Oral combination tablet containing sitagliptin, dapagliflozin and metformin

Abstract

Provided are a composite tablet comprising a first layer containing dry granules containing sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a second layer containing wet granules containing metformin, or a pharmaceutically acceptable salt thereof, and colloidal silicon dioxide, and a method for producing the same.

Description

[Technical Field]

[0001] The present invention relates to an oral composite tablet containing sitagliptin, dapagliflozin, and metformin as active ingredients, and more specifically to an oral composite tablet that has excellent storage stability and high productivity, and a method for producing the same. [Background technology]

[0002] Type 2 diabetes patients generally suffer from overweight, abdominal obesity, and hypertension. Diabetes is known to lead to secondary chronic diseases or metabolic syndromes, such as hypertension, hyperlipidemia, myocardial infarction, and stroke. The Korean Diabetes Society's clinical practice guidelines actively recommend combined drug therapy to improve symptoms. In particular, the combination of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose-linked transporter 2 (SGLT-2) inhibitors has recently been proven to be effective in diabetes treatment, and even triple therapy with metformin is being studied.

[0003] Sitagliptin (brand name: Januvia tablets) is a dipeptidyl peptidomimetic Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, and its compound 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 regulates blood glucose by inhibiting the degradation of gastrointestinal hormones called incretins, thereby improving the function of incretins, which regulate insulin and glucagon. Oral administration of sitagliptin to type 2 diabetes patients is known to significantly reduce HbA1c levels and reduce fasting and postprandial blood glucose secretion.

[0004] Dapagliflozin (trade name: Forxiga tablets) is a sodium-glucose Dapagliflozin is a sodium-glucose-linked transporter 2 (SGLT-2) inhibitor, and its compound name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. Dapagliflozin selectively inhibits SGLT-2 in the kidney, enhancing glucose excretion in the kidney, thereby improving insulin sensitivity and delaying the onset of diabetic complications, thereby normalizing plasma glucose levels. Dapagliflozin is marketed by its original developer, AstraZeneca AB, in tablet form (Forxiga tablets) containing dapagliflozin propylene glycol hydrate as the active ingredient.

[0005] Metformin is a biguanide antidiabetic agent and is used by patients with type 2 diabetes. Metformin is an oral antihyperglycemic drug primarily used for the treatment of diabetes. Its blood glucose regulation mechanism is known to act independently of insulin secretion, for example, by activating glucose transporters in the liver. Metformin induces weight loss in diabetic patients and reduces blood triglycerides and low-density lipoproteins, while increasing blood high-density lipoproteins. Therefore, it can be used as a first-line drug for patients with non-insulin-dependent diabetes who exhibit insulin resistance.

[0006] Metformin is commercially available as its hydrochloride salt in tablet form as Glucophage (Bristol-Myers Squibb Company). Commercially available Glucophage tablets contain 500 mg, 850 mg, or 1,000 mg of metformin hydrochloride. The administration of metformin is limited to a maximum daily dose of 2,550 mg, taking into consideration both efficacy and tolerability. Side effects associated with metformin use, such as loss of appetite, abdominal distension, nausea, and diarrhea, occur in 20-30% of patients. These side effects are mostly transient and usually disappear within 2-3 weeks of administration. If diarrhea or severe abdominal distension persists, it is recommended to discontinue administration. In rare cases, skin rashes and hives may occur. These side effects can be partially avoided by using sustained-release formulations, which allow for a lower minimum and / or sustained dose and a reduced dosing frequency.

[0007] Diabetes often requires the administration of one or more antidiabetic drugs in combination for the purposes of blood glucose control and reduction of side effects. Sitagliptin and dapagliflozin have no risk of hypoglycemia and, in addition to their primary effect of lowering blood glucose, sitagliptin also has pancreatic beta cell protection and GLP-1 upregulation, while dapagliflozin has weight loss and blood pressure lowering effects. Clinical results have shown that the combination of these two active ingredients has a synergistic effect. Furthermore, when blood glucose control is ineffective with sitagliptin alone or dual administration of sitagliptin and metformin, adding dapagliflozin and triple administration of sitagliptin, metformin, and dapagliflozin has been reported to be effective for blood glucose control (Diabetes Care 2014 Mar; 37(3): 740-750).

