Combined preparation containing sitagliptin and dapagliflozin, and method for producing same

Abstract

Provided are a combination formulation containing sitagliptin and dapagliflozin, and a method for producing the same.

Description

Technical Field

[0001] The present invention relates to a combined preparation containing sitagliptin and dapagliflozin, and a method for producing the same, and more specifically, to a combined preparation excellent in productivity, dissolution rate, stability, and formulation compatibility, and a method for producing the same.

Background Art

[0002] Type 2 diabetic patients generally have overweight, abdominal obesity, and hypertension, and thus diabetes is known as a disease that causes secondary chronic diseases such as hypertension, hyperlipidemia, myocardial infarction, and stroke, or metabolic syndrome. According to the treatment guidelines of the Korean Diabetes Association, drug combination therapy is actively recommended to increase symptom improvement. In particular, the combined use of DPP-4 inhibitor drugs and SGLT-2 inhibitor drugs has recently been proven to have excellent efficacy and effects in the treatment of diabetes in the academic community, and is a field that has been studied up to triple therapy with metformin.

[0003] Sitagliptin (product name: Januvia tablets) is a dipeptidyl peptidase-4 (DPP-4) inhibitor drug, and its chemical name is (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one. Sitagliptin suppresses the degradation of the gastrointestinal hormone incretin, and by improving the function of incretin that regulates insulin and glucagon in the body, it regulates blood glucose. When sitagliptin is orally administered to type 2 diabetic patients, the HbA1c level is significantly reduced, and the fasting blood glucose level and the postprandial blood glucose level are reduced.

[0004] Dapagliflozin (product name: Forxiga tablets) is a sodium-glucose linked transporter 2 (SGLT-2) inhibitor drug, and its chemical 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, enhances the excretion of glucose in urine, thereby improving insulin sensitivity and delaying the onset of diabetic complications, and can normalize plasma glucose levels. AstraZeneca AB, the original developer, is currently marketing tablets (Forxiga tablets) containing dapagliflozin propylene glycol hydrate as the active ingredient.

[0005] Sitagliptin and dapagliflozin, in addition to their main effect of lowering blood glucose without the risk of hypoglycemia, have, in the case of sitagliptin, a pancreatic beta cell protective effect and a GLP-1 increasing effect, and in the case of dapagliflozin, a weight loss effect and a blood pressure lowering effect. The combination of the two active ingredients has been introduced with clinical results showing a synergistic effect. Also, in the case of diabetic patients, the more advanced the glycosuria, the more difficult it is to regulate blood glucose, and complications will occur. In particular, in the case of elderly diabetic patients, there is a high possibility of suffering from hypertension, obesity, and hyperlipidemia at the same time. Due to the characteristics of such diabetic patients, medication compliance is a very important factor. A decrease in medication compliance not only reduces the quality of life of the patients but also decreases the treatment rate of the patients, leading to an increase in individual medical expenses and a deterioration of the insurance finance. Therefore, the development of a combined preparation containing sitagliptin and dapagliflozin is necessary.

[0006] By the way, the development of the said combined preparation has not yet been attempted due to a mountain of problems that must be overcome in order to ensure appropriate productivity, dissolution rate, stability, etc. In the case of the sitagliptin main component, since the amount contained per tablet is large and it has viscosity, there is a problem that sticking occurs easily in the production process. Also, in the case of the dapagliflozin main component, the density is low, and despite the small amount, the volume of the main component is large, the productivity is not good, there is a high possibility of layer separation from other main components and excipients, and the main components have the property of clumping together and a high possibility of aggregate formation, so there is a problem that it is difficult to ensure formulation productivity.

[0007] Furthermore, for each of the two drug components, sitagliptin and dapagliflozin, the time (T max ) at which the drug reaches the highest concentration in plasma is about 1 hour for both (sitagliptin 1 - 4 hr / dapagliflozin 1 - 2 hr). Therefore, it is necessary to develop a combined preparation that contains both components and has a high dissolution rate.

[0008] For the development of a combined preparation that can satisfy all pharmaceutical requirements such as appropriate productivity, dissolution rate, and stability, selecting excipients that satisfy the compatibility of both of two different components is one of the most important and difficult problems to solve in the field of combined preparation development.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0010] One aspect provides a combined 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 is excellent in productivity, dissolution rate, stability, and formulation compatibility.

[0011] Another aspect provides a method for manufacturing the combined preparation.

[0012] Other objects and advantages of the present application will become more apparent from the following detailed description together with the claims. Contents not described herein can be sufficiently recognized and analogized by those skilled in the art within the technical field of the present application or a similar technical field, so the description thereof is omitted.

Means for Solving the Problems

[0013] One aspect is a combined preparation comprising sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and dry granules containing sodium stearyl fumarate as a lubricant, wherein the dry granules contain sodium stearyl fumarate in an amount of 1 to 5% by weight based on the total weight of the combined preparation.

[0014] Another aspect is manufacturing a mixture containing 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; dry granulating the mixture; and further adding a lubricant to the granules and mixing them, to provide a method for manufacturing the combined preparation according to the above aspect.

