Pharmaceutical composition containing inabogliflozin

Abstract

The present invention relates to a pharmaceutical composition comprising inavogliflozin, a selective inhibitor of sodium-glucose cotransporter 2. The pharmaceutical composition comprising the compound of Chemical Formula 1 according to the present invention can realize a formulation having excellent content uniformity, formulation uniformity, dissolution profile, etc., despite containing a low dose of a drug.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing empagliflozin, a selective inhibitor of sodium-glucose cotransporter 2.

Background Art

[0002] SGLT2 (Sodium-glucose cotransporter 2) inhibitors are a new type of antihyperglycemic agent. SGLT-2 inhibitors reduce glucose reabsorption in the proximal nephron and increase glucose excretion through a mechanism independent of insulin. The safety and efficacy of SGLT2 inhibitors for the treatment of type 2 diabetes have been confirmed in many studies.

[0003] In particular, US Patent Publication No. 2015 / 0152075 discloses empagliflozin of the following Chemical Formula 1 as a compound having a diphenylmethane residue showing inhibitory activity against SGLT2, and the said document discloses that empagliflozin is excellent in the inhibitory effect on human SGLT2 activity and effective in the treatment of diabetes.

[0004]

Chemical Formula

[0005] Empagliflozin is a drug currently in the third phase of clinical trials. As a result of the phase 2 clinical trial, a statistically significant blood glucose reduction effect has been confirmed in all of the dosing groups of empagliflozin at 0.1 mg, 0.3 mg, and 0.5 mg as compared with the placebo.

[0006] This drug is considered to have demonstrated excellent efficacy in promoting urinary glucose secretion (glucose excreted in the urine) at an extremely low dose, which is 1 / 100th the dose of similar drugs. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent Publication No. 2015 / 0152075 [Non-patent literature]

[0008] [Non-Patent Document 1] Pharmaceutical dosage forms:volume 2,2nd edition,Ed.:HALieberman,L.Lachman,JBSchwartz(Chapter 3:SIZE REDUCTION) [Overview of the project] [Problems that the invention aims to solve]

[0009] As mentioned above, inabogliflozin was found to exhibit excellent blood glucose-lowering effects even at very low doses, and it was recognized that problems such as dissolution profile, content uniformity, and formulation uniformity that arise when manufacturing pharmaceutical compositions containing small amounts of the active ingredient must be addressed. [Means for solving the problem]

[0010] As a result of various studies on the formulation of inabogliflozin, the inventors have confirmed that problems such as the dissolution profile, content uniformity, and formulation uniformity of inabogliflozin-containing formulations can be solved by configuring the composition of the pharmaceutical composition as follows.

[0011] Specifically, the present invention provides a pharmaceutical composition comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant, and a binder as an active ingredient, wherein the average particle size of the compound of chemical formula 1 is 15 μm or less.

[0012] [ka]

[0013] Due to the characteristics of inabogliflozin as a drug used in the treatment of diabetes, it is preferable that it be formulated as an immediate-release type. However, as shown in the examples below, it was confirmed that the drug dissolution profile changes significantly depending on the average particle size of inabogliflozin.

[0014] In a specific example of the present invention, the average particle size of inabogliflozin may be 15 μm or less, preferably 10 μm or less.

[0015] When the average particle size of inabogliflozin exceeded 15 μm, the 5-minute dissolution rate was very low, less than 40% of the total inabogliflozin content, and the 30-minute dissolution rate was also less than 80%, indicating that the final dissolution rate was unsuitable.

[0016] When further pulverization of drug particles is required, the drug can be ground using conventional mills capable of pulverizing particles, such as Z-mills, hammer mills, ball mills, and fluid energy mills. Alternatively, the particle size can be further refined using sieving or air current classification methods. Methods for adjusting the desired particle size are well-known in the industry. For example, see the following reference: [Pharmaceutical dosage forms: volume 2, 2nd edition, Ed.: HALieberman, L. Lachman, JBSchwartz (Chapter 3: SIZE REDUCTION)].

