KR102500835B1 - Complex Preparations Comprising Lingliptin and Metformin as an active ingredients and preparing method thereof - Google Patents

Abstract

The present invention provides metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof; and linagliptin-containing granules containing 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof.
The combination preparation according to the present invention has a high dissolution rate and content uniformity even though the portion of linagliptin used as an active ingredient is only 0.2%, and stability is maintained even by long-term storage by suppressing the production of related substances. .

Description

Complex Preparations Comprising Lingliptin and Metformin as an Active Ingredients and Preparing Method thereof}

The present invention relates to a combination preparation containing linagliptin and metformin and a preparation method thereof.

Linagliptin is 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1- [(4-Methyl-2-quinazolinyl)methyl-1H-purine-2,6-dione(8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butyn-1-yl )-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl-1H-purine-2,6-dione), which has the following molecular formula.

The linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, and is widely used for the treatment of diabetes together with drugs such as metformin hydrochloride (Metformin HCl), a specific partner drug.

The DPP-4, also known as CD26, is a serine protease caused by the separation of a dipeptide from the N-terminus in a number of proteins having a proline or alanine residue at the N-terminus. Due to these properties, DPP-4 inhibitors interfere with plasma levels of bioactive peptides, including the peptide GLP-1, and are therefore considered promising drugs for the treatment of diabetes.

As DPP-4 inhibitors, the following Sitagliptin or Vildagliptin is known. Sitagliptin (MK-0431) is a commonly used DPP-4 inhibitor, (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8 -Tetrahydro-5H[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one ((3R )-3-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4- (2,4,5-trifluorophenyl)butan-1-one) or (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]tria Zolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine ((2R)-4-oxo-4-[3 -(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2- amine). In one embodiment, sitagliptin is in the form of its dihydrogenphosphate salt, i.e. sitagliptin phosphate. In a further embodiment, the sitagliptin phosphate is in the form of crystalline anhydride or monohydrate. This form is referred to as sitagliptin phosphate monohydrate.

Vildagliptin is specifically disclosed in US Patent No. 6,166,063 and the like. A particular salt of vildagliptin is disclosed in International Publication No. WO2007/019255. The crystalline form of vildagliptin is disclosed in International Publication No. WO 2006/078593.

Partner drugs used in combination with the above-mentioned DPP-4 inhibitors as pharmaceutical compositions are biguanides (e.g., Metformin), thiazolidinedione (e.g., Pioglitazone), statins (e.g., Statins). : Atorvastatin) or ARBs (e.g. Telmisartan).

A combination drug containing a DPP-4 inhibitor and its partner drug is already widely used clinically. A representative example is Trajenta DUO® containing linagliptin and metformin. The Trajenta Duo (Trajenta DUO) has a therapeutic effect by simultaneously administering the dipeptidyl peptidase-4 (DPP-4) inhibitor drug linaglitip and its partner drug metformin.

However, when preparing a combination preparation containing two or more active ingredients, such as linagliptin and metformin, a problem may arise in the stability of the active ingredients due to interactions between two or more different active ingredients. Therefore, as one way to secure the stability of these combination preparations, various combination preparations are being developed.

Combination preparations containing linagliptin and metformin are also being developed in various ways. In the case of a combination formulation of linagliptin and metformin, high dissolution rate and content uniformity of linagliptin are required to secure sufficient bioavailability and rapid effect when administered orally. However, since linagliptin is included in a very small amount, it is not easy to meet the above requirements with conventional techniques.

Korean Registered Patent No. 1111101

The inventors of the present invention found that when linagliptin, which is effective in treating diabetes, is used together with metformin, a partner drug, uniformity may be deteriorated due to a small portion, and related substances significantly increase under oxidizing conditions. After confirming this, and completing various studies to solve this problem, the present invention was completed.

The present invention is to provide a combination preparation that uses linagliptin and metformin as active ingredients, yet has a high dissolution rate and content uniformity of the active ingredients, and can be stored for a long period of time by suppressing the production of related substances and a method for preparing the same. The purpose.

In order to solve the above problems, the present invention,

metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof; and

It provides a combination preparation for treating or preventing diabetes comprising; linagliptin-containing granules containing 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof.

