A mixture according to a formula containing the compounds sitagliptin and dapagliflosin, and the preparation method as described.

Abstract

Provided are a composite formulation comprising sitagliptin and dapagliflozin and a preparation method therefor.

Description

Compound preparation containing sitagliptin and dapagliflozin and method for manufacturing the same

[0001] The present application relates to a combination preparation comprising sitagliptin and dapagliflozin and a method for manufacturing the same, and more specifically, to a combination preparation having excellent productivity, dissolution rate, stability, and compatibility with other compounds and a method for manufacturing the same.

[0002] Patients with type 2 diabetes are generally overweight, have abdominal obesity, and have high blood pressure. As a result, diabetes is known to cause secondary chronic diseases such as high blood pressure, hyperlipidemia, myocardial infarction, and stroke, or metabolic syndrome. According to the treatment guidelines of the Korean Diabetes Association, combination therapy with drugs is actively recommended to increase symptom improvement. In particular, the combination of DPP-4 inhibitors and SGLT-2 inhibitors has recently been proven to have excellent efficacy and effectiveness in the treatment of diabetes in academic circles, and triple therapy with metformin is also being studied.

[0003] Sitagliptin (product name: Januvia) is a dipeptidyl peptidase-4 (DPP-4) inhibitor drug with the chemical name (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dipidro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one. Sitagliptin controls blood sugar by inhibiting the breakdown of gastrointestinal hormones called incretins, thereby enabling the body to properly function as incretins, which regulate insulin and glucagon. When sitagliptin is administered orally to patients with type 2 diabetes, it is known to significantly reduce HbA1c levels and reduce fasting and postprandial blood sugar levels.

[0004] Dapagliflozin (product name: Forsiga) is a sodium-glucose linked transporter 2 (SGLT-2) inhibitor with the chemical name (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 kidney, increases urinary glucose excretion, and thereby improves insulin sensitivity and delays the onset of diabetic complications, thereby normalizing plasma glucose levels. It is marketed by the original developer, AstraZeneca Abe, in tablet form (Forsiga) containing dapagliflozin propylene glycol hydrate as the active ingredient.

[0005] In addition to the primary effect of lowering blood sugar without the risk of hypoglycemia, sitagliptin and dapagliflozin have pancreatic beta-cell protection and GLP-1 increasing effects, while dapagliflozin has weight loss and blood pressure lowering effects. Clinical results have shown that the combination of the two active ingredients has a synergistic effect. In addition, as diabetes progresses, it becomes difficult to control blood sugar levels, which leads to complications. In particular, elderly diabetic patients are more likely to suffer from hypertension, obesity, and hyperlipidemia. Given the characteristics of these diabetic patients, medication adherence is a very important factor, and decreased medication adherence not only lowers the quality of life of patients, but also reduces the cure rate, increases personal medical expenses, and worsens the insurance finances. Therefore, the development of a combination drug containing sitagliptin and dapagliflozin is necessary.

[0006] However, the development of the above-mentioned combination formulation has not yet been attempted due to numerous problems that must be overcome to ensure appropriate productivity, dissolution rate, and stability. In the case of the main ingredient sitagliptin, there is a problem that the amount contained per tablet is large and it is viscous, so there is a problem that the punch sticking easily occurs during the production process. In addition, in the case of the main ingredient dapagliflozin, the density is low, so the volume of the main ingredient is large despite the small amount, which results in poor productivity. In addition, there is a high possibility of layer separation with other main ingredients and excipients, and the main ingredients have a tendency to clump together, so there is a high possibility of forming aggregates, making it difficult to secure the productivity of the formulation.

[0007] Moreover, since the time to peak drug concentration in plasma (Tmax) for each of the two drug components, sitagliptin and dapagliflozin, is approximately 1 hour (sitagliptin 1-4 hr / dapagliflozin 1-2 hr), it is necessary to develop a combination formulation that includes both components and has a high dissolution rate.

[0008] In order to develop a combination formulation that can satisfy all pharmaceutical requirements such as appropriate productivity, dissolution rate, and stability, selecting excipients that satisfy compatibility for both different ingredients is one of the most important and difficult problems in the field of combination formulation development.

[0009] [Prior Art Literature]

[0010] [Patent Document] Korean Patent Publication No. 10-2016-0111237

[0011] One aspect is to provide 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, which has excellent productivity, dissolution rate, stability, and compatibility with other pharmaceuticals.

[0012] Another aspect is to provide a method for manufacturing the above-mentioned complex preparation.

[0013]

[0014] Other purposes and advantages of this application will be further clarified by the detailed description below, along with the appended claims. Anything not described herein is readily apparent and inferable to those of ordinary skill in the technical field of this application or similar technical fields, and therefore, its description is omitted.

[0015] The work aspect is

[0016] Sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof,

[0017] Dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and

[0018] A compound preparation comprising dry granules containing sodium stearyl fumarate as a lubricant,

[0019] The above dry granules provide a composite formulation containing 1 to 5 wt% of sodium stearyl fumarate based on the total weight of the composite formulation.

[0020] Another aspect of the work is

[0021] A step of preparing a mixture comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant;

[0022] A step of dry granulating the above mixed portion; and

[0023] A method for producing a composite preparation according to the above aspect is provided, which includes a step of adding a lubricant to the above granules and mixing them.