[0017] In this specification, the particle size of a drug is expressed in terms of a particle size distribution such as D(X)=Y (where X and Y are positive numbers). D(X)=Y means that when the particle size distribution of a drug obtained by measuring the particle diameter of any drug in a formulation is shown by a cumulative curve, Y is the particle diameter at the point where the cumulative percentage of the drug's particle sizes, in ascending order, reaches X% (where % is calculated based on number, volume, or weight). For example, D(10) represents the particle diameter at the point where the cumulative percentage of the drug's particle sizes, in ascending order, reaches 10%, D(50) represents the particle diameter at the point where the cumulative percentage of the drug's particle sizes, in ascending order, reaches 50%, and D(90) represents the particle diameter at the point where the cumulative percentage of the drug's particle sizes, in ascending order, reaches 90%.

[0018] Whether the particle size distribution D(X) indicates the percentage in the total cumulative particles based on number, volume, or weight depends on the method used to measure the particle size distribution. Methods for measuring the particle size distribution and the types of % associated with them are well known in the art. For example, when measuring the particle size distribution by the well-known laser diffraction method, in D(X), the X value indicates the percentage calculated by volume average. Those skilled in the art are well aware that the measurement results of the particle size distribution obtained by a specific method can be correlated with those obtained from other techniques based on experience through ordinary experiments. For example, the laser diffraction method is sensitive to the volume of particles and provides a volume average particle size, which corresponds to the weight average particle size when the density is constant.

[0019] In the present invention, the measurement of the particle size distribution of drug particles can be carried out using a commercially available device based on the laser diffraction and scattering method based on Mie theory. For example, it is measured using a commercially available device such as the Mastersizer laser diffraction device of Malvern Instruments. When this device irradiates a helium-neon laser beam and a blue light-emitting diode onto the particles, scattering occurs, and a light scattering pattern appears on the detector. The particle diameter distribution is obtained by analyzing this light scattering pattern according to Mie theory. The measurement method can be either the dry method or the wet method.

[0020] For reference, in the examples of the present invention, the particle size of the drug was measured by the volume average particle size by the laser diffraction method.

[0021] In a specific example of the present invention, the compound of Chemical Formula 1 above may be contained in less than 1 part by weight based on 100 parts by weight of the total pharmaceutical composition.

[0022] The appropriate once-daily dosing dose of inaboglivozin grasped during the clinical trial process is 0.1 mg to 0.5 mg. When the pharmaceutical composition is formulated in a unit dosage form, the content of the active ingredient in the pharmaceutical composition can be 0.1 to 0.5 mg.

[0023] The pharmaceutical composition according to the present invention contains a compound of chemical formula 1, which is the active ingredient, as well as pharmaceutically acceptable additives.

[0024] The pharmaceutical composition of the present invention includes excipients, disintegrants, and binders as additives.

[0025] Examples of excipients include lactose (including hydrate), dextrin, mannitol, sorbitol, starch, and microcrystalline cellulose [e.g., Cellfia]. TM (Celphere TM )], silicified microcrystalline cellulose, for example, Prosolve TM (Prosolv TM ), calcium phosphate hydrate, anhydrous calcium phosphate, calcium carbonate, sugars, or mixtures thereof. In specific examples of the present invention, a preferred excipient is microcrystalline cellulose.

[0026] Examples of disintegrants include crospovidone, croscarmellose sodium, sodium starch glycolate, and low-substituted hydroxypropyl cellulose. In specific examples of the present invention, a preferred excipient is croscarmellose sodium.

[0027] Examples of binders include polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose (e.g., hydroxypropylmethylcellulose), and mixtures thereof. In specific examples of the present invention, a preferred binder is hydroxypropylcellulose.

[0028] Other examples of additives include lubricants and colorants.

[0029] The lubricant includes stearic acid, stearate (e.g., magnesium stearate), light anhydrous silicic acid, talc, corn starch, carnauba wax, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white wax, titanium dioxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof.

[0030] In a specific example of the present invention, the excipient may be included in an amount of 80 to 95 parts by weight per 100 parts by weight of the total pharmaceutical composition.

[0031] In a specific example of the present invention, the disintegrant may be present in an amount of 2 to 8 parts by weight per 100 parts by weight of the total pharmaceutical composition. If the amount of disintegrant is less than 2 parts by weight per 100 parts by weight of the total pharmaceutical composition, the initial disintegration force may be low and the dissolution rate may be delayed, which can affect the body's Cmax. If the amount exceeds 8 parts by weight per 100 parts by weight of the total pharmaceutical composition, the amount of disintegrant in the post-mixing portion will be large, which may reduce the overall flowability of the granules.

