Pharmaceutical composition in the form of eye drops containing enavogliflozin

Abstract

The present invention provides a pharmaceutical composition in the form of eye drops, comprising enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient and a combination of polysorbate and polyoxyl 40 stearate as a solubilizer and stabilizer. The pharmaceutical composition of the present invention contains a specific combination of surfactants, which not only significantly improves stability but also significantly increases the intraocular exposure of enavogliflozin.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition in the form of eye drops containing enavogliflozin. More specifically, the present invention relates to a pharmaceutical composition in the form of eye drops comprising enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient and a combination of a specific surfactant that provides excellent stability and increased intraocular exposure. [Background technology]

[0002] Enavogliflozin has the chemical structure of the following chemical formula 1 and has inhibitory activity against SGLT2 (sodium-dependent glucose cotransporter 2) present in the intestine and kidney, and therefore may be useful in the treatment of metabolic disorders, particularly diabetes (WO2012 / 165914, WO2017 / 217792, etc.). [ka]

[0003] The present inventors have found that SGLT2 inhibitors, including enavogliflozin or a pharmaceutically acceptable salt thereof, have excellent preventive or therapeutic activity against diabetic eye diseases (e.g., diabetic retinopathy) (Korean Patent Publication No. 10-2022-0079480).The present inventors have also found that SGLT2 inhibitors, including enavogliflozin or a pharmaceutically acceptable salt thereof, have excellent preventive or therapeutic activity against macular degeneration (Korean Patent Publication No. 10-2023-0007963).

[0004] Since enavogliflozin has low water solubility, it is difficult to formulate it into an aqueous solution, for example, into an eye drop solution. To solve this problem, Korean Patent Publication Nos. 10-2022-0079480 and 10-2023-0007963 disclose a solubilizing agent containing polyoxyl 35 castor oil (Kolliphor TM ELP) and polysorbate 80 (Tween TM80) discloses an example of an eye drop in which enavogliflozin is solubilized.

[0005] On the other hand, intraocular delivery of drugs is essential for the treatment of posterior segment eye diseases such as diabetic retinopathy and macular degeneration. In particular, to deliver drugs to the diseased site (e.g., the retina), it is necessary not only to effectively solubilize the drug but also to increase intraocular drug exposure by allowing the solubilized drug to penetrate the cornea and conjunctiva and reach the retina. Furthermore, because patients with posterior segment eye diseases such as diabetic retinopathy and macular degeneration require long-term repeated administration, excellent stability is required, without drug precipitation or degradation product formation, from formulations (e.g., eye drops). Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have found that conventional enavogliflozin-containing eye drops (e.g., those disclosed in Korean Patent Publication Nos. 10-2022-0079480 and 10-2023-0007963) exhibit significantly reduced stability during long-term storage and do not provide satisfactory intraocular exposure. To address these issues, the present inventors conducted various formulation studies. As a result, the present inventors found that formulations using a specific surfactant combination significantly improve the physical and chemical stability of enavogliflozin-containing eye drops. Specifically, the present inventors found that a specific surfactant combination functions not only as a solubilizer but also as a stabilizer in enavogliflozin-containing eye drops. Furthermore, the present inventors found that eye drops obtained using a specific surfactant combination can provide excellent pharmacological activity by significantly increasing the intraocular exposure of enavogliflozin.

[0007] Therefore, an object of the present invention is to provide a pharmaceutical composition in the form of eye drops, which comprises a combination of enavogliflozin or a pharmaceutically acceptable salt thereof and a specific surfactant. [Means for solving the problem]

[0008] One aspect of the present invention provides a pharmaceutical composition in the form of eye drops, comprising enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient, and a combination of polysorbate and polyoxyl 40 stearate as a solubilizer and stabilizer.

[0009] Enavogliflozin or a pharmaceutically acceptable salt thereof may be at a concentration of 0.1 to 10 w / v %, preferably 0.3 to 8 w / v %, more preferably 0.5 to 5 w / v %.

[0010] The combination of polysorbate and polyoxyl 40 stearate may be at a concentration of 1 to 15 w / v%, preferably 4 to 10 w / v%. The weight ratio of polysorbate to polyoxyl 40 stearate may be 1:1 to 10, preferably 1:2 to 8.

