KR20230152960A - A single-layered composite tablet comprising dapagliflozin and citagliptin - Google Patents

Abstract

The present invention relates to a single-layer composite tablet containing dapagliflozin and sitagliptin, the tablet composition, and a method for manufacturing the same.

Description

{A single-layered composite tablet comprising dapagliflozin and citagliptin}

The present invention relates to a single-layer composite tablet containing dapagliflozin and sitagliptin, the tablet composition, and a method for manufacturing the same.

Dapagliflozin and sitagliptin are SGLT-2 and DPP-4 inhibitors, respectively, and are leading drugs in the type 2 diabetes treatment market, respectively, under the brand names Forxiga™ and Januvia®. It is on the market.

In order to administer dapagliflozin and sitagliptin in combination, there is the inconvenience of having to take the two products separately, and to improve medication compliance, it is necessary to provide a complex tablet that combines the two drugs into one.

These complex tablets can be broadly classified into two types. The first is a single-layer tablet in which both main ingredients exist in a single matrix, and the second is a two-layer tablet in which the main ingredients exist in separate matrices.

Double-layer tablets are being developed for reasons such as the efficiency of controlling the release of two components and minimizing the generation of impurities due to interaction, but the manufacturing of double-layer tablets requires a lot of man-hours and it is difficult to avoid the problem of poor medication compliance due to the increase in tablet size.

Furthermore, in the case of a single-layer tablet of sitagliptin and dapagliflozin, the content ratio of the two drugs is approximately 10:1, and the content of dapagliflozin is significantly less than that of sitagliptin. Therefore, when manufacturing single-layer composite tablets by the dry granulation method, the heterogeneity in the content of dapagliflozin for each tablet may increase. To solve this non-uniformity, granules can be manufactured using the wet granulation method and manufactured into tablets. However, dapagliflozin or sitagliptin are known to be unstable in the granulation liquid, so despite the advantages of the wet granulation method, this has not been attempted. . In the present invention, the stability problem of the drug was solved by selecting hydroxypropyl cellulose, croscarmellose sodium, and an appropriate solvent, and it was possible to manufacture tablets by the wet granulation method.

Accordingly, we aim to provide a new single-layer composite tablet that improves drug compliance and drug uniformity and release control between tablets, and minimizes the generation of impurities.

One aspect of the present invention is prepared by a wet granulation method, comprising dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof. Provided is a single-layer composite tablet.

Another aspect of the present invention is a single-layer composite tablet using wet granules containing dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof. As a composition for use, the angle of repose of the composition is 36.5° or less, and the Carr's index is 20% or less.

Another aspect of the present invention is to provide a solvent to a composition containing dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof to form granules. manufacture,

Drying the prepared granules,

Adding and mixing pharmaceutically acceptable excipients to the dried granules,

A method for producing a single-layer composite tablet comprising compressing the mixture,

The present invention relates to a method for producing a single-layer composite tablet in which the angle of repose of the mixture is 36.5° or less and the Carr's index is 20% or less.

The single-layer composite tablet according to one aspect of the present invention can be safely and effectively applied to a subject by increasing drug compliance while having good release control ability and minimizing the generation of impurities.

The method for producing a single-layer composite tablet according to one aspect of the present invention has a simple manufacturing process, which can improve economic efficiency, and provides a tablet that is reduced in size compared to the conventional tablet to be administered once a day, thereby increasing the convenience of administration.

The single-layer composite tablet according to one aspect of the present invention has excellent uniformity of the two drug components for each tablet and minimizes the generation of impurities due to interaction with excipients.

Figure 1 is a graph of the dissolution rate of dapagliflozin and sitagliptin according to each pH of tablets according to one embodiment of the present invention.

One aspect of the present invention is a monolayer prepared by a wet granulation method comprising dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof. A composition for complex tablets is provided.