[0032] In specific examples of the present invention, the binder may be included in an amount of 3 to 10 parts by weight per 100 parts by weight of the total pharmaceutical composition. If the amount of binder is less than 3 parts by weight per 100 parts by weight of the total pharmaceutical composition, it may be difficult to form and maintain suitable dry granules, which can affect the maintenance of homogeneous dispersion of the main component and the flowability of the granules due to the generation of fine powder. Furthermore, if the amount exceeds 10 parts by weight per 100 parts by weight of the total pharmaceutical composition, granules with strong binding force are formed, which affects the solubility of the granule particles that initially disintegrate during dissolution, and this can also affect the Cmax in the body.

[0033] The pharmaceutical composition according to the present invention is classified as an immediate-release formulation.

[0034] In one specific example of the present invention, the pharmaceutical composition may have a 5-minute dissolution rate of 50% or more, preferably 60% or more, of the total content of the active ingredient.

[0035] In one specific example of the present invention, the pharmaceutical composition may have a 15-minute dissolution rate of 80% or more of the total content of the active ingredient, preferably 80% or more.

[0036] In one specific example of the present invention, the pharmaceutical composition may have a 30-minute dissolution rate of 85% or more, preferably 90% or more, of the total content of the active ingredient.

[0037] The dissolution rate of the active ingredient in the pharmaceutical composition is the peak blood concentration (C) at the time of drug administration. max Since this affects the Cmax and area under the blood concentration-time curve (AUC), conversely, it is important to adjust the dissolution rate of the pharmaceutical composition in order to achieve appropriate Cmax and AUC. Inabogliflozin has a Tmax of 1-2 hours, so the drug absorption rate at the above time is considered important. The aforementioned dissolution rate was measured under the conditions of eluate 1.2 using the Korean Pharmacopoeia Dissolution Test Method 2 (Paddle Method). Specific conditions can be found in the experimental example below.

[0038] The present invention also provides a pharmaceutical composition comprising a granular product obtained by mixing a pre-mixed granule containing a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof with a post-mixed portion.

[0039] [ka]

[0040] In the process of formulating the compound of chemical formula 1, the present inventors confirmed that producing granules and then forming them into dosage forms such as tablets is advantageous from the viewpoint of uniformity of drug content and uniformity of formulation.

[0041] In the aforementioned pharmaceutical composition, the granules are produced by mixing pre-mixed granules and a post-mixed portion.

[0042] The aforementioned pre-mixed granules may contain the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, excipients, binders, and lubricants.

[0043] Furthermore, the post-mixing portion may contain excipients, disintegrants, and lubricants.

[0044] The explanations regarding excipients, binders, disintegrants, lubricants, etc., are the same as those mentioned above, so they will be omitted to avoid duplication.

[0045] In a specific example of the present invention, the pre-mixed granules and the post-mixed portion may each contain an excipient. More specifically, the pre-mixed granules and the post-mixed portion may each contain microcrystalline cellulose as an excipient.

[0046] According to the following examples, it was found that the microcrystalline cellulose contained in the pre-mixed granules and post-mixed portion affects the uniformity of the drug content depending on its particle size and volume density.

[0047] In a specific example of the present invention, the particle size of the microcrystalline cellulose in the pre-mixed granules may be 130 μm or less, preferably 60 to 130 μm. The volume density of the microcrystalline cellulose in the pre-mixed granules may be 0.26 to 0.33. When the particle size and volume density of the microcrystalline cellulose in the pre-mixed granules are as described above, a formulation with a low standard deviation (SD) of content uniformity can be ensured. When the particle size of the microcrystalline cellulose in the pre-mixed granules is 130 μm or less, the content uniformity of the pre-mixed granules, the content uniformity of the final granules, and the formulation uniformity all show good levels, the Carr's index value indicating the physical properties of the final granules is also good, and the flowability of the formulation is also confirmed to be excellent. On the other hand, when the particle size of the microcrystalline cellulose in the pre-mixed granules exceeds 130 μm, the deviations in the content uniformity of the pre-mixed granules and the content uniformity of the final granules all become large and unsuitable, and the formulation uniformity is also poor.

