TW202228701A - Oral combination preparation comprising gemigliptin and dapagliflozin, and method for preparing the same - Google Patents

Abstract

The present invention relates to an oral combination preparation for the effective treatment of type 2 diabetes. More specifically, the present invention relates to an oral combination preparation for the treatment of type 2 diabetes, which comprises gemigliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof as active ingredients; lactose and/or microcrystalline cellulose as a bulking agent; a disintegrant; and a glidant, and a method for preparing the same.

Description

Oral combined preparation comprising gmiliptin and dapagliflozin and preparation method thereof

The present invention relates to an oral combined preparation for the effective treatment of type 2 diabetes. More specifically, the present invention relates to an oral combined preparation for treating type 2 diabetes and a preparation method thereof, the oral combined preparation comprises as active ingredients Gemigliptin or a pharmaceutically acceptable salt thereof and dapagliflozin (Dapagliflozin) or a pharmaceutically acceptable salt thereof; lactose and/or microcrystalline cellulose as bulking agents; disintegrating agents; and slip agents.

In 2011, the International Diabetes Federation (IDF) estimated that there are 366 million people with diabetes worldwide. According to reports, 80% of them are concentrated in developing countries, while about 36% of them are countries in the Western Pacific region, including South Korea. However, considering that there are currently about 183 million people with diabetes who have not been diagnosed with diabetes, the actual number of people with diabetes worldwide is estimated to exceed 549 million, and it was reported that 4.6 million people died of diabetes in 2011 alone.

Diabetes mellitus is a metabolic disease that results in elevated blood glucose levels due to defects in insulin secretion, insulin action, or both. Type 1 diabetes is the result of destruction of the beta cells of the pancreas (beta cells) and is a serious disease that, if untreated, can lead to ketosis and requires insulin therapy to control blood sugar levels. Type 1 diabetes usually develops in childhood, but can sometimes develop in adults who are not obese and first develop symptoms of high blood sugar levels at an older age. Type 2 diabetes is currently on the rise, accounting for 90% to 95% of all diabetes. It is a complex disease with unclear mechanisms and usually develops in adults, but may also develop during adolescence. Type 2 diabetes does not have severe symptoms, and develops in various forms, which complexly involves β-cell dysfunction, peripheral insulin resistance, and abnormal hepatic glucose metabolism. In type 2 diabetes, blood sugar levels become increasingly difficult to control over time, requiring the use of new hypoglycemic agents every 3 to 4 years on average to properly control blood sugar levels. In addition, even with combined medication and insulin therapy, adequate control of blood glucose levels is difficult.

Oral drugs traditionally used to treat diabetes can be divided into four categories: insulin secreting agents, such as sulfonylureas and meglitinides; biguanides; thiazolidinediones ); and α-glucosidase inhibitors. Sulfonylureas and biguanides have long been used as drugs for type 2 diabetes. Sulfonylureas promote insulin secretion from beta cells, however, as beta cell function gradually deteriorates, other drugs or insulin therapy are eventually required. A representative drug belonging to the biguanide class is metformin, which is a safe drug with few side effects of hypoglycemia, and is widely used as a drug of choice for the treatment of type 2 diabetes. Because type 2 diabetes is a progressive disease and cannot adequately control blood sugar levels with long-term treatment, combination therapy is required within a few years after diagnosis.

Regarding the combination therapy for the treatment of diabetes, Korean Patent Application Publication No. 10-2019-0130432 discloses an SGLT-2 inhibitor and DPP-IV inhibitor comprising dapagliflozin and linagliptin as active ingredients pharmaceutical composition of the drug.

[Citation List]

[Patent Literature]

Korean Patent Application Publication No. 10-2019-0130432

The technical problem of the present invention is to provide a combined preparation, which can effectively treat type 2 diabetes by increasing the bioavailability and stability of active ingredients through the synergistic combination of drugs with different mechanisms, and reducing the side effects of existing single drugs.

Another technical problem of the present invention is to provide a method capable of producing a combination formulation with high productivity while increasing the stability of the active ingredients.

In order to solve the above problems, the present invention provides an oral combined preparation for the treatment of type 2 diabetes mellitus, comprising as active ingredients gmiliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof; Lactose and/or microcrystalline cellulose as bulking agents; disintegrating agents; and slip agents.