[0008] Furthermore, in the case of diabetic patients, the more advanced the diabetes becomes, the more difficult it becomes to regulate blood sugar, leading to complications, and in particular, elderly diabetic patients are more likely to suffer from high blood pressure, obesity, and hyperlipidemia. Due to the characteristics of such diabetic patients, compliance with medication is a very important factor, and poor compliance not only reduces the patient's quality of life, but also reduces the treatment rate for patients, leading to increased personal medical expenses and worsening insurance finances. Therefore, valid There is a need to develop a triple combination tablet containing sitagliptin, dapagliflozin, and metformin as ingredients.

[0009] By the way, the development of the aforementioned compound tablets valid There are many difficulties due to the various issues such as productivity and stability of tablets caused by differences in the physical properties of the active ingredients (API). For example, metformin requires wet granulation due to issues such as flowability during tablet production, while sitagliptin and dapagliflozin are characterized by being unstable in water. In addition, in the case of dapagliflozin, despite its low density and small amount, valid The volume of the ingredients is large, the productivity is not good, and other valid There is a high probability of phase separation between the ingredients and excipients. Summary of the Invention [Problem to be solved by the invention]

[0010] One aspect of the present invention provides a triple combination tablet that contains sitagliptin, dapagliflozin, and metformin, and that has excellent storage stability and high productivity.

[0011] Another aspect provides a method for producing the composite tablet.

[0012] Other objects and advantages of the present application will become more apparent from the following detailed description, taken in conjunction with the appended claims. Contents not described in this specification can be fully understood and inferred by those skilled in the art in the technical field of the present application or in a similar technical field, and therefore, the description thereof will be omitted. [Means for solving the problem]

[0013] In one aspect, Sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and Dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof a first layer comprising dry granules; A combination tablet is provided that includes a wet granule comprising metformin, or a pharmaceutically acceptable salt thereof, and a second layer comprising colloidal silicon dioxide.

[0014] Another aspect is preparing a blend comprising sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and excipients; dry granulating the blended portion; A step of further adding a lubricant to the obtained granules and mixing them to prepare a first mixed part; preparing metformin wet granulations comprising metformin, or a pharmaceutically acceptable salt thereof, and excipients; drying the resulting metformin wet granules; blending the dried metformin wet granules with colloidal silicon dioxide and a lubricant to produce a second blend part; and compressing the first mixed part into a first layer and the second mixed part into a second layer using a double-layer tablet press. [Effects of the Invention]

[0015] According to one embodiment, a first layer containing sitagliptin and dapagliflozin, and a second layer containing metformin are both contained in a single formulation, valid The stability of the ingredients can be ensured, and tableting problems such as capping or laminating do not occur, making it possible to obtain tablets with excellent productivity. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a photograph of bilayer tablets prepared by varying the moisture content of metformin wet granules when preparing a bilayer tablet according to one embodiment. [Figure 2]1 is a graph illustrating the required compression force (y-axis) as a function of metformin granule moisture content (x-axis) measured for bilayer tablets according to one embodiment containing various amounts of colloidal silicon dioxide and metformin granule moisture content. [Figure 3] 1 is a graph illustrating the difference in bilayer tablet shrinkage (y-axis) as a function of colloidal silicon dioxide content contained in the second layer (x-axis) measured for bilayer tablets according to one embodiment containing various amounts of colloidal silicon dioxide and metformin granule layer moisture content. [Figure 4] 1 is a photograph of a tablet according to one embodiment. [Figure 5] 1 is a graph showing the results of measuring the amount of total sitagliptin related substances over time for bilayer tablets according to one embodiment containing various amounts of colloidal silicon dioxide and metformin granule layer moisture content at 60°C under rigorous conditions. [Figure 6] 1 is a graph showing the results of measuring the amount of total related substances of dapagliflozin over time for bilayer tablets containing various amounts of colloidal silicon dioxide and metformin granule layer moisture contents under harsh conditions at 60°C. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention will be described in further detail below.