[0048] Furthermore, the particle size of the microcrystalline cellulose in the post-mixing section may be 130 μm or larger, preferably 130 to 250 μm. The volume density of the excipient in the post-mixing section may be 0.28 to 0.37. When the particle size of the microcrystalline cellulose in the post-mixing section is less than 130 μm, it was confirmed that the Carr's index value, which indicates the physical properties of the final granules, is not appropriate, and the flowability of the granules is weakened.

[0049] When comparing the microcrystalline cellulose in the pre-mixed granules with the microcrystalline cellulose in the post-mixed portion, it was found that a smaller particle size for the microcrystalline cellulose contained in the pre-mixed granules is preferable, while a relatively larger particle size for the microcrystalline cellulose in the post-mixed portion is preferable.

[0050] According to the examples below, it was confirmed that not only the particle size of the microcrystalline cellulose in the pre-mixed granules and the microcrystalline cellulose in the post-mixed portion, but also the weight ratio of the excipient in the pre-mixed granules and the excipient in the post-mixed portion, affects the uniformity of the drug content.

[0051] In a specific example of the present invention, the weight ratio of the pre-mixed granule excipient and the post-mixed excipient can be 4:1 to 1:1. It has been found that the higher the proportion of microcrystalline cellulose in the post-mixed portion, the better the flowability of the granules, but the greater the content deviation, and therefore it is preferable to match the weight ratio within the appropriate range.

[0052] In the pharmaceutical composition according to the present invention, the binder may be one or more selected from the group consisting of hydroxypropylcellulose, povidone, copovidone, and hypromellose.

[0053] In one specific example of the present invention, the binder is hydroxypropyl cellulose, and its weight-average molecular weight may be less than 200,000. When hydroxypropyl cellulose with a weight-average molecular weight of 200,000 or more is used, both the 5-minute and 30-minute elution rates are low, which is undesirable from the viewpoint of bioavailability.

[0054] Furthermore, in relation to the Carr's index used as a measure of flowability in formulation, the Carr's index of the granules is preferably 21 to 25.

[0055] Although not limited thereto, the granules in the pharmaceutical composition of the present invention may be dry granules. In other specific examples, the granules may be wet granules.

[0056] In the present invention, the pharmaceutical composition may have a dosage form for oral administration, such as a tablet or a capsule. In one specific example of the present invention, the pharmaceutical composition may have a tablet dosage form.

[0057] In a preferred example, the pharmaceutical composition may contain a dose of 0.3 mg of the compound of chemical formula 1.

[0058] The pharmaceutical composition according to the present invention can be administered orally once a day, but is not limited thereto. [Effects of the Invention]

[0059] The pharmaceutical composition containing the compound of chemical formula 1 according to the present invention can embody a formulation that exhibits excellent content uniformity, formulation uniformity, and dissolution profile, even when containing a low dose of the drug. [Brief explanation of the drawing]

[0060] [Figure 1] Figure 1 shows the dissolution rate evaluation results for tablets produced in Example 1, Example 2, Example 3, Comparative Example 1, and Comparative Example 2 (eluent: pH 1.2). [Figure 2] Figure 2 shows the dissolution rate evaluation results for tablets produced in Example 1, Example 2, Example 3, Comparative Example 1, and Comparative Example 2 (eluate: pH 4.0). [Figure 3] Figure 3 shows the dissolution rate evaluation results for tablets produced in Example 1, Example 2, Example 3, Comparative Example 1, and Comparative Example 2 (eluate: pH 6.8). [Figure 4]Figure 4 shows the dissolution rate evaluation results for tablets produced in Example 1, Example 2, Example 3, Comparative Example 1, and Comparative Example 2 (dissolution solution: DW). [Figure 5] Figure 5 shows the dissolution rate evaluation results for tablets produced in Example 1, Example 8, and Comparative Example 6 (eluent: pH 1.2). [Modes for carrying out the invention]

[0061] The following examples are preferred embodiments to aid in understanding the present invention, but these embodiments are merely illustrative and the scope of the present invention is not limited to these embodiments.

[0062] Tablet manufacturing of Inabogliflozin based on particle size Inabogliflozin of various particle sizes was prepared using conventional methods, and the particle size of the prepared raw materials was measured as follows.

