Novel cocrystals of inabogliflozin

Abstract

The present invention relates to a cocrystal of inavogliflozin. The inavogliflozin cocrystal of the present invention has improved solubility of inavogliflozin in artificial gastric juice and artificial intestinal juice. Such improved solubility of inavogliflozin is particularly advantageous for the development of oral preparations for indications requiring high-dose administration. The inavogliflozin cocrystal has the same stability as conventional inavogliflozin cocrystals, and is therefore very useful as an inavogliflozin raw material drug. Furthermore, the cocrystal of the present invention has a longer half-life than the conventional crystalline form A, and exhibits improved in vivo exposure (AUC inf ) and has a longer-lasting effect, it can be usefully used for various indications and / or in the development of dosage forms that require it.

Description

Technical Field

[0001] The present invention relates to a co-crystal of ipragliflozin.

Background Art

[0002] The selection of a preferred solid form of an active ingredient, such as a pharmaceutically acceptable salt form, co-crystal, polymorphs, pseudo-polymorphs, etc., has a very important impact on the manufacturing process development of the raw pharmaceutical product, the dosage form design of the finished pharmaceutical product, and the dosage form.

[0003] Specifically, salts, co-crystals, polymorphs, and pseudo-polymorphs of raw pharmaceutical products affect the recrystallization yield, process speed, and purity in the final stage of raw pharmaceutical product manufacturing, i.e., the recrystallization and purification processes. The crystallization rate in the crystallization process varies depending on the crystal size and shape, which affects productivity and manufacturing costs.

[0004] Also, in terms of pharmacy, physicochemical properties such as hygroscopicity, stability, solubility, particle fluidity, dissolution rate, etc. are affected by salts, co-crystals, polymorphs, pseudo-polymorphs, etc., and are factors that determine the production process, production and storage conditions, expiration date, etc. of the finished pharmaceutical product.

[0005] On the other hand, when the bioavailability of a drug is affected by the physicochemical properties of the raw pharmaceutical product, more attention is required in the selection of salts, co-crystals, polymorphs, pseudo-polymorphs, etc. Therefore, optimized salts, co-crystals, polymorphs, pseudo-polymorphs are very important in terms of technology development and approval.

[0006] An object of the present invention is to search for a novel co-crystal of ipragliflozin, analyze its physicochemical characteristics, develop a co-crystal capable of maximizing pharmacological activity, and improve the low solubility, which is a drawback of conventional crystal polymorphs.

[0007] SGLT-2 (sodium glucose cotransporter 2), along with SGLT-1 (sodium glucose cotransporter 1), is a transporter responsible for the reabsorption of excess glucose in the kidneys, with SGLT-2 playing the majority of the role. Therefore, when an SGLT-2 inhibitor inhibits the SGLT-2 transporter, the amount of glucose excreted in the urine increases, ultimately lowering blood glucose levels, and further reducing the calories contained in glucose, resulting in weight loss.

[0008] One of the drugs developed as an SGLT-2 inhibitor that can be useful as a treatment for type 2 diabetes due to these effects is inavogliflozin, represented by the following structural formula (Chemical Formula 1), which is disclosed in Korean Published Patent No. 2014-0022086 (Patent Document 1).

[0009] [ka]

[0010] Furthermore, Korean Published Patent No. 2017-0142904 (Patent Document 2) discloses inabogliflozin crystalline form and a method for producing inabogliflozin crystalline form.

[0011] However, the inabogliflozin crystalline form disclosed in Korean Published Patent No. 2017-0142904 (Patent Document 2) has the drawback of having a solubility of only 0.25 mg / mL.

[0012] Therefore, the inventors of the present invention conducted research on cocrystals that can improve the solubility of inabogliflozin. As a result, they found that when manufactured in a specific cocrystal form, it is possible to achieve both excellent stability and improved solubility, thus completing the present invention. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] Korean Published Patent No. 2014-0022086 [Patent Document 2] Korean Published Patent No. 2017-0142904 [Overview of the Initiative] [Problems that the invention aims to solve]

[0014] The present invention aims to provide a novel cocrystal of inabogliflozin with excellent stability and solubility, and a method for producing the same. The present invention also aims to provide a pharmaceutical composition containing the novel cocrystal of inabogliflozin as an active ingredient. [Means for solving the problem]

[0015] This invention provides a novel cocrystal of inabogliflozin represented by the following structural formula (Chemical Formula 2) and a method for producing the same.