The composition further includes hydroxypropylcellulose and croscarmellose sodium. In the present invention, as a result of testing various pharmaceutically acceptable excipients, it was found that single-layer composite tablets can be manufactured by wet granulation method when the above excipients are used. The weight ratio of the hydroxypropyl cellulose and croscarmellose sodium is 3:7 to 6:4, specifically 4:6 to 5:5. This can provide appropriate flowability and appropriate dissolution rate for tableting. The hydroxypropyl cellulose and croscarmellose sodium may be 3% to 10% by weight, specifically 4% to 8% by weight, more specifically 4% to 7% by weight, based on the total weight of the composition. It may be in the range of weight percent. The hydroxypropyl cellulose may be 1% by weight to 5% by weight based on the total weight of the composition, specifically 1.5% by weight to 4% by weight, more specifically 2% by weight to 4% by weight. You can. The above range is related to improving the flowability of the composition.

The composition has an angle of repose of 36.5° or less and a Carr's index of 20% or less. Specifically, the angle of repose is 30° to 36°, and Carr's index is 15% to 19%. The angle of repose and Carr's index are indicators of flowability, and the above range is related to the possibility of tableting and formulation into single-layer composite tablets. The flow parameters were measured for a mixture of granules prepared by the wet granulation method and other pharmaceutically acceptable excipient powders, and the granules were contained in an amount of 40% by weight to 70% by weight, specifically 50% by weight to 50% by weight of the mixture. It may be included in the range of 65% by weight.

The composition may further include a solvent, and the solvent may be used to produce wet granules. Examples of solvents may be water, ethanol, isopropanol, methylene chloride, methanol, etc. Since the solvent is removed by drying, it may not be present in the final composition or may be present in trace amounts.

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

The pharmaceutically acceptable salt refers to any pharmaceutically acceptable salt that can be commonly used in the art. In one embodiment, the sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be sitagliptin phosphate hydrate. In one embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be a pharmaceutically acceptable co-crystal of dapagliflozin. In one embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof may be dapagliflozin L-proline or dapagliflozin propanediol.

In one embodiment, the sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be included in 10 to 45% by weight, for example, 20 to 40% by weight, of the total weight of the composition. In one embodiment, the dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be included in 1 to 10% by weight, for example, 2 to 8% by weight, of the total weight of the composition.

In one embodiment, the composition may include additional pharmaceutically acceptable excipients in addition to hydroxypropylcellulose and croscarmellose sodium. The excipients may be included in 10 to 40% by weight, for example, 15 to 35% by weight of the total weight of the composition.

Such excipients may include diluents, binders, lubricants, disintegrants, or any combination thereof.

In one embodiment, the diluent is D-mannitol, calcium carbonate, dicalcium phosphate, tricalcium phosphate, powdered cellulose, lactitol, starch, sucrose, pregelatinized starch, microcrystalline cellulose, and any combinations thereof. Can be selected from the group consisting of.

In one embodiment, the binder is hydroxyethylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, sucrose, methylcellulose, ethylcellulose, maltodextrin, gelatin, sorbitol, xylitol, glucose, and It may be selected from the group consisting of any mixture, but is not limited thereto.

In one embodiment, the lubricant is magnesium stearate, talc, sodium lauryl sulfate, stearic acid, glyceryl palmitostearate, glyceryl monostearate, sodium stearyl fumarate, polyethylene glycol 4000, starch, and any mixtures thereof. It may be selected from the group consisting of, but is not limited to this.

In one embodiment, the disintegrant may be selected from the group consisting of cross-linked sodium carboxymethylcellulose, corn starch, calcium carboxymethylcellulose, sodium starch glycolate, and mixtures thereof, but is not limited thereto.