Effects of the Invention

[0015] According to one aspect, a combined preparation containing sitagliptin and dapagliflozin can produce a combined preparation excellent in productivity, dissolution rate, stability and formulation compatibility, and can improve the medication compliance of patients who require the combined administration of the two drugs. The manufacturing method according to one aspect can improve the pharmaceutical properties such as the flowability and tableting property of the combined preparation, and can enhance the manufacturing productivity.

Brief Description of the Drawings

[0016]

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Figure 15

Mode for Carrying Out the Invention

[0017] Hereinafter, the present invention will be described in more detail.

[0018] All technical terms used in this specification are used in the meaning generally understood by those skilled in the relevant art, unless otherwise defined. Also, although desirable methods and samples are described in this specification, those similar to or equivalent to them are also included in the scope of this specification. Further, the numerical values described in this specification are considered to include the meaning of "about" even if not explicitly stated. The content of all publications described as references in this specification is incorporated herein by reference in its entirety. The term "about" used in this specification means that the recited value can vary to some extent. For example, "about 5" means including any value between 4.5 and 5.5, between 4.75 and 5.25, between 4.9 and 5.1, or between 4.95 and 5.05. Expressions such as the terms "having", "capable of having", "including", or "also being inclusive of" used in this specification indicate the presence of the said feature (e.g., a component such as a numerical value or a component), but do not exclude the presence of further features.

[0019] One aspect is a composite preparation comprising sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dry granules containing sodium stearyl fumarate as a lubricant, wherein the dry granules provide a composite preparation containing 1 to 5% by weight of sodium stearyl fumarate based on the total weight of the composite preparation.

[0020] In one specific example, the composite preparation contains, outside the dry granules, sodium stearyl fumarate added as a lubricant, and the total amount of sodium stearyl fumarate present in the composite preparation is also 3 to 8% by weight based on the total weight of the preparation.

[0021] The sitagliptin or dapagliflozin which are the main components include any of their crystalline forms, hydrates, co-crystals, solvates, salts, partial stereoisomers or enantiomers.

[0022] The pharmaceutically acceptable salts thereof refer to any pharmaceutically acceptable salts commonly used in the art.

[0023] In one specific example, the sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is also sitagliptin phosphate hydrate.

[0024] In one specific example, the dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is also a co-crystal of pharmaceutically acceptable dapagliflozin. In one specific example, the dapagliflozin, or a pharmaceutically acceptable salt thereof, is also dapagliflozin L-proline or dapagliflozin propanediol.

[0025] In one specific example, the sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is also included at 10 to 40% by weight, for example, 25 to 35% by weight in the total weight of the combined preparation.

[0026] In one specific example, the dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is also included at 2 to 10% by weight, for example 2 to 6% by weight in the total weight of the combined preparation.

[0027] Experimental results generally show that magnesium stearate, which is the most commonly used lubricant, improves the productivity and tableting properties of the composite preparation of this application. However, it was confirmed to be very disadvantageous because it increases the related substances of the main component over time (Test Examples 1 and 3). In contrast, sodium stearyl fumarate not only improves productivity and tableting properties but also forms a stable composite preparation that can meet the criteria for related substances (Test Example 3). The sodium stearyl fumarate is contained in the dry granules at 1 to 5% by weight based on the total weight of the composite preparation. If the content range cannot be reached, there is a concern that sufficient productivity cannot be ensured. If it exceeds this range, a decrease in the dissolution rate and stability of the main component is feared (see Test Examples 4, 5, 6, 7, and 8). Optionally, it may also contain sodium stearyl fumarate added externally to the dry granules. The total amount of sodium stearyl fumarate present in the composite preparation containing it is also 3 to 8% by weight based on the total weight of the preparation. If this cannot be reached, there is a concern that sufficient productivity cannot be ensured. If it exceeds this range, a decrease in the dissolution rate and stability of the main component is feared (see Test Example 4 and Test Example 8).

[0028] The composite preparation may also contain one or more excipients selected from diluents, disintegrants, binders, lubricants, and release regulators.

[0029] The diluent is also selected from the group consisting of, for example, D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose (MCC), sucrose, sorbitol, xylitol, glucose, and any mixture thereof, but is not limited thereto.

[0030] In one specific example, the diluent is also selected from the group consisting of D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose, and any mixture thereof.

[0031] The disintegrant is selected from, but not limited to, the group consisting of, for example, crospovidone, cross-linked carboxymethylcellulose sodium (cross-linked CMC Na or croscarmellose sodium (C.CMC Na)), corn starch, carboxymethylcellulose calcium, sodium starch glycolate, low-substituted hydroxypropylcellulose (L-HPC), and any mixture thereof. In one specific example, the disintegrant is low-substituted hydroxypropylcellulose (L-HPC).

[0032] The binder is selected from, but not limited to, the group consisting of, for example, carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, and any mixture thereof. In one specific example, the binder is hydroxypropylcellulose.

[0033] The release regulator is selected from, but not limited to, the group consisting of, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxyvinyl polymer, polyvinyl alcohol, xanthan gum, guar gum, carboxymethylcellulose and its derivatives, methylcellulose and its derivatives, povidone-vinyl acetate copolymer, and any mixture thereof. In one specific example, the release regulator is hydroxypropylcellulose.