[0016] [ka]

[0017] To overcome the low solubility of inabogliflozin, the inventors selected amino acids and organic acids with very high solubility and rich in NH, N, O, and OH, and attempted to design a cocrystal.

[0018] The amino acids and organic acids selected for cocrystal production were aspartic acid, acetylsalicylic acid, citric acid, nicotinic acid, nicotinamide, β-cyclodextrin, propylene glycol, phenylalanine, lactose monohydrate, L-proline, urea, L-lysine, L-pyroglutamic acid, orotic acid monohydrate, maleic acid, malic acid, L-ascorbic acid, fumaric acid, succinic acid, malonic acid, oxalic acid trihydrate, L-citric acid, sodium chloride, L-serine, L-arginine, L-valine, L-methionine, threonine, glycine, L-alanine, L-cysteine, L-tryptophan, L-asparagine, L-isoleucine, L-glutamine, L-histidine, L-glutamic acid.

[0019] Attempts were made to produce inabogliflozin cocrystals with respect to the 38 kinds of amino acids and organic acids, and three kinds of cocrystals, namely inabogliflozin / proline cocrystal, inabogliflozin / methionine cocrystal, and inabogliflozin / proline hydrate, were obtained.

[0020] Regarding the inabogliflozin / proline cocrystal, inabogliflozin / methionine cocrystal, and inabogliflozin / proline hydrate cocrystal, solubility evaluations were performed using eluents at pH 1.2 and pH 6.8. As a result, it was confirmed that the solubility of the three kinds of cocrystals, namely inabogliflozin / proline cocrystal, inabogliflozin / methionine cocrystal, and inabogliflozin / proline hydrate, was higher than that of the inabogliflozin crystal form in the initial 2 hours, and the initial solubility was improved by cocrystallization.

[0021] However, the canagliflozin / proline hydrate co-crystal has a problem of poor reproducibility in the production of the co-crystal during scale-up. The canagliflozin / methionine co-crystal has a low melting point of 106 °C and was expected to have poor stability. As a result of a severe stability test at 60 °C for 4 weeks, it was confirmed that the purity of the canagliflozin / methionine co-crystal decreased by about 3% in 4 weeks, and it was less stable than the canagliflozin crystal form and the canagliflozin / proline co-crystal. Thus, it was confirmed that the canagliflozin / proline co-crystal has the best stability and solubility.

[0022] Through experimental optimization, a method for reproducibly producing the canagliflozin / proline co-crystal was established. The canagliflozin / proline co-crystal produced in this way had a solubility in artificial gastric juice increased by about 21% and a solubility in artificial intestinal juice increased by more than about 2 times compared to the conventional canagliflozin crystal form, and it was ensured that the initial solubility also increased. In addition, due to the dissolution characteristics, the effects improved in the oral absorption effect and the actual mouse pharmacokinetic experiment were confirmed.

[0023] Therefore, by using the canagliflozin / proline co-crystal of the present invention, it is possible to produce an oral preparation with improved solubility of canagliflozin. The improvement of the solubility of canagliflozin is advantageous for the development of oral preparations for indications that require high-dose administration.

[0024] The canagliflozin / proline co-crystal forms a co-crystal in a 1:1 ratio of one molecule of canagliflozin and one molecule of proline (L-proline) through hydrogen bonding.

[0025] Proline, which has high water solubility, forms a co-crystal with canagliflozin through hydrogen bonding. When proline dissolves due to the interaction with proline, canagliflozin also dissolves in water, so the water solubility and the solubility in artificial gastric juice and artificial intestinal juice increase.

[0026] The inabogliflozin / proline cocrystal of the present invention is a novel solid form of inabogliflozin that has not been reported to date.

[0027] In one embodiment of the present invention, an inabogliflozin / proline cocrystal is provided, characterized by being identified by an X-ray powder diffraction pattern having four or more diffraction peaks, for example, four, five, six, seven, or eight or more, at 2[θ] values ​​selected from 4.72±0.2, 6.81±0.2, 7.93±0.2, 8.59±0.2, 14.75±0.2, 15.21±0.2, 17.23±0.2, 18.80±0.2, 21.19±0.2, 24.42±0.2, and 27.29±0.2, as determined by X-ray diffraction (PXRD) analysis.

[0028] In particular, the X-ray powder diffraction pattern is characterized by having diffraction peaks at 2[θ] values ​​selected from 6.81±0.2, 8.59±0.2, 14.75±0.2, 17.23±0.2, and 18.80±0.2.