The composition can be manufactured as a single-layer composite tablet by wet granulation. In the present invention, dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, especially dapagliflozin propanediol hydrate or sitagliptin or a pharmaceutically acceptable salt thereof or a hydrate thereof, has the fluidity of the raw material itself. It was found that the wet granulation process was preferable to ensure mixing uniformity within the product. For example, when manufacturing tablets containing dapagliflozin, sitagliptin, or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient during mass production, granules are manufactured using a wet granulation method and then crushed. It is desirable to determine the uniformity of mixing of the two drugs and to ensure the desired hardness of the tablet. More specifically, when dapagliflozin or sitagliptin is manufactured by simply mixing it without a wet granulation process, the stability of dapagliflozin or sitagliptin can be secured to some extent, but each tablet The uneven content increases for each product, making high-speed production difficult, and as a result, mass production is not easy. In addition, it is not easy to secure appropriate hardness when manufacturing tablets through simple mixing or dry granulation methods, and as a result, many excipients must be added. In the case of dry granulation, non-uniform sludge may be produced depending on the deviation of the compression roller, and in this case, non-uniformity in the content of active ingredients may further increase. In the case of a combination preparation of sitagliptin and dapagliflozin, the content ratio is approximately 10:1, and the content of dapagliflozin is significantly lower than that of sitagliptin, which may increase the unevenness of the content of dapagliflozin in each tablet. . This content unevenness can be resolved when granules are manufactured using the wet granulation method and then manufactured into tablets. However, dapagliflozin or sitagliptin are known to be unstable in the granulation liquid, so despite the advantages of the wet granulation method, this is not an attempt. It didn't work. In the present invention, the stability problem of the drug was solved by selecting hydroxypropyl cellulose, croscarmellose sodium, and an appropriate solvent, and it was possible to manufacture tablets by the wet granulation method.

Another aspect of the present invention is dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, sitagliptin or a pharmaceutically acceptable salt or hydrate thereof, hydroxypropylcellulose and croscarmellose sodium. Provided is a single-layer composite tablet composition prepared by a wet granulation method, comprising:

Another aspect of the present invention is dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, sitagliptin or a pharmaceutically acceptable salt or hydrate thereof, hydroxypropylcellulose, croscarmellose. Provided is a single-layer composite tablet composition containing sodium, D-mannitol, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and magnesium stearate, manufactured by a wet granulation method. The composition does not contain low-substituted hydroxypropylcellulose, povidone K-30, and/or sodium stearyl fumarate.

Another aspect of the present invention is dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt thereof prepared by a wet granulation method from the composition described in the present invention. Provided is a single-layer composite tablet containing a salt or a hydrate thereof.

The tablets may be manufactured by compressing the composition into tablets, and may be additionally coated with a coating agent.

The tablet may be an oblong oval tablet, and the longest horizontal axis length may be in the range of 13.2 to 14.2 mm, the longest vertical minor axis length may be in the range of 7.2 to 8.0 mm, and the longest thickness may be in the range of 4.3 to 4.7 mm.

Another aspect of the present invention is to provide a solvent to a composition containing dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof. manufacturing granules

Drying the prepared granules,

Adding and mixing pharmaceutically acceptable excipients to the dried granules,

A method for producing a single-layer composite tablet comprising compressing the mixture,

The present invention relates to a method for producing a single-layer composite tablet in which the angle of repose of the mixture is 36.5° or less and the Carr's index is 20% or less.

Specifically, a solvent is provided to a composition containing dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof, for example, in a high-speed mixer. Add and mix to produce granules. The composition may further include hydroxypropylcellulose. The composition may further include pharmaceutically acceptable excipients. Examples of the excipient include D-mannitol.

The prepared granules are then dried at a temperature of 40°C to 70°C, specifically 40°C to 60°C for 30 minutes to 6 hours, specifically 60 minutes to 3 hours.

A process of arbitrarily sizing the dried granules can be added. The sizing may include uniformizing the granule size by rotating a perforated network of 0.1 mm to 15 mm, specifically 0.5 mm to 5 mm, at a rotation speed of 100 rpm to 1000 rpm.

Pharmaceutically acceptable excipients may be added to the dried or sized granules and mixed. Pharmaceutically acceptable excipients may include croscarmellose sodium, and other diluents, binders, lubricants, disintegrants, or any combination thereof may be added. Descriptions of diluents, binders, lubricants, disintegrants, etc. that can be used are the same as those described above. In one example, pharmaceutically acceptable excipients include microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and magnesium stearate.

Tablets can be manufactured by compressing the mixture in a tablet press. The tableting conditions may be a tableting pressure of 15 to 21 kN, specifically 16 to 20 kN, a disk speed of 1 to 50 rpm, and a feeder speed of 1 to 50 rpm.

The mixture may be a mixture of granules prepared by a wet granulation method and pharmaceutically acceptable excipients in powder form, and the angle of repose of the mixture is 36.5° or less and the Carr's index is 20% or less.