[0018] Unless otherwise defined, all technical terms used herein are used in the sense that they are commonly understood by those skilled in the art in the relevant field. Furthermore, while preferred methods and samples are described in this specification, similar or equivalent ones are also included in the scope of this specification. Furthermore, numerical values ​​described in this specification are considered to include the meaning of "about" even if not explicitly stated. The contents of all publications listed as references in this specification are incorporated herein by reference in their entirety. The term "about" used in this specification means that the reference It means that the value given can vary to some extent. For example, the value can vary by 10%, 5%, 2%, or 1%. For example, "about 5" means to include 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. As used herein, terms such as "have," "may have," "include," or "also include" indicate the presence of a given feature (e.g., a numerical value or component such as a moiety) but do not exclude the presence of additional features.

[0019] As used herein, the term "difference in shrinkage rate of a bilayer tablet" refers to the difference in shrinkage rate between the layers of a bilayer tablet. The shrinkage rate of each layer was determined by measuring the difference between the major axis diameter of the tablet immediately after tableting and the major axis diameter of the tablet after storage at 40°C for 1 hour, and then calculating the ratio of this difference to the major axis diameter of the tablet immediately after tableting, and expressing the result as a percentage.

[0020] The term "water content in wet granules of metformin" refers to the percentage (%) of the weight of water relative to the weight of the wet granules when dried after production of the wet granules.

[0021] The term "required tableting pressure" means the tableting pressure required during tableting in the tablet manufacturing process to obtain a desired tablet hardness.

[0022] In one aspect, Sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a first layer comprising dry granules comprising dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; A combination tablet is provided that includes a wet granule comprising metformin, or a pharmaceutically acceptable salt thereof, and a second layer comprising colloidal silicon dioxide.

[0023] valid The aforementioned ingredients sitagliptin and dapagliflozin include any of their crystalline forms, hydrates, cocrystals, solvates, salts, partial stereoisomers or enantiomers.

[0024] The second layer valid The component metformin includes any of its respective crystalline forms, co-crystals, solvates or isomers.

[0025] The pharmaceutically acceptable salts thereof refer to any pharmaceutically acceptable salts that can be commonly used in the art.

[0026] In one embodiment, the sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is also sitagliptin phosphate hydrate.

[0027] In one embodiment, the dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is also a pharmaceutically acceptable cocrystal of dapagliflozin. In one embodiment, the dapagliflozin, or a pharmaceutically acceptable salt thereof, is also dapagliflozin L-proline or dapagliflozin propanediol hydrate. In one embodiment, it is also dapagliflozin L-proline.

[0028] In one embodiment, the metformin is metformin hydrochloride or metformin free base.

[0029] In this specification, references to sitagliptin, dapagliflozin, and metformin should be understood to include all possible salts, solvates, and isomers of the aforementioned.

[0030] The composite tablet according to the above-mentioned embodiment comprises a first layer containing dry granules containing sitagliptin and dapagliprozin, and a second layer containing wet granules containing metformin and colloidal silicon dioxide. Since sitagliptin and dapagliprozin are relatively more vulnerable to moisture than metformin, the bilayer tablet structure allows validThe stability of the ingredients can be improved. Furthermore, metformin has low flowability, and the wet granule form ensures excellent flowability, thereby ensuring high productivity when producing the bilayer tablet.

[0031] In one specific example, the difference in shrinkage rate between the first layer and the second layer is within 1%. If the difference in shrinkage rate exceeds 1%, layer separation between the first layer and the second layer may occur during storage (see Test Example 1).

[0032] In one embodiment, the colloidal silicon dioxide present in the second layer is metformin valid It may be present in an amount of 0.7 to 2.8% by weight relative to the components.

[0033] In one embodiment, the metformin wet granules of the second layer also have a moisture content of 2.5 to 3.5% by weight.

[0034] In one embodiment, the colloidal silicon dioxide is metformin valid The metformin wet granules of the second layer are present in an amount of 0.7 to 2.8% by weight relative to the total weight of the ingredients, and the water content of the metformin wet granules of the second layer is also 2.5 to 3.5% by weight.