[0024] A combination formulation comprising sitagliptin and dapagliflozin according to one aspect can be manufactured as a combination formulation with excellent productivity, dissolution rate, stability, and compatibility, thereby enhancing medication compliance in patients requiring concomitant administration of the two drugs. The manufacturing method according to one aspect can improve the pharmaceutical properties of the combination formulation, such as flowability and tabletability, thereby increasing manufacturing productivity.

[0025] Figure 1 is a photograph of compressed flakes and tablets manufactured with and without magnesium stearate.

[0026] Figure 2 is a photograph of a tablet made by mixing sitagliptin and lactose, and a tablet made by mixing sitagliptin and an excipient other than lactose.

[0027] Figure 3 shows photographs of the properties of tablets after compression in Example 5 and Comparative Example 5, which had different amounts of sodium stearyl fumarate (PRUV®) in the composite formulation, and the results of measuring the time required for discharging the mixed powder during the manufacture of each tablet.

[0028] Figure 4 is a graph showing the results of sitagliptin dissolution tests of Examples 5 to 8 and Comparative Examples 6 and 8.

[0029] Figure 5 is a graph showing the results of the dapagliflozin dissolution test of Examples 5 to 8 and Comparative Examples 6 and 8.

[0030] Figures 6 to 9 are graphs showing the results of dissolution tests of sitagliptin and dapagliflozin of Examples 9 to 14 and Comparative Examples 9 to 14, in which the amounts of sodium stearyl fumarate (PRUV®) and / or L-HPC in the compound preparation were varied.

[0031] Figure 10 shows photographs of the appearance of tablets and the results of measuring the thickness of tablets and calculating the expansion ratio after one week of storage under accelerated exposure conditions (40°C, 75% relative humidity, open dish state) for Examples 9 to 11 and Comparative Examples 9 to 11.

[0032] Figure 11 is a photograph of the flake appearance during the compression process for manufacturing dry granules of Example 9 and Comparative Example 12, in which the presence or absence of sodium stearyl fumarate (PRUV®) was varied.

[0033] Figure 12 is a graph showing the results of measuring the total flexible substance (%) of sitagliptin under the acceleration conditions of Examples 9 to 14 and Comparative Examples 9 to 14.

[0034] Figure 13 is a graph showing the results of measuring the total flexible material (%) of dapagliflozin under the acceleration conditions of Examples 9 to 14 and Comparative Examples 9 to 14.

[0035] Figure 14 is a graph showing the results of measuring the total flexible substances (%) of sitagliptin after 1 and 2 weeks under conditions of moisture saturation (25°C, 90% relative humidity) of Examples 10, 15, and 16 and Comparative Examples 15 to 17, which had different moisture contents among the composite formulations.

[0036] Figure 15 is a graph showing the results of measuring the total flexible substances (%) of dapagliflozin after 1 and 2 weeks under conditions of moisture supersaturation (25°C, 90% relative humidity) of Examples 10, 15, and 16 and Comparative Examples 15 to 17, which had different moisture contents among the composite formulations.

[0037] Hereinafter, the present invention will be described in more detail.

[0038] All technical terms used herein, unless otherwise defined, have the same meaning as commonly understood by one of ordinary skill in the art. In addition, although preferred methods and samples are described in this specification, similar or equivalent ones are also included within the scope of this specification. In addition, numerical values ​​described in this specification are considered to include the meaning of "about" even if not explicitly stated. The contents of all publications cited as references in this specification are incorporated herein by reference in their entirety. As used herein, the term "about" means that the value being referred to can vary to some extent. For example, "about 5" means 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,” “includes,” or “may include” indicate the presence of a feature (e.g., a numerical value, or a component such as an ingredient), but do not exclude the presence of additional features.

[0039]

[0040] One aspect is sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof,

[0041] Dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and

[0042] A compound preparation comprising dry granules containing sodium stearyl fumarate as a lubricant,

[0043] The above dry granules provide a composite formulation containing 1 to 5 wt% of sodium stearyl fumarate based on the total weight of the composite formulation.

[0044] In one specific example, the composite formulation further includes sodium stearyl fumarate as a lubricant on the outside of the dry granules, and the total amount of sodium stearyl fumarate present in the composite formulation may be 3 to 8 wt% based on the total weight of the formulation.

[0045] The main ingredient, sitagliptin or dapagliflozin, includes all of their crystal forms, hydrates, co-crystals, solvates, salts, diastereomers, or enantiomers.

[0046] The above pharmaceutically acceptable salt thereof refers to any pharmaceutically acceptable salt that can be commonly used in the art.

[0047] In one specific example, the sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, may be sitagliptin phosphate hydrate.

[0048] In one specific embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, may be a pharmaceutically acceptable cocrystal of dapagliflozin. In one specific embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof may be dapagliflozin L-proline or dapagliflozin propanediol.

[0049] In one specific example, the sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, may be included in an amount of 10 to 40 wt%, for example, 25 to 35 wt%, of the total weight of the combination preparation.

[0050] In one specific example, the dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, may be included in an amount of 2 to 10 wt%, for example, 2 to 6 wt%, of the total weight of the combination preparation.

