A stable pharmaceutical composition of sitagliptin phosphate

Abstract

This invention provides a stable sitagliptin phosphate pharmaceutical composition comprising the following components: the active ingredient sitagliptin phosphate, a sulfite stabilizer, a filler, a disintegrant, and a lubricant. By adding a sulfite stabilizer to the sitagliptin phosphate pharmaceutical composition, this invention effectively controls the formation of nitrosamine impurities (NTTP) in the sitagliptin pharmaceutical composition, ensuring the quality stability of the sitagliptin phosphate pharmaceutical composition. The sitagliptin phosphate pharmaceutical composition of this invention has a dissolution effect comparable to a reference. The stable sitagliptin phosphate pharmaceutical composition of this invention is prepared using conventional preparation processes and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a sitagliptin phosphate pharmaceutical composition, and more particularly to a sitagliptin phosphate tablet and its preparation method. Background Technology

[0002] Diabetes mellitus is a metabolic disease characterized by hyperglycemia, caused by a deficiency in insulin secretion or impaired biological action, or both. Long-term hyperglycemia can lead to chronic damage or dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. Studies show that in 2015, the number of adults with diabetes in my country reached 109.6 million, ranking first in the world; furthermore, the prevalence and incidence of diabetes are gradually increasing worldwide.

[0003] Sitagliptin phosphate is a potent and highly selective dipeptidyl peptidase-IV (DPP-IV) inhibitor that helps control glycemic levels in patients with type 2 diabetes by increasing the levels of the active incretin glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Merck developed a sitagliptin phosphate tablet in 2006, which was imported to China in September 2009 under the brand name Genovit, available in 25mg, 50mg, and 100mg strengths. Clinically, this product can be used alone or in combination with other oral hypoglycemic agents (such as metformin or thiazolidinediones) to treat type 2 diabetes.

[0004] In 2022, the FDA discovered the nitrosamine impurity Nitroso-STG-19, or NTTP for short, in certain samples of sitagliptin phosphate. Its chemical structure is as follows:

[0005]

[0006] In the production process of sitagliptin, a key raw material is used—3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine (SM3). NTTP is generated by the reaction of this raw material with nitrite compounds in subsequent processes. Since the production process of sitagliptin and its compound preparations inevitably uses this raw material SM3, there is a risk of excessive nitrosamine impurity NTTP in these drugs.

[0007] Publicly available information shows that nitrosamine impurity NTTP is a potent carcinogen and one of the most important chemical carcinogens. In experimental animals, long-term exposure to low doses of NTTP may cause cancer in animals or humans, and even a single high-dose exposure can directly lead to cancer. Furthermore, numerous animal studies have demonstrated that NTTP can induce cancer in offspring through the placenta and breast milk. The FDA has set the lifetime daily exposure limit for NTTP at no more than 37 ng. Therefore, controlling the NTTP content in sitagliptin has become a crucial task in the quality control of this drug.

[0008] CN112156080A discloses a coating mixture that can maintain the stability of the active ingredient. It uses an Opadry AMB formulation without the plasticizer polyethylene glycol. The addition of antioxidants significantly improves the stability of the raw materials. That is, by adding antioxidants to the coating premix, the stability of the active ingredient can be greatly improved and the impurity content can be significantly reduced. However, CN112156080A targets Imp-A and Imp-A impurities in sitagliptin and does not involve the nitrosamine NTTP impurity of this application. Furthermore, the inventors have found that the same method cannot effectively control the formation of the NTTP impurity.

[0009] WO2024086263A1 discloses a sitagliptin-antioxidant composition that reduces the amount of NTTP formed in formulations and pharmaceutical compositions containing sitagliptin or its salts and / or hydrates by adding an antioxidant. WO2024086263A1 also discloses specific antioxidants, such as butylated hydroxyanisole (BHA) and propyl gallate (PG). These antioxidants react with nitrites under mildly acidic conditions, which can, to some extent, prevent the formation of nitrosamine impurities (NTTPs). However, the reaction product of these antioxidants and nitrites, nitrophenol, can be further metabolized into other toxic substances, such as hydroxylamine derivatives; moreover, the reaction of BHA with nitrites may lead to the formation of eight other undesirable compounds, including 1-hydroxy-2-tert-butyl-4-methoxy-6-nitrobenzene. In addition, the inventors also found that this type of antioxidant is not ideal in controlling or reducing the formation of NTTP, an impurity in sitagliptin.

