Pharmaceutical compositions comprising a co-crystal of empagliflozin

Abstract

The present invention provides a pharmaceutical composition comprising an empagliflozin co-crystal and having a water content of 3% or less in the composition, and a pharmaceutical preparation comprising the same. The pharmaceutical composition of the present invention is capable of maintaining the empagliflozin co-crystal and preventing a browning phenomenon that occurs when lactose is used in the formulation of the empagliflozin co-crystal. Furthermore, the pharmaceutical preparation of the present invention is capable of maximizing the effect of blocking moisture absorption by including a coating material capable of blocking the moisture absorption of the empagliflozin co-crystal.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions comprising empagliflozin cocrystals and pharmaceutical formulations comprising said pharmaceutical compositions. Background Technology

[0002] Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, represented by the following chemical formula (I), and is commercially available as a treatment for type 2 diabetes and is also being developed as a treatment for chronic heart failure.

[0003] [Chemical Formula I]

[0004]

[0005] Empagliflozin in crystalline or amorphous forms, such as free base, can be used as the active ingredient, and empagliflozin cocrystals can also be used.

[0006] It has been found that the structure of empagliflozin cocrystals is difficult to maintain due to the structural characteristics of the cocrystals and external factors (moisture, temperature, etc.), and in particular, moisture makes it difficult to maintain their structure. When the empagliflozin cocrystal cannot be maintained, its physicochemical properties may change, which could affect its absorption in vivo. Therefore, it is necessary to develop a pharmaceutical technology capable of maintaining the cocrystal structure.

[0007] Furthermore, browning was observed during the preparation of empagliflozin cocrystals when lactose (a diluent used in the reference drug and one of the most commonly used diluents in preparation) was used. Therefore, pharmaceutical techniques capable of improving these issues are needed. Summary of the Invention

[0008] Technical issues

[0009] One object of the present invention is to provide a pharmaceutical composition capable of maintaining the co-crystal form of empagliflozin.

[0010] Another object of the present invention is to provide a pharmaceutical composition that prevents browning when lactose is used in the formulation of empagliflozin cocrystallization, lactose being a diluent used in reference pharmaceuticals and one of the most commonly used diluents in formulation.

[0011] Another object of the present invention is to provide a pharmaceutical formulation comprising a coating material capable of blocking the hygroscopicity of empagliflozin eutectic.

[0012] Solution to the problem

[0013] The present invention will now be described in detail. Furthermore, each description and embodiment disclosed herein can be applied to every other description and embodiment. In other words, all combinations of the various elements disclosed herein fall within the scope of the present invention. Moreover, the scope of the present invention should not be considered limited by the specific description below.

[0014] According to one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising empagliflozin cocrystal and having a water content of 3% or less in the composition.

[0015] In the pharmaceutical composition of the present invention, the amount of empagliflozin cocrystal may be 0.1 to 30% by weight, preferably 0.3 to 20% by weight, based on the total weight of the composition. Furthermore, the empagliflozin cocrystal may be empagliflozin L-proline.

[0016] In the pharmaceutical compositions of the present invention, the water content in the composition can be reduced to a minimum of 3% or less, thereby maintaining the eutectic structure of empagliflozin. In other words, more preferably, the water content is reduced to a minimum, and therefore, the present invention has technical features at the upper limit of the numerical range. However, the water content can be from 0.1% to 3%.

[0017] In the pharmaceutical compositions of the present invention, an organic solvent with a water content of less than 5% can be used as a binding solvent during the kneading process with the empagliflozin cocrystallization to prepare the pharmaceutical composition. Specifically, the organic solvent can be anhydrous ethanol (e.g., USP 99.5% or higher) or isopropanol, but there are no limitations on the use of any organic solvent with less than 5% water.

[0018] In the pharmaceutical composition of the present invention, the pharmaceutical composition may further include at least one additive selected from the group consisting of diluents, binders, disintegrants and lubricants.

