Sitagliptin phosphate tablet as well as preparation method and application thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to sitagliptin phosphate tablets as well as a preparation method and application thereof. According to the specific technical scheme, the sitagliptin phosphate tablet comprises sitagliptin phosphate, a filling agent, a disintegrating agent and a lubricating agent, the filling agent comprises microcrystalline cellulose, and the moisture content of the microcrystalline cellulose is smaller than 5%. When the lubricant is selected, the use of the lubricant sodium stearyl fumarate commonly used in the industry is avoided, so that the generation of impurities is effectively reduced. Meanwhile, the moisture content of microcrystalline cellulose in the filling agent is controlled, and the generation of impurities in the sitagliptin phosphate tablet is further reduced. Finally, the sitagliptin phosphate tablet which is high in purity, low in impurity content and stable in character is provided.

Description

TECHNICAL FIELD

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

[0002] Diabetes is a metabolic disease characterized by high blood sugar. According to a study published in The Lancet, it is predicted that there will be more than 131 million people worldwide with diabetes by 2050.

[0003] Sitagliptin phosphate tablet is the first approved DPP-4 inhibitor, which also opens a new era of using "gliptin" to treat diabetes. Through the test of more than ten million prescriptions worldwide after listing, sitagliptin phosphate tablet further shows strong and effective hypoglycemic efficacy and excellent safety.

[0004] In the case that sitagliptin phosphate tablet has been verified to have superior hypoglycemic performance, how to further improve the quality of the drug becomes a research focus. According to the common knowledge in the art, there are several important indicators for drug quality control. One is drug purity, and the content of effective components is an important indicator reflecting drug purity; the other is drug impurities, and the impurities existing in the drug will directly affect the efficacy of the drug and may cause toxic side effects; the third is drug stability, and poor drug stability will directly affect the shelf life of the drug, increase the difficulty of storage and transportation, and increase the possibility of toxic side effects.

[0005] Therefore, it is of important practical significance to develop a sitagliptin phosphate tablet with high purity, low impurity level, stable properties and a preparation method thereof. SUMMARY

[0006] The present application aims to provide a sitagliptin phosphate tablet with high purity, low impurity level, stable properties and a preparation method and application thereof.

[0007] To achieve the above-mentioned application purposes, the technical solutions adopted by the present application are as follows:

[0008] The present application provides a sitagliptin phosphate tablet in the first aspect, which comprises sitagliptin phosphate, a filler, a disintegrant and a lubricant.

[0009] In some embodiments, the filler comprises microcrystalline cellulose with a moisture content < 5%, preferably microcrystalline cellulose with a moisture content < 4.5%.

[0010] In some embodiments, the filler comprises microcrystalline cellulose and anhydrous calcium hydrogen phosphate, preferably microcrystalline cellulose PH102.

[0011] In some embodiments, the lubricant does not use sodium stearyl fumarate.

[0012] In some embodiments, the lubricant is any one or a mixture of several of magnesium stearate, talc, and micronized silica gel.

[0013] In some embodiments, the disintegrant is any one or a mixture of several of croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose.

[0014] In some embodiments, the sitagliptin phosphate tablets include a tablet core and a coating film.

[0015] In some embodiments, the tablet core comprises, by weight, 31 parts sitagliptin phosphate, 60-68 parts filler, 0.3-5 parts disintegrant, and 0.1-3 parts lubricant; preferably, the tablet core comprises 31 parts sitagliptin phosphate, 64-66 parts filler, 1-4 parts disintegrant, and 0.5-2 parts lubricant.

[0016] In some embodiments, the filler comprises, by weight, 40-50 parts microcrystalline cellulose and 15-25 parts anhydrous dicalcium phosphate.

[0017] In some embodiments, the coating film accounts for 1 to 5% of the weight of the tablet core, more preferably 2 to 4%, for example 2%, 3%, or 4%.

[0018] In some embodiments, the sitagliptin phosphate tablets are obtained by the following method: taking coating material, stirring and dissolving it in a coating solvent to prepare a coating solution of a certain concentration, and coating the tablet cores with a coating pan.

[0019] In some embodiments, the coating material accounts for 8-14% of the weight of the coating liquid, preferably 10-12%, for example 10%, 11%, or 12%.

[0020] In some embodiments, the coating material is a gastrosoluble film coating premix, such as a mixture of several substances including polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and iron oxide.

[0021] In some embodiments, the coating solvent is a 50% to 70% ethanol solution, for example, 50%, 60%, or 70%.