[0063] Particle size analysis (Equipment: Malvern Mastersizer 3000) 1) Test solution 0.05%(v / v)Lecithin in Hexane solution 2) Preparation of the test solution Take approximately 10.0 mg of this drug and place it in a 20 mL beaker, then add 15 mL of the test solution. After sonicating for 30 seconds to completely disperse the mixture, use it as the test solution. 3) Analysis method After adding the test solution so that the obscuration level is between 5% and 10%, and confirming that the obscuration level has stabilized, the measurement is performed under the following conditions. [Operating conditions] Range: 0.02~2000μm Particle RI:1.59 Absorption: 0.01 Dispersant RI: 1.380 Obscuration Range: 5-10% Stirrer / Pump speed: 3000 RPM Ultrasonic sound: off Measurement cycle: 5

[0064] Immediate-release formulations of inabogliflozin with various particle sizes were manufactured through a dry granulation process using the following steps. Step 1: Mix 0.3g of inabogliflozin, 50.0g of microcrystalline cellulose (PH-102), 4.0g of hydroxypropyl cellulose (HPC-L), 1.0g of light anhydrous silicic acid, and 0.5g of magnesium stearate. Stage 2: The mixture from Stage 1 was compressed into a plate-like form using a dry granulation device, and then crushed using a co-mill to produce dry granules. Step 3: 15.7g of microcrystalline cellulose (Vivapur12), 3.0g of croscamelrosth sodium, and 0.5g of magnesium stearate were added to the pre-mixed granules from Step 2 and mixed. Stage 4: The mixed granules from Stage 3 were compressed and molded to a total weight of 75.0 mg to produce tablets.

[0065] [Table 1]

[0066] Experimental Example 1: Dissolution test of Inabogliflozin tablets based on particle size To confirm the differences in dissolution rates due to particle size for the tablets produced in Example 1, Example 2, Example 3, Comparative Example 1, and Comparative Example 2, dissolution tests were performed using the following methods and conditions. 1) Dissolution method: Dissolution method 2 (paddle method) of the Korean Pharmacopoeia 2) Eluate: pH1.2 / pH4.0 / pH6.8 / DW 3) Elution volume: 500 mL 4) Elution device temperature: 37.5℃±0.5℃ 5) Paddle speed: 50 rpm 6) Analysis method: HPLC method -Detector: Ultraviolet external absorbance spectrophotometer (measurement wavelength: 225 nm) - Column: C18 5um / 4.6x150mm column - Mobile phase: Hydrogen phosphate buffer + acetonitrile

[0067] As a result, in all four liquids, the average particle size of the raw material (D mean The elution rates of Examples 1-3, in which the particle size was 10 μm or less, showed similar characteristics. Inabogliflozin is T max Since the components are released within approximately one hour, their dissolution in gastric juice is expected to have a significant impact on bioavailability. Therefore, it was determined that the dissolution rate at pH 1.2 is particularly important, and given the characteristics of inabogliflozin, which is preferably formulated as an immediate-release type, the dissolution rates of Examples 1 to 3 were deemed suitable. Specifically, the overall dissolution rates of Examples 2 and 3 were similar to those of Example 1, and the similarity factor values ​​also showed equivalence of 50% or more.

[0068] The tablets of Comparative Examples 1 and 2, whose raw material average particle size was 19 μm or larger, showed a decrease in dissolution rate compared to Example 1, and the similarity factor value was less than 50%, indicating a significant difference. Therefore, the average particle size of the raw material of inabogliflozin (D mean It is determined that setting the particle size of the raw materials for inabogliflozin to 15 μm or less, preferably 10 μm or less as in Examples 1 to 3, ensures uniform product quality and efficacy in the body. The dissolution rate evaluation results are shown in detail in Table 2 and Figures 1 to 4 below.

[0069] [Table 2]

[0070] Granule production based on particle size distribution of pre-mixed granule excipients In order to ensure uniformity of content and formulation in the formulation of inabogliflozin, we decided to produce granules by mixing pre-mixed granules and post-mixed portions. First, we searched for the most appropriate excipient particle size for the pre-mixed granules.

[0071] Except for the difference in particle size and volume density of the microcrystalline cellulose used in the pre-mixed granules in Example 1 described above, the tablets of Example 4 and Comparative Example 3 were manufactured in the same manner as in Example 1.

