KR20180079176A - Pharmaceutical combination comprising DAPAGLIFLOZIN L-PROLINE and antidiabetic drugs - Google Patents

Abstract

The present invention relates to a pharmaceutical combination comprising a dapagliflozin L-proline and at least one antidiabetic agent. Specifically, the present invention provides a pharmaceutical combination further comprising metformin and/or a DPP-IV inhibitor in the dapagliflozin L-proline, and relates to a combination having high content uniformity and elution properties and high bioavailability.

Description

[0001] The present invention relates to a pharmaceutical composition comprising DAPAGLIFLOZIN L-PROLINE and antidiabetic drugs,

The present invention is directed to a pharmaceutical combination comprising multiparticulate L-proline and at least one anti-diabetic agent. Specifically, the present invention provides a pharmaceutical combination preparation further comprising metformin and / or a DPP-IV inhibitor in a dapagliflozin L-proline, which has excellent content uniformity and dissolution characteristics and has a high bioavailability will be.

Globally, diabetes has become one of the leading causes of adult death, and the number of diabetic patients is rapidly increasing as the obesity population grows, which is characterized by hyperglycemia due to excessive glucose production and peripheral insulin resistance. Plasma glucose is typically filtered in the renal glomeruli and is actively reabsorbed in the proximal tubules. SGLT-2 is considered to be a major transporter involved in glucose reabsorption at this site.

Thus, selective inhibition of SGLT-2 (diabetic patients) can normalize plasma glucose by increasing insulin sensitivity by delaying the onset of diabetic complications by increasing glucose excretion in the urine without significant gastrointestinal side effects . Thus, SGLT-2 inhibitors are attracting attention as a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

(2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4- ethoxybenzyl) phenyl] -6- (hydroxymethylphenyl) Hydroxy-methyl) tetrahydro-2H-pyran-3,4,5-triol) is disclosed in U.S. Patent No. 6,515,117 as a compound of Formula 1 below.

[Chemical Formula 1]

Korean Patent No. 1493102 discloses a process for producing (S) -propylene glycol (PG), (R) -PG, EtOH, ethylene glycol (EG), 1: 2 L- L-proline hemihydrate, and 1: 1 L-phenylalanine.

Because diabetes is a chronic disease and its condition is complicated, symptoms of the disease are often accompanied by multiple complications. Therefore, it is necessary to select the most suitable medicines for the individual patients at that time, and when the medicines are used alone, sufficient effects may not be obtained depending on the symptoms. In addition, And the emergence of adverse effects due to various problems, such as clinical trials are often difficult to choose. Therefore, in connection with the preparation for the treatment of diabetes mellitus, diabetes mellitus-related diseases and diabetic complications, it has been proposed to administer a combination of two or more drugs having different mechanisms, rather than administering one drug alone. However, when manufacturing a combination preparation containing two or more drugs, various factors such as interaction of two or more drugs, dissolution rate of individual drugs, uniformity of contents, and the like must be considered, .

U.S. Patent No. 6,515,117, C-aryl glucoside SGLT2 inhibitors and method; And Korean Patent No. 1493102 discloses a method for the treatment of diabetes mellitus comprising administering to a patient in need of such treatment a composition comprising (1S) -1,5-anhydro-1-C- (3 - ((phenyl) ≪ / RTI >

The present inventors intend to improve the compliance of patients with medicines by providing a combination preparation of D-phaglyplogin L-proline and an anti-diabetic agent, and to improve the effect through administration of a combined preparation having various mechanisms and to reduce side effects. Particularly, the present invention provides a combined preparation further comprising metformin and / or a DPP-IV inhibitor in the D-phaglyplated L-proline, and the present inventors have found that an optimal dissolution rate and content uniformity can be obtained, The present invention has been accomplished on the basis of these findings.

It is an object of the present invention to provide a combination preparation of diabetic therapeutic agents having various action mechanisms, thereby enhancing compliance of a patient, increasing the effect and minimizing adverse effects. In addition, the elution characteristics and content uniformity of the individual active ingredients in the combination preparation are improved, and the in vivo utilization ratio is increased.

Accordingly, the present invention provides a pharmaceutical combination comprising dapagliflozin L-proline, and at least one anti-diabetic agent.

