Pharmaceutical composition containing DPP-4 inhibitor and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition. In particular to a compound medicine composition containing a DPP-4 inhibitor and biguanide and a preparation method of the compound medicine composition. The process auxiliary materials of the pharmaceutical composition are easy to obtain and low in cost, and the produced composition has excellent bioavailability and dissolution characteristic, few impurities and satisfactory physical stability and chemical stability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a stable compound preparation containing a DPP-4 inhibitor and biguanides, and a method for preparing the preparation. Background Art

[0002] Dipeptidyl peptidase-4 (DPP-4) is an enzyme in the human body that can break down glucagon-like peptide-1 (GLP-1) which has a hypoglycemic effect. Therefore, inhibiting the activity of DPP-4 is considered to be a valuable drug for the treatment of diabetes.

[0003] In the process of preparing pharmaceutical compositions containing DPP-4 inhibitors, researchers found that DPP-IV inhibitors with primary or secondary amino groups usually produce incompatibility and easy degradation after mixing with a variety of commonly used pharmaceutical excipients. Taking linagliptin as an example, the existing linagliptin single or compound preparations have many types of excipients, poor preparation stability, easy degradation after long-term storage, and rapid growth of impurities. In addition, metformin hydrochloride, as another biguanide oral hypoglycemic drug, can be combined with DPP-4 inhibitors to achieve a synergistic hypoglycemic effect, but similarly, the existing DPP-4 inhibitors (especially linagliptin C 25 H 28 N8O2, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione)) and metformin hydrochloride C4H 11 The compound preparation of N5·HCl also has the above problems. The commonly used stabilizers arginine and meglumine in the prior art, such as patents WO2012120040A1, WO2009121945A3, WO2011039367A3, WO2016059219A1, WO2021160608A1, and WO2021246985A1, have certain pharmacological effects, and their pharmacological effects are irrelevant to the therapeutic effects of the pharmaceutical composition, and are prone to cause additional pharmacological effects.

[0004] Therefore, it is necessary to provide a stable compound preparation containing a DPP-4 inhibitor (especially linagliptin) and metformin hydrochloride, which can achieve technical effects such as fewer types of excipients, simple preparation, high stability, and less impurity growth. Summary of the invention

[0005] The object of the present invention is to provide a pharmaceutical composition containing a DPP-4 inhibitor (such as linagliptin) and a biguanide (such as metformin) with less excipients and good stability and a preparation method thereof, so as to solve the problems existing in the prior art. The present invention reduces the cost of excipients and pharmacological toxicity, so that the pharmaceutical composition still maintains excellent bioavailability and in vitro release. Specifically, the DPP-4 inhibitor and biguanide compound preparation of the present invention achieves good dissolution characteristics and the characteristics of inhibiting impurity growth by using carbonate as a stabilizer. And carbonate does not cause additional pharmacological effects. In addition, in the granulation process of the present invention, metformin hydrochloride is granulated separately, metformin hydrochloride is first mixed with a disintegrant, and then the stabilizer is dissolved in water and sprayed on the surface of metformin hydrochloride to neutralize the hydrochloric acid, and then a binder is sprayed to granulate, and the granulation process does not contact with linagliptin, which reduces the probability of the two interacting, and the stability of the preparation is higher.

[0006] The present invention adopts the following technical solution:

[0007] The first aspect of the present invention provides a pharmaceutical composition comprising a DPP-4 inhibitor, metformin hydrochloride, and one or more binders, one or more disintegrants, one or more fillers, one or more lubricants, and one or more stabilizers selected from sodium carbonate, sodium bicarbonate and potassium bicarbonate; preferably, the DPP-4 inhibitor is linagliptin.

[0008] In some embodiments, the binder is selected from hydroxypropyl cellulose and hypromellose;

[0009] In some embodiments, the disintegrant is selected from corn starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose,

[0010] Preferably, the disintegrant is one or more of cellulose, croscarmellose sodium and crospovidone, and the disintegrant is corn starch.

[0011] In some embodiments, the filler is selected from corn starch, pregelatinized starch, mannitol, lactose,

[0012] One or more of microcrystalline cellulose and calcium sulfate dihydrate; preferably the filler is selected from corn starch, pregelatinized starch and a combination thereof.

[0013] In some embodiments, the lubricant is magnesium stearate.