When the parameters, which are indicators of the flowability of the mixture, are within the above range, compression into tablets is possible.

Thereafter, the prepared tablets can be optionally coated. The coating agent may be a known coating agent such as Opadry.

Hereinafter, the present invention will be described in detail by examples. However, these examples are merely illustrative, and the scope of the present invention is not limited by the examples.

Examples 1 to 4: Single-layer composite tablet containing dapagliflozin and sitagliptin

The tablets of Examples 1 to 4 were prepared by using the compositions in Table 1 below according to the method in Table 2:

Raw material Ingredient name Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative example 2 One Dapagliflozin propanediol hydrate chief ingredient 12.30 12.30 12.30 12.30 12.30 12.30 2 Sitagliptin phosphate hydrate chief ingredient 128.50 128.50 128.50 128.50 128.50 128.50 3 D-mannitol excipient 70.00 70.00 70.00 70.00 70.00 70.00 4 Low-substituted hydroxypropyl cellulose binder - - - - 40.00 - 5 Povidone K-30 binder - - - - - 9.60 6 Hydroxypropylcellulose binder 10.00 10.00 10.00 7.00 - - 7 Microcrystalline cerulose excipient 111.05 113.55 116.05 114.05 81.05 111.45 8 Anhydrous Calcium Hydrogen Phosphate excipient 70.00 70.00 70.00 70.00 70.00 70.00 9 Croscarmellose Sodium disintegrant 15.00 12.50 10.00 15.00 15.00 15.00 10 Magnesium stearate lubricant 3.15 3.15 3.15 3.15 3.15 3.15 11 coating agent opadry pink 16.00 16.00 16.00 16.00 16.00 16.00 Total 436.00 436.00 436.00 436.00 436.00 436.00

*Unit: mg

Process Name equipment detail granulation High Speed Mixer (PTK / PM-C)- Agitator speed: 130 rpm
- Chopper speed: 3000 rpm
- Time: 60 ± 30 seconds Raw materials 1 to 6 of Table 1 and the binding solvent (ethanol) are added to a high-speed mixer and granulated. dry Top type electric heat dryer (Vision Biotech) - Temperature: 50℃
- Time: 90 ± 20 minutes The granulated material is placed in a dryer and dried under the above conditions. Formulations Cone-mill (Techsub / TSR130)- Perforated mesh: 1.5 mm
- Rotation speed: 400 rpm The dried material is added and established under the above conditions. Post-mixing (1) Drum mixer - rotation speed: 16 rpm
- Time: 15 minutes ± 1 minute The above sized product and raw materials 7 to 9 of Table 1 are placed in a drum mixer and mixed under the above conditions. Post-mixing (2) Drum mixer - rotation speed: 16 rpm
- Time: 4 minutes ± 1 minute The above mixture and raw material 10 of Table 1 are placed in a drum mixer and mixed under the above conditions. tabletting Rotary tablet press (Sejong / P130S) - Disk speed: 25 rpm
- Feeder speed: 25 rpm
- Main pressure: 18 ± 1 kN The mixture is compressed into tablets under the above conditions. coating Coating machine (Junjin / JAC450F) - Supply air temperature: 45 ± 5℃
- Purification temperature: 38 ℃ The tablet is coated under the above conditions.

Comparative Examples 1 to 2

Tablets of Comparative Examples 1 to 2 were prepared by using the compositions in Table 1 according to the method in Table 2.

Experiment example

Angle of repose and Kar index measurements

Among the processes in Table 2, post-mixing (2) before tableting was performed, and the angle of repose and Kar's index were measured for the composition, and the results are shown in Table 3:

item Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 angle of repose 35.7° 35.6° 35.9° 36.4° 41.5° 38.4° Kar index 18.57% 18.65% 18.69% 19.54% 31.74% 20.59%

The composition of Comparative Example 1 using L-HPC as a binder or the composition of Comparative Example 2 using povidone had poor flowability, which was caused by L-HPC or povidone not sufficiently wetting between the main ingredient and the additive and not binding evenly. It appears that On the other hand, the compositions of Examples 1 to 4 using HPC (hydroxypropylcellulose) as a binder had an angle of repose of 36.5° or less and a Carr's index of 20% or less, showing good flowability. The compositions of Examples 1 to 3, where the HPC usage amount was about 2.4%, had better flowability than the composition of Example 4, where the HPC usage amount was about 1.7%.