[0011] The pharmaceutical composition of the present invention may form nanomicelles having an average particle size of 1 to 500 nm, preferably 5 to 50 nm.

[0012] The pharmaceutical composition of the present invention may further comprise one or more additives selected from the group consisting of a permeation enhancer, an osmolality adjuster, and a pH adjuster. In one embodiment, the permeation enhancer may be D-α-tocopheryl polyethylene glycol succinate. In another embodiment, the osmolality adjuster may be glycerin. In yet another embodiment, the pharmaceutical composition of the present invention may have an osmolality of 230 to 350 mOsmol / kg and / or a pH of 6.0 to 7.5. [Effects of the Invention]

[0013] The pharmaceutical composition in the form of eye drops according to the present invention can significantly improve its physical and chemical stability by including a specific combination of surfactants, i.e., a combination of polysorbate and polyoxyl 40 stearate. Therefore, it has been discovered by the present inventors that the combination of polysorbate and polyoxyl 40 stearate functions not only as a solubilizer but also as a stabilizer. Furthermore, the pharmaceutical composition of the present invention, which includes the specific combination of surfactants, can provide excellent pharmacological activity by significantly increasing the intraocular exposure of enavogliflozin. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows the results obtained by measuring the saturated solubility of enavogliflozin in a surfactant mixture (a mixture of Tween™ 80 and Kolliphor™ EL). [Figure 2] The appearances of Formulation Example 1 at dissolution step 1 (40°C), dissolution step 2 (80°C), and filtration step (25°C) are shown in the manufacturing process. [Figure 3] Figures 3a, 3b, and 3c show the results obtained by analyzing the particle size distribution of the formulations of Formulation Example 3 (Figure 3a), Formulation Example 4 (Figure 3b), and Formulation Example 5 (Figure 3c), respectively. [Figure 4] 1 shows the drug concentration profile in rat eyeballs obtained by conducting a pharmacokinetic study. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides a pharmaceutical composition in the form of eye drops, which comprises enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient, and a combination of polysorbate and polyoxyl 40 stearate as a solubilizer and stabilizer.

[0016] The pharmaceutical composition of the present invention may contain enavogliflozin or a pharmaceutically acceptable salt thereof in an amount suitable for treating posterior ocular diseases such as diabetic retinopathy and macular degeneration. For example, enavogliflozin or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical composition of the present invention at a concentration of 0.1 to 10 w / v%, preferably 0.3 to 8 w / v%, and more preferably 0.5 to 5 w / v%.

[0017] The present invention has found that formulation using a specific combination of surfactants, i.e., a combination of polysorbate and polyoxyl 40 stearate, can significantly improve the physical and chemical stability of enavogliflozin-containing eye drops.The present invention has also found that the pharmaceutical composition of the present invention containing a specific combination of surfactants can significantly increase the intraocular exposure of enavogliflozin, thereby providing excellent pharmacological activity.

[0018] The polysorbate may be polysorbate 20, polysorbate 40, polysorbate 80, etc., preferably polysorbate 80. Polyoxyl 40 stearate is also known as polyethylene glycol monostearate. In the pharmaceutical composition of the present invention, the combination of the polysorbate and polyoxyl 40 stearate may be present in the pharmaceutical composition at a concentration of 1 to 15 w / v%, preferably 4 to 10 w / v%. The weight ratio of polysorbate to polyoxyl 40 stearate may be 1:1 to 10, preferably 1:2 to 8. In one embodiment, within the above weight ratio, the polysorbate may be present in the pharmaceutical composition at a concentration of 0.1 to 10 w / v%, preferably 1 to 4 w / v%, and polyoxyl 40 stearate may be present in the pharmaceutical composition at a concentration of 0.1 to 10 w / v%, preferably 3 to 7 w / v%. The pharmaceutical composition of the present invention contains a combination of polysorbate and polyoxyl 40 stearate, and thereby forms nanomicelles having an average particle size of 1 to 500 nm, preferably 5 to 50 nm.

