Combined drug use and a pharmaceutical composition and its use

Abstract

The present invention relates to the field of pharmaceutical technology, and discloses the use of cigligliptin or its analogues and metformin or its analogues in the preparation of drugs for treating metabolic disorders or in the combined use of drugs for treating metabolic disorders. The present invention proves through animal model pharmacological experiments that cigligliptin or its analogues and metformin or its analogues are used in combination to treat metabolic disorders such as diabetes, hypertension, insulin resistance, hypertriglyceridemia, etc., and have a synergistic effect. Compared with single drug use, it has better application potential for treating metabolic disorders, and is suitable for patients who cannot effectively control metabolic disorders by using either drug alone.

Description

[0001] This application is a divisional application with the application date of March 18, 2019, application number CN201910203978.0, and the name of the invention is "Combination medication application and a pharmaceutical composition and its application". Technical Field

[0002] The present invention relates to the field of pharmaceutical technology, and in particular to combined drug use and a pharmaceutical composition and application thereof. Background Art

[0003] Metformin hydrochloride is a biguanide hypoglycemic drug with multiple mechanisms of action, including: (1) acting on the liver, inhibiting gluconeogenesis and reducing hepatic glucose output; (2) acting on peripheral tissues (muscle, fat), improving muscle glycogen synthesis, reducing FFA, increasing IS, and increasing glucose uptake and utilization; (3) acting on the intestine, inhibiting intestinal wall cells from taking up glucose and increasing GLP-1 levels. As one of the most widely used oral hypoglycemic drugs in the world, metformin has good efficacy and safety in monotherapy / combination therapy, and has clear clinical evidence in preventing cardiovascular complications of diabetes. It is the core drug for diabetes treatment worldwide.

[0004] Although metformin has been unanimously recognized by domestic and foreign guidelines as the first-line drug for hypoglycemic treatment of type 2 diabetes, metformin alone cannot target all pathogenic links of diabetes. Some patients do not have ideal blood sugar control with metformin, and more patients have gradually deteriorated their blood sugar control with a single drug as the disease progresses after using metformin for a period of time. Therefore, clinical practice often uses two or more drugs in combination to better control blood sugar and reduce drug side effects. Summary of the invention

[0005] In view of this, the object of the present invention is to provide a use of cigliptin or its analogues and metformin or its analogues in the preparation of a drug for treating metabolic disorders or in combination with metformin or its analogues, so that cigliptin or its analogues and metformin or its analogues have a synergistic effect, and are suitable for patients whose metabolic disorders cannot be effectively controlled by using either drug alone;

[0006] Another object of the present invention is to provide a pharmaceutical composition comprising cigliptin or its analogs and metformin or its analogs, which has a synergistic effect on controlling metabolic abnormalities and can be used in the preparation of related drugs.

[0007] In the application of the present invention, the drug for treating metabolic disorders can be prepared only from cigliptin or its analogs and metformin or its analogs or used in combination for treating metabolic disorders, or one or more (for example, two, three, four, etc.) other active ingredients can be added to the two.

[0008] The analogs described in the present invention include, but are not limited to, stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystalline forms, amorphous forms, and pharmaceutically acceptable salts;

[0009] Sigliflozin is the active product of sitagliptin sodium, and its structural formula is as follows:

[0010]

[0011] Its pharmaceutically acceptable salt can be selected as sitagliptin sodium or sitagliptin potassium, and the structural formulas of the two are as follows:

[0012]

[0013] The pharmaceutically acceptable salt of metformin can be selected as metformin hydrochloride, also known as metformin hydrochloride.

[0014] The results of the relevant efficacy studies of the present invention show that in the diabetic db / db mouse model, the administration of sitagliptin and metformin alone has a significant effect on reducing the blood sugar level of db / db mice (P < 0.05), and the blood sugar lowering effect is more obvious when sitagliptin is administered in combination with metformin (P < 0.0001). Sitagliptin combined with metformin can significantly reduce the blood sugar concentration of model mice in the glucose tolerance test (OGTT); can significantly reduce the blood sugar concentration of model mice in the insulin tolerance test (ITT); has a significant effect on reducing TG in experimental mice, and also has significant advantages over the administration of sitagliptin and metformin alone. The test results show that sitagliptin and metformin have a significant synergistic effect on lowering blood sugar and lipids (TG) in diabetic model animals.

[0015] According to the above test results, the metabolic abnormalities described in the present invention include, but are not limited to, one or more of diabetes, hypertension, obesity, insulin resistance, hypertriglyceridemia, hyperglycemia, hypercholesterolemia, atherosclerosis, fatty liver and coronary heart disease.