Evaluation of mixing compatibility of main ingredients and additives

For the purpose of confirming whether various additives selected during the above manufacturing process development process affect the stability of the main ingredient, the compatibility of the mixture was confirmed.

Mix the main ingredient and each compounding agent at a weight ratio of 1:1 using the formulation shown in Table 4 below, store it in harsh conditions for 4 weeks, measure the content of individual flexible substances and total flexible substances (using HPLC), and the results are shown in the table. 5 and Table 6. The standard for individual related substances of dapagliflozin is 0.2% by weight or less and the total related substances is 1.0% by weight or less, and the standard for individual related substances of sitagliptin is 0.2% by weight or less and the total related substances is 0.7% by weight or less. .

chief ingredient Dapagliflozin propanediol hydrate chief ingredient Sitagliptin phosphate hydrate Mixing agent 1 Sitagliptin phosphate hydrate Compound 8 Dapagliflozin propanediol hydrate Compounding agent 2 D-mannitol Compounding agent 9 D-mannitol Compounding agent 3 Microcrystalline cerulose Compounding agent 10 Microcrystalline cerulose Compounding agent 4 Anhydrous Calcium Hydrogen Phosphate Compound 11 Anhydrous Calcium Hydrogen Phosphate Compounding agent 5 Hydroxypropylcellulose Compound 12 Hydroxypropylcellulose Compounding agent 6 Crocarmellose Sodium Compound 13 Croscarmellose Sodium Compounding agent 7 Magnesium stearate Compound 14 Magnesium stearate Storage conditions 50℃ (humidity conditions?) Storage conditions 70℃ (humidity conditions?)

chief ingredient Dapagliflozin propanediol hydrate Early 2 weeks 4 weeks Mixing agent 1 Sitagliptin phosphate hydrate N.D. N.D. N.D. Compounding agent 2 D-mannitol N.D. N.D. N.D. Compounding agent 3 Microcrystalline cerulose N.D. N.D. N.D. Compounding agent 4 Anhydrous Calcium Hydrogen Phosphate N.D. N.D. N.D. Compounding agent 5 Hydroxypropylcellulose N.D. N.D. N.D. Compounding agent 6 Croscarmellose Sodium N.D. N.D. N.D. Compounding agent 7 Magnesium stearate N.D. N.D. N.D.

chief ingredient Sitagliptin phosphate hydrate Early 2 weeks 4 weeks Compound 8 Dapagliflozin propanediol hydrate 0.050% 0.075% 0.029% Compounding agent 9 D-mannitol N.D. 0.072% N.D. Compounding agent 10 Microcrystalline cerulose 0.043% 0.075% 0.023% Compound 11 Anhydrous Calcium Hydrogen Phosphate 0.029% 0.076% 0.033% Compound 12 Hydroxypropylcellulose 0.042% 0.099% N.D. Compound 13 Croscarmellose Sodium 0.037% 0.075% 0.028% Compound 14 Magnesium stearate N.D. 0.098% N.D.

N.D.: Not Detected

From the above results, it was confirmed that there were no additives that significantly affected the generation of impurities in the main ingredient, and it was also confirmed that there were no significant impurities generated due to harsh environments or storage for a certain period of time.

Comparative dissolution test

In order to predict the results of phase 1 clinical trials (in vivo), a dissolution test was performed on the tablets of Examples 1 to 3 prepared with different amounts of disintegrants using the following method to confirm similarity in release rate. Here, the control drug was eluted by placing 10 mg of Forxi tablets and 100 mg of Januvia tablets in a rotating sample container, and the tablets of Examples 1 to 3 as test drugs were eluted according to the rotating sample container method:

- Equipment used: Distek, Evolution 6300 elutor - Sample: 6 tablets each (control drug / test drug)

- Dissolution test method: Method 1 (rotating sample container method, Basket), 75 rpm

- Temperature: 37℃

- Dissolution test solution: Ministry of Food and Drug Safety comparative dissolution test solution (pH 1.2 solution / pH 4.0 solution / pH 6.8 solution), 900 mL each

* pH 1.2 solution: Dissolve 2.0 g of sodium chloride with 7.0 mL of hydrochloric acid and water to make 1000 mL. At this time, the pH is about 1.2.