[0019] The pharmaceutical composition of the present invention may contain additives commonly used in the field of ophthalmic solutions. For example, the pharmaceutical composition of the present invention may further contain one or more additives selected from the group consisting of a permeation enhancer, an osmolality adjuster, and a pH adjuster. In one embodiment, the permeation enhancer may be D-α-tocopheryl polyethylene glycol succinate (TPGS) and may be present at a concentration of, for example, 0.1 to 0.5 w / v%. In another embodiment, the osmolality adjuster may be glycerin and may be present at a concentration of, for example, 0.5 to 6 w / v%. In yet another embodiment, the pharmaceutical composition of the present invention may have an osmolality of 230 to 350 mOsmol / kg and / or a pH of 6.0 to 7.5.

[0020] One embodiment of the present invention provides a pharmaceutical composition comprising, in an aqueous medium, 0.5-5 w / v% enavogliflozin or a pharmaceutically acceptable salt thereof, 4-10 w / v% of a combination of polysorbate and polyoxyl 40 stearate, 0.1-0.5 w / v% D-α-tocopheryl polyethylene glycol succinate, 0.5-6 w / v% glycerin, and a pH adjuster, and forming nanomicelles having an average particle size of 5-50 nm. In this embodiment, the weight ratio of polysorbate to polyoxyl 40 stearate may be 1:2-8.

[0021] The present invention will be described in more detail below through examples, but these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0022] Example 1: Formulation Study-1 (1) Evaluation of solubility Using the FDA Inactive Ingredient Database (https: / / www.accessdata.fda.gov / scripts / cder / iig / index.cfm), excipients that can be used for ophthalmic administration were dissolved in purified water at the maximum concentration recommended by the FDA, and then saturation solubility was measured by dissolving enavogliflozin until it was saturated.

[0023] (1-1) Preparation of standard solution According to Table 1 below, enavogliflozin in an amount corresponding to each standard solution and 70 mL of methanol were placed in a volumetric flask and completely dissolved by ultrasonic shaking. Then, methanol was added to bring the total volume to 100 mL. A portion of the resulting solution was sampled and filtered through a 0.45 μm RC (regenerated cellulose) membrane filter. The first 2 mL filtered was discarded, and the filtrate was used as the standard solution.

[0024] [Table 1]

[0025] (1-2) Preparation of test solution Each excipient was dissolved in 5 mL of purified water at the maximum concentration recommended by the FDA (Table 2), and then enavogliflozin was added until no further dissolution occurred. The mixture was stirred for approximately 12 hours. After confirming no further dissolution after 12 hours, each sample was centrifuged at 4000 rpm for 30 minutes, and the clear supernatant (1 mL) was removed and diluted with methanol. The resulting solution was filtered through a 0.45 μm RC membrane filter. The first 2 mL of the filtered solution was discarded, and the filtrate was used as the test solution.

[0026] (1-3)HPLC analysis The peak areas of the standard solution and the test solution were analyzed under the following HPLC conditions. -Detector: UV absorption photometer (measurement wavelength: 225 nm) - Column: Capcellpak C18 (4.6 x 250 mm, 5 μm) -Column temperature: approx. 35°C -Sample temperature: approx. 25°C Mobile phase: buffer:acetonitrile = 25:75 (v / v) (Buffer solution: prepared by dissolving 100 μL of trifluoroacetic acid in 1000 mL of water) -Flow rate: 1.0mL / min -Injection volume: 10μL -Analysis time: Approximately 20 minutes

[0027] (1-4) Solubility of each additive The results of measuring the saturated solubility of enavogliflozin in each additive are shown in Table 2 below. [Table 2]

[0028] From the results in Table 2, Tween TM 80 or Kolliphor TM It can be seen that the addition of EL improved the solubility of enavogliflozin to the highest level. In addition, the addition of the permeation enhancer TPGS also significantly improved the solubility of enavogliflozin. TM HS15, Tween TM 20, and Kolliphor TM RH40 also had a similar solubilizing effect, but had the drawback of limiting the maximum amount that could be used as an ophthalmic additive.

[0029] (2) Evaluation of saturated solubility depending on surfactant concentration According to the results of (1) above, the surfactant Tween TM 80 and Kolliphor TM EL was selected as an additive for solubilizing enavogliflozin. The target concentration of enavogliflozin in the eye drops was 0.5-5.0 w / v%, but this concentration was not reached even if saturated solubility was reached. Therefore, the two components with the best solubilizing ability were mixed, and the saturated solubility of the active ingredient was measured according to the ratio.

