KR20210082046A - Composite formulation comprising Sitagliptin and Dapagliflozin and a process for the preparation thereof - Google Patents

Abstract

Provided are a combination formulation comprising sitagliptin and dapagliflozin and a method for manufacturing the same. The combination formulation comprising sitagliptin and dapagliflozin according to an aspect has excellent stability, productivity, dissolution, and compounding compatibility, and at the same time, it is possible to reduce the size of a dosage form, thereby increasing medication compliance.

Description

Composite formulation comprising Sitagliptin and Dapagliflozin and a process for the preparation thereof

The present application relates to a combination preparation containing sitagliptin and dapagliflozin and a method for manufacturing the same, and more particularly, to a combination preparation capable of miniaturizing the size while excellent in stability, productivity, dissolution rate, and compounding compatibility; It relates to a manufacturing method thereof.

Type 2 diabetes patients are generally accompanied by overweight, abdominal obesity, and high blood pressure, and for this reason, diabetes is known as a disease that causes secondary chronic diseases or metabolic syndrome such as hypertension, hyperlipidemia, myocardial infarction, and stroke. According to the medical guidelines of the Society, drug combination therapy is actively recommended to improve symptoms. In particular, the combination of a DPP-4 inhibitor drug and an SGLT-2 inhibitor drug has recently demonstrated excellent efficacy and effectiveness in the treatment of diabetes in academia, and even a three-agent treatment with metformin is being studied.

Sitagliptin (product name: Januvia Tablet) is a dipeptidylpeptidase-4 (DPP-4) inhibitor class drug, and the compound name is (R)-3-amino-1-(3-(trifluoromethyl) -5,6-diphadro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane It is -1-one. Sitagliptin regulates blood sugar by inhibiting the breakdown of the gastrointestinal hormone called incretin so that the incretin, which regulates insulin and glucagon, functions well in the body. When sitagliptin is administered orally to type 2 diabetes patients, It is known that HbA1c levels are significantly reduced, and fasting blood glucose and postprandial blood glucose secretion are reduced.

Dapagliflozin (product name: Posigajeong) is a sodium-glucose linked transporter 2: SGLT-2 inhibitor class drug, and the compound name is (2S,3R,4R,5S,6R) -2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. Dapagliflozin selectively inhibits SGLT2 in the kidneys and may normalize plasma glucose levels by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity and delaying the onset of diabetic complications. The original developer, AstraZeneca Ave, is currently on the market in the form of a tablet containing dapagliflozin propylene glycol hydrate as an active ingredient.

Sitagliptin and dapagliflozin have main effects of lowering blood sugar without risk of hypoglycemia, Sitagliptin has pancreatic beta cell protective effects and GLP-1 increase, and dapagliflozin has weight loss effects. However, it has been introduced as a clinical result that the combination of the two active ingredients has a synergistic effect due to its blood pressure lowering effect. In addition, in the case of diabetic patients, as diabetes progresses, it is difficult to control blood sugar, resulting in complications. In particular, elderly diabetic patients are more likely to suffer from hypertension, obesity, and hyperlipidemia. Due to the characteristics of these diabetic patients, medication adherence is a very important factor, and a decrease in medication compliance may not only lower the quality of life of the patient, but also reduce the patient's treatment rate, increase personal medical expenses, and worsen insurance finances. Therefore, it is necessary to develop a combination formulation containing sitagliptin and dapagliflozin.

However, the development of the complex formulation has not yet been attempted due to numerous problems such as the physical properties of each API and the size of the tablet. In the case of the main component of sitagliptin, there is a problem in that the amount contained per tablet is large, and since it has viscosity, sticking of the punch during the production process easily occurs. In addition, in the case of the main component of dapagliflozin, the density is low and the volume of the main component is large despite a small amount, so productivity is not good, there is a high possibility of layer separation with other main components and excipients, and the main component has the property of agglomeration with each other. Since the formation possibility is high, there is a problem in that it is difficult to secure formulation uniformity.

Furthermore, the total mass of a representative tablet containing each main component of sitagliptin and dapagliflozin (total amount of 100 mg Januvia tablets containing 100 mg as sitagliptin: about 416.1 mg, including 10 mg as dapagliflozin) Considering the total amount of 10 mg of Posi family: about 260 mg), when using a combination formulation containing each active ingredient, the total amount including the main ingredient and excipients increases, and accordingly, the tablet size itself increases, so there is a problem of lowering compliance with the medication. Alternatively, if the total amount and tablet size of the combination preparation are too reduced, it may be difficult to overcome the physical properties of the main component during product production due to an increase in the ratio of the main component to the excipient. In addition, selecting an excipient that satisfies the compounding compatibility of both components included in the combined preparation is one of the most important and difficult problems in the field of complex preparation. Moreover, the time (Tmax) at which the drug reaches its maximum concentration in plasma, which is represented by each of the two drug components of sitagliptin and dapagliflozin, is about 1 hour (sitagliptin 1-4 hr/dapagliflozin 1). ~2hr), it is necessary to develop a combination formulation that contains both components and has improved dissolution rate.