[0022] A second aspect of this invention provides a method for preparing sitagliptin phosphate tablets, the method comprising the following steps:

[0023] (1) Control the moisture content of microcrystalline cellulose to <5%, preferably <4.5%;

[0024] (2) Sitagliptin phosphate, filler and disintegrant were sieved separately;

[0025] (3) Thoroughly mix the sieved sitagliptin phosphate, filler and disintegrant, then add lubricant and mix thoroughly again to obtain a powder mixture;

[0026] (4) Compress the mixture powder into tablets;

[0027] (5) Dissolve the coating material in the coating solvent to prepare a coating solution, and use the coating solution to coat the tablets obtained in step (4).

[0028] In some implementation schemes, sitagliptin phosphate described in step (2) is passed through a 60-80 mesh sieve, for example, a 60 mesh sieve, a 70 mesh sieve, or an 80 mesh sieve.

[0029] In some implementation schemes, the filler in step (2) includes microcrystalline cellulose and anhydrous dicalcium phosphate after moisture control, and the disintegrant is any one or a mixture of several of croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose; the aforementioned microcrystalline cellulose, anhydrous dicalcium phosphate and disintegrant are passed through a 60-80 mesh sieve, for example, a 60 mesh sieve, a 70 mesh sieve and an 80 mesh sieve.

[0030] In some embodiments, step (3) comprises 31 parts by weight of sitagliptin phosphate, 60 to 68 parts of filler, 0.3 to 5 parts of disintegrant and 0.1 to 3 parts of lubricant, which are thoroughly mixed; preferably, it comprises 31 parts by weight of sitagliptin phosphate, 64 to 66 parts of filler, 1 to 4 parts of disintegrant and 0.5 to 2 parts of lubricant, which are thoroughly mixed.

[0031] In some embodiments, the filler in step (3) comprises, by weight, 40 to 50 parts microcrystalline cellulose and 15 to 25 parts anhydrous dicalcium phosphate.

[0032] In some implementation schemes, in step (3), the sieved sitagliptin phosphate, microcrystalline cellulose, anhydrous dicalcium phosphate and disintegrant are placed in a three-dimensional mixer and mixed thoroughly for 30 to 50 minutes, for example, 30 minutes, 40 minutes and 50 minutes.

[0033] In some implementations, the second thorough mixing in step (3) takes 1 to 10 minutes, preferably 3 to 6 minutes, for example 3 minutes, 4 minutes, 5 minutes, or 6 minutes.

[0034] In some implementations, in step (4), the mixed powder is compressed into tablets, for example, by installing a Ф10mm shallow concave die, adjusting the amount and hardness, and then compressing the tablets.

[0035] In some implementation schemes, the coating material in step (5) is a gastrosoluble film coating premix, preferably obtained by mixing several substances such as polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and iron oxide.

[0036] In some embodiments, the coating solvent in step (5) is a 50% to 70% ethanol solution, for example, 50%, 60%, or 70%.

[0037] In some embodiments, the coating material in step (5) accounts for 8-14% of the weight of the coating liquid, preferably 10-12%, for example 10%, 11%, or 12%.

[0038] In some implementation schemes, the coating step in step (5) is carried out in a coating pan, and the coating parameters are: rotation speed 2 to 8 rpm, temperature 35 to 45℃.

[0039] A third aspect of the invention provides the use of fillers, lubricants, and / or coating solutions in improving the chemical stability of sitagliptin phosphate in tablets.

[0040] In some embodiments, the tablet is prepared by the method described above.

[0041] In some embodiments, the filler comprises microcrystalline cellulose, wherein the moisture content of the microcrystalline cellulose is <5%, preferably <4.5%.

[0042] In some embodiments, the lubricant does not contain sodium stearate fumarate.

[0043] In some embodiments, the lubricant is selected from any one or more of magnesium stearate, talc, and micronized silica gel.

[0044] In some embodiments, the coating solution is prepared by stirring and dissolving the coating material in a coating solvent, wherein the coating solvent is a 50% to 70% ethanol solution, for example, 50%, 60%, or 70%.

[0045] In some embodiments, the coating material is a gastrosoluble film coating premix, preferably obtained by mixing several substances such as polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and iron oxide.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] 1. This invention unexpectedly discovered that by avoiding the use of sodium stearate, a commonly used lubricant in the industry, the generation of impurities in sitagliptin phosphate tablets is effectively reduced. At the same time, compared with existing technologies and original formulations that use both sodium stearate and magnesium stearate as lubricants, this invention uses only magnesium stearate as a lubricant, which simplifies the "mixing" step in the direct powder pressing process, shortens the mixing time, and improves production efficiency and drug quality.