[0014] In some embodiments, the dosage form of the pharmaceutical composition is a tablet dosage form. Preferably, the tablet

[0015] Comprising a film coating; more preferably, the film coating comprises a film coating agent; further preferably, the film coating agent is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone.

[0016] In some embodiments, the film coating further comprises a plasticizer, optionally a glidant, and optionally a

[0017] one or more pigments; preferably the plasticizer is propylene glycol, the optional glidant is talc; and the optional one or more pigments are selected from titanium dioxide, red iron oxide and yellow iron oxide.

[0018] In some embodiments, the pharmaceutical composition further comprises corn starch, pregelatinized starch and magnesium stearate.

[0019] In some embodiments, the pharmaceutical composition comprises: about 0.1%-0.5% of a DPP-4 inhibitor, about 50%-90% of metformin hydrochloride, about 2%-8% of a stabilizer, about 2%-5% of a binder, about 1%-5% of a disintegrant, about 2%-8% of a filler and about 0.5%-2% of a lubricant.

[0020] In some embodiments, the pharmaceutical composition comprises: about 0.2%-0.3% of a DPP-4 inhibitor, about 80%-90% of metformin hydrochloride, about 3%-6% of a stabilizer, about 2%-3% of a binder, about 2%-4% of a disintegrant, about 3%-5% of a filler and about 0.5%-1% of a lubricant.

[0021] In some embodiments, the pharmaceutical composition comprises: about 0.25% of a DPP-4 inhibitor, about 85% of metformin hydrochloride, about 3%-5% of a stabilizer, about 2.5%-3% of a binder, about 2%-3% of a disintegrant, about 4%-5% of a filler, and about 0.85% of a lubricant.

[0022] The second aspect of the present invention provides a method for preparing the pharmaceutical composition of the first aspect of the present invention, the method comprising the step of first granulating metformin hydrochloride alone; preferably, the step of granulating metformin hydrochloride alone comprises:

[0023] a. First, the metformin hydrochloride stabilizer and the disintegrant are mixed to obtain a premixed powder;

[0024] b. Spray a certain amount of stabilizer on the premixed powder obtained in step a, and then spray a binder on the premixed powder for granulation.

[0025] In some embodiments, the preparation method further comprises granulating the metformin hydrochloride granules and then mixing with the DPP-4 inhibitor; preferably, the preparation method further comprises:

[0026] c. After the granules obtained in step b are granulated, they are mixed with the DPP-4 inhibitor, the filler, the stabilizer and the lubricant in a mixer to obtain the total mixed granules;

[0027] d. The total mixed granules obtained in step c are compressed to obtain tablets;

[0028] e. coating the tablets obtained in step d on a high-efficiency coating machine to obtain a final preparation product.

[0029] In some embodiments, the preparation method, wherein the mass ratio of the stabilizer in step b to the stabilizer in step c is about (0.01-100):1; preferably about (0.1-10):1; preferably about (0.5-5):1; preferably about (0.8-2):1; preferably about 1:1.

[0030] In some embodiments, the tablet obtained in step d has a tablet weight of 900-1100 mg and a hardness of 140-200N. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below by way of examples. The following examples are for explanation of the present invention but the present invention is not limited to the following examples.

[0032] Example 1-5 Preparation of Linagliptin and Dimethyl Biguanide Compound Preparation

[0033] Table 1. Composition of the combination preparation of linagliptin and dimethylbiguanide, expressed as “per tablet”

[0034]

[0035] Table 1. Composition of the combination preparation of linagliptin and dimethylbiguanide, expressed as “per tablet”

[0036]

[0037] According to the content of each component in the table, the corresponding composition is prepared by the following method:

[0038] a) Premixing: Metformin hydrochloride and corn starch were mixed in a mixer for 10 minutes to obtain a premixed powder.

[0039] b) Granulation: The premixed powder of metformin hydrochloride and corn starch is added into a fluidized bed, preheated, and about half of the prescribed amount of sodium carbonate stabilizer solution (or potassium bicarbonate stabilizer solution) is sprayed into it, and then the binder hydroxypropyl cellulose (or hydroxypropyl methylcellulose) solution is sprayed into it to perform fluidized bed granulation;

[0040] c) Mixing: After granulation, the granules are placed in a mixer together with linagliptin, about half of the remaining amount of sodium carbonate (or potassium bicarbonate) and pregelatinized starch and mixed for 10 minutes;

[0041] d) Total mixing: mixing the mixed granules with magnesium stearate for 5 minutes;

[0042] e) Tableting: The total mixed granules are tableted to control the tablet hardness and tablet weight, wherein the tablet weight is 900-1100 mg and the hardness is 140-200 N;

[0043] f) Coating: The tablets are coated with film coating materials (hydroxypropyl methylcellulose, propylene glycol, titanium dioxide, yellow iron oxide, red iron oxide, talc) on a high-efficiency coating machine to obtain the final product of the preparation.