The present invention further provides a preparation method of an oral combined preparation for the treatment of type 2 diabetes, comprising i) sieving as active ingredients gmiliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof salt, lactose and/or microcrystalline cellulose as bulking agents, and disintegrating agents, which are then mixed; and ii) adding a slip agent to the mixture obtained in step (i), mixing it, and adding the resulting Tablet the mixture.

The present invention is explained below.

According to one aspect of the present invention, there is provided an oral combined preparation for treating type 2 diabetes, comprising as active ingredients glmiliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof; Lactose and/or microcrystalline cellulose; disintegrating agent; slip agent.

Gmiliptin is a relatively recently developed potent and selective dipeptidyl peptidase IV (selective dipeptidyl peptidase IV, DPP-IV) inhibitor, and DPP-IV inhibitors are designed to inhibit the degradation of DPP-IV. Drugs for glucagon-like peptide-1 (GLP-1). GLP-1 is an incretin that promotes insulin secretion from beta cells, increases glucose utilization in peripheral tissues, inhibits glucagon secretion from alpha cells, and reduces hepatic glucose production.

Gmiliptin is available as a pharmaceutically acceptable salt in several forms. In the present invention, pharmaceutically acceptable salts of gmiliptin include, for example, hydrochloride, hydrobromide, phosphate, sulfate, acetate, trifluoroacetate, citrate, formate, cis-butyrate Oxalate, oxalate, succinate, benzoate, tartrate, fumarate, phenylglycolate, ascorbate, malate and mesylate, preferably tartrate 1.5 hydrate .

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, and can suppress the glucose reabsorption process by inhibiting SGLT-2 in the renal tubules and excrete glucose from the urine, thereby suppressing the blood glucose level rise. In one aspect according to the present invention, dapagliflozin can be in amorphous and particulate forms.

In one aspect according to the present invention, lactose as bulking agent may be anhydrous lactose or lactose hydrate.

In one aspect according to the present invention, the disintegrating agent may be croscarmellose sodium or crospovidone (cross-linked polyvinyl N-pyrrolidone). In one aspect according to the present invention, the slip agent may be sodium fumarate.

In one aspect according to the present invention, the oral combined preparation for the treatment of type 2 diabetes may include: as active ingredients 20 to 60% by weight of glmiliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof, 20 to 70% by weight of lactose and/or microcrystalline cellulose as bulking agent, 0.5 to 15% by weight of disintegrating agent, and 0.2 to 15% by weight of slip agent. In one aspect according to the present invention, the oral combined preparation for the treatment of type 2 diabetes may comprise: as active ingredients 30 to 50% by weight of gmilliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof, 30 to 65% by weight of lactose and/or microcrystalline cellulose as bulking agent, 1 to 10% by weight of disintegrating agent, and 0.5 to 10% by weight of slip agent.

In one aspect according to the present invention, the oral combined preparation for the treatment of type 2 diabetes mellitus may comprise gmilliptin or a pharmaceutically acceptable salt thereof and dagger in a weight ratio of 2 to 10:1 in free form. Lithionin or a pharmaceutically acceptable salt thereof. In one aspect according to the present invention, the oral combined preparation for the treatment of type 2 diabetes mellitus may comprise gmilliptin or a pharmaceutically acceptable salt thereof and dagger in a weight ratio of 3 to 7:1 in free form. Lithionin or a pharmaceutically acceptable salt thereof. In one aspect according to the present invention, the oral combined preparation for the treatment of type 2 diabetes mellitus may comprise a free form weight ratio of 5:1 of gmilliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof. For example, the oral combination formulation for treating type 2 diabetes according to the present invention may comprise 50 mg of glmiliptin and 10 mg of dapagliflozin.

In one aspect according to the present invention, the oral combination formulation for the treatment of type 2 diabetes may further comprise a coating agent. In one aspect of the present invention, usable coating agents may include coating agents commonly used in the art, such as polyvinylpyrrolidone, copovidone, Opadry series, Eudragit series, etc., but not limited thereto. In one aspect according to the present invention, the coating agent may be Opadry.

In one aspect according to the present invention, the oral combination formulation for the treatment of type 2 diabetes may be in the form of granules, capsules or lozenges.

According to another aspect of the present invention, there is provided a preparation method of an oral combined preparation for the treatment of type 2 diabetes, comprising i) sieving gmiliptin as an active ingredient or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof, lactose and/or microcrystalline cellulose as bulking agents, and disintegrating agents, which are then mixed; and ii) adding a slip agent to the mixture obtained in step (i), mixing, The resulting mixture was then tableted.