In addition, the present invention,

(a) preparing metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof;

(b) preparing linagliptin-containing granules comprising 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof; and

(c) a tableting step of mixing and tableting the metformin-containing granules and the linagliptin-containing granules prepared in the step;

The combination preparation according to the present invention includes linagliptin as an active ingredient having a small portion in total weight, but has excellent dissolution rate and content uniformity of linagliptin, and provides an effect of minimizing the production of related substances.

In addition, the combination preparation can stably secure sufficient bioavailability and fast-acting properties, and provides an effect of increasing patient compliance with the preparation.

1 is a graph showing the results of analyzing the dissolution rate of linagliptin in the dissolution test of Examples 1 to 3 and Comparative Examples 1 to 4.
Figure 2 is a graph showing the results of analyzing a related substance (RRT1.20) of linagliptin in the stability test of Examples 1 to 3 and Comparative Examples 1 to 4.
Figure 3 is a graph showing the results of analyzing a related substance (RRT1.51) of linagliptin in the stability test of Examples 1 to 3 and Comparative Examples 1 to 4.
Figure 4 is a graph showing the results of analyzing a related substance (RRT1.65) of linagliptin in the stability test of Examples 1 to 3 and Comparative Examples 1 to 4.
5 is a graph showing the results of analyzing total related substances of linagliptin in the stability test of Examples 1 to 3 and Comparative Examples 1 to 4.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless defined otherwise, are used with the same meaning as commonly understood by one of ordinary skill in the art related to the present invention. In addition, although preferred methods or samples are described in this specification, those similar or equivalent thereto are also included in the scope of the present invention. The contents of all publications cited herein by reference are hereby incorporated by reference in their entirety.

The present invention relates to metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof; and linagliptin-containing granules containing 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof.

If the metformin-containing granules contain less than 80% by weight of metformin or a pharmaceutically acceptable salt thereof, the tablet size may increase and compliance with medication may decrease, and if it exceeds 90% by weight, productivity may decrease may occur.

When less than 3% by weight of linagliptin or a pharmaceutically acceptable salt thereof is contained in the linagliptin-containing granules, the tablet size may increase and medication compliance may be lowered, and when it exceeds 10% by weight, productivity this can be lowered

Based on the total weight of the combination preparation, the metformin-containing granules and the linagliptin-containing granules may be included in 80 to 100% by weight, preferably 90 to 99.5% by weight, and more preferably 95 to 99.5% by weight.

The combination preparation may include 2 to 6 parts by weight of linagliptin-containing granules, more preferably 3 to 5 parts by weight, based on 100 parts by weight of metformin-containing granules.

The combination preparation may be formulated in various forms, but is more preferably formulated in a tablet form.

In one embodiment, the present invention provides metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof; and linagliptin-containing granules containing 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof.

The combined preparation may contain 500 to 1000 mg of metformin or a pharmaceutically acceptable salt thereof based on metformin, and 1 to 5 mg of linagliptin or a pharmaceutically acceptable salt thereof based on linagliptin. can

The metformin-containing granules are preferably wet granules, but are not limited thereto. In addition, the linagliptin-containing granules are preferably wet granules, but are not limited thereto.

The metformin-containing granules may contain 10 to 20% by weight of pharmaceutically acceptable additives, and the linagliptin-containing granules may contain 90 to 97% by weight of pharmaceutically acceptable additives.

In the present invention, additives are used as a concept including excipients, carriers, and other functional ingredients. In the present invention, the pharmaceutically acceptable additive may be used without particular limitation as long as it is a material generally used in this field.

For example, the metformin-containing granules may include corn starch as an additive; at least one selected from the group consisting of povidone, copovidone, and HPC-L; and colloidal silicon dioxide.

Also, for example, the linagliptin-containing granules may include precipitated calcium carbonate as an additive; corn starch; at least one selected from the group consisting of D-mannitol and lactose; microcrystalline cellulose; butylated hydroxytoluene; and at least one selected from the group consisting of povidone, copovidone, and HPC-L.

In addition, the combination preparation of the present invention may further include pharmaceutically acceptable additives together with the metformin-containing granules and the linagliptin-containing granules. The additive may be 0.5 to 20% by weight, preferably 0.5 to 5% by weight, based on the total weight of the combination preparation.

