellulose and croscarmellose sodium in a three-dimensional mixer for 10-30 min to obtain a first mixture;
adding magnesium stearate and sodium stearyl fumarate into the first mixture, and mixing in a three-dimensional mixer for 1-10 min to obtain a second mixture;
and pressing the second mixture into tablets by using a rotary tablet press to obtain the sitagliptin phosphate tablets.
7. The process for preparing sitagliptin phosphate tablet according to claim 6, characterized in that after said step of compressing said second mixture into tablets using a rotary tablet press, further comprises:
coating the sitagliptin phosphate tablet, and controlling the weight gain of the coating layer to be 1% -3%.
8. Use of a sitagliptin phosphate composition according to claim 1 or 2 for the manufacture of a medicament for the prevention or treatment of type 2 diabetes.
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