[0034] In one specific example, the composite preparation also contains an excipient selected from microcrystalline cellulose (MCC), mannitol, pregelatinized starch, low-substituted hydroxypropylcellulose (L-HPC), crospovidone, cross-linked carboxymethylcellulose sodium (cross-linked CMC Na), hydroxypropylcellulose (HPC), and any mixture thereof.

[0035] In one specific example, the dry granules also contain low-substituted hydroxypropyl cellulose (L-HPC) as a disintegrant in an amount of 5 to 20% by weight based on the total weight of the combined preparation. If the amount of the low-substituted hydroxypropyl cellulose (L-HPC) is not within the above range, the disintegration rate will be slow, resulting in the problem that the dissolution rate at the initial stage is slow. On the other hand, if the amount of the low-substituted hydroxypropyl cellulose (L-HPC) exceeds the above range, during storage, due to water absorption, the expansion rate of the tablets will increase rapidly, the appearance stability will decrease significantly (see Test Example 7), and the problem that the related substances of the main component will increase significantly will occur (see Test Example 8).

[0036] In one specific example, the dry granules also contain water in an amount of 5% by weight or less based on the total weight of the combined preparation. When the water content exceeds the above range, it was confirmed that the related substances of the two main components sensitive to water will increase significantly (see Test Example 9). Therefore, when selecting raw materials according to the batch / grade of the excipient, by selecting raw materials with a low water content, a stable combined preparation that can prevent the increase of the related substances of the main component can be produced.

[0037] The combined preparation is also in the form of tablets, capsules or granules. The combined preparation according to one specific example is also a mixed tablet or a two-layer tablet.

[0038] The combined preparation also contains additional pharmaceutically acceptable excipients. As the pharmaceutically acceptable excipients, components selected from the group consisting of antioxidants, sweeteners, preservatives, coating agents, viscosity regulators, and any mixtures thereof can be used.

[0039] The tablets are further coated by a generally used pharmaceutically immediate-release film coating base in the art by a general method. In one specific example, the tablets can be coated with an Opadry II coating solution to form a moisture-proof film coating of about 3% based on the total weight of the uncoated tablets.

[0040] The composite preparation is also in a form where the length and width are each about 5 to 15 mm. The thickness of the composite preparation is also about 3 to 8 mm. The composite preparation according to one specific example is also in a form where the length and width are each about 5 to 15 mm and the thickness is about 3 to 8 mm. The composite preparation according to one specific example is also in a form where the width is about 10 to 15 mm, the length is about 5 to 10 mm, and the thickness is about 3 to 8 mm. The width of the composite preparation is, for example, also about 10, 11, 12, 13, 14, 15 mm. The length of the longitudinal composite preparation is, for example, also about 5, 6, 7, 8, 9, 10 mm. The thickness of the composite preparation is, for example, also about 3, 4, 5, 6, 7, 8 mm.

[0041] The composite preparation is also a rectangular elliptical tablet. The composite preparation has better throat passage than taking two tablets each containing two active ingredients. Generally, when passing through the narrow part of the human throat after drug administration, the tablet will pass through the throat while maintaining the minimum cross-sectional area. At this time, in order to maintain the small cross-sectional area of the tablet, among the width, length, and thickness of the tablet, the throat passage is made by maintaining the two variables with small values. The composite preparation containing the two active ingredients of sitagliptin and dapagliflozin according to one specific example can reduce the size, weight, and cross-sectional area during throat passage of the drug compared to taking two single tablets of each active ingredient simultaneously, and can improve the convenience of taking for patients who feel inconvenient in the throat passage of large tablets.

[0042] The composite preparation is also one that further contains one or more diabetes therapeutic agents. For example, the composite preparation is also one that further contains metformin or a pharmaceutically acceptable salt thereof added. The composite preparation according to one specific example is also a three-agent composite preparation containing sitagliptin, dapagliflozin, and metformin.

[0043] Another aspect provides a method for manufacturing the composite preparation.

[0044] The manufacturing method according to one specific example is The step of manufacturing 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; The step of dry granulating the mixture; The step of further adding a lubricant to the granules and mixing them are also included.

[0045] The step of dry granulating is also performed by a dry granulation method commonly practiced in the pharmaceutical field. In one specific example, the dry granulation method includes the step of forming compacted flakes using a roller compactor.

[0046] In one specific example, the manufacturing method further includes the step of tableting the granules mixed with a lubricant.

[0047] Hereinafter, the present invention will be described in detail by way of examples. However, these examples are merely illustrative and the present invention is not intended to be limited by these examples.

[0048] Test Method In the following test examples, the conditions for the analysis of related substances, the analysis of eluted substances, and the content analysis were performed by the following methods.

[0049]

Table 1

[0050]

Table 2

[0051] Refer to the FDA_Clinical Pharmacology Biopharmaceutics Review. In the plasma of sitagliptin and dapagliflozin, the time (T max ) when the drug reaches the highest concentration is about 1 - 4 h and about 0.5 - 1.5 h respectively, and the bioavailability is 78% and 87% respectively. Therefore, as the IVIVC (in vitro - in vivo correlation) dissolution test solution for each main component, a pH 1.2 dissolution test solution was selected, the dissolution sampling intervals were set at 5, 10, 15, 30, 45 minutes, and then the final saturation dissolution rate was measured.