In one aspect according to the present invention, the lactose may be anhydrous lactose or lactose hydrate. In one aspect according to the present invention, the disintegrating agent may be croscarmellose sodium or crospovidone. In one aspect according to the present invention, the slip agent may be sodium fumarate.

In general, for formulations containing a small amount of active ingredients such as dapagliflozin, in order to maintain a high content uniformity, the formulation is wet granulated or dry granulated, but this granulation process may increase production time. This increases the cost of production and may reduce the stability of its active ingredients. In the preparation method according to the present invention, by adopting direct pressing, high productivity (low production cost and high yield) can be achieved, and the stability of the active ingredient can also be improved.

According to the present invention, by providing a combined preparation comprising gmiliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof, the synergistic combination of drugs with different mechanisms of action can alleviate the single drug It can effectively treat type 2 diabetes due to the high bioavailability and high stability of the active ingredient due to the high dissolution rate of the active ingredient.

In addition, according to the preparation method of the present invention, a combined preparation of active ingredients with improved stability can be provided at high productivity by adopting direct tablet compression.

FIG. 1 is a diagram showing the results of the determination of the dissolution rate of gmiliptin in the tablet of Example 16 (Zemiglo tablet: gmiliptin 50 mg tablet); and

2 is a graph showing the results of the measurement of the dissolution rate of dapagliflozin in the tablet of Example 16 (Forxiga tablet: dapagliflozin 10 mg tablet).

Hereinafter, the present invention will be explained in more detail with reference to examples. However, the following examples are only used for illustration to help understand the content of the present invention, and the scope of the present invention is not limited thereto.

Examples 1 to 4 and Comparative Examples 1 and 2: Preparation of lozenges

According to the composition in Table 1 below, sieve 68.9 mg of gmigliptin tartrate (containing 50 mg of gmigliptin), 10 mg of dapagliflozin, bulking agent and disintegrating agent, and then mix using a conical mill, and add slipping aid to it agent before final mixing. The final mixture is tableted to make a single layer tablet.

[Table 1]

Experimental Example 1: Stability Experiment 1

The tablets of Examples 1 to 4 and Comparative Examples 1 and 2 were subjected to a 6-month stability test under accelerated conditions (40° C., 75% humidity). The measurement results are shown in Table 2 and Table 3, respectively.

[Table 2]

[table 3]

DP-IMP-1:

2-[( 2S )-6,6-difluoro-2,3,5,6,7,8-hexahydroimidazo[1,2- a ]pyridin-2-yl]-1-[2, 4-Bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidin-7-yl]-1-ethanone

DP-IMP-2:

2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidin-8-one

DP-IMP-3:

(3 S )-3-amino-4-(5,5-difluoro-2-oxo-N-piperidinyl)-1-[8-hydroxy-2,4-bis(trifluoromethyl) )-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidin-7-yl]butan-1-one tartrate

From the results of Table 2 and Table 3, it can be seen that the tablet of the embodiment is more stable than the tablet of the comparative example.

Comparative Example 3

According to the composition in Table 4 below, in the same manner as Comparative Examples 1 and 2, a co-crystal containing 68.9 mg of tartrate (containing 50 mg of gmigliptin) and 14.6 mg of dapagliflozin citric acid (containing 10 mg of citrate) was prepared dapagliflozin) tablets.

[Table 4]

Experiment 2: Stability Experiment 2

In the same manner as in Experimental Example 1, two stability experiments were performed on the tablet of Comparative Example 3, and the results are shown in Table 5.

[table 5]

As can be seen from the results in Table 5, it has been confirmed that the stability of the dapagliflozin citric acid co-crystal is significantly lower than that of the amorphous dapagliflozin.

Examples 5 to 15

According to the composition in Table 6 below, in the same manner as in Examples 1 to 4, preparations containing different contents of gmiliptin tartrate, dapagliflozin, microcrystalline cellulose, anhydrous lactose, croscarmellose Tablets of sodium veganum and sodium fumaric stearate.

[Table 6]

Experimental Example 3: Measurement of Dissolution Rate

The dissolution rates of the tablets prepared in Examples 5 to 15 were measured under the following conditions, and the results are shown in Table 7.

- Dissolution method: pH 6.8 solution

- Dissolution medium volume: 900mL

- Blade speed: 50rpm

- Number of test sets: 4

- Sample collection time: 15 minutes

[Table 7]

Example 16

Based on the experimental results of Examples 5 to 15, lozenges were prepared in the same manner as in Examples 1 to 4 according to the compositions in Table 8 below.