[0030] (2-1) Test method Tween TM80 and Kolliphor TM EL were mixed in the proportions shown in Table 3 below. The resulting mixture was heated to 40°C, and enavogliflozin was added in fixed amounts and dissolved. The point at which enavogliflozin no longer dissolved and the appearance became cloudy was defined as saturated solubility. [Table 3]

[0031] (2-2) Test results The amount of enavogliflozin dissolved until the appearance was maintained was added up to analyze the saturated solubility. As can be seen from the results in Figure 1, the solubility of enavogliflozin increased in proportion to the increase in the total surfactant concentration. To dissolve enavogliflozin to the target concentration of 5.0 w / v%, the surfactant must be used at a concentration of at least 5.0 w / v%.

[0032] (3) Preparation and evaluation (3-1) Preparation Based on the test results, enavogliflozin-containing eye drops (Formulation Example 1: 5.0 w / v%, Formulation Example 2: 2.0 w / v%) were prepared according to the ingredients and contents in Table 4 below. TM 80 and Kolliphor TM EL was used, TPGS was used as a permeation enhancer, and glycerin was used as an osmotic pressure adjuster. TM 80, Kolliphor TM The mixture (EL, glycerin, anhydrous sodium dihydrogen phosphate, and sodium hydroxide) and water for injection were heated to approximately 40°C with stirring (dissolution step 1). The active ingredient (enavogliflozin) was added, and the mixture was heated to approximately 80°C (dissolution step 2). The solution was then cooled to 25°C and filtered through a 0.2 μm RC membrane filter, PTFE membrane filter, or PVDF membrane filter (filtration step). Each of the resulting eye drops was filled into a polyethylene tube. [Table 4]

[0033] (3-2) Evaluation of formulations The solution was filtered using a membrane filter made of RC, PTFE, or PVDF, and the content of the active ingredient was analyzed by HPLC before and after filtration in the same manner as in (1) above to confirm whether the active ingredient was adsorbed onto the filter. The results are shown in Table 5 below. [Table 5]

[0034] As can be seen from the results in Table 5, regardless of the material of the filter used in the filtration process, the active ingredient did not show significant adsorption, and the most commonly used RC material was selected as the filter for the filtration process.

[0035] Furthermore, the appearance, content, pH, and osmotic pressure of Formulation Example 1 and Formulation Example 2 were evaluated. The appearance was confirmed with the naked eye, and the content was analyzed by HPLC analysis in the same manner as in (1) above. The pH was measured using a Metrohm 913 instrument, and the osmotic pressure was measured using an OSMOMAT 3000D instrument. The results of the evaluation of the formulations as described above are shown in Table 6 below. [Table 6]

[0036] During the process of dissolving the active ingredient, a temporary phenomenon was observed in which the active ingredient did not dissolve sufficiently and remained suspended during heating. This is presumably due to the active ingredient precipitating at temperatures above the cloud point of the nonionic surfactant. When the solution was cooled to a temperature below the cloud point during the subsequent cooling process, the surfactant re-associated to form nanomicelles, which is thought to have dissolved the active ingredient (see Figure 2).

[0037] The osmotic pressure of Formulation Example 1 slightly exceeded the target standard, so it is thought that the amount of osmotic pressure adjuster used needs to be adjusted. Although the osmotic pressure of Formulation Example 1 did not meet the target standard, it was used as a sample to observe the tendency of degradation products in Formulation Study 2 of Example 2.

[0038] Example 2: Formulation Study-2 (1) Manufacturing of pharmaceutical preparations Based on the test results of Example 1, eye drops were prepared using the same method as in Example 1 (3-1) (filtration using an RC membrane filter) as in Example 1 (3-1), with the active ingredient concentrations of 1.0 w / v%, 3.0 w / v%, and 5.0 w / v% according to the ingredients and amounts listed in Table 7. Considering that an eye drop containing 1.0 w / v% of the active ingredient is sufficient in terms of saturated solubility, the amount of surfactant was reduced by 30%. The amounts of pH adjuster and osmolality adjuster were also adjusted to meet the pH or osmolality criteria (Table 7). [Table 7]

[0039] (2) Evaluation of appearance, content, pH, and osmolality The appearance, content, pH, and osmotic pressure of Formulation Examples 3, 4, and 5 were evaluated in the same manner as in (3-2) of Example 1. The results are shown in Table 8 below. [Table 8]

[0040] The results in Table 8 confirm that the formulations of Formulation Examples 3, 4, and 5 meet the target standards. Since the measured pH values ​​were nearly identical at all concentrations, it is believed that the pH adjuster adequately fulfills its buffering function. Furthermore, the osmotic pressure did not increase in proportion to the amount of active ingredient or surfactant.