Korean Patent Publication No. 10-2016-0111237

In one aspect, sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is excellent in stability, productivity, dissolution, and compounding compatibility, and at the same time can miniaturize the dosage form, thereby increasing medication compliance. , and dapagliflozin or a pharmaceutically acceptable salt thereof sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof It is to provide a combination formulation containing a hydrate.

Another aspect is to provide a method for preparing the combination formulation.

Other objects and advantages of the present application will become more apparent from the following detailed description in conjunction with the appended claims. Content not described in this specification will be omitted because it can be sufficiently recognized and inferred by a person skilled in the art within the technical field of the present application or a similar technical field.

the work aspect

sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and

A combination preparation comprising dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof,

Provided is a combination formulation comprising sodium stearyl fumarate, magnesium stearate, or a combination thereof as a lubricant.

Another aspect is

preparing a mixing part comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a lubricant;

granulating the mixing part; and

It provides a method for producing a composite preparation according to the one aspect, comprising the step of adding a lubricant to the granules and mixing them further.

The combination formulation comprising sitagliptin and dapagliflozin according to an aspect has excellent stability, productivity, dissolution, and compounding compatibility, and at the same time, it is possible to miniaturize the size of the dosage form, thereby increasing medication compliance. The manufacturing method according to one aspect can improve manufacturing productivity by improving pharmaceutical properties such as flowability and tabletting properties of the composite formulation.

1 is a photograph of compressed flakes and tablets prepared by varying the presence or absence of magnesium stearate.
Figure 2 is a photograph of a tablet compressed by mixing sitagliptin and lactose, and a tablet compressed by mixing with an excipient other than sitagliptin and lactose.
3 is a photograph of the properties of the tablets after tableting of Example 5 and Comparative Example 5 in which the amount of sodium stearyl fumarate (PRUV®) was different, and the result of measuring the time required for discharging the mixed powder during the manufacture of each tablet will be.
4 is a graph showing the results of the sitagliptin dissolution test of Examples 5 to 8 and Comparative Examples 6 and 8.
5 is a graph showing the results of the dapagliprozin dissolution test of Examples 5 to 8 and Comparative Examples 6 and 8.
6 is a process chart showing a process for manufacturing the composite tablet of Examples 9 to 12.
7 shows (a) Januvia 100 mg (100 mg as sitagliptin), (b) Forsiga 10 mg (dapagliflozin propanediol hydrate 12.3 mg), and (c) the combination tablet prepared in Example 13. is a picture taken of

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

All technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, unless otherwise defined. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present specification. In addition, the numerical values described herein are considered to include the meaning of "about" even if not specified. The contents of all publications incorporated herein by reference are hereby incorporated by reference in their entirety. As used herein, the term “about” means that the referenced value may vary to some extent. For example, the value may vary by 10%, 5%, 2%, or 1%. For example, “about 5” is meant to include any value between 4.5 and 5.5, between 4.75 and 5.25, or between 4.9 and 5.1, or between 4.95 and 5.05. As used herein, the terms “has”, “may have”, “comprises”, or “may include” indicate the presence of a corresponding characteristic (eg, a numerical value or a component such as a component). and does not exclude the presence of additional features.

One aspect is a combination preparation comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof,

Provided is a combination formulation comprising sodium stearyl fumarate, sodium stearate, or a combination thereof as a lubricant.

In one embodiment, the combination formulation includes sodium stearyl fumarate as a lubricant.

The main component, sitagliptin or dapagliflozin, includes all of their crystalline forms, hydrates, co-crystals, solvates, salts, diastereomers or enantiomers.

The pharmaceutically acceptable salt thereof refers to any pharmaceutically acceptable salt that can be commonly used in the art.

In one embodiment, the sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be a sitagliptin phosphate hydrate.

In one embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be a pharmaceutically acceptable co-crystal of dapagliflozin. In one embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof may be dapagliflozin L-proline or dapagliflozin propanediol hydrate. In one embodiment, it may be dapagliflozin L-proline.

In one embodiment, the sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be included in an amount of 10 to 40% by weight, for example, 25 to 35% by weight of the total weight of the combined preparation.

In one embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be included in an amount of 2 to 10% by weight, for example, 2 to 6% by weight of the total weight of the combined preparation.

In one embodiment, as the lubricant, sodium stearyl fumarate may be included in an amount of 3 to 8% by weight based on the total weight of the combined formulation.