Examples of additives used together with the metformin-containing granules and the linagliptin-containing granules include a lubricant mixed with the metformin-containing granules and the linagliptin-containing granules before tableting. It may include at least one selected from polyethylene glycol 4000, sodium lauryl sulfate, talc, stearic acid, lead, etc., but is not limited thereto. As one specific example, magnesium stearate and the like may be used.

The combination preparation of the present invention may contain an antioxidant together with an active ingredient to suppress the production of related substances caused by the decomposition of linagliptin. The antioxidant is sodium sulfite, sodium bisulfite, sodium metabisulfite, butylated hydroxytoluene, propyl gallate, cysteine , And is selected from the group consisting of tocopherol (tocopherol), but is not necessarily limited thereto. According to one embodiment of the present invention, among the above-mentioned antioxidants, butylated hydroxytoluene or propyl gallate may be preferably used, and butylated hydroxytoluene may be more preferably used.

The content of the antioxidant in the combination preparation may be adjusted according to the content of linagliptin capable of producing related substances. The content of the antioxidant in the combination preparation may be 2 to 80 parts by weight based on 100 parts by weight of linagliptin or a pharmaceutically acceptable salt thereof. If the content of the antioxidant is less than the above range, the effect of inhibiting the production of related substances by the antioxidant is insignificant, and if the content of the antioxidant is more than the above range, the efficacy of the pharmaceutical composition due to the active ingredient may be reduced. According to one embodiment of the present invention, the antioxidant may preferably contain 4 to 40 parts by weight based on 100 parts by weight of linagliptin or a pharmaceutically acceptable salt thereof.

The combined preparation of the present invention may further include a basic stabilizer. The basic stabilizer is from the group consisting of precipitated calcium carbonate, L-arginine, meglumine, sodium hydrogen carbonate (NaHCO ₃ ), magnesium carbonate (MgCO ₃ ) and magnesium oxide (Mg oxide) It may be one or more selected, but is not necessarily limited thereto.

According to one embodiment of the present invention, the basic stabilizer is from the group consisting of precipitated calcium carbonate, meglumine, sodium hydrogen carbonate (NaHCO ₃ ), magnesium carbonate (MgCO ₃ ) and magnesium oxide (Mg oxide) It may be one or more selected stabilizers, and more specifically, it may be precipitated calcium carbonate.

When the basic stabilizer is used alone, the effect of inhibiting the production of related substances is not great, but when used together with the above-mentioned antioxidant, it exhibits an excellent effect of inhibiting the production of related substances. The basic stabilizer is not particularly limited as long as it is a material commonly used in the art, but when using precipitated calcium carbonate as the basic stabilizer, it may be preferable in relation to the above-mentioned antioxidant.

The content of the basic stabilizer may be adjusted according to the content of linagliptin like the antioxidant. In one embodiment of the present invention, the amount of the basic stabilizer may be 20 to 100 parts by weight based on 100 parts by weight of linagliptin or a pharmaceutically acceptable salt thereof. If the content of the basic stabilizer is less than the above range, it is difficult to expect the effect of adding the basic stabilizer, and if the content of the basic stabilizer is greater than the above range, the efficacy of the pharmaceutical composition by the active ingredient may be reduced.

In addition, in the combination preparation of the present invention, the content of the basic stabilizer may be adjusted according to the content of the antioxidant. In one embodiment of the present invention, the amount of the basic stabilizer may be 200 to 300 parts by weight based on 100 parts by weight of the antioxidant. Within the above range, a synergistic effect is exhibited according to the combined use of an antioxidant and a basic stabilizer.

In the combination preparation of the present invention, the antioxidant is preferably included in the linagliptin-containing granules. In this case, the metformin-containing granules may not contain antioxidants.

In addition, the linagliptin-containing granules containing the antioxidant may further include a basic stabilizer.

The combination preparation of the present invention may have a dissolution rate of 80% by weight or more, more preferably 85% or more, of linagliptin or a pharmaceutically acceptable salt thereof within 30 minutes in a dissolution test according to the general test methods of the Korean Pharmacopoeia.

In one embodiment, metformin-containing granules containing 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof; and linagliptin-containing granules containing 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof. A dissolution rate of gliptin or a pharmaceutically acceptable salt thereof within 30 minutes is 80% by weight or more.