[0035] The second layer contains colloidal silicon dioxide, which allows the preparation of composite tablets with an appropriate hardness (about 20 kp). Experimental results have shown that when colloidal silicon dioxide is included, the tableting pressure during tableting can be reduced to ensure that the composite tablet has an appropriate hardness. When tableting pressure is high, tableting problems such as capping or laminating of the tablets can occur. However, by including colloidal silicon dioxide, the tableting pressure can be reduced, and it has been confirmed that a bilayer tablet with an appropriate hardness can be prepared without tableting problems (see Test Example 2). Furthermore, experimental results have shown that the colloidal silicon dioxide content is low when metformin is used. validWhen present at a concentration of more than 2.8% by weight relative to the components, both sitagliptin and dapagliflozin showed increases in related substances that exceeded or were close to the standard during the rigorous 4-week test. In addition, generally, the higher the amount of colloidal silicon dioxide, the higher the levels of related substances for sitagliptin and dapagliflozin. Therefore, the amount of colloidal silicon dioxide is similar to that of metformin. valid It was evaluated that stability could be ensured when used within 2.8% by weight of the total components (Test Example 3).

[0036] It was confirmed that the moisture content of the metformin wet granules in the second layer affects productivity and the difference in shrinkage between each layer. When metformin wet granules contained more than 3.5% moisture, no tableting problems occurred when compressing bilayer tablets. However, when coating tablets and under accelerated and severe conditions, the difference in shrinkage between the first and second layers was greater than approximately 1%, indicating layer separation. Furthermore, when metformin wet granules contained less than 2.0% moisture, the moisture content was insufficient, resulting in insufficient tablet hardness and easy breakage during compression (see Test Example 1). It was also found that the higher the moisture content of metformin wet granules, the lower the compression pressure required to produce a composite tablet with the desired hardness, i.e., the required compression pressure. When tableting is performed with high tableting pressure, tableting problems such as capping or laminating of the tablets may occur. However, by incorporating an appropriate amount of moisture, it is possible to reduce the tableting pressure, and it has been confirmed that bilayer tablets with appropriate hardness can be produced without tableting problems (see Test Example 2).

[0037] Therefore, the bilayer tablet contains colloidal silicon dioxide in the metformin-containing second layer, which prevents tableting problems, has high productivity, and ensures physical stability without layer separation during storage, while also maintaining chemical stability by maintaining the generation of related substances within standard values ​​during storage. Therefore, it was confirmed that the bilayer tablet can also be manufactured as a composite tablet with excellent productivity and stability.

[0038] In one embodiment, the first layer also includes one or more excipients selected from diluents, disintegrants, binders, and lubricants.

[0039] The diluent may be selected from the group consisting of, for example, but not limited to, D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose, sucrose, sorbitol, xylitol, glucose, and any combination thereof.

[0040] The lubricant may also be selected from the group consisting of, but not limited to, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oils, polyethylene glycol, sodium benzoate, talc, and any combination thereof. In one embodiment, the lubricant is sodium stearyl fumarate.

[0041] In one embodiment, the diluent is also selected from the group consisting of D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose, and any combination thereof.

[0042] The disintegrant may be, for example, crospovidone, cross-linked carboxymethylcellulose sodium (CMC Na), or croscarmellose sodium. The disintegrant may also be selected from the group consisting of, but not limited to, cross-linked sodium carboxymethylcellulose, corn starch, calcium carboxymethylcellulose, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), and any combination thereof. In one embodiment, the disintegrant is cross-linked sodium carboxymethylcellulose.

[0043] 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 combination thereof. In one embodiment, the binder is cross-linked sodium carboxymethylcellulose.

[0044] In one embodiment, the first layer is made of a material selected from the group consisting of microcrystalline cellulose (MCC), D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, cross-linked sodium carboxymethylcellulose (cross-linked CMC Na), and sucrose. It may further comprise an excipient selected from magnesium tearate, sodium stearyl fumarate, and any combination thereof.

[0045] In one embodiment, the second layer further comprises one or more excipients selected from the group consisting of diluents, binders, sustained release carriers, lubricants, and any combination thereof.

[0046] The diluent may be microcrystalline cellulose, anhydrous calcium hydrogen phosphate, D-mannitol, sucrose, lactose, sorbitol, xylitol, glucose, hydroxypropyl It may also be selected from the group consisting of, but not limited to, cellulose, hydroxypropyl methylcellulose, and any combination thereof.

[0047] The binder may be selected from the group consisting of, for example, but not limited to, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, and any combination thereof.

[0048] The sustained-release carrier is known in the art and may be any sustained-release carrier. For example, the sustained-release carrier may be selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyethylene oxide, guar gum, locust bean gum, xanthan gum, glyceryl distearate, sodium carboxymethylcellulose, polyvinylpyrrolidone, and any combination thereof. In one specific example, the sustained-release carrier is a combination of hydroxypropyl methylcellulose 2208, hydroxypropyl methylcellulose 2910, and locust bean gum. The sustained-release carrier may be present in an amount of 10 to 50 parts by weight, specifically about 20 to 40 parts by weight, per 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof.