[0072] The compositions of Example 1, Example 4, and Comparative Example 3 are as shown in Table 3 below.

[0073] [Table 3]

[0074] [Table 4]

[0075] Experimental Example 2: Evaluation of the uniformity of content between pre-mixed granules and final granules. The results of evaluating the uniformity of content between the pre-mixed granules and the final granules for the tablets produced in Example 1, Example 4, and Comparative Example 3 are shown in Table 5 below. The evaluation of content uniformity was carried out by the following method.

[0076] 1) Method for content testing: Take 1.5 g of the granules to be measured and place it in a 100 mL dose flask. Add 50 mL of extract and sonicate extract for 20 minutes to completely disperse. Then, while stirring for 30 minutes, allow to cool completely to room temperature, add the extract, and adjust to the mark. Take an appropriate amount of this liquid and centrifuge at 3000 rpm for 10 minutes. Filter the supernatant through a 0.45 μm RC membrane filter, discard the first 2 mL, and use the filtrate as the test solution. 2) Extract: Precisely weigh 1.36 g of potassium dihydrogen phosphate, dissolve it in 1000 mL of water, and then adjust the pH to 3.0 with phosphoric acid. 3) Temperature conditions: 35℃±0.5℃ maintenance 4) Analysis method: HPLC method -Detector: Ultraviolet external absorbance spectrophotometer (measurement wavelength: 225 nm) - Column: C18 5um / 4.6x150mm column - Mobile phase: Hydrogen phosphate buffer + acetonitrile

[0077] Table 5 details the test results for the uniformity of content of the pre-mixed granules and the final granules in Examples 1, 4, and Comparative Example 3, using the method described above.

[0078] Since the main component inabogliflozin is present in very small amounts (less than 0.5%) within the tablets and has a small average particle size, it is expected that the average particle size of the microcrystalline cellulose used in the pre-mixed granule portion will have a significant impact on the uniformity of the main component's content within the granules and tablets.

[0079] When the average particle size of the microcrystalline cellulose used in the pre-mixed granule portion was varied and the uniformity of the content was confirmed, it was determined that all of Examples 1 to 4 were satisfactory. In Comparative Example 3, where the average particle size of the microcrystalline cellulose was 180 μm or larger, it was confirmed that the content of inabogliflozin in the granules and tablets was significantly non-uniform compared to Example 1. Therefore, it was determined that when the average particle size (D50) of the microcrystalline cellulose used in the pre-mixed granule portion is 130 μm or less and the volume density is 0.28 to 0.33 or less (Example 1), it is possible to manufacture tablets with uniform quality.

[0080] [Table 5]

[0081] Production of granules based on particle size distribution of excipients in the post-mixing stage Following the search for the particle size of the excipient in the pre-mixed granules, the most appropriate excipient particle size for the post-mixed portion was then searched for.

[0082] The tablets of Comparative Example 4 and Example 5 were manufactured in the same manner as in Example 1, except that the particle size distribution of the microcrystalline cellulose used in the post-mixing stage was varied as shown in Table 6 below.

[0083] [Table 6]

[0084] Experimental Example 3: Evaluation of the uniformity of the content of the final granules The results of evaluating the uniformity of the final granule content for the tablets produced in Comparative Example 4 and Example 5 are shown in Table 7 below. In this case, the uniformity of the content was evaluated using the same method as in Experimental Example 2.

[0085] The results of the tests for the uniformity of content in the post-mixed granules and the final granules in Comparative Example 4 and Example 5, using the method described above, showed excellent results in terms of content in the final granules and uniformity of formulation (uniformity of content between tablets). However, as in Comparative Example 4, it was confirmed that the flowability of the granules weakened as the average particle size of the microcrystalline cellulose decreased, which is summarized in detail in Table 7.

[0086] [Table 7]

[0087] Manufacturing of granules based on the ratio of pre-mixed granules and post-mixed excipients. In producing granules by mixing pre-mixed granules and post-mixed components, the most appropriate diluent ratio for the pre-mixed and post-mixed components was explored.

[0088] Tablets were manufactured in the same manner as in Example 1, except that the proportions of microcrystalline cellulose used in the pre-mixed granules and post-mixed portion were different as shown in Table 8 below.