In addition, when the combination preparation of the present invention is stored at 60° C. for 4 weeks or more, the total amount of related substances may be about 1.0% by weight or less, preferably 0.4% by weight or less.

In addition, the present invention

(a) preparing metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof;

(b) preparing linagliptin-containing granules comprising 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof; and

(c) a tableting step of mixing and tableting the metformin-containing granules and the linagliptin-containing granules prepared in the step;

The contents of the combination preparation described above can be applied to all methods for preparing the combination preparation.

In the step (c), the metformin-containing granules and the linagliptin-containing granules are included in 80 to 100% by weight, preferably 90 to 99.5% by weight, and more preferably 95 to 99.5% by weight, based on the total weight of the combination preparation. can

The combination preparation prepared by the above preparation method may include 2 to 6 parts by weight of linagliptin-containing granules, more preferably 3 to 5 parts by weight, based on 100 parts by weight of metformin-containing granules.

In step (c), the mixing of the metformin-containing granules and the linagliptin-containing granules may be performed for 5 to 45 minutes, preferably 15 to 45 minutes, and more preferably 15 to 30 minutes. Regarding the mixing time, mixing uniformity may be lowered when mixing is less than the time, and when mixing exceeds the time, granules may be broken or deformed, and productivity is lowered, which is not preferable.

In the manufacturing method of the present invention, the step (c) may have a feature that includes a step of mixing the metformin-containing granules and the linagliptin-containing granules with a lubricant and tableting them.

By the above process, the high dissolution rate of the combination preparation, excellent content uniformity, and the effect of inhibiting the production of related substances can be obtained more easily.

As described above, when the metformin-containing granules and linagliptin-containing granules and the lubricant are mixed in step (c), the mixing may be performed for 5 to 45 minutes, preferably 5 to 30 minutes, more preferably 5 It can be performed for ~10 minutes. Regarding the mixing time, mixing uniformity may be lowered when the mixing time is less than the above time, and overlubrication may occur when the mixing time is exceeded, and granules may be broken or deformed, and productivity may be lowered. Not desirable.

In addition, when a lubricant is used in step (c) as described above, it may be preferable not to use a lubricant in the step of preparing the metformin-containing granules of step (a) and the linagliptin-containing granules of step (b). there is.

The combination preparation may be formulated in various forms, but is more preferably formulated in a tablet form.

The metformin-containing granules of step (a) are preferably prepared in a wet process, but are not limited thereto.

The linagliptin-containing granules of step (b) are preferably prepared in a wet process, but are not limited thereto.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for exemplifying the present invention, but the scope of the present invention is not limited thereto.

Example

Example 1: Preparation of tablets containing linagliptin granules and metformin granules

(1) Preparation of linagliptin wet granules

According to the composition of Table 1 below, linagliptin, corn starch, D-mannitol, microcrystalline cellulose, and butylated hydroxytoluene were mixed. Wet granules were prepared by mixing povidone and precipitated calcium carbonate dissolved in purified water as a binder, drying, and then sieving through a 20 mesh sieve.

(2) Manufacture of metformin wet granules

According to the composition shown in Table 1 below, metformin and corn starch were mixed. Wet granules were prepared by mixing povidone-dissolved purified water as a binding solution, drying, and then sieving through a 20 mesh sieve. Colloidal silicon dioxide was mixed with the granules prepared above.

(3) Manufacture of tablets

The prepared linagliptin granules and metformin granules were mixed for 30 minutes. Magnesium stearate was added to the prepared mixture and mixed to prepare granules, which were then prepared into tablets using a tablet press.

(Unit: mg) Example 1 Linagliptin Granules Metformin granules Linagliptin 2.5 - metformin hydrochloride - 1000 Precipitated Calcium Carbonate 2.5 - corn starch 4.5 75.0 D-mannitol 25.0 - microcrystalline cellulose 7.5 - Butylated Hydroxytoluene 1.0 - povidone 1.3 45.0 colloidal silicon dioxide - 5.0 Sub weight 44.3 1125 magnesium stearate 10.7 gross weight 1180

Example 2: Preparation of tablets containing linagliptin granules and metformin granules

(1) Preparation of linagliptin wet granules

According to the composition of Table 2 below, linagliptin, corn starch, D-mannitol, microcrystalline cellulose, and butylated hydroxytoluene were mixed. Wet granules were prepared by mixing povidone and precipitated calcium carbonate dissolved in purified water as a binding solution, drying, and then sieving through a 20 mesh sieve.