[Table 8]

Experimental Example 4: Measurement of Stability and Dissolution Rate

The stability of the tablet prepared in Example 16 was measured in the same manner as in Experimental Example 1, and the results are shown in Tables 9 and 10, respectively. In the same manner as in Experimental Example 3, the elution rate was measured in a solution of pH 1.2, a solution of pH 4.5, a solution of pH 6.8, and water, and the results are shown in FIG. 1 and FIG. 2 .

[Table 9]

[Table 10]

From the above results, it was confirmed that the combination formulation of Example 16 imparted stability to gmiliptin and dapagliflozin, and that the respective dissolution rates of glmiliptin and dapagliflozin in the combination formulation were comparable to those in the individual formulations.

Claims (18)

An oral combined preparation for the treatment of type 2 diabetes mellitus, comprising as active ingredients gmiliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof; lactose and/or as a bulking agent Microcrystalline cellulose; disintegrating agents; and slip agents. The oral combined preparation for treating type 2 diabetes as claimed in claim 1, wherein the pharmaceutically acceptable salt of gmiliptin is selected from the group consisting of: hydrochloride, hydrobromide, Phosphate, Sulfate, Acetate, Trifluoroacetate, Citrate, Formate, Maleate, Oxalate, Succinate, Benzoate, Tartrate, Fumarate, Phenylethanol acid salts, ascorbate, malate and mesylate. The oral combined preparation for treating type 2 diabetes according to claim 2, wherein the pharmaceutically acceptable salt of gmiliptin is tartrate. The oral combined preparation for treating type 2 diabetes as described in claim 1, wherein the dapagliflozin is amorphous dapagliflozin. The oral combined preparation for treating type 2 diabetes as claimed in claim 1, wherein the lactose is anhydrous lactose or lactose hydrate. The oral combined preparation for treating type 2 diabetes according to claim 1, wherein the disintegrating agent is croscarmellose sodium or crospovidone. The oral combined preparation for treating type 2 diabetes according to claim 1, wherein the slip agent is sodium fumarate. The oral combined preparation for treating type 2 diabetes as claimed in claim 1, comprising 20 to 60% by weight of the active ingredient, 20 to 70% by weight of the bulking agent, and 0.5 to 15% by weight of the disintegrating agent , and 0.2 to 15% by weight of the slip agent. The oral combined preparation for treating type 2 diabetes as claimed in claim 8, comprising 30 to 50% by weight of the active ingredient, 30 to 65% by weight of the bulking agent, 1 to 10% by weight of the disintegrating agent, and 0.5 to 10% by weight of this slip agent. The oral combined preparation for treating type 2 diabetes as claimed in claim 1, comprising the gmilliptin or a pharmaceutically acceptable salt thereof and the Dag in a weight ratio of 2 to 10:1 in free form Lithionin or a pharmaceutically acceptable salt thereof. The oral combined preparation for treating type 2 diabetes as described in claim 10, comprising the gmiliptin or its pharmaceutically acceptable salt and the dapagliflozin in a weight ratio of 5:1 in free form or a pharmaceutically acceptable salt thereof. The oral combined preparation for the treatment of type 2 diabetes as claimed in claim 1, further comprising a coating agent. The oral combined preparation for treating type 2 diabetes as claimed in claim 12, wherein the coating agent is Opadry. The oral combined preparation for the treatment of type 2 diabetes as claimed in claim 1 in the form of granules, capsules or lozenges. A preparation method of an oral combined preparation for treating type 2 diabetes as described in claim 1, comprising: i) sieving gmiliptin or a pharmaceutically acceptable salt thereof and dapagliflozin or a pharmaceutically acceptable salt thereof as active ingredients, lactose and/or microcrystalline cellulose as bulking agent, and disintegrating agent, and then be mixed; and ii) A slip agent is added to the mixture obtained in step (i), mixed, and the resulting mixture is tabletted. The method for preparing an oral combined preparation for treating type 2 diabetes according to claim 15, wherein the lactose is anhydrous lactose or lactose hydrate. The preparation method of the oral combined preparation for treating type 2 diabetes according to claim 15, wherein the disintegrating agent is croscarmellose sodium or crospovidone. The preparation method of the oral combined preparation for treating type 2 diabetes according to claim 15, wherein the slip agent is sodium fumarate.

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