[0029] More specifically, the inabogliflozin / proline cocrystal is characterized by being identified by an X-ray powder rotation pattern in which the peak positions listed in Table 1 below coincide.

[0030] [Table 1]

[0031] In another embodiment of the present invention, the inabogliflozin / proline cocrystal is characterized by exhibiting endothermic peaks at an endothermic onset temperature of 217.71°C ± 3°C and an endothermic temperature of 219.42°C ± 3°C in scanning calorimetry (DSC) analysis. The inabogliflozin / proline cocrystal according to the present invention is in a form in which one equivalent of inabogliflozin is bound to one equivalent of proline. Nuclear magnetic resonance (NMR) spectroscopy analysis confirms that the inabogliflozin / proline cocrystal consists of one molecule of inabogliflozin and one molecule of proline, as can be seen from the H-NMR spectrum.

[0032] Another embodiment of the present invention provides a method for producing the inabogliflozin / proline cocrystal.

[0033] Inabogliflozin / proline cocrystals are produced by a process that includes (a) mixing inabogliflozin and an organic solvent and adding proline thereto, (b) stirring the product from step (a), and (c) vacuum drying the product from step (b) to obtain inabogliflozin cocrystals.

[0034] The method of the present invention for producing inabogliflozin / proline cocrystals is described in detail step by step as follows.

[0035] (a) Mixing inabogliflozin with an organic solvent and adding proline. First, the method of the present invention includes the step of mixing solid inabogliflozin with an organic solvent and adding proline thereto. The physicochemical form of the solid inabogliflozin used herein is not particularly limited. For example, the solid inabogliflozin may be inabogliflozin crystalline form A, crystalline form B, crystalline form C, crystalline form D, or inabogliflozin amorphous, which are reported to have the following X-ray diffraction spectra according to Experimental Example 4 of Korean Published Patent No. 2017-0142904.

[0036] Crystal type A: A crystal type having an X-ray diffraction (XRD) spectrum containing peaks at 2[θ] values ​​selected from 6.2°±0.2°, 7.2°±0.2°, 8.8°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2°. Crystal type B: A crystal type having an X-ray diffraction (XRD) spectrum that includes peaks at 2[θ] values ​​selected from 7.0°±0.2°, 14.9°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 23.5°±0.2°. Crystal type C: A crystal type having an X-ray diffraction (XRD) spectrum containing peaks at 2[θ] values ​​selected from 5.6°±0.2°, 7.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.9°±0.2°, 21.2°±0.2°, and 21.9°±0.2°. Crystal type D: A crystal type having an X-ray diffraction (XRD) spectrum that includes peaks at 2[θ] values ​​selected from 5.5°±0.2°, 7.2°±0.2°, 15.3°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.9°±0.2°, and 21.1°±0.2°. The aforementioned crystal types A, B, C, and D can each be identified by an X-ray diffraction spectrum having four or more peaks at the aforementioned 2[θ] value, for example, four, five, six, seven, or eight or more peaks.

[0037] The organic solvent in step (a) above may be any organic solvent that can well dissolve inabogliflozin and prolyl and produce inabogliflozin / proline cocrystals. Organic solvents that have been proven to produce inabogliflozin / proline cocrystals in high yield and to be effective in removing excess proline may be one or more organic solvents selected from the group consisting of methanol, ethanol, isopropyl alcohol, 1-butanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, MTBE (Methyl t-Butyl ether), toluene, and dioxane. The organic solvent may be a single solvent or a mixture of solvents.

[0038] Preferably, the organic solvent may be one or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, and acetone. More preferably, the organic solvent may be ethanol.

[0039] The organic solvent in step (a) may be used in a volume of 10 times or more relative to the weight of inabogliflozin, for example, 10 to 200 times relative to the weight of inabogliflozin, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 150, or 200 times relative to the weight of inabogliflozin.

[0040] The amount of organic solvent used varies depending on the type of organic solvent, or whether it is used as a single solvent or a mixed solvent. For example, with methanol, dioxane, and tetrahydrofuran, cocrystals can be formed with 10 times the amount of solvent relative to the weight of inabogliflozin. With ethanol, isopropyl alcohol, 1-butanol, acetone, and acetonitrile, cocrystals can be formed even with 50 times the amount of solvent relative to the weight of inabogliflozin. When using ethyl acetate as a solvent, crystallization is required after heating to a level of 50 times the weight of inabogliflozin due to the low solubility of inabogliflozin. Dichloromethane also has low solubility for inabogliflozin, requiring a level of solvent 100 times the weight of inabogliflozin. With MTBE and toluene, the solubility of inabogliflozin in these solvents is very low, requiring more than 150 times the amount of solvent relative to the weight of inabogliflozin.