[0010] Therefore, how to avoid the generation of nitrosamines during the preparation process, or to minimize the amount of nitrosamine impurities in drug raw materials and drug products, is an urgent problem that pharmaceutical companies need to solve. Developing a stable sitagliptin drug composition with an acceptable level of NTTP impurities is imminent. Summary of the Invention

[0011] This invention provides a stable sitagliptin phosphate pharmaceutical composition by adding a sulfite stabilizer. The nitrosamine impurity NTTP in this pharmaceutical composition can be effectively controlled below the FDA-required daily exposure level of 37 ng. The sitagliptin phosphate pharmaceutical composition of this invention has a dissolution rate that meets the requirements compared to the reference.

[0012] The present invention provides a stable sitagliptin phosphate pharmaceutical composition comprising the following components: the active ingredient sitagliptin phosphate, a sulfite stabilizer, a filler, a disintegrant, and a lubricant.

[0013] The inventors discovered that the aforementioned stabilizer can undergo a redox reaction with any nitrites that may be generated, consuming the nitrites produced during the reaction process. This reduces the chance of sitagliptin reacting with nitrites to form nitrosamine impurities, thereby controlling the amount of nitrosamine (NTTP) formed. Compared to the antioxidants such as butylated hydroxyanisole (BHA) and propyl gallate (PG) disclosed in WO2024086263A1, which reduce NTTP formation, the inventors provide a sitagliptin phosphate pharmaceutical composition with superior stability and more effective control over NTTP production, meeting impurity control limits.

[0014] In the stable sitagliptin phosphate pharmaceutical composition of the present invention, the sulfite stabilizer is further selected from one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; preferably, the stabilizer is selected from sodium thiosulfate and sodium metabisulfite.

[0015] In the stable sitagliptin phosphate pharmaceutical composition of the present invention, the stabilizer accounts for 0.05%-4% by weight in the pharmaceutical composition; preferably, the stabilizer accounts for 0.10%-1% by weight in the pharmaceutical composition.

[0016] In the stable sitagliptin phosphate pharmaceutical composition of the present invention, the filler includes, but is not limited to, one or more of sorbitol, dicalcium phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch.

[0017] In the stable sitagliptin phosphate pharmaceutical composition of the present invention, the disintegrant includes, but is not limited to, one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose.

[0018] In the stable sitagliptin phosphate pharmaceutical composition of the present invention, the lubricant includes, but is not limited to, one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearoyl fumarate.

[0019] The stable sitagliptin phosphate pharmaceutical composition of the present invention comprises the following components in weight percentages: 20%-45% sitagliptin phosphate, 0.05%-4% sulfite stabilizer, 50%-70% filler, 1%-5% disintegrant, and 1%-6% lubricant.

[0020] In one specific embodiment of the present invention, the stable sitagliptin phosphate pharmaceutical composition comprises the following components in the indicated weight percentages: 32% sitagliptin phosphate, 0.1% sulfite stabilizer, 62% filler, 2% disintegrant, and 4% lubricant.

[0021] In one specific embodiment of the present invention, the sulfite stabilizer is one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; the filler is one or more of sorbitol, calcium hydrogen phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose; and the lubricant is one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearoyl fumarate.

[0022] Specifically, the stable sitagliptin phosphate pharmaceutical composition of the present invention comprises the following components in the indicated weight percentages: 32% sitagliptin phosphate, 0.1% sodium thiosulfate, 31% anhydrous calcium hydrogen phosphate, 31% microcrystalline cellulose, 2% croscarmellose sodium cellulose, 1% magnesium stearate, and 3% sodium stearoyl fumarate.