[0051] As a result of the experiment, it was confirmed that magnesium stearate, which is generally the most common lubricant, increases the productivity and tabletability of the composite preparation of the present application, but is very disadvantageous because it increases the amount of flexible substances of the main ingredient over time (Test Examples 1 and 3). In contrast, sodium stearyl fumarate not only increases the productivity and tabletability, but also forms a stable composite preparation that can satisfy the standard of flexible substances (Test Example 3). The sodium stearyl fumarate may be included in the dry granules at 1 to 5 wt% based on the total weight of the composite preparation. If the content is below the above range, there is a concern that sufficient productivity may not be secured, and if it exceeds the above content, there may be a concern that the dissolution rate and stability of the main ingredient may be lowered (see Test Examples 4, 5, 6, 7, and 8). Optionally, sodium stearyl fumarate may be additionally included outside the dry granules, and the total amount of sodium stearyl fumarate present in the composite formulation including the same may be 3 to 8 wt% based on the total weight of the formulation. If this amount is less than the amount, there is a concern that sufficient productivity may not be secured, and if it exceeds the amount, there may be a concern that the dissolution rate of the main ingredient may decrease and the stability may decrease (see Test Examples 4 and 8).

[0052] The above-mentioned combination preparation may include one or more excipients selected from a diluent, a disintegrant, a binder, a lubricant, and a release-controlling agent.

[0053] The diluent may be selected from the group consisting of, but not limited to, D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose (MCC), sucrose, sorbitol, xylitol, glucose, and any mixture thereof.

[0054] 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 mixture thereof.

[0055] The disintegrant may be selected from the group consisting of, but is not limited to, crospovidone, cross-linked carboxymethylcellulose sodium (Cross-linked CMC Na, C.CMC Na, or croscarmellose sodium), corn starch, carboxymethylcellulose calcium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), and any mixture thereof. In one specific example, the disintegrant is low-substituted hydroxypropyl cellulose (L-HPC).

[0056] The binder may be selected from the group consisting of, but not limited to, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, and any mixture thereof. In one specific embodiment, the binder is hydroxypropylcellulose.

[0057] The release-controlling agent may be selected from the group consisting of, but not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxyvinyl polymer, polyvinyl alcohol, xanthan gum, guar gum, carboxymethyl cellulose and derivatives thereof, methylcellulose and derivatives thereof, and povidone-polyvinylacetate copolymers, and any mixtures thereof. In one specific example, the release-controlling agent is hydroxypropyl cellulose.

[0058] In one embodiment, the combination formulation may include excipients selected from microcrystalline cellulose (MCC), mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, cross-linked carboxymethylcellulose sodium (Cross-Linked CMC Na), hydroxypropyl cellulose (HPC), and any mixture thereof.

[0059] In one specific example, the dry granules may contain low-substituted hydroxypropyl cellulose (L-HPC) as a disintegrant in an amount of 5 to 20 wt% based on the total weight of the composite formulation. If the L-HPC content is less than the above range, the disintegration rate becomes slow, which causes a problem in that the initial dissolution rate becomes low. On the other hand, if the L-HPC content exceeds the above range, the swelling rate of the tablet rapidly increases due to moisture absorption during storage, which significantly reduces the stability of the properties (see Test Example 7) and causes a problem in that the content of the main ingredient's flexible substances significantly increases (see Test Example 8).

[0060] In one specific example, the dry granules may contain moisture in an amount of 5 wt% or less relative to the total weight of the composite formulation. When the moisture content exceeds the above range, it has been confirmed that the elastomeric content of the two moisture-sensitive main ingredients significantly increases (see Test Example 9). Therefore, when selecting raw materials for batch / grade variations of excipients, selecting raw materials with low moisture content can prevent the increase in elastomeric content of the main ingredient, thereby producing a stable composite formulation.

[0061] The above combination preparation may be in the form of a tablet, capsule, or granule. In one specific example, the combination preparation may be a mixed tablet or a bilayer tablet.

[0062] The above-mentioned compound preparation may additionally contain a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient may be a component selected from the group consisting of an antioxidant, a sweetener, a preservative, a coating agent, a viscosity modifier, and any mixture thereof.

[0063] The tablets may additionally be coated with a pharmaceutically acceptable rapid-release film coating agent commonly used in the art, using a conventional method. In one specific example, the tablets may be coated with a moisture-proof film using an Opadry II coating solution at a concentration of about 3% based on the total weight of the tablet.

[0064] The above-mentioned composite formulation may have a horizontal and vertical length of about 5 to 15 mm, respectively. The thickness of the above-mentioned composite formulation may be about 3 to 8 mm. According to one specific example, the composite formulation may have a horizontal and vertical length of about 5 to 15 mm, and a thickness of about 3 to 8 mm. According to one specific example, the composite formulation may have a horizontal length of about 10 to 15 mm, a vertical length of about 5 to 10 mm, and a thickness of about 3 to 8 mm. The horizontal length of the above-mentioned composite formulation may be, for example, about 10, 11, 12, 13, 14, or 15 mm. The vertical length of the above-mentioned vertical composite formulation may be, for example, about 5, 6, 7, 8, 9, or 10 mm. The thickness of the above-mentioned composite formulation may be, for example, about 3, 4, 5, 6, 7, or 8 mm.

[0065] The above combination formulation may be an oblong oval tablet. The combination formulation may be easier to swallow than two tablets each containing two active ingredients. Generally, when a drug is administered and passes through the narrow part of the human throat, the tablet maintains the smallest cross-sectional area and passes through the throat. At this time, in order to maintain the small cross-sectional area of ​​the tablet, swallowing occurs by maintaining two variables with smaller values ​​among the width, length, and thickness of the tablet. According to one specific example, the combination formulation containing two active ingredients of sitagliptin and dapagliflozin can reduce the size, weight, and cross-sectional area of ​​the drug when swallowed compared to taking two single tablets of each active ingredient simultaneously, and can increase the convenience of swallowing for patients who feel discomfort when swallowing large tablets.