Dapagliflozin L-proline can contain 5 to 20 mg as a dapagliflozin.

The anti-diabetic agent may be selected from the group consisting of an alpha-glucosidase inhibitor, a biguanide, an insulin secretagogue, an insulin sensitizer, a cannabinoid receptor 1 antagonist), a DPP-IV inhibitor, and the like.

In particular, the anti-diabetic agent may be metformin or a pharmaceutically acceptable salt thereof, wherein the dapagliflozin L-proline is present in an amount of from 0.1% to 10%, relative to metformin and a pharmaceutically acceptable salt thereof, as a dapagliflozin % ≪ / RTI > by weight.

In addition, the anti-diabetic agent may be a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, wherein the dapagliflozin L-proline is a dapagliflozin and the DPP-IV inhibitor and a pharmaceutically acceptable salt thereof By weight based on the total weight of the composition.

DPP-IV inhibitors may be selected from the group consisting of citagliptin, billagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin.

The pharmaceutical combination provided in the present invention may comprise a first granule comprising at least one anti-diabetic agent, and a dipalmitoyl L-proline.

The first granule may comprise one or more polymeric polymers. Examples of the polymeric polymer include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (HPC-L), purified shellac, a methacrylate polymer, an acrylate copolymer, Guar gum, tragacanth, acacia gum, locust bean gum, xanthan gum, and the like can be used, and HPMC 2208, HPMC 2910, HPC-L or locust bean gum can be preferably used.

In addition, the pharmaceutical combination preparation provided by the present invention may comprise a core layer comprising a first granule comprising at least one anti-diabetic agent and at least one lubricant and / or a dipalmitoyl L-proline; And a coating layer coating the core layer.

The weight of the coating layer may be preferably 1 to 20% by weight based on the weight of the core layer.

As the lubricant, silicon dioxide, magnesium salt of stearic acid, zinc salt, magnesium aluminum silicate, talc and the like can be used, and silicon dioxide or magnesium stearate is preferably used, but not limited thereto.

The first granule may comprise one or more polymeric polymers.

Wherein said coating layer is selected from the group consisting of dapagliflozin L-proline, metformin, cetagliptin, vedagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and its pharmaceutically acceptable salts One or more active ingredients selected from the group consisting of

In addition, the pharmaceutical combination preparation provided in the present invention may be formulated into an oral administration form, and the oral administration form may be a tablet or a capsule.

The pharmaceutical combination preparation comprising the polygalloglobulin L-proline and the anti-diabetic agent according to the present invention has a very excellent content uniformity and dissolution rate, and is thus excellent in the bioabsorption rate in the living body. Therefore, the diabetic, diabetic-related and diabetic complications As a preventive or therapeutic agent.

FIG. 1 shows the results of the content uniformity test of the D-phaglyplated L-proline in Examples 1 to 3. FIG.
Fig. 2 shows the results of the content uniformity test of D-phaglyplated L-proline in Examples 4 to 7. Fig.
FIG. 3 shows the results of the content uniformity test of the D-phaglyplated L-proline in Examples 8 to 11. FIG.
FIG. 4 shows the results of the content uniformity test of D-phaglyplated L-proline in Examples 12 to 15. FIG.
Fig. 5 shows the results of metformin dissolution rate test in Examples 1 to 3. Fig.
Figure 6 shows the results of metformin dissolution rate tests in Examples 8-11.
7 shows the results of metformin dissolution rate tests in Examples 12-15.

Dopagliflozin L-proline, an SGLT-2 inhibitor for the prevention or treatment of diabetes, diabetes-related diseases and diabetic complications, improves insulin sensitivity by enhancing glucose excretion in the urine without significant gastrointestinal side effects, and the onset of diabetic complications The plasma glucose can be normalized.

The polyparagraph L-proline used in the present invention is a crystalline complex of the following formula (2).

(2)

(In the above formula (2), x is 1 or 2 and y is 0 to 1)

Preferably, the multipagraphy L-proline of the present invention may be a 1: 2 crystalline complex.