(2) Manufacture of metformin wet granules

Metformin and corn starch were mixed according to the composition shown in Table 2 below. Wet granules were prepared by mixing povidone-dissolved purified water as a binding solution, drying, and then sieving through a 20 mesh sieve. Colloidal silicon dioxide was mixed with the granules prepared above.

(3) Manufacture of tablets

The prepared linagliptin granules and metformin granules were mixed for 15 minutes. Magnesium stearate was added and mixed to the prepared mixture to prepare granules, which were then prepared into tablets using a tablet press.

(Unit: mg) Example 2 Linagliptin Granules Metformin granules Linagliptin 2.5 - metformin hydrochloride - 1000 Precipitated Calcium Carbonate 2.5 - corn starch 4.5 75.0 D-mannitol 25.0 - microcrystalline cellulose 7.5 - Butylated Hydroxytoluene 1.0 - povidone 1.3 45.0 colloidal silicon dioxide - 5.0 Sub weight 44.3 1125 magnesium stearate 10.7 gross weight 1180

Example 3: Preparation of tablets containing linagliptin granules and metformin granules

(1) Preparation of linagliptin wet granules

According to the composition of Table 2 below, linagliptin, corn starch, D-mannitol, microcrystalline cellulose, and butylated hydroxytoluene were mixed. Wet granules were prepared by mixing povidone and precipitated calcium carbonate dissolved in purified water as a binding solution, drying, and then sieving through a 20 mesh sieve.

(2) Manufacture of metformin wet granules

Metformin and corn starch were mixed according to the composition shown in Table 2 below. Wet granules were prepared by mixing povidone-dissolved purified water as a binding solution, drying, and then sieving through a 20 mesh sieve. Colloidal silicon dioxide was mixed with the granules prepared above.

(3) Manufacture of tablets

The prepared linagliptin granules and metformin granules were mixed for 45 minutes. Magnesium stearate was added and mixed to the prepared mixture to prepare granules, which were then prepared into tablets using a tablet press.

(Unit: mg) Example 3 Linagliptin Granules Metformin granules Linagliptin 2.5 - metformin hydrochloride - 1000 Precipitated Calcium Carbonate 2.5 - corn starch 4.5 75.0 D-mannitol 25.0 - microcrystalline cellulose 7.5 - Butylated Hydroxytoluene 1.0 - povidone 1.3 45.0 colloidal silicon dioxide - 5.0 Sub weight 44.3 1125 magnesium stearate 10.7 gross weight 1180

Comparative Example 1: Preparation of Tablets Containing Linagliptin Granules and Metformin Granules

According to the composition shown in Table 4 below, linagliptin, metformin, corn starch, D-mannitol and microcrystalline cellulose were mixed. Wet granules were prepared by combining povidone, precipitated calcium carbonate, and purified water in which butylated hydroxytoluene was dissolved as a binder solution, drying, and then sieving through a 20 mesh sieve.

Colloidal silicon dioxide and magnesium stearate were added to the prepared granules and mixed for 30 minutes to prepare granules, which were then prepared into tablets using a tablet press.

(Unit: mg) Comparative Example 1 Linagliptin 2.5 metformin hydrochloride 1000 Precipitated Calcium Carbonate 2.5 corn starch 79.5 D-mannitol 25.0 microcrystalline cellulose 7.5 Butylated Hydroxytoluene 1.0 povidone 46.3 colloidal silicon dioxide 5.0 magnesium stearate 10.7 gross weight 1180

Comparative Example 2: Preparation of Tablets Containing Linagliptin Granules and Metformin Granules

(1) Preparation of linagliptin wet granules

According to the composition of Table 5 below, linagliptin, corn starch, D-mannitol, microcrystalline cellulose, and butylated hydroxytoluene were mixed. Wet granules were prepared by mixing povidone and precipitated calcium carbonate dissolved in purified water as a binding solution, drying, and then sieving through a 20 mesh sieve. Magnesium stearate was mixed with the prepared granules.