[0066] The combination formulation may further include one or more antidiabetic agents. For example, the combination formulation may further include metformin or a pharmaceutically acceptable salt thereof. In one specific example, the combination formulation may be a triple combination formulation comprising sitagliptin, dapagliflozin, and metformin.

[0067] Another aspect provides a method for preparing the above complex formulation.

[0068] The above manufacturing method according to one specific example is

[0069] A step of preparing a mixture comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a lubricant;

[0070] A step of dry granulating the above mixed portion; and

[0071] A step of adding a lubricant to the above granules and mixing them may be included.

[0072] The above dry granulation step may be performed using a dry granulation method commonly used in the pharmaceutical field. In one specific example, the dry granulation method may include a step of forming compressed flakes using a roller compactor.

[0073] In one specific example, the manufacturing method may further include a step of compressing a granule mixed with a lubricant.

[0074]

[0075] 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.

[0076] Test method

[0077] In the following test examples, the conditions for analysis of flexible substances, analysis of dissolved substances, and analysis of content were performed in the following manner.

[0078]

[0079]

[0080] According to FDA_Clinical Pharmacology Biopharmaceutics Review, the time to peak drug concentration in plasma (Tmax) of sitagliptin and dapagliflozin is approximately 1 to 4 h and approximately 0.5 to 1.5 h, respectively, and the bioavailability is 78% and 87%, respectively. Accordingly, a pH 1.2 dissolution test solution was selected as the IVIVC (in vitro-in vivo correlation) dissolution test solution for each main ingredient, and the dissolution sampling intervals were set to 5, 10, 15, 30, and 45 minutes, after which the final saturation dissolution rate was measured.

[0081]

[0082]

[0083] Test Example 1: Flexible Material Test According to Lubricant

[0084] The stability of a compound formulation using magnesium stearate, a commonly used lubricant, was tested. Tablets were manufactured according to the following [Sample Preparation Method], using the formulations shown in Table 1 below. Then, the flexible substances were measured for each sample (Tables 1-3), and the properties of the compressed flakes and tablets were compared according to the presence or absence of magnesium stearate (Figure 1). Figure 1 shows photographs of compressed flakes and tablets, taken with or without magnesium stearate.

[0085]

[0086] [Sample Manufacturing Method]

[0087] (1) Weighing: 1000T of each ingredient was weighed.

[0088] (2) Sieve: All ingredients except the lubricant added to the final mixture were passed through a 30 mesh sieve.

[0089] (3) Mixing: The powder passing through the sieve was mixed using a Bin Mixer at 17 rpm for 30 min.

[0090] (4) Compacting: Using a roller compactor, compressed flakes were formed using a roll rpm of 3.0 / screw rpm of 35.0 rpm and hydraulic pressure of 2.5 Mpa.

[0091] (5) Formation: The flakes manufactured in step (4) were formed into 20 mesh using an oscillator.

[0092] (6) Final mixing: The result manufactured in step (5) above and the remaining final mixing agent were added and mixed at 17 rpm for 5 minutes using a bin mixer.

[0093] (7) Tableting: Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a round punch with a diameter of 8.0 mm was used to tablet with a hardness of 10 to 12 kp.

[0094]

[0095]

[0096]

[0097] According to the above experimental results, when magnesium stearate was used as a lubricant in mixed granules containing sitagliptin and dapagliflozin, the amount of volatile substances significantly increased under accelerated storage conditions. Furthermore, when magnesium stearate was excluded, productivity decreased due to adhesion issues with punches and production equipment during the granulation process and product compression. Therefore, while a lubricant is necessary for productivity and tableting, magnesium stearate was confirmed to be unsuitable because it lowers the stability of the main ingredient.

[0098]

[0099] Test Example 2: Flexible substance test according to excipient

[0100] Manufacturing Example 1

[0101] To evaluate the stability of the two main ingredients, sitagliptin and dapagliflozin, when coexisting, tablets containing 128.5 mg of sitagliptin phosphate hydrate (100 mg as sitagliptin) and 12.3 mg of dapagliflozin propanediol (10 mg as dapagliflozin) were manufactured by compression. Using an AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan) tablet press, flakes were formed, and the stability was confirmed by measuring the amount of reactive substances generated under accelerated conditions (40°C / 75% RH) for 1 month and 2 months.

[0102]

[0103] Manufacturing Example 2

[0104] To determine the compatibility of the active ingredient, sitagliptin, with excipients, different types of excipients were mixed with sitagliptin. The excipients and the active ingredient, sitagliptin, were passed through a 20-mesh sieve and mixed for 30 minutes each using a tubular mixer. Afterwards, the other active ingredient, dapagliflozin, was added, mixed, and compressed to manufacture tablets. Flake was formed using an AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan) tableting machine, and the stability was confirmed by measuring the amount of flexible substances generated under accelerated conditions (40°C / 75% RH) for 1 month and 2 months.

[0105]

[0106] Manufacturing Example 3

[0107] To determine the compatibility of the active ingredient dapagliflozin with excipients, different types of excipients were mixed with dapagliflozin. The above excipients and the active ingredient dapagliflozin were passed through a 20 mesh sieve and mixed for 30 minutes each using a tubular mixer. Afterwards, the other active ingredient, sitagliptin, was added, mixed, and compressed to manufacture tablets. Flake was formed using an AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan) tableting machine, and the stability was confirmed by measuring the amount of flexible substances generated under accelerated conditions (40℃ / 75% RH) for 1 month and 2 months.