Metformin is an acetaminophen, an antihyperglycemic agent used to treat non-insulin dependent diabetes mellitus (NIDDM). Metformin increases sensitivity to insulin in peripheral tissues, inhibits the uptake of sugar in the gastrointestinal tract, and reduces the production of blood sugar in the liver. Metformin does not promote the secretion of insulin, it has the action of reducing the amount of insulin in the blood, and also has the action of protecting blood vessels. It is also a drug suitable for use in patients with obesity or hyperlipemia, or in patients who are difficult to control blood glucose, which is ideal for food control, because it reduces fat in the body and does not cause hypoglycemia or the like.

Pharmaceutically acceptable salts of metformin that can be used in the present invention may be selected from the group consisting of hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate and toluenesulfonate, but is not limited thereto.

DPP-IV inhibitors also serve to cleave GLP-1, which stimulates glucose-dependent insulin secretion from pancreatic [beta] -cells and increases pancreatic [beta] -cell populations.

The DPP-VI inhibitors that can be used in the present invention may also be selected from the group consisting of citagliptin, valdagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and a pharmaceutically acceptable salt thereof But is not limited thereto.

Examples of pharmaceutically acceptable salts of DPP-VI inhibitors include salts with alkali metals (e.g., lithium, sodium and potassium); Salts with alkaline earth metals (e.g., calcium and magnesium); Salts with zinc or aluminum; It is also possible to use organic bases such as ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N- methyl-glucosamine, ≪ / RTI >abiethylamine); Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; Salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid and benzenesulfonic acid; And salts with acidic amino acids (e.g., aspartic acid and glutamic acid).

In the pharmaceutical combination preparation of the present invention, the dapagliflozin L-proline may be contained as 5 to 20 mg as the dapagliflozin. Dapagliflozin L-proline can be included in 0.1% to 10% by weight, based on metformin and its pharmaceutically acceptable salts, as dapagliflozin. In addition, the dapagliflozed L-proline can be included as a dapagliflozin in an amount of 5% by weight to 1,000% by weight, and preferably 5% by weight to the DPP-IV inhibitor and a pharmaceutically acceptable salt thereof, 500% by weight.

The pharmaceutical combination preparation of the present invention can be prepared by conventional pharmaceutical preparations such as tablets, capsules, beads, beads, granules, granules and the like by adding a conventional pharmaceutically acceptable carrier, excipient, binder, A parenteral formulation, a parenteral formulation, a parenteral formulation, a parenteral formulation, a parenteral formulation, or the like.

Examples of excipients that may be added to the present invention include, but are not limited to, lactose, starch, celluloses, dextrin, microcrystalline cellulose, potassium monohydrogen phosphate, calcium carbonate, saccharides and the like.

Examples of the binder include polyvinyl pyrrolidone derivatives such as povidone and copovidone, cellulosic derivatives such as methylcellulose, ethylcellulose, sodium carboxymethylcellulose, starch, gelatin, and the like, but are not limited thereto.

Examples of the disintegrator include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glyconate, sodium croscarmellose, low-substituted hydroxypropylcellulose, sodium starch glycolate, starch, Starch, alginic acid or its sodium salt, but is not limited thereto.

In addition, the pharmaceutical preparation of the present invention may further contain a pH adjusting agent, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetening agent, an absorbent and the like, if necessary. The content of such an additive is not particularly limited in the present invention and can be appropriately adjusted as needed.

When the pharmaceutical preparation of the present invention is a complex tablet, the tablet may be prepared by incorporating purified water into metformin or a pharmaceutically acceptable salt thereof, and then granulating and combining to prepare a first granule; Preparing a final granule by mixing the prepared first granule with dipalmitoyl L-proline and a pharmaceutically acceptable additive; And tabletting the final granulate with the tablet.

When the pharmaceutical preparation of the present invention is a complex tablet, the tablet may be prepared by mixing a DPP-IV inhibitor and a pharmaceutically acceptable additive to form a first granule; Preparing a final granule by mixing the prepared first granule with dipalmitoyl L-proline and a pharmaceutically acceptable additive; And tabletting the final granulate with the tablet.

Also, when the pharmaceutical preparation of the present invention is a complex tablet, adding purified water to metformin or a pharmaceutically acceptable salt thereof and combining and forming the first granule; Mixing the prepared first granule with a lubricant and a pharmaceutically acceptable additive to prepare a final granule; Tableting the final granulate with the tablet; And coating with a coating solution comprising L-proline, which is diglypholized in a tableted tablet.