[0052]

Table 3

[0053] Test Example 1: Related Substances Test with Lubricants The stability of the compound preparation was tested when magnesium stearate, which is generally widely used, was used as a lubricant. Tablets were manufactured by the following [Sample Manufacturing Method] with the formulation shown in the following Table 1. Then, related substances were measured for each sample, and the compression flakes and the appearance of the tablets were compared depending on the presence or absence of magnesium stearate (Tables 1 - 3, Figure 1). Figure 1 is a photograph of the compression flakes and tablets taken depending on the presence or absence of magnesium stearate.

[0054] [Sample Manufacturing Method] (1) Weighing: Each component in an amount of 1,000 T was weighed.

[0055] (2) Sieving: All components except the lubricant to be added to the final mixture were passed through a 30 - mesh sieve for sieving.

[0056] (3) Mixing: The powder that passed through the sieve was mixed for 30 minutes at 17 rpm using a Bin Mixer.

[0057] (4) Compacting: A roller compactor was used, with a roll rpm of 3.0 / screw rpm of 35.0 rpm and a hydraulic pressure of 2.5 Mpa to form crimped flakes.

[0058] (5) Granulation: An oscillator was used to granulate the flakes produced in step (4) to 20 mesh.

[0059] (6) Final mixing: The product produced in step (5) and the remaining final mixing lubricant were charged, and a Bin Mixer was used to mix them at 17 rpm for 5 minutes.

[0060] (7) Tableting: An AutoTab - 200TR (Ichibashi Seiki Co., Ltd., Japan) was used, with a circular punch of 8.0 mm in diameter, and tableting was performed at a tablet hardness of 10 - 12 kp.

[0061]

Table 4

[0062]

Table 5

[0063]

Table 6

[0064] According to the experimental results, in the mixed granules containing both sitagliptin and dapagliflozin, when magnesium stearate is used as a lubricant, the related substances increase significantly under accelerated storage conditions. When magnesium stearate is excluded, productivity decreases due to issues such as adhesion to punches and production equipment during the granulation process and tablet pressing of the product. Therefore, although the lubricant is necessary for productivity and tabletability, magnesium stearate was confirmed to be inappropriate as it reduces the stability of the main components.

[0065] Test Example 2: Related Substances Test with Excipients Production Example 1 When two main components, sitagliptin and dapagliflozin, coexist, in order to evaluate the stability, 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. An AutoTab-200TR (Ichihashi Seiki Co., Ltd., Japan) tableting machine was used to form flakes, and the amount of related substances generated was measured under accelerated conditions (40°C / 75% RH) for 1 month / 2 months to confirm the stability.

[0066] Production Example 2 To examine the compatibility of the main component sitagliptin with different types of excipients, the types of the excipients were varied and mixed with sitagliptin. After sieving through a 20-mesh sieve for the aforementioned excipients and the main component sitagliptin, a Tubular Mixer was used to mix them for 30 minutes each. Then, the other main component, dapagliflozin, was added, and the mixture was mixed and compressed to produce tablets. An AutoTab-200TR (Ichihashi Seiki Co., Ltd., Japan) tableting machine was used to form flakes, and the amount of related substances generated was measured under accelerated conditions (40°C / 75% RH) for 1 month / 2 months to confirm the stability.

[0067] Production Example 3 To examine the compatibility of the main component dapagliflozin with excipients, different types of excipients were varied and mixed with dapagliflozin. After sieving through a 20-mesh sieve for the aforementioned excipients and the main component dapagliflozin, a Tubular Mixer was used to mix them for 30 minutes each. Subsequently, sitagliptin, another main component, was added, and mixing and compression were performed to produce tablets. An AutoTab-200TR (Ichibashi Seiki Co., Ltd., Japan) tableting machine was used to form flakes, and the amount of related substances generated was measured under accelerated conditions (40°C / 75%RH) for 1 month / 2 months to confirm stability.

[0068] Standard for total related substances The commonly used standard for total related substances is that according to the domestic approved related substance standard, in the case of sitagliptin, the total related substances are less than 0.2%, and in the case of dapagliflozin, the total related substances are less than 2.0%.

[0069] [Table 7]

[0070] The related substance test results measured using the tablets produced in Production Example 1 and Production Example 2 are shown in Table 4 above. As shown in Table 4 above, in the case of sitagliptin, when the excipient contains lactose hydrate or dicalcium phosphate hydrate (DCP hydrate), the total related substance content exceeds 0.2% respectively and could not meet the standard.

[0071] In particular, when sitagliptin is mixed with lactose hydrate, when observing the appearance at high temperature during the 2-month acceleration, it was confirmed that it shows a phenomenon of turning brown due to the Maillard Reaction, which produces a brown substance, and is not suitable for the formulation (Figure 2). Figure 2 is a photograph of the tablets obtained by mixing and tableting sitagliptin and lactose hydrate, and the tablets obtained by mixing sitagliptin with excipients other than lactose and tableting.