[0048] 2. The Chinese Pharmacopoeia stipulates that the drying loss of microcrystalline cellulose should not exceed 7.0%, and microcrystalline cellulose is hygroscopic, and its moisture content may increase during storage. This invention unexpectedly discovered that controlling the moisture content of the filler microcrystalline cellulose to below 5% can effectively reduce the generation of impurities in sitagliptin phosphate tablets.

[0049] 3. An unexpected discovery in this invention is that sitagliptin phosphate tablets prepared using 50% ethanol solution as a coating solvent have low impurity content, effectively improving product quality. Attached Figure Description

[0050] Figure 1 The chromatogram of sitagliptin phosphate tablets prepared in Comparative Example 1 of this invention (day 0);

[0051] Figure 2 The chromatogram of sitagliptin phosphate tablets prepared in Example 4 of this invention (high temperature for 10 days). Detailed Implementation

[0052] To facilitate understanding of this application, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0053] definition

[0054] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the scope of this patent. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0055] As used in this article, the term "impurity" refers to substances in a drug that have no therapeutic effect or affect the stability and efficacy of the drug, or even are harmful to human health.

[0056] As used in this article, the term "maximum single impurity" refers to the largest unknown single impurity.

[0057] As used in this article, the term "0 days" refers to the day the sample was prepared.

[0058] As used in this article, the term "10-day high temperature" refers to a sample placed at a temperature of 60°C for 10 days.

[0059] Experimental Example 1: Effect of Sodium Stearate on Impurity Content in Sitagliptin Phosphate Tablets

[0060] 1. Preparation of Example 1

[0061] Sitagliptin phosphate was passed through an 80-mesh sieve, while microcrystalline cellulose, anhydrous calcium phosphate, and croscarmellose sodium were each passed through a 60-mesh sieve. The moisture content of the microcrystalline cellulose was controlled to be less than 5% (the actual measured moisture content was 4.18%).

[0062] Take 124g of the previously sieved sitagliptin phosphate, 80g of anhydrous calcium phosphate, 180g of microcrystalline cellulose, and 8g of croscarmellose sodium and place them in a three-dimensional mixer. Mix for 40 minutes, then stop the mixer and add 4g of magnesium stearate. Mix for 5 minutes to obtain an intermediate powder. After installing a Ф10mm shallow concave die, adjust the amount and hardness for tableting. Take 32g of gastric-soluble film coating premix and dissolve it in 234g of 50% ethanol solution to prepare a 12.0% coating solution. Adjust the coating pan speed, air inlet temperature, and pressure for coating to obtain sitagliptin phosphate tablets of Example 1.

[0063] 2. Preparation of Comparative Example 1

[0064] In Example 1, "stop the machine and add 4g of magnesium stearate" was changed to "stop the machine and add 4g of magnesium stearate and 4g of sodium stearate fumarate". All other preparation conditions and formulations were exactly the same as in Example 1, and sitagliptin phosphate tablets of Comparative Example 1 were prepared.

[0065] 3. Chemical stability study

[0066] Sitagliptin phosphate tablets prepared in Example 1 and Comparative Example 1 were stored at 60°C for 10 days. The impurity content in the tablets on day 0 and day 10 was then determined by HPLC. The results are shown in Table 1. The chromatogram of the sitagliptin phosphate tablets prepared in Comparative Example 1 on day 0 is shown below. Figure 1 As shown.

[0067] Table 1 Comparison of impurity content in each experimental group

[0068]

[0069]

[0070] The above experimental results show that, compared with Example 1 without sodium stearate, the total impurity content of Comparative Example 1 with sodium stearate lubricant doubled after 10 days of high-temperature treatment, indicating that not adding sodium stearate to the lubricant can avoid the generation of impurities in sitagliptin phosphate tablets.

[0071] Experimental Example 2: Effect of moisture content of microcrystalline cellulose on impurity content in sitagliptin phosphate tablets

[0072] 1. Preparation Examples 2-4

[0073] Microcrystalline cellulose with moisture contents of 3.26%, 4.21%, and 2.28% were selected, and the remaining preparation conditions and formulations were exactly the same as in Example 1, to prepare Examples 2 to 4.