When the pharmaceutical preparation of the present invention is a complex tablet, metformin or a pharmaceutically acceptable salt thereof, and a DPP-IV inhibitor are mixed with purified water to form a first granule; Mixing the prepared first granule with a lubricant and a pharmaceutically acceptable additive to prepare a final granule; Tableting the final granulate with the tablet; And a coating liquid containing L-proline, which is subjected to desalted tablets and is subjected to digestion.

Also, when the pharmaceutical preparation of the present invention is a complex tablet, adding purified water to metformin or a pharmaceutically acceptable salt thereof and combining and forming the first granule; Preparing a final granule by mixing the prepared first granule with a lubricant and D-polylysine L-proline; Tableting the final granulate with the tablet; And coating the tableted tablet with a coating solution containing a DPP-IV inhibitor.

The granules can be prepared by a conventional wet granulation method or dry granulation method known in the art. In addition, the tablets may be prepared by a direct tableting method, and tableting may be carried out using a conventional tableting machine, for example, a rotary tableting machine.

When the tablets are produced by such a production method, the efficiency of tableting is increased, securing a certain tablet hardness, preventing defects such as capping and laminating, and securing the effect of improving productivity, which is desirable.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

[Example]

Examples 1 to 3: Complex purification of D-phaglylofrozen L-proline and metformin hydrochloride

Tablets containing the dapagliflozin and L-proline 1: 2 crystalline complex (Hanmi Precision, Korea) were prepared with the composition shown in Table 1 below.

Specifically, metformin hydrochloride was mixed with HPMC2208, HPMC2910 and locust bean gum, and purified water was added thereto, followed by sieving with a 20 mesh sieve to prepare a first granule.

The prepared primary granules were mixed with dipalmitoyl L-proline, microcrystalline cellulose, silicon dioxide, crospovidone, and magnesium stearate to prepare final granules.

The final granules were tableted using a rotary tablet press (GRC-18, Sejong Machinery Co., Korea) and contained 15.6 mg (10 mg as dapagliflozin) as D-phaglyphrolated L-proline in one tablet A complex tablet containing paglyplloin L-proline was prepared.

Constituent Content (mg) Example 1 Example 2 Example 3 Wet granule Metformin hydrochloride 250 500 1000 HPMC 2208 67.5 135 270 HPMC 2910 2 4 8 Locust Blind Sword 10 20 40 mix Dapagliflozin L-proline 15.6 15.6 15.6 Microcrystalline cellulose 25 50 100 Silicon dioxide 8 8 8 Crospovidone 5 10 20 Magnesium stearate 4 8 16 Gross weight 387.1 750.6 1477.6 Weight (%) of dapagliflozin for metformin hydrochloride 4 % 2 % One %

Examples 4 to 7: Complex purification of D-phaglyplloin L-proline and DPP-IV inhibitor

Tablets containing the dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) were prepared with the compositions shown in Table 2 below.

Specifically, citagliptin or linagliptin was mixed with microcrystalline cellulose, lactose and HPC-L, and compacted using a roller compactor (TF-1-A60, Freund vector, USA) Primary dry granules were prepared.

L-proline, microcrystalline cellulose, lactose, crospovidone, and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules.

The final granulate was tableted using a rotary tablet press (GRC-18, Sejong Machinery Co., Korea), and contained 15.6 mg (10 mg as dapagliflozin) as D-phaglyphrolated L-proline in one tablet A complex tablet containing paglyplloin L-proline was prepared.

Constituent Content (mg) Example 4 Example 5 Example 6 Example 7 Dry granule Sytagliptin 50 100 - - Linagliptin - - 5 10 Microcrystalline cellulose 80 160 80 160 Lactose 25 50 25 50 HPC-L 5 10 5 10 mix Dapagliflozin L-proline 15.6 15.6 15.6 15.6 Lactose 20 40 20 40 Microcrystalline cellulose 10 20 10 20 Crospovidone 10 20 10 20 Magnesium stearate 3 6 3 6 Gross weight 218.6 421.6 173.6 331.6 Dopagliflozin weight (%) for DPP-IV inhibitor 20% 10% 200% 100%

Examples 8 to 11: Drug-coated complex tablets of D-phaglyplloin L-proline

Tablets containing the dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) were prepared according to the composition shown in Table 3 below.