[0049] The lubricants include calcium stearate, colloidal silicon dioxide (fumed silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, stearin The lubricant may also be selected from the group consisting of, but not limited to, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oils, polyethylene glycol, sodium benzoate, talc, and any combination thereof. In one embodiment, the lubricant is magnesium stearate.

[0050] In one embodiment, the combination tablet is an oral combination tablet in which the total content of sitagliptin analogues is 0.2 wt % or less and the total content of dapagliflozin analogues is 2 wt % or less when stored under harsh conditions at 60°C for 4 weeks.

[0051] The combination tablet may contain 25 to 100 mg of sitagliptin as a sitagliptin free base, 5 to 10 mg of dapagliprozin as a free base, and 500 to 1,000 mg of metformin as a free base per unit dosage form. For example, the combination tablet may contain 500 mg, 750 mg, 850 mg, or 1,000 mg of metformin as a free base, 50 mg of sitagliptin, and 5 mg of dapagliprozin per unit dosage form.

[0052] The composite tablet can also be formed by compressing dry granules containing sitagliptin and dapigluloprusin into a first layer and wet granules containing metformin into a second layer to form a bilayer tablet.

[0053] The bilayer tablet may also include an additional film coating layer on the outer surface. The film coating layer may include any film coating agent that exhibits immediate release properties and a colorant. Examples of film coating agents include, but are not limited to, a mixture of HPC and HPMC, or a mixture of polyvinyl alcohol (PVA) and polyethylene glycol (PEG). Examples of colorants include, but are not limited to, titanium dioxide and iron oxide. A representative commercially available film coating agent is Opadry®. The film coating layer may serve to mask the taste and / or provide stability to the final composite tablet. The role of granting can be performed.

[0054] The bilayer tablet can be used to treat adult patients with type 2 diabetes who are not adequately controlled with sitagliptin, dapagliflozin, or metformin alone or in combination, or who are already receiving triple therapy with sitagliptin, dapagliflozin, and metformin. valid Depending on the strength of the ingredient, it may be administered once a day, twice a day, three times a day, or four times a day.

[0055] Another aspect is preparing a blend comprising sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and excipients; dry granulating the blended portion; A step of further adding a lubricant to the obtained granules and mixing them to prepare a first mixed part; preparing metformin wet granulations comprising metformin, or a pharmaceutically acceptable salt thereof, and excipients; drying the resulting metformin wet granules; blending the dried metformin wet granules with colloidal silicon dioxide and a lubricant to produce a second blend part; and compressing the first mixed part into a first layer and the second mixed part into a second layer using a double-layer tablet press.

[0056] The details of the method for producing the composite tablet are the same as those of the composite tablet according to one embodiment of the present invention.

[0057] The dry granulation step in the first layer manufacturing step may be carried out by a general dry granulation method known in the art. In one embodiment, the dry granulation is carried out by: valid The method also includes forming a compaction using a roller compactor with a mixture including the ingredients, diluents, binders, and lubricants.

[0058] The wet granulation step in the second layer preparation step may be carried out by a conventional wet granulation method known in the art. In one embodiment, the metformin wet granules may be dried to a moisture content of 2.5 to 3.5 wt%.

[0059] The steps involved in the manufacturing method of the composite tablet can be performed based on the general manufacturing process of bilayer tablets performed in the art.

[0060] In one specific example, the tableting pressure required for producing the bilayer tablet is about 2,000 to 2,500 kN. [Example]

[0061] The present invention will be described in more detail below with reference to the following examples, which are intended to illustrate the present invention only and are not intended to limit the scope of the present invention.

[0062] Test Example 1: Evaluation based on metformin layer moisture content (1) Sample manufacturing method Sitagliptin, dapagliflozin, microcrystalline cellulose, D-mannitol, low-substituted hydroxypropyl cellulose, croscamellose sodium, and sodium stearyl fumarate are sieved through a No. 20 sieve to crush large lumps, and then thoroughly mixed. The mixture is compressed using a roller press to produce slugs. The slugs are sieved through a No. 20 sieve to produce dry granules. The dry granules are mixed with sodium stearyl fumarate as a lubricant to produce the first layer, the final blend.