[0072] [Table 8]

[0073] The results of the related substance test measured using the tablets produced in Production Example 1 and Production Example 3 are shown in Table 5 above. As shown in Table 5 above, in the case of dapagliflozin, when dibasic calcium phosphate anhydrate (DCP anhydrate) was included as an excipient, the total related substance content exceeded 2.0% respectively and could not meet the criteria. Also, when dibasic calcium phosphate hydrate (DCP hydrate) was included as the excipient, although the total related substance content criteria were met, the amount of related substances generated was large compared to other excipients.

[0074] Test Example 3: Related Substance Test with Lubricants and Excipients Based on the results of the stability comparison by formulation in Test Examples 1 and 2 above, it was confirmed that it was necessary to select lubricants or excipients suitable for production and ensuring stability. Therefore, stability tests were conducted with various types of lubricants and excipients. After completing tablet production, stability evaluations were carried out under accelerated conditions and severe conditions.

[0075] Tablets were produced by the following [Sample Production Method] according to the formulation shown in Table 6 below.

[0076] [Sample Production Method] (1) Weighing: Each component was weighed in an amount of 1,000 T.

[0077] (2) Sieving: All excipients except the lubricant to be added to the final mixture were passed through a 30-mesh sieve and sieved.

[0078] (3) Mixing: The powder that passed through the sieve was mixed using a Bin Mixer at 17 rpm for 30 minutes.

[0079] (4) Compression: Using a roller compactor, roll rpm 3.0 / screw rpm 35.0 rpm, and hydraulic pressure 2.5 Mpa, compression flakes were formed.

[0080] (5) Granulation: Using an oscillator, granulate the flakes produced in the above step (4) to 20 mesh

[0081] (6) Final mixing: Feed the product produced in the above step (5) and the remaining final mixing lubricant, and use a Bin Mixer to mix at 17 rpm for 5 minutes

[0082] (7) Tableting: Using an AutoTab-200TR (Ichibashi Seiki Co., Ltd., Japan), and using a rectangular punch with a width of 12.8 mm and a length of 7.0 mm, tablet at a tablet hardness of 12 - 14 kp

[0083]

Table 9

[0084] The results of evaluating the total related substances of sitagliptin during storage under accelerated conditions (40 °C, relative humidity 75%) are shown in Table 7 below.

[0085]

Table 10

[0086] The results of evaluating the total related substances of dapagliflozin during storage under accelerated conditions (40 °C, relative humidity 75%) are shown in Table 8 below.

[0087]

Table 11

[0088] The results of evaluating the total related substances of sitagliptin during storage under severe conditions (60 °C) are shown in Table 9 below.

[0089]

Table 12

[0090] The results of evaluating the total related substances of dapagliflozin during storage under severe conditions (60 °C) are shown in Table 10 below.

[0091]

Table 13

[0092] According to the results in Tables 7 to 10 above, when sodium stearyl fumarate (PRUV (registered trademark)) is used as a lubricant (Examples 1 to 3), it is shown to satisfy the related substance standard and is confirmed to be a suitable lubricant that does not inhibit stability. In contrast, according to Comparative Examples 1 to 4, it was confirmed that any of glyceryl monostearate, magnesium stearate, calcium stearate, and sucrose stearate, which are other lubricants, are not suitable for the standards of accelerated conditions and severe conditions.

[0093] Also, when microcrystalline cellulose, D-mannitol, and / or low-substituted hydroxypropyl cellulose are used as excipients together with sodium stearyl fumarate (PRUV (registered trademark)), the stability of related substances was ensured (Examples 1 to 3). However, when dicalcium phosphate anhydrate is used as an excipient together with sodium stearyl fumarate (PRUV (registered trademark)) (Example 4), the related substance standards of dapagliflozin under accelerated conditions and severe conditions could not be satisfied.

[0094] Test Example 4: Evaluation of productivity based on the amount of lubricant In Test Example 3 above, productivity evaluation based on the amount of lubricant was carried out for sodium stearyl fumarate (PRUV (registered trademark)) for which stability was ensured, as well as microcrystalline cellulose, D-mannitol, and low-substituted hydroxypropyl cellulose. Also, after the production of the samples was completed, stability evaluation was carried out under accelerated conditions and severe conditions, and the production of the samples was carried out in the same manner as the method in Test Example 3.

[0095]

Table 14

[0096] The tablet appearances after tableting of Example 5 and Comparative Example 5 were photographed, and the time required for granule discharge during each tableting was measured. The results are shown in Fig. 3. The "time required for granule discharge during tableting" refers to the time required for all the granules filled inside the feeder to be tableted into tablets and for all the granules inside the feeder to be exhausted during the progress of tableting. In this test, the evaluation was based on the condition where the amount of granules filled to the brim in the feeder was 420 g.

[0097] Test Example 5: Stability Evaluation by Lubricant Amount For the samples manufactured according to Table 11 above, the results of evaluating the total related substances of sitagliptin in the tablets according to the lubricant amount during storage under accelerated conditions (40°C, relative humidity 75%) are shown in Table 12 below.

[0098]

Table 15

[0099] The results of evaluating the total related substances of dapagliflozin in the tablets according to the lubricant amount during storage under accelerated conditions (40°C, relative humidity 75%) are shown in Table 13 below.