[0041] (3) Evaluation of particle size distribution and zeta potential Tween, a solubilizer used to achieve the target concentration of the active ingredient (enavogliflozin) TM 80 and Kolliphor TM EL forms micelles at concentrations above the critical micelle concentration. Because the formation of micelles or nanomicelles affects drug delivery efficiency, we investigated whether formulations 3, 4, and 5 formed nanomicelles. Dynamic light scattering (DLS) was used to analyze the particle size distribution formed in solution. Zeta potential was also measured to confirm the charge formed on the particle surface. The DLS measurement device used was an ELSZ-2000 from Otsuka Electronics Co., Ltd. The measurement conditions are shown in Table 9 below. [Table 9]

[0042] The particle size distribution of the formulations of Formulation Examples 3, 4, and 5 was analyzed and the results are shown in Table 10 and Figure 3 (i.e., Figures 3a, 3b, and 3c). The zeta potential was measured and the results are shown in Table 10 below. [Table 10]

[0043] As can be seen from the results in Table 10, the mean particle size (Z-average) ranged from 11.9 to 29.4 nm and tended to increase as the proportion of active ingredient increased. However, based on the particle number distribution (number distribution), all formulations showed particle diameters less than 10 nm. The zeta potential was confirmed to be weakly negatively charged.

[0044] Example 3: Formulation Study-3 (1) Stability evaluation Kolliphor TM EL and Tween TM The stability of Formulation Example 2 containing 80 combinations was evaluated while storing it under accelerated conditions or room temperature conditions for 2 months or 4 months. The results are shown in Table 11 below. [Table 11]

[0045] As can be seen from the results in Table 11, Formulation Example 2 exhibited precipitation or a content below the standard value in the stability tests at room temperature for 4 months, accelerated conditions for 2 months, and accelerated conditions for 4 months, and was therefore unsuitable. When the content decreases due to decomposition of the active ingredient, the amount of degradation products increases significantly. However, the increase in degradation products derived from enavogliflozin was not significant.

[0046] (2) Improved formulation Because the use of surfactants improved the solubility of the poorly soluble enavogliflozin, it is possible that interactions between the active ingredient and surfactants may affect stability during storage. Therefore, such effects can be indirectly evaluated by measuring the cloud point, at which solubility rapidly decreases due to dehydration of the water-soluble groups of the nonionic surfactant upon heating. Based on this, we investigated the cause of the formulation instability and conducted formulation studies, including changing the solubilizer, to stabilize the formulation.

[0047] (2-1) Evaluation of solubilization by polyoxyl stearate 40 Polyoxyl 40 stearate (Myrj) in 5 mL of purified water TM S40) was dissolved at a concentration of 7.0 w / v%, and then enavogliflozin was added until it no longer dissolved, followed by stirring for approximately 12 hours. Thereafter, the degree of solubilization was evaluated in the same manner as in Example 1.

[0048] (2-2) Cloud point measurement The cloud point was measured by visual observation of the time when the test formulations became opaque while gradually warming. 5 mL of the test formulations (i.e., the formulations of Formulation Examples 6, 7, and 8 prepared in (2-3) below, and Formulation Example 1) were placed in a transparent glass vial, and the temperature was raised in 0.5°C increments while stirring in a water bath. The temperature at which the appearance of the formulation changed from a transparent liquid to a cloudy suspension was determined as the cloud point.

[0049] (2-3) Preparation According to the ingredients and contents in Table 12, eye drops were prepared in the same manner as in (3-1) of Example 1, except that the concentrations of the active ingredients were 1.0 w / v%, 3.0 w / v%, and 5.0 w / v%, respectively. [Table 12]

[0050] (2-4-1) Evaluation of solubilization by polyoxyl stearate 40 According to the FDA's recommended use of excipients, Kolliphor is administered by ophthalmic route. TM EL can be used at a maximum concentration of 5.0 w / v%, and polyoxyl 40 stearate can be used at a maximum concentration of 7.0 w / v%. Based on this, the results obtained by comparing the degree of solubilization of the two additives are shown in Table 13 below. [Table 13]

[0051] As can be seen from the results in Table 13, when considering the maximum amount, polyoxyl 40 stearate is TM Compared with EL, it can solubilize approximately twice as much enavogliflozin.