[0063] After sieving metformin, hydroxypropyl methylcellulose, and locust bean gum, a high-speed granulator is used to produce wet granules using water as the binder solvent. The resulting granules are dried in a fluidized bed dryer to meet the moisture standard and then sized using a sieving machine. Colloidal silicon dioxide is sieved and mixed with the granules, and vegetable magnesium stearate is similarly sieved to produce the second layer, the final blend.

[0064] The first layer and the second layer are compressed into tablets of appropriate hardness using a double-layer tablet press, and then the outer coating is carried out.

[0065] (2) Evaluation of shrinkage rate and productivity Using the sample manufacturing method, bilayer tablets of Examples 1, 2, 3, and 4 and Comparative Examples 1, 2, and 3 were manufactured with the compositions shown in Table 1. During the manufacturing process, when producing metformin granules, the moisture content in the metformin granule layer was adjusted according to the drying time in the drying step, and the moisture content was adjusted as shown in Table 1 below. In addition, when tableting using a bilayer tablet press, tableting was carried out at a constant tableting pressure of 2,000 kN, and each bilayer tablet was manufactured.

[0066] [Table 1]

[0067] As a result, the shrinkage rate of each layer of the produced tablets was measured.

[0068] The shrinkage rate of each layer was determined by measuring the difference between the long axis diameter of the tablet immediately after tableting and the long axis diameter of the tablet after storage at 40°C for 1 hour, and then calculating the ratio of this to the long axis diameter of the tablet immediately after tableting, and expressing it as a percentage.

[0069] The results are shown in Table 2 below. In addition, the properties of each tablet were observed, and the hardness and friability were compared. Photographs of each tablet are shown in Figure 1.

[0070] [Table 2]

[0071] According to the results in Table 2 and Figure 1, when the moisture content of the metformin granule layer (second layer) was 4.0% or higher (Comparative Example 1), there were no problems with productivity, but layer separation due to the difference in shrinkage rate between the first and second layers was observed when coating tablets and under severe and accelerated conditions. Furthermore, when the moisture content was less than 2.0% (Comparative Examples 2 and 3), the moisture content was insufficient at a constant tableting pressure, and the tablets were not able to secure sufficient hardness, resulting in easy breakage of the tablets. When the moisture content of the metformin granule layer (second layer) was 2.0 to 3.5 wt%, sufficient hardness was secured and no layer separation was observed.

[0072] Test Example 2: Evaluation of shrinkage rate based on the amount of colloidal silicon dioxide The tablets of Examples 5 to 19 below were produced by the same manufacturing method and formulation as in Test Example 1 above, except that the moisture content of the metformin granule layer and the colloidal silicon dioxide content were set to the conditions in Table 3 below, and the produced bilayer tablets were compressed to have the same hardness (20 kp). The compression pressure required to compress each bilayer tablet to have the same hardness (20 kp) was measured, and after compression, the properties of each tablet were observed to determine whether or not there was any tableting trouble. The difference in shrinkage rate of the produced bilayer tablets was also evaluated using the same method as in Test Example 1 above.

[0073] The required tableting pressure and the difference in tablet shrinkage rate for each bilayer tablet were measured, and the results are shown in Table 4 below. Based on the required tableting pressure and tablet shrinkage rate difference data obtained as the evaluation results, the required tableting pressure depending on the moisture content of the metformin granule layer is shown in Figure 2, and the difference in tablet shrinkage rate depending on the colloidal silicon dioxide content is shown in Figure 3. As a result of observing the properties of the produced composite tablets, it was found that in Examples 5 to 13 and Examples 17 to 19, smooth tablets were produced without any tableting problems (Figure 4: photograph of tablet in Example 6), and only in Examples 14 to 16 tableting problems such as capping or laminating occurred were observed.

[0074] [Table 3]

[0075] [Table 4]

[0076] FIG. 2 is a graph illustrating the required compression force (y-axis) as a function of the moisture content of the topormin granule layer (x-axis) measured for bilayer tablets containing various amounts of colloidal silicon dioxide and metformin granule layer moisture.