[0016] The present invention also proposes a pharmaceutical composition for treating metabolic abnormalities, comprising cigliptin or its stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystal forms, amorphous forms, and pharmaceutically acceptable salts, and metformin or its stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystal forms, amorphous forms, and pharmaceutically acceptable salts.

[0017] Wherein, the preparation unit dosage of the cigligol or its stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystal forms, amorphous forms, and pharmaceutically acceptable salts is 5-50 mg, and the preparation unit dosage of the metformin or its stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystal forms, amorphous forms, and pharmaceutically acceptable salts is 200-1000 mg. The preparation unit dosage refers to the dosage of one tablet, one package, one pill, etc. when the pharmaceutical composition is made into a specific preparation.

[0018] In addition, the pharmaceutical composition of the present invention further comprises:

[0019] Active ingredients for treating metabolic disorders and / or other diseases that do not cause adverse reactions with cigligliptin or its stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystalline forms, amorphous forms, and pharmaceutically acceptable salts, and metformin or its stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystalline forms, amorphous forms, and pharmaceutically acceptable salts; and / or

[0020] Pharmaceutically acceptable excipients.

[0021] The pharmaceutical composition of the present invention can be prepared into tablets, granules, capsules or suspensions, and the pharmaceutically acceptable excipients can be adjusted and selected according to the dosage form to be prepared; in the present invention, the excipients can be selected from one or more of fillers, disintegrants, binders, pH regulators, and lubricants. The amount of filler can be 0% to 80%, preferably 5% to 20%; the amount of disintegrant can be 0% to 10%, preferably 3% to 8%; the amount of binder can be 0% to 20%, preferably 0% to 5%; the amount of pH regulator can be 0% to 20%, preferably 0% to 5%; the amount of lubricant can be 0% to 5%, preferably 0.2% to 1%;

[0022] The filler is selected from one or more of microcrystalline cellulose, lactose, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hexadecanol, octadecyl alcohol, ethyl cellulose, pregelatinized starch, powdered sugar, microcrystalline cellulose, mannitol, calcium hydrogen phosphate, calcium phosphate, colloidal silicon dioxide, etc.;

[0023] The disintegrant is one or more selected from starch, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl fiber, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, etc.;

[0024] The binder is selected from one or more of water, ethanol, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl pyrrolidone;

[0025] The pH regulator is selected from one or more of sodium carbonate, sodium bicarbonate, sodium metaphosphate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium citrate;

[0026] The lubricant is selected from one or more of stearic acid, magnesium stearate, sodium stearyl fumarate, micro powder silica gel, and talc;

[0027] In addition, in order to improve the poor compressibility of metformin (tablets), 0-5% polyethylene glycol 4000-8000 can be added.

[0028] Since the pharmaceutical composition of the present invention contains cigliptin or its analogs and metformin or its analogs, it can also be used in drugs for treating metabolic abnormalities.

[0029] It can be seen from the above technical scheme that the present invention proves through animal model pharmacological experiments that the combined use of cigliptin or its analogues and metformin or its analogues in the treatment of metabolic disorders such as diabetes, hypertension, insulin resistance, hypertriglyceridemia, etc. has a synergistic effect, and has better application potential for the treatment of metabolic disorders than single medication, and is suitable for patients who cannot effectively control metabolic disorders by using one of the drugs alone. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Shown is the effect of sitagliptin combined with metformin on blood glucose in the diabetic db / db mouse model;

[0031] Figure 2 Shown are the results of the glucose tolerance test (OGTT) of sitagliptin combined with metformin;

[0032] Figure 3 Shown are the results of insulin tolerance test (ITT) of sitagliptin combined with metformin;

[0033] Figure 4 Shown is the effect of sitagliptin combined with metformin on triglyceride (TG) in mice. DETAILED DESCRIPTION

[0034] The present invention discloses a combination drug application and a pharmaceutical composition and its application. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The application and pharmaceutical composition of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the application and pharmaceutical composition described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention.

[0035] The following further describes the combined drug application and a pharmaceutical composition and its application provided by the present invention.

[0036] Example 1: Preparation of compound sitagliptin sodium metformin coated tablets

[0037] prescription

[0038]

[0039] The preparation method is as follows:

[0040] (1) Preparation of Granule 1

[0041] Metformin hydrochloride was crushed to pass through a 100-mesh sieve, and povidone K30 and polyethylene glycol 6000 were added. The mixture was granulated in a fluidized bed using a 70% ethanol aqueous solution as a wetting agent, dried, and granulated using a 20-mesh sieve.