[0108]

[0109] Total flexible material content standard

[0110] The total flexible substance content standard for commercial use is less than 0.2% of total flexible substances for sitagliptin and less than 2.0% of total flexible substances for dapagliflozin, according to the domestically approved flexible substance standard.

[0111]

[0112] The results of the flexible substance test measured using the tablets manufactured in Manufacturing 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 flexible substance content exceeded 0.2%, respectively, and did not meet the standard.

[0113] In particular, when sitagliptin and lactose hydrate were mixed, it was confirmed that browning occurred due to the Maillard reaction, which produces a brown substance at high temperatures, when observing the properties after 2 months of acceleration, making it unsuitable for prescription (Fig. 2). Fig. 2 is a photograph of a tablet compressed by mixing sitagliptin and lactose hydrate, and a tablet compressed by mixing sitagliptin with an excipient other than lactose.

[0114]

[0115] The results of the flexible substance test measured using the tablets manufactured in Manufacturing Examples 1 and 3 are shown in Table 5 above. As shown in Table 5 above, in the case of dapagliflozin, when dicalcium phosphate anhydrous (DCP anhydrous) was included as an excipient, the total flexible substance content exceeded 2.0%, which did not meet the standard. In addition, when dicalcium phosphate hydrate (DCP hydrate) was included as an excipient, the total flexible substance content standard was met, but the amount of flexible substances generated was higher than that of other excipients.

[0116]

[0117] Test Example 3: Flexible Material Test According to Lubricant and Excipient

[0118] Based on the stability comparison results for each formulation in Test Examples 1 and 2, it was confirmed that the selection of lubricants and excipients suitable for production and with guaranteed stability was necessary. Therefore, stability tests were conducted on various types of lubricants and excipients. After completing tablet production, stability evaluations were conducted under accelerated and harsh conditions.

[0119] According to the prescription in Table 6 below, tablets were manufactured according to the following [Sample Manufacturing Method].

[0120] [Sample Manufacturing Method]

[0121] (1) Weighing: 1000T of each ingredient was weighed.

[0122] (2) Sieve: All excipients except the lubricant added to the final mixture were passed through a 30 mesh sieve.

[0123] (3) Mixing: The powder passing through the sieve was mixed using a Bin Mixer at 17 rpm for 30 min.

[0124] (4) Compression: Using a roller compactor, compressed flakes were formed using a roll rpm of 3.0 / screw rpm of 35.0 rpm and hydraulic pressure of 2.5 Mpa.

[0125] (5) Establishment: The flakes manufactured in step (4) were established to 20 mesh using an oscillator.

[0126] (6) Final mixing: The result manufactured in step (5) above and the remaining final mixing agent were added and mixed using a Bin mixer at 17 rpm for 5 minutes.

[0127] (7) Tableting: Using AutoTab-200TR (Ichihachi Seiki Co., Ltd, Japan), a rectangular punch measuring 12.8 mm in width and 7.0 mm in length was used to tablet with a hardness of 12 to 14 kp.

[0128]

[0129] The results of evaluating the total organic compounds of sitagliptin when stored under accelerated conditions (40°C, 75% relative humidity) are shown in Table 7 below.

[0130]

[0131] The results of evaluating the total flexible substances of cidapagliflozin stored under accelerated conditions (40 ℃, 75% relative humidity) are shown in Table 8 below.

[0132]

[0133] The results of evaluating the total flexible substances of sitagliptin when stored under harsh conditions (60 ℃) are shown in Table 9 below.

[0134]

[0135] The results of evaluating the total organic compounds of dapagliflozin when stored under harsh conditions (60 ℃) are shown in Table 10 below.

[0136]

[0137] According to the results in Tables 7-10 above, when sodium stearyl fumarate (PRUV®) was used as a lubricant (Examples 1-3), it was confirmed to be an appropriate lubricant that does not impair stability, as it satisfied the criteria for flexible substances. In contrast, according to Comparative Examples 1-4, it was confirmed that other lubricants, such as glyceryl monostearate, magnesium stearate, calcium stearate, and sucrose stearate, all did not meet the criteria for accelerated and harsh conditions.

[0138] In addition, when microcrystalline cellulose, D-mannitol, and / or low-substituted hydroxypropyl cellulose were used as excipients together with sodium stearyl fumarate (PRUV®), the stability of the flexible material was secured (Examples 1 to 3). However, when dicalcium phosphate anhydrous was used as an excipient together with sodium stearyl fumarate (PRUV®) (Example 4), the dapagliflozin flexible material standards under accelerated and harsh conditions were not satisfied.

[0139]

[0140] Test Example 4: Productivity Evaluation According to the Amount of Lubricant

[0141] In the above Test Example 3, the stability of sodium stearyl fumarate (PRUV®), microcrystalline cellulose, D-mannitol, and low-substituted hydroxypropyl cellulose was confirmed, and the productivity according to the amount of lubricant was evaluated. In addition, after sample preparation was completed, the stability was evaluated under accelerated and harsh conditions, and the sample preparation was performed in the same manner as in the above Test Example 3.

[0142]

[0143] The appearance of the tablets after tableting in Example 5 and Comparative Example 5 was photographed, and the time required for granule discharge during tableting of each tablet was measured, and the results are shown in Fig. 3. The “time required for granule discharge during tableting” refers to the time required for all granules filled in the feeder during tableting to be compressed into tablets and for all granules in the feeder to be exhausted. In this test, the evaluation was made based on the case where the amount of granules filled in the feeder was 420 g.