[0100]

Table 16

[0101] The results of evaluating the total related substances of sitagliptin in the tablets according to the lubricant amount during storage under severe conditions (60°C) are shown in Table 14 below.

[0102]

Table 17

[0103] The results of evaluating the total related substances of dapagliflozin in tablets according to the amount of lubricant during storage under harsh conditions (60 °C) are shown in Table 15 below.

[0104] [Table 18]

[0105] Test Example 6: Evaluation of dissolution rate according to the amount of lubricant For the samples manufactured according to Table 11 above, dissolution rate evaluation was performed, and the results are shown in FIGS. 4 and 5.

[0106] FIG. 4 is a graph showing the sitagliptin dissolution test results of Examples 5 to 8 and Comparative Examples 6 and 8.

[0107] FIG. 5 is a graph showing the dapagliprozin dissolution test results of Examples 5 to 8 and Comparative Examples 6 and 8.

[0108] At the same time, the main component contents of Examples 5 to 8 and Comparative Examples 6 and 8 were evaluated. The results are shown in Tables 16 and 17 below.

[0109] [Table 19]

[0110] [Table 20]

[0111] According to the test results of Test Example 4, when sodium stearyl fumarate could not reach 3% of the total tablet weight (Comparative Examples 5 and 7), the amount of lubricant was insufficient, and tableting failure occurred during tablet compression. Also, during the progress of the tableting process, it was confirmed that productivity decreased because the time required for discharging granules during tableting was delayed. On the contrary, when sodium stearyl fumarate was 3% or more of the total tablet weight (Examples 5 to 8 and Comparative Example 6, Comparative Example 8), tablets were compressed without tableting failure. According to FIG. 3, when sodium stearyl fumarate was 3% or more of the total tablet weight in Example 5, it was confirmed that tablets were smoothly manufactured without tableting failure and the discharge time of the mixed powder was also significantly shorter than in the case of Comparative Example 5 where it was less than 3% by weight.

[0112] According to the test results of Test Example 5, although Comparative Examples 5 to 8 and Examples 5 to 8 ensured the stability of related substances suitable for the standard under accelerated conditions and severe conditions, Comparative Example 6 and Comparative Example 8 with a relatively high ratio of lubricant showed a tendency to increase both components of sitagliptin and dapagliflozin closer to the related substance standard under severe conditions.

[0113] According to the test results of Test Example 6, it was confirmed that when sodium stearyl fumarate was present in an amount exceeding 8% of the total tablet weight, a decrease in the dissolution rate of the main component was shown. Specifically, when comparing the dissolution patterns of Comparative Example 6 and Comparative Example 8 with Example 6 and Example 8, a decrease in the dissolution rate was shown (see FIGS. 4 and 5). Furthermore, according to the content evaluation results of Test Example 8, it was confirmed that there was no decrease in the main component content in each tablet (see Tables 16 and 17). When considering this comprehensively, it was determined that the decrease in the dissolution rate was shown due to excessive lubrication of the granules.

[0114] Test Example 7: Evaluation of Dissolution Rate, Productivity, and Appearance Stability by Amount of Lubricant and Excipient Tablets containing sitagliptin and dapagliflozin as main components were manufactured according to the compositions described in Tables 18 and 19 below.

[0115] 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 20-mesh sieve, large lumps were pulverized, and they were mixed well. Using a roller compactor (TF-1-A60 (Freund Vector)) for the mixture, after forming flakes, they were sized with a 20-mesh sieve to produce dry granules. To the produced dry granules, sodium stearyl fumarate was further mixed as a lubricant for 5 minutes to produce a final mixing part. The produced final mixing part was tabletted using a tabletting machine (Autotab-200TR (manufactured by Ichihashi Seiki Co., Ltd.)) to the appropriate hardness to produce a semi-finished product in the form of a naked tablet.

[0116]

Table 21

[0117]

Table 22

[0118] The dissolution rates of sitagliptin and dapagliflozin in Examples 9 to 14 and Comparative Examples 9 to 14 were measured, and the results are shown in FIGS. 6 to 9.

[0119] Also, for Examples 9 to 11 and Comparative Examples 9 to 11, after storage for 1 week under accelerated exposure conditions (40°C, relative humidity 75%, open dish state), the appearance of the tablets was observed, the tablet thickness was measured, and the swelling rate was calculated. The results are shown in FIG. 10.

[0120] Also, the appearance of flakes during the compression step for the production of dry granules of Example 9, which is a granule containing sodium stearyl fumarate in the granules, and Comparative Example 12, which does not contain it, was compared, and a photograph of the appearance of the flakes is shown in FIG. 11.