[0023] The present invention provides a stable sitagliptin phosphate pharmaceutical composition, which is preferably prepared as a tablet.

[0024] The present invention also provides a method for preparing sitagliptin phosphate tablets, specifically by mixing the active ingredient sitagliptin phosphate, a filler, a disintegrant and a stabilizer, then adding a lubricant, mixing evenly, and then compressing and coating the mixture to obtain the tablets.

[0025] The stable sitagliptin phosphate pharmaceutical composition of the present invention can control the formation of NTTP impurities. Simultaneously, it has the same control effect on pharmaceutical compositions containing multiple active ingredients including sitagliptin phosphate, such as pharmaceutical compositions also containing active ingredients such as simvastatin, atorvastatin, metformin, repaglinide, etc.; preferably, the other active ingredient is metformin. The applicant has discovered that the above-mentioned stabilizer can also be added to sitagliptin-metformin pharmaceutical compositions, and the resulting sitagliptin-metformin pharmaceutical compositions can also achieve the required level of nitrosamine impurity NTTP.

[0026] This invention achieves effective control of the formation of nitrosamine impurities (NTTP) in sitagliptin phosphate drug compositions by adding sulfite stabilizers, thus ensuring the quality stability of the sitagliptin phosphate drug compositions. The sitagliptin phosphate drug compositions of this invention have dissolution rates comparable to those of the reference. Furthermore, the stable sitagliptin phosphate drug compositions of this invention are prepared using conventional preparation processes, making them suitable for industrial production. Detailed Implementation

[0027] To better understand the technical solution of the present invention, further explanation is provided below with reference to specific implementation examples. However, those skilled in the art should recognize that the present invention is not limited to these embodiments.

[0028] Example 1

[0029]

[0030] Preparation method:

[0031] (1) Mixing: Mix sitagliptin phosphate, microcrystalline cellulose, anhydrous dicalcium phosphate, croscarmellose sodium cellulose, sodium thiosulfate, and then add sodium stearate fumarate and magnesium stearate, and mix evenly.

[0032] (2) Tableting: The mixture from step (1) is tableted using a shallow concave circular die;

[0033] (3) Coating: The tablets after compression in step (2) are coated with a film coating premix, and the coating weight gain is 2-4.5%.

[0034] Example 2

[0035]

[0036] Preparation method:

[0037] (1) Mixing: Mix sitagliptin phosphate, microcrystalline cellulose, mannitol, crospovidone, and sodium metabisulfite, then add sodium stearoyl fumarate and stearic acid, and mix evenly.

[0038] (2) Tableting: The mixture from step (1) is tableted using a shallow concave circular die;

[0039] (3) Coating: Coating is carried out using a film coating premix, and the coating weight gain is 2-4.5%.

[0040] Example 3

[0041]

[0042] Preparation method:

[0043] (1) Mixing: Sitagliptin phosphate, pregelatinized starch, microcrystalline cellulose, anhydrous dicalcium phosphate, low-substituted hydroxypropyl cellulose, sodium bisulfite, and then add sodium stearoyl fumarate and calcium stearate, and mix evenly.

[0044] (2) Tableting: The mixture from step (1) is tableted using a shallow concave circular die;

[0045] (3) Coating: Coating is carried out using a film coating premix, and the coating weight gain is 2-4.5%.

[0046] Example 4

[0047]

[0048]

[0049] Preparation method:

[0050] (1) Mixing: Mix sitagliptin phosphate, microcrystalline cellulose, lactose, croscarmellose sodium cellulose and sodium sulfite, then add sodium stearate fumarate and talc, and mix well;

[0051] (2) Tableting: The mixture from step (1) is tableted using a shallow concave circular die;

[0052] (3) Coating: Coating is carried out using a film coating premix, and the coating weight gain is 2-4.5%.