(2) Manufacture of metformin wet granules

Metformin and corn starch were mixed according to the composition shown in Table 5 below. Wet granules were prepared by mixing povidone-dissolved purified water as a binding solution, drying, and then sieving through a 20 mesh sieve. Colloidal silicon dioxide and magnesium stearate were added to the prepared granules and mixed.

(3) Manufacture of tablets

The prepared granules of linagliptin and granules of metformin were mixed to prepare final granules, which were then prepared into tablets using a tablet press.

(Unit: mg) Comparative Example 2 Linagliptin Granules Metformin granules Linagliptin 2.5 - metformin hydrochloride - 1000 Precipitated Calcium Carbonate 2.5 - corn starch 4.5 75.0 D-mannitol 25.0 - microcrystalline cellulose 7.5 - Butylated Hydroxytoluene 1.0 - povidone 1.3 45.0 colloidal silicon dioxide - 5.0 Sub weight 44.3 1125 magnesium stearate 0.7 10.0 gross weight 1180

Comparative Example 3: Preparation of wet granules containing linagliptin and metformin, followed by preparation of a double-layer tablet

(1) Preparation of linagliptin wet granules

According to the composition of Table 6 below, linagliptin, metformin, corn starch, D-mannitol, microcrystalline cellulose, and butylated hydroxytoluene were mixed. Wet granules were prepared by mixing povidone and precipitated calcium carbonate dissolved in purified water as a binding solution, drying, and then sieving through a 20 mesh sieve. Magnesium stearate was mixed with the prepared granules.

(2) Manufacture of metformin wet granules

Metformin and corn starch were mixed according to the composition shown in Table 6 below. Wet granules were prepared by mixing povidone-dissolved purified water as a binding solution, drying, and then sieving through a 20 mesh sieve. Colloidal silicon dioxide and magnesium stearate were added to the prepared granules and mixed.

(3) Manufacture of tablets

A bi-layer tablet was prepared using the above-prepared linagliptin granules and metformin granules.

(Unit: mg) Example 3 Linagliptin Granules Metformin granules Linagliptin 2.5 - metformin hydrochloride - 1000 Precipitated Calcium Carbonate 2.5 - corn starch 4.5 75.0 D-mannitol 25.0 - microcrystalline cellulose 7.5 - Butylated Hydroxytoluene 1.0 - povidone 1.3 45.0 colloidal silicon dioxide - 5.0 Sub weight 44.3 1125 magnesium stearate 0.7 10.0 gross weight 1180

Comparative Example 4: Control drug (Trajenta DUO)

Trajenta DUO (manufacturer: Boehringer Ingelheim), a commercially available product containing linagliptin and metformin as active ingredients, was used as Comparative Example 4.

test example

Test Example 1: Linagliptin content uniformity test

Using 10 formulations of Examples 1 to 3 and Comparative Examples 1 to 4, respectively, a linagliptin content uniformity test was conducted under the following conditions to measure the content uniformity of linagliptin, and the results are shown in the table below. 8.

<Analysis method>

Detector: UV absorbance photometer (measurement wavelength: 295 nm)

Column: YMC Pack Pro C8, 5um, 50 x 4.6mm

Column temperature: constant temperature around 50

Mobile phase: A - Dissolve 2.6 g of ammonium dihydrogen phosphate in water to make 1,000 mL and adjust the pH to 3.0 with phosphoric acid.

B - 500 mL methanol + 500 mL acetonitrile

Flow rate: 1.0 ml/min

Injection volume: 10 μl

time (minutes) Mobile phase A (%) Mobile phase B (%) 0.0 75 25 5.0 60 40 5.1 20 80 8.0 20 80 8.1 75 25 13.0 75 25

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Linagliptin
(%) 99.9 99.7 99.8 98.7 99.4 99.1 98.6 RSD (%) ±1.7 ±2.8 ±2.0 ±3.8 ±2.3 ±5.2 ±3.1

As shown in Table 8, the solid formulations of Examples 1 to 3 showed excellent results with a linagliptin content of 99.9 to 99.7%. In addition, the content uniformity showed good results with RSD 1.7~2.8%.

On the other hand, Comparative Example 2 had good content and content uniformity, but in Comparative Examples 1 and 3 to 4, the linagliptin content was good at 99.1 to 98.6%, but RSD was 3.1 to 5.2%, compared to Examples. showed low uniformity.