[0121] [Comparison of Dissolution Patterns and Appearance Stability Based on the Amount of Low-Substitution-Degree Hydroxypropyl Cellulose (L-HPC)] As shown in Figures 6 and 7, when comparing the dissolution patterns of Examples 9 to 11 and Comparative Examples 9 to 11, it was confirmed that in the case of Examples 9 to 11, each main component was similar compared to the reference drug. Generally, low-substitution-degree hydroxypropyl cellulose (L-HPC) simultaneously serves as a diluent and a disintegrant. Thus, the increased disintegration force in the early stage leads to an increase in the dissolution rate in the early stage, resulting in a pattern similar to the dissolution of the reference drug. In the case of Comparative Examples 9 and 10 where the amount of low-substitution-degree hydroxypropyl cellulose (L-HPC) was relatively small, it was confirmed that the dissolution rate in the early stage was slow. Furthermore, due to the increase in the amount of microcrystalline cellulose, an excipient with a relatively slow disintegration rate and water-insolubility, a large deviation in dissolution rate was caused, which is a problem for uniform drug administration to patients. On the other hand, in the case of Comparative Example 11 where the amount of low-substitution-degree hydroxypropyl cellulose (L-HPC) was relatively large, although the dissolution rate in the early stage was fast and showed a pattern similar to the reference drug, it was confirmed that the excessive use of the disintegrant could cause problems in the appearance of the tablets and accelerated stability. As shown in Figure 10, in the case of Comparative Example 11 where 30% by weight of low-substitution-degree hydroxypropyl cellulose (L-HPC) was used, due to water absorption, the swelling rate increased rapidly, which could cause problems in appearance stability as the appearance of the tablets changed significantly.

[0122] In conclusion, through dissolution evaluation, the amount of low-substitution-degree hydroxypropyl cellulose (L-HPC) for ensuring the disintegration force in the early stage is effective in the range of 5% by weight or more based on the total weight of the tablets. However, when it contains an excessive amount, problems in appearance stability were confirmed.

[0123] [Comparison of Dissolution Patterns and Productivity Based on the Amount of PRUV] 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 component showed a dissolution pattern similar to that of the reference drug. As shown in Table 20, in the case of Comparative Example 12 where no PRUV lubricant was added inside the granules, the dissolution pattern was good, but in the dry granulation process, a crimping phenomenon (FIG. 11) occurred on the roller, which caused trouble in the equipment during the process, resulting in a low granule yield and reduced productivity. This means that productivity improvement can be shown through the addition of a lubricant during the granule manufacturing process. In the case of Comparative Examples 13 and 14, it corresponded to a formulation with a relatively large amount of PRUV (more than 5% by weight in the granule content), and in such cases of excessive lubrication, a phenomenon of delayed dissolution was shown. In particular, surprisingly, in the case of Comparative Examples 13 and 14, compared with Example 14, the dissolution rate of the drug was significantly reduced, and even at the dissolution time point (Max) when the drug was saturated, a relatively low dissolution rate was shown. This poses a problem for uniform drug administration to patients and indicates a relatively slow onset of drug efficacy. Therefore, it can be judged that the amount of PRUV in the dry granulation process is effective in the range of 1 to 5% by weight.

[0124]

Table 23

[0125] Test Example 8: Evaluation of Related Substances by Lubricant Amount and Excipient Amount In order to confirm the stability of the dosage form with the dosage form selected by Test Example 7, an accelerated test was performed to evaluate related substances. As the packaging material, it was packaged in an HDPE bottle with silica gel enclosed and managed in an accelerated chamber.

[0126] The total related substances (%) of sitagliptin and dapagliflozin in Examples 9 to 14 and Comparative Examples 9 to 14 were measured, and the results are shown in FIGS. 12 and 13.

[0127] [Comparison of Total Related Substances under Accelerated Conditions] As shown in FIGS. 12 and 13, when comparing the total related substances (%) of Examples 9 to 14 and Comparative Examples 9 to 14, in the case of Examples 9 to 11, each main component has a smaller amount of total related substances compared to the reference drug, and furthermore, accelerated stability can be ensured. In the case of Examples 12 to 14, the amount of total related substances is larger compared to the reference drug, but it is suitable within the standard. In the case of Comparative Example 11 (containing 30% by weight of low-substituted hydroxypropyl cellulose (L-HPC)), even if the amount of related substances is within the standard after 3 months of acceleration, it increases significantly, and furthermore, the stability after 6 months of acceleration is also low. When the product is approved according to the "Stability Test Standards for Pharmaceuticals, etc.", the basis for stability problems will arise. Compared with other formulations, the related substances increase significantly and meaningfully, so it is judged as an inappropriate pharmaceutical formulation. It is interpreted that this is due to the excessive use of low-substituted hydroxypropyl cellulose (L-HPC), which shows moisture instability due to hygroscopicity. Therefore, according to the data of Test Examples 7 and 8, it is confirmed that it is desirable to set low-substituted hydroxypropyl cellulose (L-HPC) at 5 to 20% by weight based on the total tablet weight.

[0128] Also, it was confirmed that the excessive use of PRUV also affects related substances. Looking at Examples 10, Examples 12 to 14, and Comparative Examples 12 to 14 where the amount of low-substituted hydroxypropyl cellulose (L-HPC) in the formulation is constant, in the case of Example 10, Examples 12 to 14, and Comparative Example 12, the content of total PRUV is within 3 to 7% by weight compared to the total tablet weight, and the content of PRUV in the granules corresponds to 1 to 5% by weight, and stability was ensured. However, in the case of Comparative Examples 13 and 14, the PRUV in each case exceeds 5% by weight in the granules compared to the total weight, and the content of total PRUV is 7.5 and 10% by weight respectively, and the generation of related substances increased significantly, and the storage stability was significantly low. This shows that when the total PRUV is 1 to 7% by weight compared to the total weight of the compound preparation and the content of PRUV in the granules is 1 to 5% by weight, it is suitable for pharmaceutical formulation compounding, and at the same time, improved storage stability can be ensured.