Magnesium stearate, which is most commonly used as a lubricant, increases productivity and tabletting properties of the composite formulation of the present application, but is found to be very disadvantageous because it increases the related substances of the main component over time (Test Examples 1 and 3). On the other hand, sodium stearyl fumarate can form a combination formulation stable enough to satisfy the standards of related substances as well as increase productivity and tabletting properties (Test Example 3). The sodium stearyl fumarate may be included in an amount of 3 to 8% by weight based on the total weight of the combined formulation. If it is less than 3% by weight, there is a fear that sufficient stability and productivity may not be ensured, and if it does not exceed 8% by weight, there may be concerns about a decrease in the dissolution rate of the main component (Test Examples 4, 5, and 6).

The combined formulation may include one or more excipients selected from diluents, disintegrants, binders, lubricants, and release controlling agents.

The diluent may be selected from the group consisting of, for example, D-mannitol, pregelatinized starch, low-substituted hydroxypropylcellulose (L-HPC), microcrystalline cellulose (MCC), sucrose, sorbitol, xylitol, glucose, and any mixtures thereof. However, the present invention is not limited thereto.

In one embodiment, the diluent may be selected from the group consisting of D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose, and any combination thereof.

The disintegrant is, for example, crospovidone, sodium cross-linked carboxymethylcellulose (Cross-linked CMC Na, C.CMC Na, or croscarmellose sodium), corn starch, calcium carboxymethylcellulose, sodium starch glycolate, low-substituted hydroxypropyl It may be selected from the group consisting of cellulose (L-HPC) and mixtures thereof, but is not limited thereto. In one embodiment, the disintegrant is sodium crosslinked carboxymethylcellulose.

The binder may be selected from the group consisting of, for example, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, and mixtures thereof, but is limited thereto no. In one embodiment, the binder is hydroxypropylcellulose.

The release controlling agent such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxyvinyl polymer, polyvinyl alcohol, xanthan gum, guar gum, carboxymethyl cellulose and its derivatives, methylcellulose and its derivatives, and povidone-polyvinylacetate public It may be selected from the group consisting of coalesces, and mixtures thereof, but is not limited thereto. In one embodiment, the binder is hydroxypropylcellulose.

In one embodiment, the combination preparation is microcrystalline cellulose (MCC), mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, cross-linked carboxymethyl cellulose sodium (Cross-Linked CMC Na), and an excipient selected from any mixture thereof.

The combination preparation may be in the form of a tablet, capsule, or granule. The combination preparation according to one embodiment may be a mixed tablet or a double-layer tablet.

In one embodiment, the combination preparation may be in the form of a tablet including compressed granules including the main ingredient and excipients. In the case of a tablet including compressed granules, it was confirmed that the flowability of the mixture supplied to the inside of the cavity during tableting was excellent, and thus the productivity was excellent and the content uniformity was excellent (Test Example 7), compared to the direct-actuated tablet.

The combination formulation may further include a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, sweeteners, preservatives, coating agents, viscosity modifiers, and any combination thereof. ingredients can be used.

The composite formulation may be in the form of about 5 to 15 mm in width and length, respectively. The thickness of the composite formulation may be about 3 to 8 mm. The composite formulation according to one embodiment may have a horizontal and vertical length of about 5 to 15 mm, respectively, and a thickness of about 3 to 8 mm. The composite formulation according to one embodiment may be in the form of about 10 to 15 mm in width, about 5 to 10 mm in length, and about 3 to 8 mm in thickness. The transverse length of the combination formulation may be, for example, about 10, 11, 12, 13, 14, 15 mm. The vertical length of the vertical combination formulation may be, for example, about 5, 6, 7, 8, 8, 10 mm. The thickness of the combination formulation may be, for example, about 3, 4, 5, 6, 7, 8 mm.

The combined formulation may be a rectangular oval tablet. The combined formulation may be easier to swallow than when taking two tablets each containing two active ingredients. In general, when passing through a narrow part of the neck of the human body after drug administration, the tablet crosses the neck while maintaining the smallest cross-sectional area. At this time, in order to maintain a small cross-sectional area of the tablet, the neck-rolling occurs by maintaining two variables having a smaller value among the width, length and thickness of the tablet. For example, Figure 7 shows (a) Januvia tablet (sitagliptin 100 mg), (b) Fosiga tablet (dapagliflozin propanediol hydrate 12.3 mg), and (c) the tablet prepared in Example 13. The image shows the appearance of each tablet that is predicted to align upon throat swallowing. The combination preparation comprising two active ingredients of sitagliptin and dapagliflozin according to one embodiment is compared with the case of taking a tablet containing each active ingredient at the same time, when the size, weight, and throat of the drug are swallowed. The cross-sectional area can be reduced, and the convenience of taking a large tablet can be increased for patients who feel uncomfortable when swallowing.

The combination formulation may further include one or more antidiabetic agents. For example, the combination preparation may further include metformin or a pharmaceutically acceptable salt thereof. The combination preparation according to one embodiment may be a three-agent combination preparation comprising sitagliptin, dapagliflozin, and metformin.