* pH 4.0 solution: Use 0.05 mol/L sodium acetate buffer [0.05 mol/L acetic acid·0.05 mol/L sodium acetate mixture (82:18)].

* pH 6.8 solution: Add 118 mL of 0.2 mol/L sodium hydroxide solution and water to 250 mL of 0.2 mol/L potassium dihydrogen phosphate solution to make 1000 mL. At this time, the pH is about 6.8.

- Analysis method: HPLC method

Test result

As a result of examining the PK data of the main ingredients as a preliminary work before in vitro testing, it was confirmed that the Tmax (time to reach maximum concentration in blood) of dapagliflozin was approximately 0.5 to 0.75 hr. Since it has the characteristic of being absorbed into the body relatively quickly, the dissolution rate during the first 5 to 15 minutes was mainly checked in the dissolution results. In the following dissolution graph of dapagliflozin, the tablets of Examples 2 and 3 were similar to the reference drug, but considering the dissolution rate in the first 5 minutes, the tablets of Example 2 showed the most similar results to the reference drug.

On the other hand, sitagliptin is a BCS class I drug, known as a drug with excellent dissolution and absorption in the body, and has a Tmax of about 1.5 hr. Considering this, it was decided to exclude the tablet of Example 1 from the final candidates. This is because from the beginning, there were concerns that if the release rate was excessive, the absorption rate in the body would increase and the time to reach Tmax would be shortened.

Considering the above results comprehensively, the tablet of Example 2 was finally selected and it was decided to conduct a phase 1 clinical trial on it.

tablet stability

To predict the stability of the tablets of Example 2 when packaged in the same manner as commercially available and stored under accelerated conditions, tablet stability was evaluated using the following method.

○ Test method

- Specimen preparation and storage methods

→ Packaging: 30 tablets bottled (bottle: HDPE / cap: LDPE)

→ Storage conditions: 40℃ / 75% RH

HPLC method was used as the analysis method.

The standard for individual related substances of dapagliflozin is 0.2% by weight or less, and the standard for total related substances is 1.0% by weight or less. The standard for individual related substances of sitagliptin is 0.2% by weight or less, and the standard for total related substances is 0.7% by weight or less.

The test results are shown in Tables 7 and 8 below:

item Early 3 months 4-bromo analogues N.D. 0.0 Methoxy impurity N.D. N.D. acetyl impurity N.D. N.D. bromine compound N.D. N.D. Other individual related substances (max) 0.0% 0.1% Total related substances 0.0% 0.4%

item Early 3 months impurity B N.D. N.D. impurity C N.D. N.D. Impurity E N.D. N.D. Other individual related substances (max) N.D. N.D. Total related substances N.D. N.D.

N.D. : Not Detected

Phase 1 clinical PK trial

The following test was conducted to evaluate whether equivalent pharmacological effects were observed in the body through PK analysis in the blood of test subjects who administered the control drug (Forxi Tablet 10 mg, Januvia Tablet 100 mg) and the tablet of Example 2.

The test method is shown in Table 9 below:

Test type BE (Phase 1 clinical trial) test design Single oral administration, randomized 2×2 crossover test Ingredients and Dosage Dapagliflozin 10 mg, Sitagliptin 100 mg test subject 35 healthy adult subjects

The PK experiment results are shown in Tables 10 and 11 below:

Dapagliflozin 10 mg (12.30 mg as dapagliflozin propanediol hydrate) Least Squares Geometric Means, Ratio of Means, 90% Confidence Intervals and acceptance criteria of 90% confidence intervals Parameter GLSM GLSM Ratio (test drug/reference drug) test drug control drug Point Estimate 90% Confidence Interval AUCt(hr·ng/mL) 485.6 482.6 1.0064 0.9768 1.0369 Cmax (ng/mL) 144.8 144.0 1.0051 0.8885 1.1370

In Table 10, for AUCt, the point estimate, which is the two ratios, is log1.0064 and 90% C.I is log0.9768 to log1.0396, and for Cmax, the point estimate, which is the two ratios, is log1.0051 and 90% C.I is log0. It is .8885 ~ log1.1370, which is within the Ministry of Food and Drug Safety standard of log0.8 ~ log1.25, so it appears to satisfy bioequivalence.