[0041] Therefore, considering the solubility of inabogliflozin in the solvent and the degree of cocrystal formation, the type of organic solvent and whether or not it is mixed may be selected, and the amount of organic solvent used may be adjusted. In addition, if necessary, heating may be used in combination to dissolve inabogliflozin.

[0042] In one embodiment of the present invention, the organic solvent is ethanol and may be used in an amount 10 to 60 times the weight of inabogliflozin.

[0043] According to another embodiment of the present invention, proline is added to inabogliflozin in a molar ratio of 1 to 1.5 equivalents.

[0044] (b) Stirring of the product Next, the present invention method includes a step of stirring the product of step (a).

[0045] According to another embodiment of the present invention, the stirring in step (b) can be carried out at 0 to 50°C, for example, 15 to 40°C, preferably 15 to 30°C, and more preferably 20 to 25°C.

[0046] According to another embodiment of the present invention, the stirring in step (b) can be carried out for 0.5 to 24 hours, preferably 1 to 12 hours, and more preferably 4 to 8 hours.

[0047] (c) Vacuum drying of the above product and acquisition of inabogliflozin / proline cocrystal Finally, the method of the present invention involves vacuum drying the product from step (b) to obtain an inabogliflozin / proline cocrystal.

[0048] According to another embodiment of the present invention, the vacuum drying in step (c) can be carried out at a temperature of 30 to 65°C, preferably 40 to 55°C, more preferably 45 to 50°C, for 8 to 12 hours.

[0049] In this manner, inabogliflozin / proline cocrystals can be produced by combining one equivalent of inabogliflozin with one equivalent of proline. This method allows inabogliflozin to regulate blood glucose levels by inhibiting glucose reabsorption in the kidneys and excreting glucose in the urine, making it suitable as a therapeutic agent for type 2 diabetes.

[0050] The present invention also provides a pharmaceutical composition comprising the inabogliflozin / proline cocrystal and a pharmaceutically acceptable carrier as an active ingredient.

[0051] The aforementioned pharmaceutical composition may, but is not limited to, be for the treatment or prevention of diabetes.

[0052] The inabogliflozin / proline cocrystal according to the present invention may be administered in various oral and parenteral dosage forms at the time of clinical administration, and when formulated, it is manufactured using commonly used fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other diluents or excipients. [Effects of the Invention]

[0053] The inabogliflozin / proline cocrystal according to the present invention improves the solubility of inabogliflozin in artificial gastric and artificial intestinal fluids. This improvement in the solubility of inabogliflozin is particularly advantageous for the development of oral formulations for indications requiring high-dose administration. The inabogliflozin / proline cocrystal also has the same stability as the conventional crystalline form of inabogliflozin, making it very useful as an inabogliflozin raw material for pharmaceuticals. Furthermore, the inabogliflozin / proline cocrystal of the present invention has a longer half-life compared to the conventional crystalline form A, and its exposure to the body (AUC) is lower. inf Because it has a high efficacy and a longer-lasting effect, it can be usefully used in the development of various indications and / or dosage forms that require it. [Brief explanation of the drawing]

[0054] [Figure 1] This figure shows the nuclear magnetic resonance (NMR) H-NMR spectrum results of the inabogliflozin / proline cocrystal produced by Production Example 2. [Figure 2] This figure shows the nuclear magnetic resonance (NMR) H-NMR spectrum results of inabogliflozin crystal type A produced by Production Example 1. [Figure 3] This figure shows the powder X-ray diffraction (PXRD) pattern results of the inabogliflozin / proline cocrystal produced by Production Example 2. [Figure 4] This figure shows the powder X-ray diffraction (PXRD) pattern results of inabogliflozin crystal type A produced by Production Example 1. [Figure 5] This figure shows the caloric curve results of the temperature difference scanning calorific value (DSC) of the inabogliflozin / proline cocrystal produced by Production Example 2. [Figure 6] This figure shows the caloric curve results of temperature difference scanning calorimetry (DSC) for inabogliflozin / proline cocrystals, proline, and inabogliflozin crystal types produced according to embodiments of the present invention. [Figure 7] This figure shows a comparison of the solubility of inabogliflozin / proline cocrystals and inabogliflozin crystalline form in artificial intestinal fluid produced by this embodiment. [Modes for carrying out the invention]

[0055] The advantages and features of the present invention, as well as methods for achieving them, will become apparent by referring in detail to the embodiments described below. However, the present invention is not limited to the embodiments disclosed below and can be carried out in a variety of different forms, which are provided to complete the disclosure of the present invention and to fully inform those who are ordinary skill in the art to which the present invention pertains, and the present invention is defined only by the scope of the claims.