Specifically, metformin hydrochloride was mixed with HPMC2208, HPMC2910 and locust bean gum, and then purified water was added thereto, followed by sieving with a 20 mesh sieve to prepare a first granule.

Silicon dioxide and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules. The final granules were tableted using a rotary tablet machine (GRC-18, Sejong Machinery, Korea).

The coated tablet was coated with a coating solution (SFC-30F, Sejong Pharmatech, Korea) containing the D-phalllinized D-proline and Kollicaot IR, PVP (K-30) and PEG 6000, A complex tablet containing 15.6 mg of dapagliflozin L-proline (10 mg as dapagliflozin) was prepared.

Constituent Content (mg) Example 8 Example 9 Example 10 Example 11 Wet granule Metformin hydrochloride 500 500 1000 1000 HPMC 2208 135 135 270 270 HPMC 2910 4 4 8 8 Locust Blind Sword 20 20 40 40 mix Silicon dioxide 7 7 14 14 Magnesium stearate 15 15 30 30 Core weight 681 681 1362 1362 Drug coating portion Dapagliflozin L-proline 15.6 15.6 15.6 15.6  Kollicoat IR 80 10 20 5 PVP (K-30) 4 2 4 2 PEG 6000 8 4 8 4 Coating weight 107.6 31.6 47.6 26.6 Gross weight 788.6 712.6 1409.6 1388.6 Coating weight (%) to core weight 15.8% 4.6% 3.5% 2.0%

Examples 12 and 13: Complex purification of dapagliflozin L-proline and metformin hydrochloride, DPP-IV inhibitor

Tablets containing the dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) were prepared according to the composition shown in Table 4 below.

Metformin hydrochloride was mixed with cytarglyptin, HPMC2208, HPMC2910 and locust bean gum, and purified water was added thereto, followed by sieving with a 20 mesh sieve to prepare a first granule.

Silica dioxide and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules. The final granules were tableted using a rotary tablet machine (GRC-18, Sejong Machinery, Korea).

The coated tablet was coated with a coating solution (SFC-30F, Sejong Pharmatech, Korea) containing D-PallflaLine and Kollicoat IR, PVP (K-30) and PEG 6000, A complex tablet containing 15.6 mg of dapagliflozin L-proline (10 mg as dapagliflozin) was prepared.

Constituent Content (mg) Example 12 Example 13 Wet granule Metformin hydrochloride 500 1000 Sytagliptin 50 100 HPMC 2208 135 270 HPMC 2910 4 8 Locust Blind Sword 20 40 mix Silicon dioxide 7 14 Magnesium stearate 15 30 Core weight 731 1462 Drug coating portion Dapagliflozin L-proline 15.6 15.6 Kollicoat IR 10 20 PVP (K-30) 2 4 PEG 6000 4 8 Coating weight 31.6 47.6 Gross weight 762.6 1509.6 Dapagliflozin weight (%) for metformin hydrochloride 2 % One % For sitagliptin
Da pagliproced weight (%) 20% 10% Coating weight (%) to core weight 4.3% 3.3%

Examples 14 and 15: Compound purification of dapagliflozin L-proline and metformin hydrochloride, DPP-IV inhibitor

Tablets containing the dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) were prepared with the compositions shown in Table 5 below.

Specifically, metformin hydrochloride was mixed with HPMC2208, HPMC2910 and locust bean gum, and then purified water was added thereto, followed by sieving with a 20 mesh sieve to prepare a first granule.

D-paglyphrolized L-proline, microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules. The final granules were tableted using a rotary tablet machine (GRC-18, Sejong Machinery, Korea).

The coating solution containing linalglytin and Kollicoat IR, PVP (K-30) and PEG 6000 was coated on the tableted tablet using a coater (SFC-30F, Sejong Pharmatech, Korea) A complex tablet containing 15.6 mg of L-proline (10 mg as dapagliflozin) was prepared.