[0042] (2) Preparation of Granule 2

[0043] Microcrystalline cellulose, povidone K30 and sodium bicarbonate were added to sitagliptin sodium, and the mixture was granulated in a fluidized bed using water as a wetting agent, dried, and granulated using a 20-mesh granulator.

[0044] (3) Tablet pressing

[0045] Granule 1, Granule 2, the prescribed amount of sodium carboxymethyl cellulose and colloidal silicon dioxide were mixed in a three-dimensional mixer for 10 minutes, and the prescribed amount of magnesium stearate was added and mixed in the three-dimensional mixer for 3 minutes, and tableting was performed.

[0046] (4) Coating

[0047] Opadry was added to water and stirred for one hour, and the above tablets were coated to obtain coated tablets.

[0048] Example 2: Preparation of compound sitagliptin sodium metformin granules

[0049] prescription

[0050]

[0051] The preparation method is as follows:

[0052] (1) Preparation of Granule 1

[0053] Metformin hydrochloride was crushed to pass through a 100-mesh sieve, and povidone K30 and polyethylene glycol 6000 were added. The mixture was wet-granulated using a 70% ethanol aqueous solution as a wetting agent, dried, and granulated using a 20-mesh sieve.

[0054] (2) Preparation of Granule 2

[0055] Microcrystalline cellulose, povidone K30 and sodium bicarbonate were added to sitagliptin sodium, and wet granulation was performed using water as a wetting agent. The granules were dried and sized using a 20-mesh granulation method.

[0056] (3) Mixed packaging

[0057] Granules 1, granules 2 and the prescribed amount of colloidal silicon dioxide were mixed in a three-dimensional mixer for 10 minutes and packaged to obtain granules.

[0058] Example 3: Preparation of compound sitagliptin sodium metformin tablets

[0059] prescription

[0060]

[0061] The preparation method is as follows:

[0062] (1) Preparation of Granule 1

[0063] Metformin hydrochloride was crushed to pass through a 100-mesh sieve, and povidone K30 and polyethylene glycol 6000 were added. The mixture was granulated in a fluidized bed using a 70% ethanol aqueous solution as a wetting agent, dried, and granulated using a 20-mesh sieve.

[0064] (2) Preparation of Granule 2

[0065] Microcrystalline cellulose, povidone K30 and sodium bicarbonate were added to sitagliptin sodium, and wet granulation was performed using water as a wetting agent. The granules were dried and sized using a 20-mesh granulation method.

[0066] (3) Tablet pressing

[0067] Granule 1, Granule 2, the prescribed amount of sodium carboxymethyl cellulose and colloidal silicon dioxide were mixed in a three-dimensional mixer for 10 minutes, and the prescribed amount of magnesium stearate was added and mixed in the three-dimensional mixer for 3 minutes, and tableting was performed to obtain plain tablets.

[0068] Example 4: Preparation of compound sitagliptin sodium metformin coated tablets

[0069] prescription:

[0070]

[0071] The preparation method is as follows:

[0072] (1) Crushing

[0073] Grind metformin hydrochloride to pass through a 100-mesh sieve.

[0074] (2) Preparation of adhesive:

[0075] Siglistat sodium, sodium carbonate and water are prepared into an adhesive solution containing sitagliptin sodium.

[0076] (3) Wet granulation

[0077] The crushed metformin hydrochloride and hydroxypropyl cellulose were added into a wet granulator, wet granulated with the above-mentioned binder, dried, and granulated into 20 mesh size.

[0078] (4) Total mixing and tableting

[0079] Add the prescribed amount of magnesium stearate to the above granules and mix in a three-dimensional mixer for 3 minutes, and then tablet press.

[0080] (5) Coating

[0081] Opadry was added to water and stirred for one hour, and the above tablets were coated to obtain coated tablets.

[0082] Example 5: Preparation of compound sitagliptin sodium metformin granules

[0083] prescription:

[0084]

[0085]

[0086] The preparation method is as follows:

[0087] (1) Crushing

[0088] Grind metformin hydrochloride to pass through a 100-mesh sieve.

[0089] (2) Preparation of adhesive:

[0090] Hydroxypropyl cellulose and water are prepared into a binder solution.

[0091] (3) Wet granulation

[0092] The crushed metformin hydrochloride and other raw materials are added into a fluidized bed granulator, granulated with the above-mentioned binder, dried, and granulated into 20 mesh size.