[0053] Example 5

[0054]

[0055] Preparation method:

[0056] (1) Mixing: Mix sitagliptin phosphate, microcrystalline cellulose, anhydrous dicalcium phosphate, croscarmellose sodium cellulose, sodium thiosulfate, and then add sodium stearate fumarate and magnesium stearate, and mix evenly.

[0057] (2) Tableting: The mixture from step (1) is tableted using a shallow concave circular die;

[0058] (3) Coating: Coating is carried out using a film coating premix, and the coating weight gain is 2-4.5%.

[0059] Example 6

[0060]

[0061] Preparation method:

[0062] (1) Mixing: Mix sitagliptin phosphate, microcrystalline cellulose, anhydrous dicalcium phosphate, croscarmellose sodium cellulose, sodium thiosulfate, and then add sodium stearate fumarate and magnesium stearate, and mix evenly.

[0063] (2) Tableting: The mixture from step (1) is tableted using a shallow concave circular die;

[0064] (3) Coating: Coating is carried out using a film coating premix, and the coating weight gain is 2-4.5%.

[0065] Comparative Example

[0066]

[0067]

[0068] The sitagliptin phosphate drug composition of Comparative Example 1 did not contain any stabilizer; the stabilizers selected in the sitagliptin phosphate drug compositions of Comparative Examples 2 and 3 were propyl gallate and BHA, respectively; Comparative Example 4 was a sitagliptin phosphate drug composition obtained by adding sodium thiosulfate as a stabilizer to the coating layer, and its tablet core did not contain any stabilizer.

[0069] The preparation methods for Comparative Examples 1-3 are the same as those for Example 1; the preparation method for Comparative Example 4 is as follows:

[0070] (1) Mixing: Mix sitagliptin phosphate, microcrystalline cellulose, anhydrous dicalcium phosphate, and croscarmellose sodium, then add sodium stearate fumarate and magnesium stearate, and mix evenly.

[0071] (2) Tableting: The mixture from step (1) is tableted using a shallow concave circular die;

[0072] (3) Coating layer: Sodium thiosulfate is added to the coating solution prepared by the film coating premix to coat the tablets after compression.

[0073] Stability test

[0074] Tablets from Examples 1-6 and Comparative Examples 1-4 were simultaneously stored at 40±2℃ and RH 75%±5% for 3 months. High-performance liquid chromatography (HPLC) was used to detect the nitrosamine impurity NTTP (%) and other maximum single impurities (%) of sitagliptin at 0 days and 3 months of accelerated storage. The results are as follows:

[0075]

[0076] The stability test results of the above examples and comparative examples show that: the nitrosamine impurity NTTP in the sitagliptin phosphate tablets obtained in Examples 1-6 of this invention can be controlled at a low level. Even after 3 months of accelerated testing, the NTTP content in the sitagliptin phosphate tablets can still be effectively controlled and maintained below 0.10 ppm, ensuring patient safety. No stabilizer was added in Comparative Example 1. Comparative Examples 2 and 3 used propyl gallate and BHA as stabilizers, and the resulting sitagliptin phosphate tablets had NTTP content far exceeding the FDA-required daily exposure limit of 0.37 ppm after 3 months of accelerated testing. In Comparative Example 4, where the stabilizer was added to the coating layer instead of the tablet core, the NTTP content in the tablets remained at a high level. The stability tests demonstrate that only when sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, or sodium bisulfite are added as stabilizers to the sitagliptin phosphate tablets, and these stabilizers are added to the tablet core, can the formation of nitrosamine impurity NTTP be effectively controlled, resulting in stable sitagliptin phosphate tablets.

[0077] Dissolution test

[0078] Using water as the dissolution medium, the dissolution rate (%) of sitagliptin phosphate tablets from Examples 1-6 was determined according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, 0931, Dissolution and Release Determination Method (Method I)) at a rotation speed of 75 rpm. The results are as follows:

[0079]

[0080] As can be seen from the above data, Examples 1-6 of this invention and the reference formulation The results were consistent, with a dissolution rate of over 85% within 15 minutes, achieving rapid dissolution and meeting the drug dissolution requirements.