Constituent Content (mg) Example 14 Example 15 Wet granule Metformin hydrochloride 500 1000 HPMC 2208 135 270 HPMC 2910 4 8 Locust Blind Sword 20 40 mix Dapagliflozin L-proline 15.6 15.6 Microcrystalline cellulose 50 100 Silicon dioxide 8 8 Crospovidone 10 20 Magnesium stearate 8 16 Tablet weight 750.6 1477.6 Drug coating portion Linagliptin 10 10 Kollicoat IR 10 20 PVP (K-30) 2 4 PEG 6000 4 8 Coating weight 26 42 Gross weight 776.6 1519.6

≪ Test Example 1 > Evaluation of content uniformity of D-phaglyphrolated L-proline

The formulation uniformity test was conducted on the tablets of Examples 1 to 15 according to the item of USP Pharmaceutical Formulation Uniformity Test, and liquid chromatography was carried out under the following conditions. Tables 6 to 9 and Figs.

& Lt; Liquid chromatography conditions >

- Column: A column (Hypersil BDS C18, Thermo fisher scientific) filled with octadecylsilylated silica gel for liquid chromatography having a particle diameter of 5 탆 was inserted into a stainless steel tube having an inner diameter of about 4.6 mm and a length of 25 cm.

- Column temperature: 30 ° C

- Sample injection amount: 20 μL

- mobile phase: 0.1% phosphoric acid (pH 6.8 titrated with triethylamine) / acetonitrile = 50/50 (v / v)

- Flow rate: 1.0 mL / min

- Detector: Ultraviolet absorptiometer (measuring wavelength 240 nm)

Example 1 Example 2 Example 3 Average (%) 99.4 100.3 98.9 Deviation 1.0 0.5 0.3 Judgment 2.4 1.3 0.8 fitness fitness fitness

Example 4 Example 5 Example 6 Example 7 Average (%) 99.4 98.9 100.1 100.4 Deviation 0.5 0.4 0.8 0.8 Judgment 1.2 0.9 1.8 1.8 fitness fitness fitness fitness

Example 8 Example 9 Example 10 Example 11 Average (%) 100.3 100.1 99.8 99.5 Deviation 0.3 0.6 0.6 0.8 Judgment 0.8 1.4 1.5 1.8 fitness fitness fitness fitness

Example 12 Example 13 Example 14 Example 15 Average (%) 101.3 100.4 100.4 100.8 Deviation 0.3 0.5 0.4 0.3 Judgment 0.8 1.2 1.0 0.8 fitness fitness fitness fitness

As shown in Tables 6 to 9, it was confirmed that the tablets of Examples 1 to 15 were all suitable as a result of the content uniformity test.

Test Example 2: Metformin dissolution rate

Using 1000 mL of pH 6.8 phosphate solution according to the first method of the USP dissolution test, the cells of Examples 1 to 3 and Examples 8 to 8 were measured at a dissolution temperature of 37 DEG C and a rotation speed of 100 rpm using 1000 mL of pH 6.8 phosphate solution. 15 were subjected to a dissolution test.

Samples of the dissolution test liquid at 0, 0.5, 1, 2, 3, 4 and 6 hours after the start of the test were taken and subjected to liquid chromatography under the following conditions. The dissolution rates of metformin were calculated and shown in Tables 10-12 and 5-7 Respectively.

& Lt; Liquid chromatography conditions >

- Column: A column (Hypersil BDS C18, Thermo fisher scientific) filled with octadecylsilylated silica gel for liquid chromatography having a particle diameter of 5 탆 was inserted into a stainless steel tube having an inner diameter of about 4.6 mm and a length of 25 cm.