[0093] (4) Mixed packaging

[0094] The granules obtained in step 3 are packaged to obtain granules.

[0095] Example 6: Preparation of compound sitagliptin sodium metformin tablets

[0096] prescription:

[0097]

[0098] The preparation method is as follows:

[0099] (1) Crushing

[0100] Grind metformin hydrochloride to pass through a 100-mesh sieve.

[0101] (2) Preparation of adhesive:

[0102] Hydroxypropyl cellulose, sodium carbonate and water are prepared into a binder solution.

[0103] (3) Wet granulation

[0104] The crushed metformin hydrochloride and sitagliptin sodium were added into a wet granulator, granulated with the above-mentioned binder, dried, and granulated into 20 mesh size.

[0105] (4) Total mixing and tableting

[0106] Add the prescribed amount of magnesium stearate to the above granules, mix in a three-dimensional mixer for 3 minutes, and press into tablets to obtain plain tablets.

[0107] Example 7: Preparation of drug-loaded micropellet capsules

[0108] prescription:

[0109]

[0110] The preparation method is as follows:

[0111] (1) Preparation of pill core

[0112] Microcrystalline cellulose and metformin hydrochloride are mixed, water is added to obtain a soft material, and a pellet core containing metformin is obtained by using an extrusion spheronization method. The pellet core is placed in a fluidized bed and dried at 40° C. for 30 minutes, and finally sieved to obtain a pellet core containing metformin hydrochloride.

[0113] (2) Preparation of coating solution

[0114] Siglitstat sodium and hydroxypropyl methylcellulose were added to an ethanol aqueous solution of appropriate concentration to dissolve, thereby preparing a coating solution containing sitagliptin sodium.

[0115] (3) Preparation of drug-loaded micropellet capsules

[0116] The metformin hydrochloride drug-containing pellet cores are placed in a fluidized bed, and the surface of the drug-containing pellet cores is coated with the coating liquid to obtain drug-loaded pellets. The pellets are dried at 40°C for 30 minutes. The obtained combined drug pellets are filled into empty capsule shells to obtain capsules.

[0117] Example 8: Preparation of drug-loaded micropellet capsules

[0118] prescription:

[0119]

[0120] The preparation method is as follows:

[0121] (1) Preparation of pill core

[0122] Microcrystalline cellulose and metformin hydrochloride are mixed, water is added to obtain a soft material, and a pellet core containing metformin is obtained by using an extrusion spheronization method. The pellet core is placed in a fluidized bed and dried at 40° C. for 30 minutes, and finally sieved to obtain a pellet core containing metformin hydrochloride.

[0123] (2) Preparation of coating solution

[0124] Siglitstat sodium and hydroxypropyl methylcellulose were added to an ethanol aqueous solution of appropriate concentration to dissolve, thereby preparing a coating solution containing sitagliptin sodium.

[0125] (3) Preparation of drug-loaded micropellet capsules

[0126] The metformin hydrochloride drug-containing pellet cores are placed in a fluidized bed, and the surface of the drug-containing pellet cores is coated with the coating liquid to obtain drug-loaded pellets. The pellets are dried at 40°C for 30 minutes. The obtained combined drug pellets are filled into empty capsule shells to obtain capsules.

[0127] Example 9: Preparation of drug-loaded micropellet capsules

[0128] prescription:

[0129]

[0130]

[0131] The preparation method is as follows:

[0132] (1) Preparation of pill core

[0133] Sitagliptin sodium, metformin hydrochloride, microcrystalline cellulose and hydroxypropyl methylcellulose are used to prepare a soft material, and the drug-containing pellet core is prepared by extrusion spheronization. The pellet core is placed in a fluidized bed and dried at 40°C for 30 minutes, and finally sieved to obtain the combined drug pellet core.

[0134] (2) Preparation of coating solution

[0135] Add Opadry to water and stir for 1 hour to coat the above-mentioned micropellets to obtain coated pellet cores.

[0136] (3) Preparation of drug-loaded micropellet capsules

[0137] The obtained micropellets are filled into empty capsule shells to obtain capsules.

[0138] Example 10: Determination of dissolution of the pharmaceutical composition of the present invention

[0139] The dissolution of metformin and sitagliptin sodium in the preparations obtained in the above examples was evaluated using phosphate buffer (1000 mL, 37° C., pH 6.8) according to the dissolution and release assay method (second method) of Part IV of the 2015 edition of the Chinese Pharmacopoeia. The results are shown in Table 1.