[0144]

[0145] Test Example 5: Stability Evaluation According to the Amount of Lubricant

[0146] For the samples manufactured according to Table 11 above, the total flexible substances of the tablets of sitagliptin were evaluated according to the amount of the active agent when stored under accelerated conditions (40°C, 75% relative humidity), and the results are shown in Table 12 below.

[0147]

[0148] The results of evaluating the total flexible substances of dapagliflozin in tablets according to the amount of the active agent when stored under accelerated conditions (40°C, 75% relative humidity) are shown in Table 13 below.

[0149]

[0150] The results of evaluating the total flexible substances of the purified sitagliptin according to the amount of the active agent when stored under harsh conditions (60 ℃) are shown in Table 14 below.

[0151]

[0152] The results of evaluating the total flexible substances of dapagliflozin in tablets according to the amount of active agent when stored under harsh conditions (60 ℃) are shown in Table 15 below.

[0153]

[0154] Test Example 6: Evaluation of dissolution rate according to the amount of lubricant

[0155] For the samples manufactured according to Table 11 above, the dissolution rate was evaluated, and the results are shown in Figures 4 and 5.

[0156] Figure 4 is a graph showing the results of sitagliptin dissolution tests of Examples 5 to 8 and Comparative Examples 6 and 8.

[0157] Figure 5 is a graph showing the results of the dapagliflozin dissolution test of Examples 5 to 8 and Comparative Examples 6 and 8.

[0158] In addition, the contents of the main components of Examples 5 to 8 and Comparative Examples 6 and 8 were evaluated. The results are shown in Tables 16 and 17 below.

[0159]

[0160]

[0161] According to the test results of the above Test Example 4, when the sodium stearyl fumarate was less than 3% of the total tablet weight (Comparative Examples 5 and 7), the amount of lubricant was insufficient, resulting in tableting problems. In addition, it was confirmed that productivity was reduced because the time required for granule discharge during tableting was delayed during the tableting process. In contrast, when the sodium stearyl fumarate was 3% or more of the total tablet weight (Examples 5 to 8 and Comparative Examples 6 and 8), tablets were compressed without tableting problems. According to Fig. 3, in the case of Example 5 in which the sodium stearyl fumarate was 3% or more of the total tablet weight, it was confirmed that tablets were manufactured smoothly without tableting problems and the mixed powder discharge time was also significantly reduced compared to the case of Comparative Example 5 in which the sodium stearyl fumarate was less than 3 wt%.

[0162] According to the test results of the above Test Example 5, Comparative Examples 5 to 8 and Examples 5 to 8 secured the stability of flexible substances suitable for the standard under accelerated and harsh conditions, but Comparative Examples 6 and 8, which had a relatively high ratio of lubricant, showed a tendency for both sitagliptin and dapagliflozin to increase close to the standard for flexible substances under harsh conditions.

[0163] According to the test results of the above Test Example 6, it was confirmed that when sodium stearyl fumarate is present in excess of 8% of the total weight of the tablet, the dissolution rate of the main ingredient decreases. Specifically, Comparative Examples 6 and 8 showed a decrease in the dissolution rate when comparing the dissolution profiles with Examples 6 and 8 (see Figures 4 and 5). In addition, according to the content evaluation results of Test Example 8, it was confirmed that there was no decrease in the content of the main ingredient in each tablet (see Tables 16 and 17). In summary, it was determined that the decrease in the dissolution rate occurred due to excessive lubrication of the granules.

[0164]

[0165] Test Example 7: Evaluation of dissolution rate, productivity, and stability according to the amount of lubricant and excipients.

[0166] Tablets containing sitagliptin and dapagliflozin as main ingredients were manufactured according to the compositions described in Tables 18 and 19 below.

[0167] Specifically, sitagliptin hydrochloride monohydrate, dapagliflozin propanediol, microcrystalline cellulose, D-mannitol, low-substituted hydroxypropyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, and sodium stearyl fumarate were sieved through a No. 20 sieve to crush large lumps and mixed well. The mixture was formed into flakes using a roller compactor (TF-1-A60, Freund vector), and then sieved through a No. 20 sieve to prepare dry granules. The prepared dry granules were further mixed with sodium stearyl fumarate as a lubricant for 5 minutes to prepare a final mixed portion. The prepared final mixed portion was compressed into tablets of an appropriate hardness using a tablet press (Autotab-200TR, Ichihashi Seiki) to prepare semi-finished products in the form of uncoated tablets.

[0168]

[0169]

[0170] The dissolution rates of sitagliptin and dapagliflozin of Examples 9 to 14 and Comparative Examples 9 to 14 were measured, and the results are shown in Figures 6 to 9.

[0171] In addition, for Examples 9 to 11 and Comparative Examples 9 to 11, the tablets were observed for their appearance, their thicknesses were measured, and their expansion ratios were calculated after one week of storage under accelerated exposure conditions (40°C, 75% relative humidity, open dish). The results are shown in Fig. 10.

[0172] In addition, the flake properties were compared during the compression process for manufacturing the dry granules of Example 9, which are granules containing sodium stearyl fumarate in the granules, and Comparative Example 12, which do not contain it, and the photographs of the flake properties are shown in Figure 11.