[0129] Test Example 9: Stability Test by Initial Moisture Content Based on the moisture instability of the main component, tablets with different moisture contents were manufactured based on Example 10 selected by Test Examples 7 and 8, and the stability depending on the moisture content was evaluated.

[0130] The compatibility between the dosage form and the main component was confirmed. Relatively, diluents (microcrystalline cellulose) and disintegrants (croscarmellose sodium) with a wide moisture standard range of the raw materials were selected. Among them, with the formulations combined according to the moisture content by batch / grade, the moisture content was confirmed and the stability aspect was confirmed (by batch: selected according to the moisture test results in the manufacturing performance record through investigation for each batch within the same grade; by grade: selected according to the moisture test results in the manufacturing performance record through the manufacturer grade inspection of microcrystalline cellulose / croscarmellose sodium).

[0131] The excipients were combined by batch / grade, and Examples 10, 15, 16 and Comparative Examples 15 to 17 were manufactured, and the total moisture content (including surface water and crystal water) per dosage form was measured. In the moisture measurement method (Karl Fischer titration) in the general test method of the Korean Pharmacopoeia, the moisture content was measured by the volumetric titration method using methanol for moisture measurement and the direct titration method. The results are shown in Table 21 below.

[0132] In addition, Examples 10, 15, 16 and Comparative Examples 15 to 17 were stored for 1 to 2 weeks under the conditions of moisture supersaturation (25°C, relative humidity 90%), and the total related substances (%) of sitagliptin and dapagliflozin were measured, and the results are shown in Figures 14 and 15.

[0133]

Table 24

[0134] Regarding the moisture content measurement results, in the cases of Examples 10, 15, and 16, the total moisture content per dosage form was within about 5%, and in the cases of Comparative Examples 15 to 17, the initial dosage form contained more than 5% of moisture. This was shown as a high initial total moisture content as a result of combining batches / grades with a high moisture content of the raw materials of the diluent and the disintegrant.

[0135] The storage results for 1 to 2 weeks under the condition of water supersaturation (25°C, relative humidity 90%) showed a remarkable tendency for the amount of related substances to increase depending on the initial water content. In the case of Comparative Examples 15 to 17, results exceeding the standard were shown. This means that the initial water content can be adjusted and a more stable dosage form can be designed. When selecting batch / grade-specific raw materials so that the initial water content is within 5% during the design of the dosage form, a dosage form with improved stability can be produced for the two main components sensitive to moisture.

[0136] 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 merely exemplary in all respects and not restrictive. Therefore, the scope of the present invention is presented by the claims rather than the foregoing description. All meanings equivalent to the claims and all modifications within the scope thereof are included in the scope of the present invention.

Claims

Claim 1. A combined preparation comprising dry granules containing: (a) sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; (b) dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; (c) sodium stearyl fumarate in an amount of 1% to 5% by weight based on the total weight of the combined preparation as a lubricant. Claim 2. The combined preparation according to Claim 1, wherein sodium stearyl fumarate is additionally contained outside the dry granules as a lubricant, and the total amount of sodium stearyl fumarate present in the combined preparation is 3 to 8% by weight based on the total weight of the combined preparation. Claim 3. The combined preparation according to Claim 1, wherein the sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is sitagliptin phosphate hydrate. Claim 4. The combined preparation according to Claim 1, wherein the dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is dapagliflozin L-proline or dapagliflozin propanediol. Claim 5. Excipients selected from microcrystalline cellulose (MCC), mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, cross-linked sodium carboxymethyl cellulose (cross-linked CMC Na), and any mixtures thereof. Claim 6. The combined preparation according to Claim 1, wherein the dry granules contain low-substituted hydroxypropyl cellulose (L-HPC) as a disintegrant in an amount of 5% to 20% by weight based on the total weight of the combined preparation. Claim 7. The combined preparation according to Claim 1, wherein the dry granules contain water in an amount of 5% or less by weight based on the total weight of the combined preparation. Claim 8. The combined preparation according to Claim 1, which is in the form of tablets, capsules or granules. Claim 9. The combined preparation according to Claim 1, wherein the sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is contained in an amount of 10% to 40% by weight in the total weight of the combined preparation. Claim 10. The combined preparation according to Claim 1, wherein the dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof is contained in an amount of 2% to 10% by weight in the total weight of the combined preparation. Claim 11. ​ ​ The combined preparation according to claim 1, further comprising metformin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

12. Manufacturing a mixture containing 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 1% to 5% by weight of sodium stearyl fumarate based on the total weight of the combined preparation as a lubricant; Dry granulating the mixture; Further adding and mixing sodium stearyl fumarate to the granules; A method for manufacturing a combined preparation according to any one of claims 1 to 11, comprising the above steps.

13. The manufacturing method according to claim 12, wherein the granulating step includes a step of forming a compact using a roller compactor.

14. The method for manufacturing a combined preparation according to claim 12, further comprising a step of tableting the granules mixed with sodium stearyl fumarate.

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