Test Example 2: Dissolution test

A 30-minute dissolution rate of linagliptin was measured by carrying out a dissolution test of linagliptin under the following conditions using six formulations of Examples 1 to 3 and Comparative Examples 1 to 4, respectively. The results are shown in Table 9 below.

<Analysis method>

Detector: UV absorbance photometer (measurement wavelength: 295 nm)

Column: YMC Pack Pro C8, 5um, 50 x 4.6mm

Column temperature: constant temperature around 50

Mobile phase: Dissolve 2.6 g of ammonium dihydrogen phosphate in water to make 1,000 mL, adjust the pH to 3.0 with phosphoric acid, and mix 780 mL of this solution with 220 mL of acetonitrile.

Flow rate: 1.0 ml/min

Injection volume: 20 μl

30min Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Linagliptin
(%) 94.2 96.7 95.8 94.5 77.2 92.1 94.3 RSD (%) ±2.5 ±2.7 ±2.9 ±4.1 ±7.2 ±5.3 ±3.9

As shown in Table 9, the solid formulations of Examples 1 to 3 showed very excellent results with a linagliptin dissolution rate of 94% or more at 30 minutes. In addition, dissolution uniformity showed good results with RSD of 2 ~ 3%.

On the other hand, in the case of Comparative Examples 1 and 3 to 4, the linagliptin dissolution rate showed relatively good results of 92% or more, but in the case of RSD, 4 to 6% showed low uniformity compared to the examples. In addition, in the case of Comparative Example 2, the 30-minute dissolution rate was 77.2%, which was very low, and the dissolution uniformity was also very poor, with an RSD of 7% or more.

Test Example 3: Linagliptin stability test

The formulations of Examples 1 to 3 and Comparative Examples 1 to 4 were placed in HDPE bottles and exposed to 60° C. conditions for 4 weeks. A stability test was conducted under the following conditions using 10 samples each before (start), 1 week, 2 weeks, and 4 weeks after exposure, and related substances of each component were analyzed. The results are shown in Tables 10 and 11 and FIGS. 1 to 4 below.

<Analysis method>

Detector: UV absorbance photometer (measurement wavelength: 225 nm)

Column: YMC Pack Pro C8, 5um, 50 x 4.6mm

Column temperature: constant temperature around 50

Mobile phase: A - Dissolve 2.6 g of ammonium dihydrogen phosphate in water to make 1,000 mL and adjust pH to 3.0 with phosphoric acid, B - 500 mL of methanol + 500 mL of acetonitrile

time (minutes) Mobile phase A (%) Mobile phase B (%) 0.0 80 20 10.0 50 50 20.0 30 70 20.1 80 20 25.0 80 20

Flow rate: 1.0 ml/min

Injection volume: 10 μl

harsh conditions
(60℃) Example comparative example One 2 3 One 2 3 4 related substances
(RRT1.20) inital N/D N/D N/D 0.02 N/D N/D 0.02 1w N/D N/D N/D 0.03 N/D N/D 0.18 2w N/D N/D N/D 0.02 N/D N/D 0.22 4w N/D N/D N/D 0.03 N/D N/D 0.26 related substances
(RRT1.51) inital N/D N/D N/D 0.03 N/D N/D 0.09 1w N/D N/D N/D 0.04 N/D N/D 0.07 2w N/D N/D N/D 0.04 N/D N/D 0.09 4w N/D N/D N/D 0.04 N/D N/D 0.13 related substances
(RRT1.65) inital N/D N/D N/D 0.04 N/D N/D 0.02 1w 0.01 0.01 0.02 0.07 0.02 0.01 0.03 2w 0.02 0.03 0.03 0.09 0.03 0.02 0.06 4w 0.04 0.05 0.05 0.10 0.05 0.06 0.11 total related substances inital 0.00 0.00 0.00 0.09 0.00 0.00 0.13 1w 0.01 0.01 0.02 0.14 0.02 0.01 0.28 2w 0.02 0.03 0.03 0.15 0.03 0.02 0.37 4w 0.04 0.05 0.05 0.17 0.05 0.06 0.50

Note) N/D: No Detection

As a result of the test, Comparative Example 1 showed a significant increase in related substances during the stability test under harsh conditions, compared to Examples 1 to 3.