[0140] Table 1 Release characteristics of active ingredients in different dosage forms

[0141]

[0142] It can be seen from the results in Table 1 that the pharmaceutical composition of the present invention has a better release rate of the active ingredient.

[0143] Example 11: Effect of Siglistatin combined with Metformin on blood glucose concentration in db / db mice

[0144] Siglitstat combined with metformin can effectively reduce blood glucose concentration in db / db mice. The number of mice in each group of experiments was 10. Figure 1 The figure shows the experimental results of measuring the blood glucose of mice 17 days after administration. The drug dosage is expressed as mg / kg body weight, the dosage of sitagliptin is 10 mg / kg, and the dosage of metformin is 200 mg / kg. There are 10 mice in each group of experiments. The experimental results show that both sitagliptin and metformin can significantly reduce the blood glucose concentration of the experimental animals (P < 0.05), and the effect of sitagliptin combined with metformin in reducing blood glucose is more obvious (P < 0.0001). This extremely significant effect shows that sitagliptin combined with metformin has a synergistic effect.

[0145] Example 12: Effect of Siglistatin combined with Metformin on Blood Glucose Concentration in OGTT

[0146] Siglitstat combined with metformin can significantly reduce blood glucose concentration in glucose tolerance test (OGTT). The number of mice in each group of experiments was 10. The animals were fasted overnight for 16 hours, and the animals were weighed on the second day, and the blood glucose at 0 min was measured with a blood glucose meter. Glucose solution (1g / kg) was immediately orally administered at the same time as the test substance was intraperitoneally administered, and the blood glucose values ​​were measured at 15min, 30min, 60min, and 120min after administration. The area under the blood glucose time curve AUC was calculated. Figure 2 The test results showed that sitagliptin combined with metformin could significantly (P < 0.0001) reduce the blood glucose concentration of the test animals, while the effect of sitagliptin and metformin was significantly lower than the effect of the combination of the two.

[0147] Example 13: Effect of Sitagliptin combined with Metformin on Blood Glucose Concentration in Insulin Tolerance Test (ITT)

[0148] Sitagliptin combined with metformin can significantly reduce blood glucose concentration in insulin tolerance test (ITT). The number of mice in each group of experiments was 10. The animals were fasted for 1 hour, and blood glucose at 0 min was measured with a blood glucose meter. The test substance was intraperitoneally administered with insulin solution (1.0 IU / kg) at the same time, and the blood glucose values ​​were measured at 15 min, 30 min, and 60 min after administration. The area under the blood glucose time curve AUC was calculated. Figure 3 The experimental results showed that sitagliptin combined with metformin can significantly reduce the blood glucose concentration of experimental animals, while the effect of sitagliptin and metformin alone is not significant.

[0149] Example 14: Effect of Siglistatin combined with Metformin on triglycerides (TG) in mice

[0150] Siglitstat combined with metformin can significantly reduce triglycerides in experimental animals. The number of mice in each group of experiments was 10. The animals were fasted for hours on the day of sacrifice, and blood was collected in a 1.5 ml centrifuge tube. After being placed at room temperature for more than 30 minutes, the supernatant serum was centrifuged (12000rpm, 5min) and the blood triglyceride level was detected by an automatic biochemical analyzer. Figure 4 The test results show that sitagliptin can only significantly reduce the triglyceride level of the test animals, while metformin cannot significantly reduce it. The combination of sitagliptin and metformin can extremely significantly (P < 0.0001) reduce the triglyceride level of the test animals.

[0151] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for treating metabolic abnormalities, characterized in that: The active ingredients are composed of sitagliptin sodium and metformin or a pharmaceutically acceptable salt thereof. The unit dosage of the sitagliptin sodium is 5-50 mg, and the unit dosage of the metformin or a pharmaceutically acceptable salt thereof is 200-1000 mg.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutically acceptable salt of metformin is metformin hydrochloride.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that Pharmaceutically acceptable excipients are also included.

4. The pharmaceutical composition according to claim 3, characterized in that: The pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant, a binder, a pH adjuster, and a lubricant.

5. Use of sitagliptin sodium in combination with metformin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating metabolic abnormalities, wherein the metabolic abnormalities are one or more of diabetes, hypertriglyceridemia and hyperglycemia, the unit dosage of the sitagliptin sodium preparation is 5-50 mg, and the unit dosage of the metformin or a pharmaceutically acceptable salt thereof is 200-1000 mg.

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