[0089] [Table 8]

[0090] Experimental Example 4: Evaluation of the flowability and uniformity of the content of the final granules The results of evaluating the flowability and content uniformity of the final granules for the tablets produced in Examples 6, 7, and Comparative Example 5 are shown in Table 9 below. In this case, the content uniformity was evaluated using the same method as in Experimental Example 2.

[0091] The flowability of the final granules in Examples 6, 7, and Comparative Example 5 was evaluated using the method described above. The results confirmed that the flowability of the granules improved as the proportion of microcrystalline cellulose in the post-mixing portion increased. In the case of uniform content, it was found that the content deviation (SD) also increased as the proportion of microcrystalline cellulose in the post-mixing portion increased. This is summarized in detail in Table 9.

[0092] [Table 9]

[0093] Manufacturing of tablets using the weight-average molecular weight of hydroxypropyl cellulose As shown in Table 10 below, tablets were manufactured in the same manner as described in Example 1, except that hydroxypropyl cellulose of various weight-average molecular weights was used as the binder.

[0094] [Table 10]

[0095] Experimental Example 5: Dissolution Test Dissolution tests were evaluated to compare the dissolution rate of hydroxypropylcellulose as a binder based on its weight-average molecular weight. The dissolution tests were conducted under the following conditions, using a pH of 1.2 as the eluent, taking into account the maximum absorption concentration time (Tmax) of inabogliflozin and its solubility at pH. 1) Dissolution method: Dissolution method 2 (paddle method) of the Korean Pharmacopoeia 2) Eluate: pH1.2 3) Elution volume: 500 mL 4) Dissolution device temperature: 37.5℃ ± 0.5℃ 5) Paddle speed: 50 rpm 6) Analysis method: HPLC method -Detector: Ultraviolet external absorbance spectrophotometer (measurement wavelength: 225 nm) - Column: C18 5um / 4.6x150mm column - Mobile phase: Hydrogen phosphate buffer + acetonitrile

[0096] As a result, in Comparative Example 6, where the weight-average molecular weight of the binder hydroxypropyl cellulose was the highest at 700,000, the initial dissolution rate was less than 30%, indicating a delayed dissolution rate, and the 30-minute dissolution rate did not exceed 85%. Since inabogliflozin is a component with a Tmax of around 1 hour, dissolution in gastric juice is expected to have a significant impact on bioavailability. Therefore, the dissolution rate at pH 1.2 is considered important, and using hydroxypropyl cellulose with a high weight-average molecular weight of 200,000 or more, as in Comparative Example 6, is deemed undesirable from the viewpoint of bioavailability because it has a significant impact on the initial dissolution rate. The evaluation results for each dissolution rate are shown in detail in Table 11 and Figure 5 below.

[0097] [Table 11]

Claims

1. A pharmaceutical composition comprising, as an active ingredient, a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant, and a binder, wherein the volume-average particle size (D mean) of the compound of chemical formula 1 is 15 μm or less, the compound of chemical formula 1 is present in an amount of less than 1 part by weight per 100 parts by weight of the total pharmaceutical composition, the excipient is microcrystalline cellulose, the disintegrant is crospovidone, croscarmellose sodium, sodium starch glycolate, or low-substituted hydroxypropyl cellulose, and the binder is povidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose. 【Chemistry 1】

2. The pharmaceutical composition according to claim 1, wherein the amount of active ingredient contained in the pharmaceutical composition is 0.1 to 0.5 mg.

3. The pharmaceutical composition according to claim 1, wherein the excipient is contained in an amount of 80 to 95 parts by weight per 100 parts by weight of the total pharmaceutical composition.

4. The pharmaceutical composition according to claim 1, wherein the disintegrant is contained in an amount of 2 to 8 parts by weight per 100 parts by weight of the total pharmaceutical composition.

5. The pharmaceutical composition according to claim 1, wherein the binder is contained in an amount of 3 to 10 parts by weight per 100 parts by weight of the total pharmaceutical composition.

6. The pharmaceutical composition according to claim 1, wherein the dissolution rate after 5 minutes is 50% or more of the total content of the active ingredient.

7. The pharmaceutical composition according to claim 1, wherein the dissolution rate after 15 minutes is 80% or more of the total content of the active ingredient.

8. The pharmaceutical composition according to claim 1, wherein the dissolution rate after 30 minutes is 85% or more of the total content of the active ingredient.

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