Sitagliptin 100 mg (128.50 mg as sitagliptin phosphate hydrate) Least Squares Geometric Means, Ratio of Means, 90% Confidence Intervals and acceptance criteria of 90% confidence intervals Parameter GLSM GLSM Ratio (test drug/reference drug) test drug control drug Point Estimate 90% Confidence Interval AUCt(hr·ng/mL) 3329 3323 1.0018 0.9777 1.0264 Cmax (ng/mL) 415.6 412.5 1.0076 0.9253 1.0971

In Table 11, for AUCt, the point estimate, which is the two ratios, is log1.0018 and 90% C.I is log0.9777 to log1.0264, and for Cmax, the point estimate, which is the two ratios, is log1.0076 and 90% C.I is log0. It is .9253 ~ log1.0971, which is within the Ministry of Food and Drug Safety standards of log0.8 ~ log1.25, so it appears to satisfy bioequivalence.

From the above results, it can be seen that the single-layer composite tablet of the present invention was successful in controlling the drug release rate of dapagliflozin and sitagliptin, and based on this, the control drug and the test drug were tested in a phase 1 clinical trial conducted on healthy adults. It was possible to prove that the pharmacological effects of the drugs were similar. Furthermore, through verification of compatibility and tablet stability tests, it was confirmed that each of the ingredients was stable even when the two ingredients existed in a single matrix.

Claims (9)

A single-layer composite tablet containing dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof, manufactured by a wet granulation method. The method of claim 1, wherein when the single-layer composite tablet is stored for 3 months under harsh conditions of 40°C and 75% RH, the content of individual related substances of dapagliflozin or its pharmaceutically acceptable salt or hydrate thereof is as follows. Based on the weight, it is 0.2% by weight or less, the total related substances content is 1.0% by weight or less, and the content of individual related substances of sitagliptin or its pharmaceutically acceptable salt or hydrate thereof is 0.2% by weight based on the tablet weight. % or less, and the total related substances content is 0.5% by weight or less. The single-layer composite tablet according to claim 1, wherein the solvent for the wet granulation method is water, ethanol, isopropanol, methylene chloride, or methanol. The method according to any one of claims 1 to 3, wherein the tablet further comprises hydroxypropylcellulose and croscarmellose sodium, and the weight ratio of the hydroxypropylcellulose and croscarmellose sodium Monolayer composite tablet, with a ratio of 3:7 to 6:4. A single-layer composite tablet composition containing dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof, wherein the angle of repose of the composition is 36.5° or less. and a Carr's index of 20% or less, a composition for single-layer composite tablets by wet granulation. The method of claim 5, wherein the composition further comprises hydroxypropylcellulose and croscarmellose sodium, and the weight ratio of the hydroxypropylcellulose and croscarmellose sodium is 3:7 to 6:4. Composition for single-layer composite tablets. The composition for single-layer composite tablets according to claim 6, wherein the hydroxypropylcellulose and croscarmellose sodium are in an amount of 3% to 10% by weight based on the total weight of the composition. Providing a solvent to a composition containing dapagliflozin or a pharmaceutically acceptable salt or hydrate thereof, and sitagliptin or a pharmaceutically acceptable salt or hydrate thereof to prepare granules,
Drying the prepared granules,
Adding and mixing pharmaceutically acceptable excipients to the dried granules,
A method for producing a single-layer composite tablet comprising compressing the mixture,
A method for producing a single-layer composite tablet, wherein the angle of repose of the mixture is 36.5° or less and the Carr's index is 20% or less. The method for producing a single-layer composite tablet according to claim 8, wherein the mixture further contains hydroxypropylcellulose and croscarmellose sodium.