[0081] Example 7

[0082] This invention also provides a sitagliptin-metformin pharmaceutical composition, the specific formulation of which is as follows:

[0083]

[0084] The preparation method is as follows:

[0085] (1) Granulation: Take an appropriate amount of purified water, add povidone and sodium dodecyl sulfate, stir to dissolve, and obtain a binder solution for later use; mix sitagliptin phosphate with sodium thiosulfate, then add it and metformin hydrochloride into a fluidized bed, mix, add the above binder solution to granulate, and dry and granulate.

[0086] (2) Mixing: Mix microcrystalline cellulose, sodium stearate fumarate and the granules after granulation in step (1) for later use;

[0087] (3) Tableting: The total mixture from step (3) is compressed into tablets.

[0088] (4) Coating: Coating is carried out using a film coating premix, and the weight gain of coating is 1-3%.

[0089] The tablets from Example 7 were stored continuously at 40±2℃ and RH 75%±5% for 3 months. High-performance liquid chromatography (HPLC) was used to detect the nitrosamine impurity NTTP (%) at 0 days and at 3 months of accelerated storage, as well as other maximum single impurities (%). The results are as follows:

[0090]

[0091] The experimental results show that the nitrosamine impurity NTTP in the sitagliptin metformin tablets of Example 7 was controlled at a low level. Even after 3 months of accelerated treatment, the NTTP content in the tablets was still effectively controlled at 0.11 ppm, which is far below the FDA's limit for this impurity. This indicates that the stabilizer of this application can still effectively control the formation of the impurity NTTP in the sitagliptin metformin drug composition, thereby ensuring the safety of patients taking the medication.

[0092] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of the invention and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of the invention should be included within the protection scope of the invention. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. A stable sitagliptin phosphate pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the following components: sitagliptin phosphate, sulfite stabilizer, filler, disintegrant, and lubricant.

2. The pharmaceutical composition according to claim 1, characterized in that, The sulfite stabilizer is selected from one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; preferably, the stabilizer is selected from sodium thiosulfate and sodium metabisulfite.

3. The pharmaceutical composition according to claim 1, characterized in that, The sulfite stabilizer constitutes 0.05%-4% of the weight of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 1, characterized in that, The sulfite stabilizer constitutes 0.10%-1% of the weight of the pharmaceutical composition.

5. The pharmaceutical composition according to claim 1, characterized in that, The filler is selected from one or more of sorbitol, dicalcium phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch.

6. The pharmaceutical composition according to claim 1, characterized in that, The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose.

7. The pharmaceutical composition according to claim 1, characterized in that, The lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearoyl fumarate.

8. The pharmaceutical composition according to claim 1, characterized in that, It includes the following components by weight percentage: sitagliptin phosphate 20%-45%, sulfite stabilizer 0.05%-4%, filler 50%-70%, disintegrant 1%-5%, and lubricant 1%-6%.

9. The pharmaceutical composition according to claim 8, characterized in that, The sulfite stabilizer is one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; the filler is one or more of sorbitol, calcium hydrogen phosphate, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose; and the lubricant is one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearoyl fumarate.

10. The pharmaceutical composition according to claim 8 or 9, characterized in that, It includes the following components by weight percentage: sitagliptin phosphate 32%, sodium thiosulfate 0.1%, anhydrous dicalcium phosphate 31%, microcrystalline cellulose 31%, croscarmellose sodium cellulose 2%, magnesium stearate 1%, and sodium stearoyl fumarate 3%.

11. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is prepared into tablets.

12. A method for preparing the pharmaceutical composition according to claim 11, characterized in that, The active ingredient sitagliptin phosphate, filler, disintegrant, and sulfite stabilizer are mixed together, and then a lubricant is added and mixed evenly. After even mixing, the mixture is compressed into tablets and coated to obtain the final product.

13. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition may further include another active pharmaceutical ingredient; preferably, the other active pharmaceutical ingredient is metformin.

Images