[0044] Comparative Example 1

[0045] Oshuangning (linagliptin metformin tablets) 2.5 / 850mg purchased from Boehringer Ingelheim Products. The composition of the tablets is as follows: linagliptin, metformin hydrochloride, copovidone, L-arginine, corn starch, colloidal silicon dioxide, magnesium stearate, coating powder (hydroxypropyl methylcellulose, propylene glycol, titanium dioxide, iron oxide yellow, iron oxide red, talc).

[0046] Comparative Example 2: Compound preparation containing linagliptin and metformin using arginine as alkaline stabilizer

[0047] Table 2. Prescription composition of the pharmaceutical composition of Comparative Example 2, expressed as "per tablet"

[0048] Component / composition (mg) mg / tablet percentage% Linagliptin 2.5 0.25 Metformin Hydrochloride 850 85 Arginine 30 3 Copolyvidone 70 7 Corn starch 29 2.9 Magnesium Stearate 8.5 0.85 Silicon dioxide 10 1 Total(chip) 1000 100

[0049] The preparation method of Reference Example 2 is as follows:

[0050] a. Premixing: Place metformin hydrochloride, linagliptin, arginine, corn starch and copovidone in a wet granulator and mix evenly;

[0051] b. Granulation: spray the prepared copovidone adhesive solvent into a wet granulator for granulation;

[0052] c. Drying: adding the wet granules after granulation into a fluidized bed for drying;

[0053] d. Total mixing: Mix the mixed granules with magnesium stearate and silicon dioxide for 5 minutes;

[0054] e. Tableting: The total mixed granules are tableted to control the tablet hardness and weight, wherein the tablet weight is 900-1100 mg and the hardness is 140-200 N;

[0055] f. Coating: The tablets are coated on a high-efficiency coating machine using the same coating material as in the example to obtain a final preparation product.

[0056] Comparative Example 3: Compound preparation containing linagliptin and dimethylbiguanide without adding alkaline stabilizer

[0057] Table 3. Prescription composition of the pharmaceutical composition of Comparative Example 3, expressed as "per tablet"

[0058] Component / composition (mg) mg / tablet percentage% Linagliptin 2.5 0.25 Metformin Hydrochloride 850 85 Copolyvidone 80 8 Corn starch 49 4.9 Magnesium Stearate 8.5 0.85 Silicon dioxide 10 1 Total(chip) 1000 100

[0059] The preparation method of Reference Example 3 is as follows:

[0060] a. Premixing: Place metformin hydrochloride, linagliptin, corn starch and copovidone in a wet granulator and mix evenly;

[0061] b. Granulation: spray the prepared copovidone adhesive solvent into a wet granulator for granulation;

[0062] c. Drying: adding the wet granules after granulation into a fluidized bed for drying;

[0063] d. Total mixing: Mix the mixed granules with magnesium stearate and silicon dioxide for 5 minutes;

[0064] e. Tablet pressing: The total mixed granules are tableted to control the tablet hardness and tablet weight;

[0065] f. Coating: Coat the tablets on a high-efficiency coating machine to obtain the final product.

[0066] Comparative Example 4: Linagliptin and dimethylbiguanide compound preparation with meglumine as alkaline stabilizer

[0067] Table 4. Prescription composition of the pharmaceutical composition of Comparative Example 4, expressed as "per tablet"

[0068] Component / composition (mg) mg / tablet percentage% Linagliptin 2.5 0.25 Metformin Hydrochloride 850 85 Meglumine 30 3 Povidone 80 8 Mannitol 29.5 2.95 Magnesium Stearate 8 0.8 Total(chip) 1000 100

[0069] The preparation method of Reference Example 4 is as follows:

[0070] a. Preparing the first granule: mixing linagliptin, mannitol and meglumine uniformly, adding a povidone aqueous solution and fluidizing the granule in a fluidized bed;

[0071] b. preparing the second granules: adding metformin hydrochloride into a fluidized bed, and adding a polyvidone aqueous solution to perform fluidized bed granulation;

[0072] c. Granule mixing: Mix the two granules, add magnesium stearate and mix for 5 minutes;

[0073] d. Tableting: The total mixed granules are tableted to control the tablet hardness and tablet weight;

[0074] e. Coating: Coat the tablets on a high-efficiency coating machine to obtain the final product.