[0074] 2. Preparation of Comparative Example 2

[0075] Microcrystalline cellulose with a moisture content of 7.41% was selected, and the remaining preparation conditions and formulation were exactly the same as in Example 1 to prepare Comparative Example 2.

[0076] 3. Chemical stability study

[0077] Sitagliptin phosphate tablets prepared in Examples 2-4 and Comparative Example 2 were stored at 60°C for 10 days. The impurity content in the tablets on day 0 and day 10 was determined by HPLC, and the results are shown in Table 2. The chromatogram of the sitagliptin phosphate tablets prepared in Example 4 after 10 days of high-temperature storage is shown in Table 2. Figure 2 As shown.

[0078] Table 2 Comparison of impurity content in each experimental group

[0079]

[0080] The above experimental results show that after the samples in each experimental group were placed at high temperature for 10 days, the total impurity content of Comparative Example 2 was about 3 to 5 times that of Examples 2 to 4, indicating that controlling the water content of microcrystalline cellulose can effectively inhibit the formation of impurities in sitagliptin phosphate tablets.

[0081] Experimental Example 3: Effect of Coating Solvent Type on Impurity Content in Sitagliptin Phosphate Tablets

[0082] 1. Preparation of Comparative Example 3

[0083] The coating solvent was replaced with pure water instead of 50% ethanol, and the remaining preparation conditions and formulation were the same as in Example 3, to prepare sitagliptin phosphate tablets for Comparative Example 3.

[0084] 2. Chemical stability study

[0085] Sitagliptin phosphate tablets prepared in Example 3 and Comparative Example 3 were stored at 60°C for 10 days. The impurity content in the tablets on day 0 and day 10 was detected by HPLC. The results are shown in Table 3.

[0086] Table 3 Comparison of impurity content in each experimental group

[0087]

[0088] The above experimental results show that after being placed at a high temperature of 60°C for 10 days, the total impurity content of Comparative Example 3 was more than twice that of Example 3, indicating that choosing 50% ethanol as the coating solvent can effectively inhibit the formation of impurities in sitagliptin phosphate tablets.

[0089] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Any modifications, alterations, substitutions, or variations made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention shall fall within the protection scope defined by the claims of the present invention.

Claims

1. A tablet of siglitarin phosphate, characterized by: The sitagliptin phosphate tablet comprises sitagliptin phosphate, a filler, a disintegrant and a lubricant, the filler comprises microcrystalline cellulose, and the moisture content of the microcrystalline cellulose is less than 5%.

2. The sitagliptin phosphate tablet according to claim 1, wherein: The filler comprises microcrystalline cellulose and anhydrous calcium hydrogen phosphate.

3. The sitagliptin phosphate tablet according to claim 1, wherein: The lubricant does not use sodium stearyl fumarate.

4. The sitagliptin phosphate tablet according to claim 3, wherein: The lubricant is any one or a mixture of several of magnesium stearate, talc and micronized silica gel.

5. The sitagliptin phosphate tablet according to claim 1, wherein: The disintegrant is any one or a mixture of several of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and cross-linked povidone.

6. The sitagliptin phosphate tablet according to claim 1, wherein: The sitagliptin phosphate tablet comprises a tablet core and a coating film, and the components of the tablet core comprise, by weight fraction, 31 parts of sitagliptin phosphate, 60-68 parts of a filler, 0.3-5 parts of a disintegrant and 0.1-3 parts of a lubricant.

7. The sitagliptin phosphate tablet according to claim 6, wherein: The coating film accounts for 1-5% of the weight of the tablet core.

8. The sitagliptin phosphate tablet according to claim 6, wherein: The sitagliptin phosphate tablet is obtained by the following method: taking a gastric-soluble film coating premix, stirring and dissolving in a 50%-70% ethanol solution to prepare a coating liquid of a certain concentration, and coating the tablet core.

9. Process for the preparation of the sitagliptin phosphate tablets according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: (1) controlling the moisture content of the microcrystalline cellulose to be less than 5%; (2) sieving sitagliptin phosphate, a filler and a disintegrant respectively; (3) fully mixing the sieved sitagliptin phosphate, filler and disintegrant, then adding a lubricant and mixing again to obtain a mixture powder; (4) tabletting the mixture powder to obtain a tablet.

10. The method of claim 9, wherein: The method further comprises the following steps: (5) dissolving a coating material in a coating solvent to prepare a coating liquid, and coating the tablet obtained in step (4) with the coating liquid.

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