Another aspect provides a method for preparing the combination formulation.

The manufacturing method according to one embodiment

preparing a mixing part comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a lubricant;

granulating the mixing part; and

It may include the step of mixing by further adding a lubricant to the granules.

The manufacturing method according to another embodiment is

preparing a first mixing part comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant;

preparing a second mixing part comprising dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant;

granulating the first mixing unit and/or the second mixing unit; and

It may include the step of mixing a lubricant with the obtained granules.

In one embodiment, the granulating step may be performed by a dry granulation method. The dry granulation method may include forming compressed flakes using a roller compactor.

In one embodiment, the manufacturing method may further include the step of tableting the granulated material mixed with the lubricant.

Hereinafter, the present invention will be described in detail by way of Examples. However, these examples are merely exemplary, and the present invention is not intended to be limited by these examples.

Test Methods

In the following test examples, the conditions for analysis of related substances, analysis of eluates, and content analysis were performed in the following manner.

1. Conditions for analysis of related substances [HPLC method]

2. Conditions for analysis of elution items [HPLC method]

3. Content analysis conditions [HPLC method]

Test Example 1: Test of related substances according to lubricant

The stability of the combination formulation was tested when magnesium stearate, which is commonly used widely, was used as a lubricant. With a prescription according to Table 1 below, tablets were prepared according to the following [Sample Preparation Method]. Then, related substances were measured for each sample (Tables 1 to 3), and the properties of compressed flakes and tablets according to the presence or absence of magnesium stearate were compared ( FIG. 1 ). 1 is a photograph of compressed flakes and tablets according to the presence or absence of magnesium stearate.

[Sample recipe]

(1) Weighing: Each component was weighed in an amount of 1000T.

(2) Sieve: All excipients except the lubricant to be added to the final mixing were passed through a 30 mesh sieve and sieved.

(3) Mixing: The powder passed through the sieve was mixed at 17 rpm for 30 min using a Bin Mixer.

(4) Compacting: Compression flakes were formed using a Roller Compactor, Roll rpm 3.0/ Screw rpm 35.0 rpm, and hydraulic pressure 2.5 Mpa.

(5) Sizing: Using an oscillator, the flakes prepared in the step (4) were sized to 20 mesh.

(6) Final mixing: The result prepared in step (5) and the remaining final mixed lubricant were added and mixed at 17 rpm for 5 minutes using a bin mixer.

(7) Tableting: Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a circular punch having a diameter of 8.0 mm was used, and the tablet hardness was 10 to 12 kp.

According to the experimental results, when magnesium stearate was used as a lubricant in the mixed granules containing sitagliptin and dapagliflozin together, the amount of related substances increased significantly under accelerated storage conditions, and when magnesium stearate was excluded, the granules There was a decrease in productivity due to the issue of adhesion to punches and production equipment during process and product tableting. Therefore, it was confirmed that the lubricant is necessary for productivity and tabletting property, but magnesium stearate reduces the stability of the main ingredient and is not suitable.

Test Example 2: Testing of related substances according to excipients

Preparation Example 1

To evaluate the stability of the two main components of sitagliptin and dapagliflozin, sitagliptin phosphate hydrate 128.5 mg (sitagliptin 100 mg) and dapagliflozin L-proline 15.6 mg (dapagliflozin) Ginro 10 mg) was prepared by compression. Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan) tableting machine, flakes are formed and the amount of related substances generated under accelerated conditions (40℃/75% RH) 1 month/2 months is measured to confirm stability. did.

Preparation 2

In order to examine the suitability of mixing the main component sitagliptin and the excipient, different types of excipient were mixed with sitagliptin. After sieving the above excipients and the main component sitagliptin for 20 mesh, they were mixed for 30 minutes each using a tubular mixer. Then, another main component, dapagliflozin, was added, mixed and compressed to prepare tablets. Using an AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan) tableting machine, flakes were formed and the amount of related substances generated under accelerated conditions (40℃/75% RH) 1 month/2 months was measured to confirm stability.

Preparation 3

In order to examine the compatibility of mixing of the main component dapagliflozin and excipients, different types of excipients were mixed with dapagliflozin. The above excipients and the main component dapagliflozin were sieved through a 20 mesh sieve, and then mixed for 30 minutes each using a tubular mixer. Thereafter, sitagliptin, another main component, was added, mixed and compressed to prepare tablets. Using an AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan) tableting machine, flakes were formed and the amount of related substances generated under accelerated conditions (40℃/75% RH) 1 month/2 months was measured to confirm stability.

Based on total related substances content

The standard for the total amount of related substances used is, according to the domestic approved related substance standards, for sitagliptin, less than 0.2% of the total related substances, and for dapagliflozin, less than 2.0% of the total related substances.