[0056] [Manufacturing Example 1] Production of Inabogliflozin Crystal Type A Inabogliflozin crystalline form A, as reported through Experimental Example 4 of Korean Published Patent No. 2017-0142904, was produced.

[0057] Unpurified inabogliflozin was mixed with ethyl acetate (15 times the weight of unpurified inabogliflozin), dissolved by refluxing and stirring, and cooled to room temperature. After a suspension formed at room temperature, the mixture was stirred for a further 30 minutes. Isopropyl ether (15 times the weight of unpurified inabogliflozin) was added dropwise to the resulting mixture over 30 minutes, and the mixture was stirred further at room temperature for 30 minutes. The resulting precipitate was filtered, washed with ethyl acetate (2 times the weight of inabogliflozin) at 0°C, and dried in a vacuum oven (50°C, 12 hours) to obtain white crystals (yield: 88.3%).

[0058] [Manufacturing Example 2] Production of Inabogliflozin / Proline Cocrystal 300 mg of inabogliflozin crystalline form A and 10 ml of ethanol were added and stirred at room temperature for 20 minutes. Then, 77.3 mg (1 equivalent) of L-proline was added and stirred at 20°C-25°C for 1 hour. The precipitated crystals were filtered under reduced pressure, washed with 1 ml of ethanol, and vacuum dried at 50°C for 12 hours to obtain inabogliflozin / proline cocrystals in crystalline form in 78% yield.

[0059] [Production Example 3] Evaluation of 13 solvents for L-proline cocrystal formation 100 mg (0.224 mmol, 1 equivalent) of inabogliprozin crystalline type A was dissolved in each solvent, and then L-proline (0.224 mmol, 1 equivalent) was added at room temperature. The mixture was stirred for at least 1 hour, and the formation of proline cocrystals was evaluated.

[0060] [Table 2]

[0061] In the case of methanol, dioxane, and tetrahydrofuran, inabogliflozin completely dissolved even with 10 times the amount of solvent relative to its weight, and when L-proline was added, it precipitated as a cocrystal. In the case of ethanol, isopropyl alcohol, 1-butanol, acetone, and acetonitrile, cocrystals were formed even with 50 times the amount of solvent relative to the weight of inabogliflozin.

[0062] Ethyl acetate and dichloromethane required large amounts of solvent to dissolve inabogliflozin, and it was confirmed that cocrystal precipitation occurred when L-proline was added. When ethyl acetate was used as the solvent, the solubility of inabogliflozin was low, and it was confirmed that crystallization was necessary after heating to a level of 50 times the weight of inabogliflozin. Dichloromethane also showed low solubility of inabogliflozin, and it was confirmed that a level of solvent of 100 times the weight of inabogliflozin was required.

[0063] In the case of MTBE and toluene, the solubility of inabogliflozin in these solvents was very low, requiring more than 150 times the weight of inabogliflozin in solvent. However, it was confirmed that cocrystals gradually formed when L-proline was added.

[0064] On the other hand, in the case of DMSO, it was confirmed that it has high solubility in cocrystals and does not precipitate.

[0065] While it was necessary to adjust the amount of solvent according to the solubility due to the polarity of the solvent, proline cocrystals could not be obtained with solvents that affected the solubility of inabogliflozin, L-proline, and the cocrystal, such as water and DMSO. However, proline cocrystals could be obtained with solvents that exhibited a certain level of solubility.

[0066] [Experimental Example 1] Nuclear Magnetic Resonance (NMR) Spectrum Nuclear magnetic resonance (NMR) 1H-NMR spectra were measured for the crystalline form of inabogliflozin obtained by Production Example 2. As a result, the nuclear magnetic resonance (NMR) 1H-NMR spectra of the inabogliflozin / proline cocrystal shown in Figure 1 were obtained. Figure 2 shows the nuclear magnetic resonance (NMR) 1H-NMR spectra of inabogliflozin crystal type A from Production Example 1. According to Figure 1, the stoichiometric ratio of inabogliflozin / proline is exactly 1:1 and its peak is integrated accordingly, confirming that the crystalline form of inabogliflozin obtained by Production Example 2 is an inabogliflozin / proline cocrystal.