[0019] In the pharmaceutical compositions of the present invention, the diluent may not include lactose. Furthermore, the diluent may include sugar alcohols. For example, the sugar alcohol may be at least one selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol, and preferably, mannitol may be used. When a sugar alcohol is used instead of lactose as a diluent, browning observed in formulations containing lactose can be prevented. Meanwhile, the amount of sugar alcohol may be 30 to 70% by weight, specifically 40 to 60% by weight, based on the total weight of the composition.

[0020] Furthermore, the diluent may further include at least one selected from the group consisting of: microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, silicified microcrystalline cellulose, dextran binder, glucose, fructose, and sucrose, but is not limited thereto. Meanwhile, based on the total weight of the composition, the amount of other diluents to be added, excluding sugar alcohols, may be 10 to 40% by weight, specifically 15 to 30% by weight.

[0021] Furthermore, the adhesive may be at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, starch, pregelatinized starch, carbomer, xanthan gum, polyvinyl alcohol, vinylpyrrolidone, and povidone, but is not limited thereto. Meanwhile, based on the total weight of the composition, the amount of adhesive may be from 0.5% to 10% by weight, specifically from 1% to 4% by weight.

[0022] Furthermore, the disintegrant may be at least one selected from the group consisting of: crospovidone, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, croscarmellose sodium, and low-substituted hydroxypropyl cellulose, but is not limited thereto. Meanwhile, the amount of disintegrant may be 2 to 20% by weight, specifically 4 to 12% by weight, based on the total weight of the composition.

[0023] Furthermore, the lubricant may be at least one selected from the group consisting of talc, colloidal silica, sodium stearoyl fumarate, magnesium stearate, sodium lauryl sulfate, and glyceryl behenate, but is not limited thereto. Meanwhile, based on the total weight of the composition, the amount of lubricant may be from 0.1 to 10% by weight, specifically from 0.5 to 4% by weight.

[0024] In another general aspect, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition of the present invention.

[0025] In the pharmaceutical formulation of the present invention, the formulation may be a tablet, capsule, pellet, granule, or powder, preferably a tablet. Furthermore, the tablet may be a film-coated tablet.

[0026] In the pharmaceutical formulations of the present invention, particularly in the film-coated tablets of the present invention, the coating material may not include hydroxypropyl methylcellulose. Instead, the coating material may include polyvinyl alcohol (PVA). Empagliflozin L-proline has the problem of high hygroscopicity, and therefore polyvinyl alcohol coating material can be used to block moisture absorption as much as possible.

[0027] Furthermore, the pharmaceutical formulation of the present invention can be used to treat diabetes, diabetic complications, or chronic heart failure. Diabetes can be type 1 or type 2, preferably type 2. In addition, diabetic complications can be retinopathy, nephropathy or neuropathy, diabetic foot ulcers, tumors, or macrovascular disease. Furthermore, chronic heart failure can be heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).

[0028] Furthermore, according to one embodiment of the present invention, the pharmaceutical formulation of the present invention may further comprise at least one drug for treating diabetes, diabetic complications, or chronic heart failure. Specifically, the drug may be at least one drug selected from the group consisting of: biguanides, thiazolidinediones (TZDs), DPP-IV inhibitors, SGLT2 inhibitors, SGLT1 / SGLT2 dual inhibitors, GLP-1 receptor agonists, sulfonylureas (SUs), meglitinide analogs, and α-glucosidase inhibitors (AGIs).

[0029] Examples of biguanides, thiazolidinediones (TZDs), DPP-IV inhibitors, SGLT2 inhibitors, SGLT1 / SGLT2 dual inhibitors, GLP-1 receptor agonists, sulfonylureas (SUs), megglitinide analogs, and alpha-glucosidase inhibitors (AGIs) are provided below:

[0030] Biguanide drugs: metformin, etc.;

[0031] Thiazolidinediones (TZDs): lobeglitazone, rosiglitazone, pioglitazone, etc.

[0032] DPP-IV inhibitors: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, teneligliptin, anagliptin, evogliptin, etc.