The test results of related substances measured using the tablets prepared in Preparation Examples 1 and 2 are shown in Table 4 above. As shown in Table 4 above, in the case of sitagliptin, when lactose hydrate or dicalcium phosphate hydrate (DCP hydrate) was included as an excipient, the total related substance content was more than 0.2%, respectively, and did not satisfy the standard.

In particular, it was confirmed that when sitagliptin and lactose hydrate were mixed, they showed browning due to the Maillard reaction, which produces a brown substance at high temperature, when the properties were observed at accelerated 2 months (Fig. 2). 2 is a photograph of a tablet obtained by mixing sitagliptin and lactose and tabletting the tablet with an excipient other than lactose.

The test results of related substances measured using the tablets prepared in Preparation Examples 1 and 3 are shown in Table 5 above. As shown in Table 5 above, in the case of dapagliflozin, when dicalcium phosphate anhydride (DCP anhydride) was included as an excipient, the total related substance content was more than 2.0%, respectively, and did not satisfy the standard. In addition, even when dicalcium phosphate hydrate (DCP hydrate) was included as an excipient, the total related substance content standard was satisfied, but the amount of related substance generation was higher than that of other excipients.

Test Example 3: Testing of related substances according to lubricants and excipients

Based on the stability comparison results for each prescription in Test Examples 1 and 2, it was confirmed that it was necessary to select a lubricant or excipient suitable for production and having secured stability. Therefore, stability tests were performed according to various types of lubricants and excipients. After completion of tablet production, stability evaluation was performed under accelerated and severe conditions.

With a prescription according to Table 6 below, tablets were prepared according to the following [Sample Preparation Method].

[Sample recipe]

(1) Weighing: Each component was weighed in an amount of 1000T.

(2) Sieve: All excipients except the lubricant to be added to the final mixing were passed through a 30 mesh sieve and sieved.

(3) Mixing: The powder passed through the sieve was mixed at 17rpm for 30min using a Bin Mixer.

(4) Compression: Compression flakes were formed using a roller compactor, Roll rpm 3.0/ Screw rpm 35.0 rpm, and hydraulic pressure 2.5 Mpa.

(5) Sizing: Using an oscillator, the flakes prepared in step (4) were sized to 20 mesh.

(6) Final mixing: The result prepared in step (5) and the remaining final mixed lubricant were added and mixed using a bin mixer at 17rpm for 5 minutes.

(7) Tableting: Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a rectangular punch having a width of 12.8 mm and a length of 7.0 mm was used to tablet hardness of 12 to 14 kp.

Table 7 below shows the results of evaluating the total related substances of sitagliptin when stored under accelerated conditions (40° C., 75% relative humidity).

Table 8 below shows the results of evaluating the total related substances of dapagliflozin when stored under accelerated conditions (40 ℃, 75% relative humidity).

Table 9 below shows the results of evaluating the total related substances of sitagliptin when stored under severe conditions (60 °C).

Table 10 below shows the results of evaluating the total related substances of dapagliprozin when stored under severe conditions (60 ℃).

According to the results of Tables 7 to 10, when sodium stearyl fumarate (PRUV®) was used as a lubricant (Examples 1 to 3), it was found to be an appropriate lubricant that does not impair stability, as it satisfies the standards for related substances. became On the other hand, according to Comparative Examples 1 to 4, it was confirmed that all of the other lubricants, glyceryl monostearate, magnesium stearate, calcium stearate, and sucrose stearate, did not meet the criteria for acceleration and severe conditions.

In addition, when microcrystalline cellulose, D-mannitol, and/or low-substituted hydroxypropyl cellulose was used as an excipient together with sodium stearyl fumarate (PRUV®), stability of related substances was secured (Examples 1 to 3), but fumarate stearyl When dicalcium phosphate anhydride was used as an excipient together with aryl sodium (PRUV®) (Example 4), the criteria for dapagliflozin related substances under accelerated conditions and severe conditions were not satisfied.

Test Example 4: Productivity evaluation according to the amount of lubricant

Productivity evaluation was performed according to the amount of lubricant for sodium stearyl fumarate (PRUV®), microcrystalline cellulose, D-mannitol, and low-substituted hydroxypropyl cellulose, which were secured in Test Example 4 above. In addition, stability evaluation was performed under accelerated and severe conditions after sample preparation was completed, and the sample preparation was performed in the same manner as in Test Example 3 above.

The properties of the tablets after tableting of Example 5 and Comparative Example 5 were photographed, and the time required for discharging the granules during tableting of each tablet was measured, and the results are shown in FIG. 3 . The “time required for discharging granules during tableting” refers to the time it takes for all the granules filled inside the feeder to be tableted into tablets during tableting, and for all the granules inside the feeder to be exhausted. In this test, the amount of granules filled in the feeder It was evaluated based on the time of 420g.