[0077] FIG. 3 is a graph illustrating the difference in tablet shrinkage (y-axis) as a function of colloidal silicon dioxide content (x-axis) measured for bilayer tablets containing various amounts of colloidal silicon dioxide and metformin granule layer moisture.

[0078] The results in Figure 2 indicate that, to ensure the same hardness of 20 kp, the more moisture in the metformin granules, the lower the required tableting pressure. Furthermore, based on the same granule moisture content, the greater the amount of colloidal silicon dioxide, the lower the required tableting pressure. Furthermore, in the cases of Examples 14, 15, and 16, it was found that the tableting pressure was 2,500 kN or higher. Tableting pressures of 2,500 kN or higher can cause tableting problems, such as capping and lamination, due to air release from within the tablets caused by excessive tableting pressure, especially in bilayer tablets. Therefore, it was confirmed that Examples with a tableting pressure of 2,500 kN or less are suitable.

[0079] Furthermore, the results shown in Figure 3 indicate that for each metformin granule moisture content, the difference in tablet shrinkage rate tends to decrease as the amount of colloidal silicon dioxide increases.

[0080] Taking the results of Figures 2 and 3 together, it can be seen that colloidal silicon dioxide acts as a stimulant for metformin when the metformin granules have a moisture content of 2.5 to 3.5% by weight, which corresponds to Examples 5 to 13 and Examples 17 to 19. validIt was confirmed that when colloidal silicon dioxide is contained in an amount of 0.7 to 3.5% by weight relative to the components, there are no problems with tableting properties and tablet shrinkage rate difference. Furthermore, according to Figure 1, which shows the results of Test Example 1, in the case of Example 4, it was confirmed that there are no problems with tableting properties and tablet shrinkage rate difference (criterion: 1% or less) by adjusting the tableting pressure to approximately 2,000 kN. Therefore, when colloidal silicon dioxide is contained in metformin granules with a moisture content of 2.5 to 3.5% by weight, valid It was evaluated that if the amount of the compound is 0.7 to 3.5% by weight relative to the ingredients and the tableting pressure is adjusted to 2,500 kN or less, specifically 2,000 to 2,500 kN, it is possible to obtain a composite tablet that has no problems with tableting properties and differences in tablet shrinkage rate.

[0081] Test Example 3: Evaluation of related substances based on the amount of colloidal silicon dioxide The stability of composite tablets over time was evaluated based on the amount of colloidal silicon dioxide by evaluating the amounts of sitagliptin and dapagliflozin analogues in Examples 5 to 7 and Comparative Examples 17 to 19. Specifically, the stability of each bilayer tablet was evaluated after 1, 2, and 4 weeks under severe conditions at 60°C. valid The total related substances of the components were measured.

[0082] The method for measuring the related substances is as follows.

[0083] Sample Production Five tablets prepared in the example were weighed and placed in a 1,000 mL volumetric flask. A magnetic bar and approximately 600 mL of diluent were added and stirred for 60 minutes to fully dissolve the tablets. The magnetic bar was then removed and the diluent was adjusted to the marked line. The resulting solution was filtered through a 0.45 μm membrane filter to prepare the test solution. The test was conducted under the following conditions:

[0084] mobile phase Solution A: pH 3.0 buffer solution, Solution B: acetonitrile (ACN) Diluent Mobile phase A solution: Mobile phase B solution = 60:40 HPLC conditions Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm, packed with a 2.7 μm C18 chromatography phase. Pump: 0.8mL / min Injection volume: 10 μL UV lamp: 220 nm Analysis time: 80 minutes

[0085] [Table 5]

[0086] The results are shown in Tables 6 and 7 below and are illustrated graphically in FIGS.

[0087] FIG. 5 is a graph showing the results of measuring the amount of total sitagliptin related substances over time for bilayer tablets containing various amounts of colloidal silicon dioxide and metformin granule layer moisture content under severe conditions at 60°C.

[0088] FIG. 6 is a graph showing the results of measuring the amount of total related substances of dapagliflozin over time for bilayer tablets containing various amounts of colloidal silicon dioxide and various amounts of moisture in the metformin granule layer under stress conditions at 60°C.

[0089] [Table 6]

[0090] [Table 7]

[0091] The standards of the United States Pharmacopoeia (USP) and existing commercially available single agents were applied, and the total related substances were set at 0.2% or less for sitagliptin and 2.0% or less for dapagliflozin.