[0075] Comparative Example 5: Linagliptin and dimethylbiguanide compound preparation with meglumine as alkaline stabilizer

[0076] Table 5. Prescription composition of the pharmaceutical composition of Comparative Example 5, expressed as "per tablet"

[0077] Component / composition (mg) mg / tablet percentage% Linagliptin 2.5 0.25 Metformin Hydrochloride 850 85 Meglumine 25 2.5 Povidone 80 8 Corn starch 34.5 3.45 Magnesium Stearate 8 0.8 Total(chip) 1000 100

[0078] The preparation method of Reference Example 5 is as follows:

[0079] a. Preparing the first granules: mixing linagliptin, corn starch and meglumine uniformly, adding a povidone aqueous solution and performing fluidized bed granulation;

[0080] b. preparing the second granules: adding metformin hydrochloride into a fluidized bed, and adding a povidone aqueous solution for fluidized bed granulation;

[0081] c. Granule mixing: Mix the two granules, add magnesium stearate and mix for 5 minutes;

[0082] d. Tableting: The total mixed granules are tableted to control the tablet hardness and tablet weight;

[0083] e. Coating: Coat the tablets on a high-efficiency coating machine to obtain the final product.

[0084] Test Example 1 Comparative test on the stability of different compound preparations

[0085] 1.1 Place the bare chips (products to be packaged) of the pharmaceutical compositions of different embodiments and control examples under accelerated conditions (40°C, 75% relative humidity), take samples at 0, 7, 15, and 30 days, and perform impurity detection: take the sample in a brown volumetric bottle, add diluent to dilute to the scale, add a magnetic bar (50 mm long) and stir vigorously for 40 minutes, filter, and take the filtrate as the test solution. Accurately measure 10 microliters and inject it into the liquid chromatograph (SHIMADZU, LC-2030C), and record the chromatogram. If there are impurity peaks in the chromatogram of the test solution, calculate the content of each impurity by peak area according to the main component external standard method with correction factor, and the total amount of impurities = the sum of the single impurity content. The detection results of impurities are shown in Table 6.

[0086] Table 6. Stability test of different compositions under bare chip conditions

[0087]

[0088] It can be seen from the results in Table 6 that the impurity content and the impurity growth of Examples 1-5 are lower than those of Control Examples 1-5, so the formulations of Examples 1-5 have higher stability.

[0089] 1.2 The samples of Examples 1, 2, 3 and Comparative Examples 1 and 3 were packaged and placed under accelerated conditions (40°C, 75% relative humidity). Samples were taken at 0, 1, 3 and 6 months, respectively, for impurity testing using the same testing method as in 1.1. The test results are shown in Table 7.

[0090] Table 7. Stability test of different compositions after packaging

[0091]

[0092] From the experimental results in Table 6 and Table 7, it can be seen that Examples 1-5 of the present invention all use carbonate (sodium carbonate or potassium bicarbonate) as a stabilizer, and compared with the prescription sample without a stabilizer (Control Example 3), the growth of impurities is significantly suppressed; at the same time, compared with the composition of Control Example 1, the growth rate of impurities in the preparation of the present invention has a better inhibitory effect. The formulations of Examples 1-5 have a higher stability.

[0093] In addition, sodium carbonate or potassium bicarbonate, as raw materials for industrial production, has a lower cost than arginine or meglumine. It can be seen that the preparation ingredients of the present invention not only achieve a better impurity inhibition effect and high preparation stability, but also significantly reduce production costs.

[0094] Test Example 2 Dissolution Test

[0095] The pharmaceutical compositions of different embodiments and control examples were subjected to dissolution tests according to the dissolution determination method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0931 First Method (Basket Method)), with 900ml of 0.1mol / L hydrochloric acid solution as the dissolution medium, the speed was 50 revolutions per minute, and the operation was carried out in accordance with the law. After 30min, an appropriate amount of solution was taken, filtered, and more than 1ml of the initial filtrate was discarded, and the subsequent filtrate was taken as the test solution. The amount of each tablet dissolved was calculated by the peak area according to the external standard method. The dissolution results (with pH 1.0 medium as the evaluation index) are shown in Table 8.