[0033] SGLT-2 inhibitors: dapagliflozin, canagliflozin, ipragliflozin, etc.;

[0034] SGLT1 / SGLT2 dual inhibitors: such as sotagliflozin;

[0035] GLP-1 receptor agonists: semaglutide, etc.;

[0036] Sulfonylurea (SU) drugs: glimepiride, glibenclamide, gliclazide, glipizide, etc.;

[0037] Meglinide analogues: nateglinide, repaglinide, etc.; and

[0038] Alpha-glucosidase inhibitors (AGIs): acarbose, voglibose, miglitol, etc.

[0039] Advantages of the invention

[0040] The pharmaceutical composition of the present invention is able to maintain the eutectic form of empagliflozin.

[0041] Furthermore, the pharmaceutical composition of the present invention prevents browning when lactose is used in the formulation of empagliflozin cocrystals, lactose being a diluent used in the reference drug and one of the most commonly used diluents in formulation.

[0042] Furthermore, the pharmaceutical formulation of the present invention can maximize the effect of hygroscopic barrier by including a coating material that can block the hygroscopicity of empagliflozin eutectic. Attached Figure Description

[0043] Figure 1 The XRD results obtained by observing whether the eutectic in Experimental Example 1 was maintained or changed are shown.

[0044] Figure 2 and Figure 3 The XRD results obtained by observing whether the eutectic in Experiment 2 was maintained or changed are shown. Figure 2 : Ethanol, Figure 3 (Isopropanol).

[0045] Figure 4 The images were obtained by observing whether browning occurred depending on the type of diluent in Experiment Example 3. Detailed Implementation

[0046] The invention will be described in more detail below by way of examples and experimental examples. However, these examples and experimental examples are provided to illustrate the invention, and the scope of the invention is not limited to these examples and experimental examples.

[0047] Experimental Example 1. Confirmation Test on Eutectic Maintenance Depends on Water Content

[0048] The coated tablets of Example 1 were prepared according to the compositions shown in Table 1. The water content of Example 1 was 1.6%.

[0049] [Table 1]

[0050]

[0051]

[0052] Furthermore, the coated tablets of Examples 2 and 3 were prepared with the same composition as in Example 1, except that the water content was adjusted to 2.6% and 2.9%, respectively. Additionally, the coated tablets of Comparative Examples 1 to 3 were prepared with the same composition as in Example 1, except that the water content was adjusted to 3.2%, 3.6%, and 4.0%, respectively.

[0053] Depending on the water content in Examples 1 to 3 and Comparative Examples 1 to 3, the results of whether the eutectic was maintained or changed are summarized in Table 2 below.

[0054] [Table 2]

[0055]

[0056] As shown in Table 2 above and Figure 1 It was confirmed that the coated tablets of Examples 1 to 3 maintained the presence of empagliflozin cocrystal (L-proline), while the empagliflozin cocrystal (L-proline) was altered in the coated tablets of Comparative Examples 1 to 3.

[0057] Example 2. Confirmation Test of Eutectic Maintenance Depends on Water Content in Organic Solvent

[0058] The composition of Example 4 was prepared according to the composition shown in Table 3. Anhydrous ethanol was used during the kneading process when preparing the composition of Example 4.

[0059] [Table 3]

[0060]

[0061]

[0062] Furthermore, the compositions of Comparative Examples 4 and 5 were prepared with the same composition as in Example 4, except that the water content of the adhesive solution was adjusted to 5% and 10%, respectively. Additionally, the compositions of Examples 5, 6, and 7 were prepared with the same composition as in Example 4, except that isopropanol was used instead of ethanol and the water content of the adhesive solution was adjusted to 0%, 5%, and 10%, respectively.

[0063] The results of whether the eutectic in Examples 4 and 5 and Comparative Examples 4 to 7 was maintained or changed are summarized in Table 4 below.

[0064] [Table 4]

[0065]

[0066] As shown in Table 4 above and Figure 2 and Figure 3 It was confirmed that the compositions of Examples 4 and 5 maintained the presence of empagliflozin cocrystal (L-proline), while the empagliflozin cocrystal (L-proline) was altered in the compositions of Comparative Examples 4 to 7.