[0092] According to the results of Tables 6 and 7 and Figures 5 and 6, in Examples 5, 6, and 7 containing colloidal silicon dioxide at 2.8 wt% or less, increases in sitagliptin and dapagliflozin related substances were within the standard range up to the 4-week severe test. In contrast, in Examples 17, 18, and 19 containing colloidal silicon dioxide at 3.5 wt%, increases in sitagliptin and dapagliflozin related substances exceeded or were close to the standard range at the 4-week severe test. Furthermore, generally, the increase in the amount of colloidal silicon dioxide was accompanied by an increase in the amount of sitagliptin and dapagliflozin related substances. Therefore, it was determined that using colloidal silicon dioxide at an amount of 2.8 wt% or less can ensure stability.

[0093] The present invention has been described above with reference to preferred embodiments. Those skilled in the art will recognize that the present invention may be embodied in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is defined by the claims, not the foregoing description, and all variations within the scope of the claims should be construed as being within the scope of the present invention.

Claims

1. Sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a first layer comprising dry granules comprising dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; a wet granule comprising metformin, or a pharmaceutically acceptable salt thereof, and a second layer comprising colloidal silicon dioxide; A composite tablet, wherein the colloidal silicon dioxide is present in an amount of 0.7 to 2.8% by weight relative to the metformin active ingredient, and the metformin wet granules in the second layer have a moisture content of 2.0 to 3.5% by weight.

2. 2. The composite tablet according to claim 1, wherein a difference in shrinkage rate between the first layer and the second layer is within 1%.

3. 2. The composite tablet according to claim 1, wherein the metformin wet granules of the second layer have a moisture content of 2.5 to 3.5% by weight.

4. The composite tablet according to claim 1, wherein the first layer contains sitagliptin phosphate and dapagliflozin L-proline as active ingredients.

5. 2. The composite tablet according to claim 1, wherein the second layer comprises metformin free base or metformin hydrochloride as an active ingredient.

6. The first layer is Microcrystalline cellulose (MCC), D-mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), crospovidone, cross-linked sodium carboxymethylcellulose (cross-linked CMC Na), magnesium stearate, fumaric acid 10. The composite tablet of claim 1, further comprising an excipient selected from the group consisting of sodium stearyl, and any combination thereof.

7. The second layer may contain hydroxypropyl methylcellulose, locust bean gum, microcrystalline cellulose, D-mannitol, sucrose, lactose, sorbitol, and xylitol.

10. The composite tablet of claim 1, further comprising an excipient selected from the group consisting of glucose, colloidal silicon dioxide, magnesium stearate, and any combination thereof.

8. 2. The composite tablet according to claim 1, wherein when the composite tablet is stored under harsh conditions at 60°C for 4 weeks, the total content of sitagliptin analogues is 0.2% by weight or less and the total content of dapagliflozin analogues is 2% by weight or less.

9. 2. The combination tablet according to claim 1, wherein the sitagliptin is contained in an amount of 25 to 100 mg as a free base, the dapagliflozin is contained in an amount of 5 to 10 mg as a free base, and the metformin is contained in an amount of 500 to 1,000 mg as a free base per unit dosage form.

10. preparing a blend comprising sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and excipients; dry granulating the blended portion; A step of further adding a lubricant to the obtained granules and mixing them to prepare a first mixed part; preparing metformin wet granulations comprising metformin, or a pharmaceutically acceptable salt thereof, and excipients; drying the resulting metformin wet granules; blending the dried metformin wet granules with colloidal silicon dioxide and a lubricant to produce a second blend part; and compressing the first mixed part into a first layer and the second mixed part into a second layer using a double-layer tablet press; 10. The method for producing a composite tablet according to claim 1, wherein the colloidal silicon dioxide is mixed in an amount of 0.7 to 2.8% by weight relative to the metformin active ingredient, and the metformin wet granules are dried to a moisture content of 2.0 to 3.5% by weight.

11. The method of claim 10, wherein the dry granulating step comprises forming a compact using a roller compactor.

12. The method according to claim 10, wherein the metformin wet granules are dried to a moisture content of 2.5 to 3.5% by weight.

13. The method according to claim 10, wherein the tableting pressure required for bilayer tableting in the tableting step is 2,000 to 2,500 kN.

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