Test Example 5: Stability evaluation according to the amount of lubricant

The results of evaluating the total related substances of sitagliptin in tablets according to the amount of lubricant when stored under accelerated conditions (40° C., 75% relative humidity) for the samples prepared according to Table 11 are shown in Table 12 below. shown in

Table 13 below shows the results of evaluating the total related substances of dapagliflozin in tablets according to the amount of lubricant when stored under accelerated conditions (40° C., 75% relative humidity).

Table 14 below shows the results of evaluating the total related substances of sitagliptin in tablets according to the amount of lubricant when stored under severe conditions (60° C.).

Table 15 below shows the results of evaluating the total related substances of dapagliflozin in tablets according to the amount of lubricant when stored under severe conditions (60° C.).

Test Example 6: Evaluation of dissolution rate according to the amount of lubricant

For the samples prepared according to Table 11, dissolution rate evaluation was performed, and the results are shown in FIGS. 4 and 5 .

4 is a graph showing the results of the sitagliptin dissolution test of Examples 5 to 8 and Comparative Examples 6 and 8.

5 is a graph showing the results of the dapagliprozin dissolution test of Examples 5 to 8 and Comparative Examples 6 and 8.

In addition, the content of the main component of Examples 5 to 8 and Comparative Examples 6 and 8 was evaluated. The results are shown in Tables 16 and 17 below.

According to the test result of Test Example 4, when the sodium stearyl fumarate did not reach 3% of the total weight of the tablet (Comparative Examples 5 and 7), the amount of lubricant was insufficient, resulting in tablet compression failure. In addition, during the tableting process, it was confirmed that the productivity was lowered because the time required for discharging the granules during tableting was delayed. On the other hand, when the sodium stearyl fumarate was 3% or more of the total weight of the tablet (Examples 5 to 8 and Comparative Examples 6 and 8), the tablet was compressed without a tableting disorder. According to FIG. 3, in the case of Example 5, in which sodium stearyl fumarate is 3% or more of the total weight of the tablet, compared to Comparative Example 5, which is less than 3% by weight, the tablet is produced smoothly without tableting disorder, and the mixed powder discharge time is also significantly low can be seen.

According to the test results of Test Example 5, Comparative Examples 5 to 8 and Examples 5 to 8 secured the stability of related substances suitable for the standard under accelerated and severe conditions, but Comparative Examples 6 and Comparative Examples 6 and Comparative Examples having a relatively high lubricant ratio In Example 8, both components of sitagliptin and dapagliflozin showed a tendency to increase close to the related substance standard under severe conditions.

According to the test results of Test Example 6, when sodium stearyl fumarate was present in excess of 8% of the total weight of the tablet, it was confirmed that the dissolution rate of the main component decreased. Specifically, Comparative Examples 6 and 8 showed a decrease in the dissolution rate when comparing the dissolution pattern with Examples 6 and 8 (see FIGS. 4 and 5). In addition, according to the content evaluation result of Test Example 8, it was confirmed that there was no decrease in the content of the main component in each tablet (see Tables 16 and 17). Taken together, it was determined that the dissolution rate decreased due to the over-lubrication of the granules.

Test Example 7: Formulation Uniformity Test

The contents of one tablet of Examples 9 and 10 are shown in Table 18 below, and were prepared in the following order.

Preparation of Example 9

(1) Each component was weighed in a quantity of 1000T. (2) All components except 28.0 mg of sodium stearyl fumarate (PRUV) were passed through a 30 mesh sieve and sieved. (3) The powder passed through the sieve was mixed at 17rpm for 30min using a Bin Mixer. (4) Sodium stearyl fumarate (PRUV) and the result prepared in step (3) were mixed at 17 rpm for 5 minutes using a Bin Mixer. (5) Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a rectangular punch having a width of 12.8 mm and a length of 7.0 mm was used, and the tablet hardness was 12 to 14 kp.

Preparation of Example 10

(1) Each component was weighed in a quantity of 1000T. (2) All components except 8.0 mg of sodium stearyl fumarate (PRUV) were passed through a 30 mesh sieve and sieved. (3) The powder passed through the sieve was mixed at 17rpm for 30min using a Bin Mixer. (4) Compression flakes were formed using a Roller Compactor, Roll rpm 3.0/ Screw rpm 35.0 rpm, and hydraulic pressure 2.5 Mpa. (5) The flakes prepared in step (4) were sieved through a 20 mesh using an oscillator. (6) The remaining 8.0 mg of sodium stearyl fumarate (PRUV) and the result prepared in step (5) were mixed using a bin mixer at 17 rpm for 5 minutes. (7) Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a rectangular punch having a width of 12.8 mm and a length of 7.0 mm was used to tablet the tablet to a tablet hardness of 12 to 14 kp.

For future property comparison, the coating process was performed at a product temperature of 40° C. using a PVA base in an amount equivalent to about 3% of the total mass of the tablet under the trade name Opadry (Example 13).