- Column temperature: 30 ° C

- Sample injection amount: 20 μL

- mobile phase: 0.1% phosphoric acid (pH 6.8 titrated with triethylamine) / acetonitrile = 50/50 (v / v)

- Flow rate: 1.0 mL / min

- Detector: Ultraviolet absorptiometer (measuring wavelength 240 nm)

time
(hr) Metformin dissolution rate (%) Example 1 Example 2 Example 3 0 0 0 0 0.5 9 10 10 One 19 20 19 2 37 39 36 3 49 51 47 4 61 64 60 6 70 69 65

time
(hr) Metformin dissolution rate (%) Example 8 Example 9 Example 10 Example 11 0 0 0 0 0 0.5 4 10 14 16 One 7 18 23 27 2 13 35 41 44 3 17 48 52 56 4 22 58 61 65 6 30 67 70 78

time
(hr) Metformin dissolution rate (%) Example 12 Example 13 Example 14 Example 15 0 0 0 0 0 0.5 8 9 6 8 One 17 21 18 21 2 37 37 39 41 3 49 53 50 51 4 61 64 62 62 6 70 69 67 69

When the elution level of metformin was 20% or more and less than 80% at 6 hours, it was judged to be appropriate. As shown in Tables 10 to 12, the tablets of Examples 1 to 3 and Examples 8 to 15 all had excellent elution levels .

Claims (20)

Dopagliflo L-proline and at least one anti-diabetic agent. The pharmaceutical combination according to claim 1, wherein the antidiabetic agent is metformin or a pharmaceutically acceptable salt thereof. The pharmaceutical combination according to claim 1, wherein the anti-diabetic agent is a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof. The method according to claim 3, wherein the DPP-IV inhibitor is at least one selected from the group consisting of citagliptin, billagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin Pharmaceutical combination. 3. The pharmaceutical combination according to claim 1, wherein the multipageletyl L-proline comprises 5 to 20 mg as a dipalmitoylglycerol. 3. The pharmaceutical combination preparation according to claim 2, wherein the multipageletyl L-proline is in the range of 0.1 to 10% by weight, based on the metformin and its pharmaceutically acceptable salt as a dipalmitoylglycerol. 4. The pharmaceutical composition according to claim 3, wherein the multipageletyl L-proline is contained in an amount of 5 to 1,000% by weight, based on the DPP-IV inhibitor and a pharmaceutically acceptable salt thereof, Compound preparation. 7. The composition of claim 1, further comprising: a first granule comprising at least one anti-diabetic agent; And D-paglyplloin L-proline. 9. The method of claim 8, wherein the anti-diabetic agent is selected from the group consisting of metformin, citagliptin, valdagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and a pharmaceutically acceptable salt thereof. Lt; RTI ID = 0.0 > 1, < / RTI > The pharmaceutical combination according to claim 8, wherein the first granule comprises at least one polymer. 11. The composition of claim 10, wherein the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (HPC-L), purified shellac, a methacrylate polymer, At least one member selected from the group consisting of a copolymer, natural gum, guar gum, tragacanth, acacia gum, locust gum gum and xanthan gum. The method according to claim 1,
A first granulate comprising at least one anti-diabetic agent, and
A core layer comprising at least one lubricant or a dapagliflozed L-proline, or a lubricant and a dipalmitoyl L-proline; And
And a coating layer for coating the core layer. 13. The method of claim 12, wherein the anti-diabetic agent is selected from the group consisting of metformin, citalogliptin, valdagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and a pharmaceutically acceptable salt thereof. Lt; RTI ID = 0.0 > 1, < / RTI > 13. The pharmaceutical combination preparation according to claim 12, wherein the first granule comprises at least one polymer. 15. The method of claim 14, wherein the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (HPC-L), purified shellac, a methacrylate polymer, At least one member selected from the group consisting of a copolymer, natural gum, guar gum, tragacanth, acacia gum, locust gum gum and xanthan gum. 13. The pharmaceutical composition according to claim 12, wherein the coating layer comprises at least one selected from the group consisting of dapagliflof L-proline, metformin, cetagliptin, vedagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, A pharmaceutically acceptable salt thereof and at least one active ingredient selected from the group consisting of pharmaceutically acceptable salts thereof. The pharmaceutical combination according to claim 12, wherein the weight of the coating layer is 1 to 20% by weight based on the weight of the core layer. 2. The pharmaceutical combination preparation according to claim 1, wherein the preparation is formulated in an oral administration form. 19. The pharmaceutical combination preparation according to claim 18, wherein the oral administration form is a tablet or a capsule. The pharmaceutical combination preparation according to claim 1, for the prevention or treatment of diabetes, diabetes related diseases or diabetic complications.

Images