[0067] [Experimental Example 2] Powder X-ray Diffraction (PXRD) The inabogliflozin / proline cocrystal obtained by Production Example 2 was subjected to PXRD measurements using a Bruker PXRD (30kV, 10mA, Cu target). A 5-40° 2θ scan was performed with a 0.02° step size, yielding the results shown in Figure 3. The main peaks are summarized in Table 3 below. The PXRD results shown in Figure 3 were clearly distinguishable from the PXRD results of inabogliflozin crystal type A from Production Example 1 (Figure 4).

[0068] [Table 3]

[0069] [Experimental Example 3] Scanning Calorimetry (DSC) Using a DSC Q20 obtained from TA Corporation, DSC measurements were performed on inabogliflozin crystal type A produced by Production Example 1 and inabogliflozin / proline cocrystal obtained by Production Example 2 under nitrogen gas at a scan speed of 10°C from 30°C to 300°C. Figure 5 shows the calorific value curve results of the temperature difference scanning calorific value (DSC) of the inabogliflozin / proline cocrystal produced by Production Example 2. In the temperature difference scanning calorific value (DSC) analysis of the inabogliflozin / proline cocrystal, it was confirmed that endothermic peaks were observed at the endothermic onset temperature of 217.71°C ± 3°C and the endothermic temperature of 219.42°C ± 3°C. Figure 6 shows a comparison of the calorific value curves of the temperature difference scanning calorific value (DSC) of the inabogliflozin / proline cocrystal, proline, and inabogliflozin crystal type produced by embodiments of the present invention. This demonstrates that inabogliflozin crystal type A produced by Production Example 1 and inabogliflozin / proline cocrystals obtained by Production Example 2 clearly exhibit endothermic peaks at different endothermic onset temperatures and endothermic temperatures.

[0070] [Experimental Example 4] Evaluation of crystal polymorphism of inabogliflozin / L-proline cocrystals 10 mg each of inabogliflozin / L-proline cocrystals were mixed with 1 mL each of the solvents listed in the table below. After standing in the suspension and dissolved state for 24 hours, the presence or absence of crystalline polymorphism in the inabogliflozin / L-proline cocrystals was evaluated.

[0071] [Table 4]

[0072] DSC evaluation of the crystals obtained in the experiment showed that when water was used, a deformation of crystal type A was obtained. However, when other solvents were used, it was confirmed that all were inabogliflozin / L-proline cocrystals with an endothermic onset temperature of approximately 217.71°C ± 3°C, and no other crystal polymorphs were observed.

[0073] [Experimental Example 5] Evaluation of the solubility of inabogliflozin / proline cocrystal Since inabogliflozin is poorly soluble with a water solubility of 0.25 mg / ml, the objective was to improve the water and gastrointestinal solubility of inabogliflozin by producing a proline cocrystal. Through solubility measurements in artificial gastric and intestinal fluids containing many substances that maintain solubility, it was confirmed that the solubility of the inabogliflozin / proline cocrystal was improved compared to the inabogliflozin crystalline form. The results are summarized in Tables 5 and 6 and Figure 7 below.

[0074] [Table 6]

[0075] [Table 6]

[0076] As shown in Tables 5 and 6 above, the solubility of the inabogliflozin / proline cocrystal of the present invention in artificial gastric and intestinal fluids increased compared to the inabogliflozin crystalline form. In particular, as shown in Table 6 and Figure 7, the solubility in artificial intestinal fluid up to 2 hours increased by more than twofold, and it was confirmed that the solubility remained high up to 4 hours. Therefore, the inabogliflozin / proline cocrystal of the present invention is a novel solid form that can overcome the low water solubility problem of the inabogliflozin crystalline form. The doubling of initial solubility in artificial intestinal fluid is expected to significantly improve oral absorption and maximize pharmacological efficacy. Such improvement in the solubility of inabogliflozin is particularly advantageous for the development of oral formulations for indications requiring high-dose administration.