Preparation of Examples 11 and 12

The contents of one tablet of Examples 11 and 12 are shown in Table 19 below, and were prepared in the following order.

Preparation of Example 11

(1) Each component was weighed in a quantity of 1000T. (2) Sitagliptin phosphate hydrate 128.5 mg, microcrystalline cellulose 56.8 mg, croscarmellose sodium 4.3 mg, and sodium stearyl fumarate 8.0 mg were passed through a 30 mesh sieve and sieved. (3) The powder passed through the sieve was mixed at 17rpm for 30min using a Bin Mixer. (4) Compression flakes were formed using a Roller Compactor, Roll rpm 3.0/ Screw rpm 35.0 rpm, and hydraulic pressure 2.5 Mpa. (5) The flakes prepared in step (4) were sieved through a 20 mesh using an oscillator. (6) The remaining dapagliflozin L-proline 15.6 mg, microcrystalline cellulose 56.8 mg, Cross-Linked CMC Na 4.3 mg, sodium stearyl fumarate 8.0 mg and the result prepared in step (5) were mixed with a bin mixer 17 rpm, mixed for 5 minutes. (7) Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a rectangular punch having a width of 12.8 mm and a length of 7.0 mm was used to tablet the tablet to a tablet hardness of 12 to 14 kp.

Preparation of Example 12

(1) Each component was weighed in a quantity of 1000T. (2) Each component except dapagliflozin L-proline 15.6 mg, microcrystalline cellulose 56.8 mg, croscarmellose sodium 4.3 mg, and sodium stearyl fumarate 8.0 mg was passed through a 30 mesh sieve and sieved. (3) The powder passed through the sieve was mixed at 17rpm for 30min using a Bin Mixer. (4) Compression flakes were formed using a Roller Compactor, Roll rpm 3.0/ Screw rpm 35.0 rpm, and hydraulic pressure 2.5 Mpa. (5) The flakes prepared in step (4) were sieved through a 20 mesh using an oscillator. (6) 128.5 mg of sitagliptin phosphate hydrate excluded in (2), 56.8 mg of microcrystalline cellulose, 4.3 mg of Cross-Linked CMC Na, 8.0 mg of sodium stearyl fumarate, and the result prepared in step (5) were mixed with a bin mixer. 17 rpm, and mixed for 5 minutes. (7) Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a rectangular punch having a width of 12.8 mm and a length of 7.0 mm was used to tablet the tablet to a tablet hardness of 12 to 14 kp.

6 is a process chart showing a process for manufacturing the composite tablet of Examples 9 to 12. The tablets of Example 9 were prepared according to the direct pressing method, and the composite formulations of Examples 10 to 12 were prepared by a compression process (roller   compaction).

Content uniformity test

Sample preparation

Take 20 tablets prepared in Examples 9 to 12, grind them, take the equivalent of 10 tablets, put them in a 500 mL volumetric flask, add 300 mL, add a magnetic bar, stir for 60 minutes to completely dissolve, remove the magnetic bar and mark the mark with a diluent match Take 4 mL of this solution, put it in a 50 mL volumetric flask, adjust it to the mark with the diluent, and filter it through a 0.45 µm membrane filter to use as the sample solution. It was tested under the following conditions.

mobile phase

pH 2.0 buffer: acetonitrile (ACN) = 15: 5 (v/v)

diluent

Same as mobile phase

HPLC conditions

Column: 15 cm x 4.6 mm, 5 μm CN column or equivalent column

Pump: 1.0 mL/min

Injection Vol. : 20 uL

UV ramp: 205 nm

Analysis time: 30 min

The results of the formulation uniformity test for the tablets prepared in Examples 9 to 12 are shown in the table below. When judging according to the determination method of content uniformity test during the formulation uniformity test of the 11th revision general test method of the Korean Pharmacopoeia, it was judged as suitable when the judgment value was 15% or less (n=10).

As shown in Tables 20 and 21, in the case of the tablet manufactured by the direct hitting method according to Example 9, it can be seen that the content uniformity of the tablet exceeds the standard or approaches the standard. This occurs due to the low density characteristics (small particle size and large volume) of sitagliptin and dapagliflozin. It is not uniform when filling the disk, and it is expected that it is due to the occurrence of layer separation between the mixed powders during mixing and transport.

In comparison, the tablets prepared in Examples 11 and 12 prepared by a compression process (roller   compaction) by mixing sitagliptin and dapagliflozin at the same time were excellent in terms of content uniformity. The well-mixed powder was formed into lumps under strong pressure and then pulverized to a certain size, thereby improving the physical properties that were problematic such as separation between the main ingredient and excipient and layer separation between fine particles and large particles, and improved product quality. . On the other hand, in Example 12, in which the mixing part containing dapagliflozin and the excipient was separately compacted, the loss of dapagliflozin may be small, and the sitagliptin raw material has larger particles than dapagliflozin. , it seems that the content uniformity of sitagliptin is superior to that of dapagliflozin because of its large amount. In addition, it seems that the flowability is somewhat improved by granulation of the compacted dapagliflozin mixing part, so that the mass deviation is also good. However, the total surface area of the formulation to be lubricated by the lubricating agent increased, showing that the surface lubrication of the final tablet was insufficient.