[0067] Experimental Example 3. Confirmation Test of Browning Phenomenon Depends on Diluent Type

[0068] The compositions of Example 6 and Comparative Example 8 were prepared according to the compositions shown in Table 5.

[0069] [Table 5]

[0070]

[0071] like Figure 4 As shown, discoloration was observed in Comparative Example 8, which used lactose as a diluent. This is presumably due to browning caused by the reaction between the amino group of L-proline and the reducing sugar of lactose (Maillard reaction).

[0072] On the other hand, no browning was observed in Example 6, in which mannitol was used instead of lactose.

[0073] Experimental Example 4. Confirmation Test of Hygroscopicity Depends on Coating Material Type

[0074] The coated tablets of Example 7 with a water content of 2.3% were prepared with the same composition as in Example 1. Furthermore, the coated tablets of Comparative Example 9 with a water content of 2.3% were prepared with the compositions shown in Table 6 below.

[0075] [Table 6]

[0076]

[0077] The hygroscopicity of Example 7 and Comparative Example 9 was compared under accelerated conditions (40±2℃ / RH 75±5%, close to 6M), and the results are shown in Table 7 below.

[0078] [Table 7]

[0079] Examples / Comparative Examples Coating material Changes in water content (%) Example 7 PVA 2.3→2.6 Comparative Example 9 HPMC 2.3→4.5

[0080] As confirmed in Table 7 above, given the changes in water content, it was observed that the water content of Comparative Example 9, which used HPMC as the coating material, increased by approximately 2.2% (from 2.3% to 4.5%), while the water content of Example 7, which used PVA as the coating material, increased only slightly by approximately 0.3% (from 2.3% to 2.6%). Therefore, to prevent the hygroscopicity of empagliflozin L-proline, it is preferable to use PVA instead of HPMC as the coating material.

[0081] Based on the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical spirit or essential characteristics. It should be understood that the above embodiments are exemplary in all respects and not restrictive. Regarding the scope of the invention, it should be understood that all variations or modifications derived from the meaning and scope of the appended claims and their equivalents, rather than those described in the detailed description above, are included within the scope of the invention.

Claims

1. A pharmaceutical preparation comprising a pharmaceutical composition comprising an empagliflozin co-crystal and having a water content of 3% or less in the composition, wherein the empagliflozin co-crystal is empagliflozin L-proline, the preparation is a tablet, the tablet is a film-coated tablet, the coating material does not include hydroxypropyl methylcellulose, and the coating material includes polyvinyl alcohol.

2. The pharmaceutical preparation according to claim 1, wherein the water content in the composition is 0.1% to 3%.

3. The pharmaceutical preparation according to claim 1, wherein an organic solvent having a water content of less than 5% is used as a binding solvent in a kneading process with the empagliflozin co-crystal.

4. The pharmaceutical preparation according to claim 1, further comprising at least one additive selected from the group consisting of a diluent, a binder, a disintegrant, and a lubricant.

5. The pharmaceutical preparation according to claim 4, wherein the diluent does not include lactose.

6. The pharmaceutical preparation according to claim 5, wherein the diluent includes a sugar alcohol.

7. The pharmaceutical preparation according to claim 6, wherein the sugar alcohol is at least one selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol.

8. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation is used for treating diabetes, diabetic complications, or chronic heart failure.

9. The pharmaceutical preparation according to claim 8, further comprising at least one drug for treating diabetes, diabetic complications, or chronic heart failure.

10. The pharmaceutical preparation according to claim 9, wherein the drug is at least one drug selected from the group consisting of a biguanide drug, a thiazolidinedione (TZD) drug, a DPP-IV inhibitor, a SGLT2 inhibitor, a SGLT1 / SGLT2 dual inhibitor, a GLP-1 receptor agonist, a sulfonylurea (SU) drug, a meglitinide analogue, and an alpha-glucosidase inhibitor (AGI).

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