[0173]

[0174] [Comparison of dissolution patterns and stability according to the amount of L-HPC]

[0175] As shown in Figures 6-7, when comparing the dissolution patterns of Examples 9-11 and Comparative Examples 9-11, it was confirmed that each main ingredient in Examples 9-11 was similar to the control drug. This is because L-HPC usually functions as both a diluent and a disintegrant, which leads to an increase in the initial dissolution rate due to an increase in the initial disintegration power, and thus shows a dissolution pattern similar to that of the control drug. In the case of Comparative Examples 9 and 10, where the amount of L-HPC was relatively small, it was confirmed that the initial dissolution rate was low. Additionally, this causes a large dissolution rate deviation due to the increase in the amount of microcrystalline cellulose, which is a water-insoluble excipient with a relatively slow disintegration rate, and this may cause problems in uniform drug administration to patients. On the other hand, in the case of Comparative Example 11, where the amount of L-HPC was relatively large, the initial dissolution rate was fast and a similar pattern to the control drug was shown, but it was confirmed that excessive use of a disintegrant may cause problems in the appearance and accelerated stability in the future. As shown in Fig. 10, in the case of Comparative Example 11 in which 30 wt% of L-HPC was used, the swelling ratio rapidly increased due to moisture absorption, and it was confirmed that this could cause a problem in the stability of the tablet because the tablet's properties changed significantly.

[0176] In conclusion, the amount of L-HPC to secure initial disintegration power through dissolution evaluation was effective in the range of 5 wt% or more based on the total weight of the tablet, but it was confirmed that there was a problem with the stability of the properties when it was contained in an excessive amount.

[0177]

[0178] [Comparison of dissolution patterns and productivity according to PRUV amount]

[0179] As shown in FIGS. 8 and 9, when comparing the dissolution patterns of Examples 10, 12 to 14 and Comparative Examples 12 to 14, in the case of Examples 10, 12 to 14, each main ingredient showed a dissolution pattern similar to the control drug. As shown in Table 20, in the case of Comparative Example 12 in which no PRUV lubricant was added to the granules, the dissolution pattern was good, but a pressing phenomenon (FIG. 11) occurred in which the granules were stuck to the rollers during the dry granulation process, which caused equipment trouble during the process, lowered the granule yield, and lowered productivity. This means that productivity can be improved by adding a lubricant during the granulation process. In the case of Comparative Examples 13 to 14, they correspond to a prescription with a relatively large amount of PRUV (content in the granules exceeding 5 wt%), and this excessive lubricating caused a phenomenon in which dissolution was delayed. In particular, surprisingly, Comparative Examples 13 and 14 showed a significantly reduced drug dissolution rate compared to Example 14, and exhibited a relatively low dissolution rate even at the dissolution point (Max) where the drug was saturated. This may pose a problem in uniform drug administration to patients, and the drug effect onset time appears to be relatively slow. Therefore, the amount of PRUV in the dry granulation process can be considered effective in the range of 1 to 5 wt%.

[0180]

[0181] Test Example 8: Evaluation of flexible substances according to the amount of lubricant and excipients

[0182] To confirm the stability of the formulation selected according to Test Example 7, an accelerated test was conducted and the flexible substances were evaluated. The formulation was packaged in an HDPE bottle containing silica gel and managed in an acceleration chamber.

[0183] The total flexible substances (%) of sitagliptin and dapagliflozin of Examples 9 to 14 and Comparative Examples 9 to 14 were measured, and the results are shown in Figures 12 and 13.

[0184]

[0185] [Comparison of total flexible materials under accelerated conditions]

[0186] As shown in Figures 12 and 13, when comparing the total flexible substances (%) of the accelerated stability of Examples 9 to 14 and Comparative Examples 9 to 14, in the case of Examples 9 to 11, the total amount of flexible substances of each main ingredient was less than that of the control drug, and accelerated stability can also be secured in the future. In the case of Examples 12 to 14, the total amount of flexible substances was greater than that of the control drug, but it was within the standard and appropriate. In the case of Comparative Example 11 (containing 30 wt% of L-HPC), even if the amount of flexible substances after 3 months of acceleration was within the standard, it increased significantly, which may cause stability problems when the product is approved according to the 'Standards for Stability Tests for Pharmaceuticals, etc.' since the accelerated stability after 6 months in the future is also low, and since the amount of flexible substances is significantly and significantly increased compared to other prescriptions, it is judged to be an unsuitable pharmaceutical prescription. This is interpreted as indicating moisture instability due to hygroscopicity caused by the excessive use of L-HPC. Therefore, according to the data of Test Examples 7 and 8, it is confirmed that it is desirable to set L-HPC to 5 to 20 wt% of the total weight of the tablet.

[0187] In addition, it was confirmed that excessive use of PRUV also affects the production of flexible substances. Looking at Example 10, Examples 12 to 14, and Comparative Examples 12 to 14, where the amount of L-HPC in the formulation was constant, in the case of Examples 10, Examples 12 to 14, and Comparative Example 12, the total PRUV content was within 3 to 7 wt% based on the total weight of the tablet, and the PRUV content in the granules was 1 to 5 wt%, and stability was ensured. However, in the case of Comparative Examples 13 and 14, the PRUV exceeded 5 wt% in the granules based on the total weight, and the total PRUV content was 7.5 and 10 wt%, respectively, and the production of flexible substances increased significantly, resulting in significantly lowered storage stability. This shows that when the total PRUV is 1 to 7 wt% based on the total weight of the complex formulation, and the PRUV content in the granules is 1 to 5 wt%, it is suitable for pharmaceutical formulation compounding and at the same time, improved storage stability can be secured.

[0188]

[0189] Test Example 9: Stability Test According to Initial Moisture Content

[0190] Due to the moisture instability of the main ingredient, tablets were manufactured with only different moisture contents based on Example 10 selected according to Test Examples 7 and 8, and the stability according to moisture contents was evaluated.