Density and particle size distribution test

Bulk density, tapped density, and mesh profile were measured using the granules prepared in Examples 11 and 12, and are shown in Table 22.

As shown in Table 22, the hausner ratio (tap density/bulk density) was measured from the bulk density and tapped density values measured for Examples 11 and 12. As a result, it can be seen that Example 12 has a smaller hausner ratio value than that of Example 11, thus exhibiting good flowability and improving tableting properties. In addition, as shown in Table 22, it can be seen that the sample of Example 12 has a more uniform particle size distribution than the sample of Example 11. Compared with Example 11, in Example 12, the granules of 30 to 60 mesh increased, and it was confirmed that the particle size was increased compared to the existing mixed powder, and the particle size deviation was uniformly changed.

Test Example 8: Tablet size measurement test

Preparation of Example 13

The composite formulation of Example 13 was prepared in the same content and sequence as in Example 10. Then, for the comparison of properties, the coating process was performed at a temperature of 40° C. using the Opadry film coating base under the PVA base in an amount corresponding to about 3% of the total mass of the tablet.

Tablet size measurement

The width, length, thickness, and mass of the tablets prepared in Example 13, Janubia tablets and Posiga tablets were measured. 7 shows (a) Januvia 100 mg (100 mg as sitagliptin), (b) Forsiga 10 mg (dapagliflozin propanediol hydrate 12.3 mg), and (c) the tablet prepared in Example 13. It is a picture taken

As shown in Table 23 and FIG. 7, in the case of Example 13, while simultaneously including 100 mg of sitagliptin and 10 mg of dapagliflozin, the size of the tablets is visually or numerically larger than those of the two tablets. not. In addition, in the case of Example 13, the width increased by about 30% compared to the circular tablet of Januvia, but the vertical length decreased by about 30% and had a similar area. It has a small cross-sectional area and is designed to pass through the esophagus. Through this, it can be seen that the size, weight, and cross-sectional area at the time of swallowing the drug were dramatically improved compared to taking two tablets of Januvia Tablet or Posiga Tablet at the same time.

Those skilled in the art will recognize that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are in all respects illustrative only and not restrictive. The scope of the invention is therefore indicated by the appended claims rather than by the foregoing description. All modifications within the meaning and scope equivalent to the claims are to be embraced within the scope of the present invention.

Claims (16)

sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and
A combination preparation comprising dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof,
Combination formulation comprising sodium stearyl fumarate, magnesium stearate, or a combination thereof as a lubricant. The combination formulation according to claim 1, comprising sodium stearyl fumarate as the lubricant. The combination formulation according to claim 1, wherein the sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof is sitagliptin phosphate hydrate. The combination preparation according to claim 1, wherein the dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof is dapagliflozin L-proline. The combination formulation according to claim 1, wherein the sodium stearyl fumarate contains 3 to 8% by weight based on the total weight of the tablet. The method according to claim 1, microcrystalline cellulose (MCC), mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, cross-linked carboxymethyl cellulose sodium (Cross-Linked CMC Na), and mixtures thereof Combination formulation comprising an excipient selected from among. The combination formulation according to claim 1, wherein the combination formulation is in the form of a tablet, capsule, or granule. The method according to claim 1, wherein the combination preparation is sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof; Dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And Combination formulation comprising compressed granules comprising sodium stearyl fumarate. The method according to claim 1, wherein the combination preparation is in the form of a width and length of 5 to 15 mm, respectively, and a thickness of 3 to 8 mm. The combination preparation according to claim 1, wherein sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof is included in an amount of 10 to 40% by weight of the total weight of the combination preparation. The combination preparation according to claim 1, wherein dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof is included in 2 to 10% by weight of the total weight of the combined preparation. The combination formulation according to claim 1, further comprising metformin or a pharmaceutically acceptable salt thereof, or a hydrate thereof. preparing a mixing part comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a lubricant;
granulating the mixing part; and
13. The method of any one of claims 1 to 12, comprising the step of mixing by further adding a lubricant to the granulated material. preparing a first mixing part comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant;
preparing a second mixing part comprising dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant;
granulating the first mixing unit and/or the second mixing unit; and
13. A method for producing a composite formulation according to any one of claims 1 to 12, comprising the step of mixing a lubricant with the obtained granules. The method according to claim 13, wherein the granulating step comprises the step of forming a compact using a roller compactor (Roller compactor). The method according to claim 13, further comprising the step of tableting granules mixed with a lubricant.

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