[0077] [Experimental Example 6] Comparative evaluation of the severe stability of inabogliflozin cocrystals and inabogliflozin crystalline forms. To confirm the commercialization potential of the inabogliflozin / proline cocrystal of the present invention (Production Example 2), inabogliflozin crystal type A (Production Example 1) was used as a control group, and its thermal stability was tested at 60°C for 4 weeks. The results were then analyzed using liquid chromatography (HPLC) qualitative analysis, and are shown in Table 7.

[0078] As shown in Table 7, it was confirmed that inabogliflozin / proline and inabogliflozin crystalline form remain stable regardless of purity.

[0079] Therefore, the thermal stability of the inabogliflozin / proline cocrystal was confirmed to be equivalent to that of the inabogliflozin crystalline form.

[0080] [Table 7]

[0081] [Experimental Example 7] Evaluation of the pharmacokinetics of inabogliflozin / proline cocrystal in beagle dogs The improvement in the pharmacokinetic profile of inabogliflozin / proline cocrystal in beagle dogs was confirmed. Inabogliflozin crystal type A was set as the control group and proline cocrystal as the comparison group. Male beagle dogs were orally administered inabogliflozin crystal type A and proline cocrystal at a dose of 1 mg / kg. Blood samples were collected before administration (0 hours), and at 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours (13 times in total). Blood drug concentrations were analyzed by LC-MS / MS using plasma separated from the collected samples, and pharmacokinetic parameters such as the maximum observed plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were recorded using the WinNonlin 5.0.1 program. last and AUC inf ), time vs. maximum observed plasma concentration (Tmax), half-life (T 1 / 2 The following was calculated and analyzed:

[0082] The results are summarized in Table 8 below.

[0083] [Table 8]

[0084] As shown in Table 8 above, the proline cocrystal of the present invention has a time-to-maximal observed plasma concentration (Tmax) and half-life (T) compared to inabogliflozin crystal type A. 1 / 2 ) is slow, and the PK exposure parameter AUC last and AUC inf It was confirmed that the % was high. Therefore, the proline cocrystal of the present invention has a longer half-life and lower in vivo exposure (AUC) compared to conventional crystal type A. inf Because of its high crystalline form, the proline crystals are maintained in the body for a longer period, and it was confirmed that the drug effect lasts longer. Compared to crystalline form A, these pharmacokinetic properties of proline cocrystals allow the drug effect to last longer in the body, causing energy to be consumed to lower blood glucose levels, and as a result, the body's metabolism becomes more active through secondary effects. Therefore, these pharmacokinetic properties can be usefully used in the development of various indications and / or dosage forms.

Claims

1. Inabogliflozin / proline cocrystal, characterized by being identified by an X-ray powder diffraction pattern having four or more diffraction peaks at 2[θ] values ​​selected from 4.72±0.2, 6.81±0.2, 7.93±0.2, 8.59±0.2, 14.75±0.2, 15.21±0.2, 17.23±0.2, 18.80±0.2, 21.19±0.2, 24.42±0.2, and 27.29±0.2, The inabogliflozin / proline cocrystal is characterized in that one equivalent of inabogliflozin is bound to one equivalent of proline. Inabogliflozin / proline cocrystals

2. The inabogliflozin / proline cocrystal according to claim 1, characterized in that the X-ray powder diffraction pattern has diffraction peaks at 2[θ] values ​​selected from 6.81±0.2, 8.59±0.2, 14.75±0.2, 17.23±0.2, and 18.80±0.

2.

3. The inabogliflozin / proline cocrystal according to claim 1, characterized in that it is identified by an X-ray powder rotation pattern in which the peak positions listed in the table below coincide. Table 1

4. The inabogliflozin / proline cocrystal according to claim 1, characterized in that it shows endothermic peaks at an endothermic onset temperature of 217.71°C ± 3°C and an endothermic temperature of 219.42°C ± 3°C as determined by scanning calorimetry (DSC) analysis of temperature difference.

5. A method for producing an inabogliflozin / proline cocrystal according to any one of claims 1 to 4, comprising the steps of (a) mixing inabogliflozin with 10 to 60 ml of ethanol per 1 g of solid inabogliflozin and adding proline thereto, (b) stirring the product from step (a), and (c) vacuum drying the product from step (b) to obtain an inabogliflozin cocrystal.

6. A pharmaceutical composition characterized by comprising, as an active ingredient, an inabogliflozin / proline cocrystal as described in any one of claims 1 to 4, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that it is for the treatment or prevention of diabetes.

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