[0191] Although the compatibility of the formulation and the main ingredient was confirmed, a diluent (microcrystalline cellulose) and a disintegrant (croscarmellose sodium) with a relatively wide moisture standard range of the raw material were selected, and among them, the moisture content was confirmed and the stability pattern was confirmed with a combined prescription according to the moisture content by batch / grade (By batch: selected according to the moisture test results in the manufacturer's performance report through investigation of each batch within the same grade, By grade: selected according to the moisture test results in the manufacturer's performance report through investigation of the manufacturer's grade of microcrystalline cellulose / croscarmellose sodium.)

[0192] Examples 10, 15, and 16, and Comparative Examples 15 to 17 were prepared by combining excipients by batch / grade, and the total moisture content (including surface water and crystal water) per formulation was measured. The moisture content was measured using the direct titration method using methanol for moisture measurement, among the volumetric titration methods (Karl Fischer method) of the general test methods of the Korean Pharmacopoeia. The results are shown in Table 21 below.

[0193] In addition, Examples 10, 15, 16 and Comparative Examples 15 to 17 were stored for 1 and 2 weeks under conditions of moisture saturation (25°C, relative humidity 90%), and then the total flexible substances (%) of sitagliptin and dapagliflozin were measured, and the results are shown in Figures 14 and 15.

[0194]

[0195] As a result of moisture content measurement, for Examples 10, 15, and 16, the total moisture content per formulation was within approximately 5%, and for Comparative Examples 15 to 17, the initial formulation contained moisture of 5% or more. This is because the initial total moisture content was also high as a result of combining batches / grades with high moisture content of diluent and disintegrant raw materials.

[0196] When stored for 1 and 2 weeks under moisture supersaturation conditions (25℃, 90% relative humidity), the amount of flexible substances tended to increase significantly depending on the initial moisture content, and in the case of Comparative Examples 15 to 17, results exceeding the standard were shown. This means that a more stable formulation can be designed by controlling the initial moisture content. If raw materials are selected by batch / grade so that the initial moisture content is within 5% when designing the formulation, a formulation with improved stability can be manufactured for two moisture-sensitive main ingredients.

[0197]

[0198] Those skilled in the art will recognize that the present invention can be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are intended in all respects to be illustrative and not restrictive. Therefore, the scope of the present invention is defined by the appended claims rather than the foregoing description. All changes that come within the meaning and range of equivalency of the claims are intended to be embraced within the scope of the present invention.

Claims

DEPCT6605 / 04 / 25661. Formulated mixture consisting of: dry granules containing sitagliptin or pharmaceutically acceptable salts of these, or hydrates of these; dapagliflozin or pharmaceutically acceptable salts of these, or hydrates of these; and sodium stearyl fumarate as a lubricant, in which the dry granules contain 1% by weight to 5% by weight of sodium stearyl fumarate, depending on the total weight of the formulated mixture.

2. Mixture 3. The compound formulation of claim 1, which includes the addition of sodium stearyl fumarate as a lubricant on the outside of the dry granules, where the total amount of sodium stearyl fumarate present in the compound formulation is 3% by weight to 8% by weight, depending on the total weight of the compound formulation.

4. The compound formulation of claim 1, in which citagliptin or its pharmaceutically acceptable salts, or its hydrate, is citagliptin phosphate hydrate.A compound formulation of claim I, in which dapagliflosin or pharmaceutically acceptable salts of these, or hydrates of these, is dapagliflosin L-proline or dapagliflosin propanediol5. A compound formulation of claim I, in which a selected filler is added from microcrystalline cellulose (MCC), mannitol, pregelatinized starch, low molecular weight hydroxypropyl cellulose substituted (L-HPC), crospovidone, carboxymethylcellulose sodium substituted 6. A compound formulation of claim 1, in which the dry granules contain 5% by weight to 20% by weight of low molecular weight substituted hydroxypropyl cellulose (L-HPC) as the dissociating agent, depending on the total weight of the compound formulation.

7. A compound formulation of claim 1, in which the dry granules contain water in an amount of 5% by weight or less, depending on the total weight of the compound formulation. 8.

9. A formulation of the compounds prescribed under claim 1, in which the compounds are in the form of tablets, capsules, or granules.

10. A formulation of the compounds prescribed under claim 1, in which citagliptin or pharmaceutically acceptable salts of these, or hydrates of these, are included in an amount of 10% by weight to 40% by weight, depending on the total weight of the compounds.

11. A formulation of the compounds prescribed under claim 1, in which dapagliflozin or pharmaceutically acceptable salts of these, or hydrates of these, are included in an amount of 2% by weight to 10% by weight, depending on the total weight of the compounds.

12. A formulation of the compounds prescribed under claim 1, which is further incorporated with metformin or pharmaceutically acceptable salts of these, or hydrates of these.Methods of preparing compound formulations according to any of the claims 1 through 12, which include: preparation of the compounds containing citagliptin or pharmaceutically acceptable salts of these, or hydrates of these, and dapagliflozin or pharmaceutically acceptable salts of these, or hydrates of these, a pharmaceutical filler, and a lubricant; drying of the compounds; and addition of a lubricant to the granulated material and mixing.

13. Method of claim 12, in which drying of the compounds includes compaction by the use of a roller press.

14. Method of claim 12, in which additionally includes the compaction of the granulated material into round tablets with a lubricant.

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