[0096] Table 8 Dissolution of different compositions

[0097] Linagliptin

[0098]

[0099] Metformin

[0100]

[0101] From the experimental results, it can be seen that the dissolution rates of the two active ingredients of linagliptin and metformin in the pH 1.0 medium are both above 92% in 30 minutes, which is greater than 75% of the labeled amount, and compared with the control example 1, the dissolution effect is better.

Claims

1. A pharmaceutical composition comprising a DPP-4 inhibitor, metformin hydrochloride, and one or more binders, one or more disintegrants, one or more fillers, one or more lubricants, and one or more stabilizers selected from sodium carbonate, sodium bicarbonate and potassium bicarbonate; preferably, the DPP-4 inhibitor is linagliptin.

2. The pharmaceutical composition of claim 1, wherein the binder is selected from hydroxypropyl cellulose and hypromellose; and / or The disintegrant is selected from one or more of corn starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone, preferably the disintegrant is corn starch; and / or The filler is selected from one or more of corn starch, pregelatinized starch, mannitol, lactose, microcrystalline cellulose and calcium sulfate dihydrate, preferably the filler is selected from corn starch, pregelatinized starch and a combination thereof; and / or The lubricant is magnesium stearate.

3. The pharmaceutical composition according to claim 1, which is in the form of a tablet, preferably, the tablet comprises a film coating; more preferably, the film coating comprises a film coating agent; further preferably, the film coating agent is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone.

4. A pharmaceutical composition as claimed in claim 3, wherein the film coating further comprises a plasticizer, optionally a glidant, and optionally one or more pigments; preferably the plasticizer is propylene glycol, the optional glidant is talc; and the optional one or more pigments are selected from titanium dioxide, red iron oxide and yellow iron oxide.

5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising corn starch, pregelatinized starch and magnesium stearate.

6. The pharmaceutical composition of any one of claims 1 to 5, comprising: about 0.1% to 0.5% of a DPP-4 inhibitor, about 50% to 90% of metformin hydrochloride, about 2% to 8% of a stabilizer, about 2% to 5% of a binder, about 1% to 5% of a disintegrant, about 2% to 8% of a filler, and about 0.5% to 2% of a lubricant; Preferably, the pharmaceutical composition comprises: about 0.2%-0.3% of a DPP-4 inhibitor, about 80%-90% of metformin hydrochloride, about 3%-6% of a stabilizer, about 2%-3% of a binder, about 2%-4% of a disintegrant, about 3%-5% of a filler and about 0.5%-1% of a lubricant; More preferably, the pharmaceutical composition comprises: about 0.25% of a DPP-4 inhibitor, about 85% of metformin hydrochloride, about 3%-5% of a stabilizer, about 2.5%-3% of a binder, about 2%-3% of a disintegrant, about 4%-5% of a filler and about 0.85% of a lubricant.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, the method comprising the step of first granulating metformin hydrochloride alone; preferably, the step of granulating metformin hydrochloride alone comprises: a. First, the metformin hydrochloride stabilizer and the disintegrant are mixed to obtain a premixed powder; b. Spray a certain amount of stabilizer on the premixed powder obtained in step a, and then spray a binder on the premixed powder for granulation.

8. The preparation method according to claim 7, further comprising granulating the metformin hydrochloride granules and then mixing them with the DPP-4 inhibitor; preferably, the preparation method further comprises: c. After the granules obtained in step b are granulated, they are mixed with the DPP-4 inhibitor, the filler, the stabilizer and the lubricant in a mixer to obtain the total mixed granules; d. The total mixed granules obtained in step c are compressed to obtain tablets; e. The tablets obtained in step d are coated on a high-efficiency coating machine to obtain a final preparation product.

9. The preparation method as claimed in claim 8, wherein the mass ratio of the stabilizer in step b to the stabilizer in step c is about (0.01-100):1; preferably about (0.1-10):1; more preferably about (0.5-5):1; further preferably about (0.8-2):1; most preferably about 1:

1.

10. The preparation method according to claim 9, wherein the tablet obtained in step d has a tablet weight of 900-1100 mg and a hardness of 140-200N.

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