So far, the present invention has been looked at with respect to its preferred embodiments. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the equivalent scope will be construed as being included in the present invention.

Claims (22)

metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof; and
Linagliptin-containing granules comprising 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof;
The metformin-containing granules further include 10 to 20% by weight of additives, the additives being starch; At least one selected from the group consisting of povidone and copovidone; and colloidal silicon dioxide;
The linagliptin-containing granules further include 90 to 97% by weight of additives, wherein the additives include starch; at least one selected from the group consisting of D-mannitol and lactose; And at least one selected from the group consisting of povidone and copovidone;
Combination preparation for the treatment or prevention of diabetes, which is a single-layer tablet. According to claim 1,
A combination preparation, characterized in that the metformin-containing granules and linagliptin-containing granules are included in 80 to 100% by weight based on the total weight of the combination preparation. According to claim 1,
A combination preparation comprising 2 to 6 parts by weight of linagliptin-containing granules based on 100 parts by weight of metformin-containing granules. delete According to claim 1,
The combination preparation contains 500 to 1000 mg of metformin or a pharmaceutically acceptable salt thereof based on metformin, and 1 to 5 mg of linagliptin or a pharmaceutically acceptable salt thereof based on linagliptin. Combination preparation, characterized in that. According to claim 1,
A combination preparation, characterized in that the metformin-containing granules are wet granules. According to claim 1,
The combination preparation, characterized in that the linagliptin-containing granules are wet granules. According to claim 1,
A combination preparation characterized in that it further comprises an antioxidant. According to claim 8,
A combination preparation characterized in that it further comprises a basic stabilizer. According to claim 8,
The antioxidant is a combination preparation, characterized in that included in the linagliptin-containing granules. According to claim 10,
The combination preparation characterized in that the antioxidant is included in 2 to 80 parts by weight based on 100 parts by weight of linagliptin or a pharmaceutically acceptable salt thereof. According to claim 11,
A combination preparation comprising 20 to 100 parts by weight of a basic stabilizer based on 100 parts by weight of the linagliptin or a pharmaceutically acceptable salt thereof. delete According to claim 1,
The combination preparation is a combination preparation, characterized in that the dissolution rate of linagliptin or a pharmaceutically acceptable salt thereof within 30 minutes of 85% or more in a dissolution test according to the general test method of the Korean Pharmacopoeia. (a) preparing metformin-containing granules comprising 80 to 90% by weight of metformin or a pharmaceutically acceptable salt thereof;
(b) preparing linagliptin-containing granules comprising 3 to 10% by weight of linagliptin or a pharmaceutically acceptable salt thereof; and
(c) a tableting step of mixing and tableting the metformin-containing granules and the linagliptin-containing granules prepared in the above step;
The metformin-containing granules further include 10 to 20% by weight of additives, the additives being starch; At least one selected from the group consisting of povidone and copovidone; and colloidal silicon dioxide;
The linagliptin-containing granules further include 90 to 97% by weight of additives, wherein the additives include starch; at least one selected from the group consisting of D-mannitol and lactose; And at least one selected from the group consisting of povidone and copovidone;
A method for producing a combination preparation for treating or preventing diabetes, which is a single-layer tablet. According to claim 15,
Method for producing a combination preparation, characterized in that in step (c), the metformin-containing granules and the linagliptin-containing granules are mixed in an amount of 80 to 100% by weight based on the total weight of the combination preparation. According to claim 15,
A method for producing a combination preparation, characterized in that the linagliptin-containing granules are included in 2 to 6 parts by weight based on 100 parts by weight of the metformin-containing granules. delete According to claim 15,
A method for preparing a combination preparation, characterized in that the metformin-containing granules of step (a) are prepared in a wet process. According to claim 15,
Method for producing a combination preparation, characterized in that the linagliptin-containing granules of step (b) are prepared in a wet method. According to claim 15,
The step (c) comprises a step of mixing the metformin-containing granules and the linagliptin-containing granules with a lubricant and tableting them. According to claim 21,
A method for preparing a combined preparation, characterized in that a lubricant is not used in the step of preparing the metformin-containing granules of step (a) and the linagliptin-containing granules of step (b).

Images