[0052] (2-4-2) Evaluation of appearance, content, pH, osmolality, and cloud point Based on the above results, Kolliphor TM The EL was replaced with polyoxyl 40 stearate to produce formulations Formulation Examples 6, 7, and 8. Their appearance, content, pH, osmolality, and cloud point were evaluated. For comparison, the cloud point of Formulation Example 1 was also measured. The results are shown in Table 14 below. [Table 14]

[0053] As can be seen from the results in Table 14, when Formulation Example 1 and Formulation Example 8, which have the same active ingredient concentration, are compared, the cloud point is found to be increased by about 40°C. TM In contrast to EL, this shows that the solubilizing ability of polyoxyl 40 stearate is maintained even if dehydration of the water-soluble portion occurs to some extent upon heating. Formulation Examples 6, 7, and 8 showed favorable values ​​in all evaluation items.

[0054] (2-4-3) Stability evaluation The formulations of Formulation Example 1, Formulation Example 2, Formulation Example 6, Formulation Example 7, and Formulation Example 8 were stored under accelerated conditions for 6 months, and the content of the active ingredient was measured to evaluate their stability. The results obtained are shown in Table 15 below. [Table 15]

[0055] As can be seen from the results in Table 15, the formulation of Formulation Example 1 showed a content reduction of more than 90% when stored under accelerated conditions for 6 months, while the formulation of Formulation Example 8 containing the same concentration showed significantly better stability. The low-concentration formulations, i.e., Formulation Examples 6 and 7, also showed significantly better stability. Therefore, it can be confirmed that the use of polyoxyl 40 stearate significantly improves the stability of enavogliflozin-containing eye drops.

[0056] Example 4: Formulation Study-4 (1) Manufacturing of pharmaceutical preparations Based on the above test results, eye drops were prepared in the same manner as in Example 1 (3-1), with the active ingredient concentration set to 2.0 w / v % according to the ingredients and contents in Table 16. [Table 16]

[0057] (2) Stability evaluation The formulations of Formulation Example 9 and Formulation Example 10 were stored under accelerated conditions for 6 months, and the contents of the active ingredient and total decomposition products were measured to evaluate their stability. The results are shown in Table 17 below. [Table 17]

[0058] From the results in Table 17, it can be seen that the use of polyoxyl 40 stearate according to the present invention exhibits superior stability.

[0059] (3) Pharmacokinetic study in rat eyes To compare the intraocular exposure of each formulation in rats, ocular administration was performed. Ten rats were administered each formulation. After restraining the rats outside their cages, the upper and lower eyelids were opened, and 5 μL of each test formulation was instilled into each eye using a pipette. The rats were held for a certain period of time after instillation to prevent spillage of the test formulation. At sampling time points corresponding to 1, 2, 4, 6, and 12 hours after instillation, two rats were anesthetized with isoflurane by inhalation, and the left and right eyes were enucleated using surgical scissors and forceps. The retinal tissues isolated from the left and right eyes were immediately collected into 1.5 mL Eppendorf tubes. The retinal tissues collected from each individual at each sampling time point were pooled in 1.5 mL Eppendorf tubes and immediately frozen in liquid nitrogen after weighing. The enavogliflozin concentration in the retina was analyzed using LC-MS / MS.

[0060] The intraocular drug concentration profile obtained by the pharmacokinetic test in rat eyes as described above is shown in Figure 4. As can be seen from the results in Figure 4, the eye drop preparation obtained using polyoxyl 40 stearate according to the present invention maintained a significantly high intraocular concentration. Therefore, the eye drop preparation obtained according to the present invention can provide excellent pharmacological activity by increasing the intraocular exposure of enavogliflozin.

Claims

1. A pharmaceutical composition in the form of eye drops, comprising enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient, and a combination of polysorbate and polyoxyl 40 stearate as a solubilizer and stabilizer.

2. 2. The pharmaceutical composition according to claim 1, wherein enavogliflozin or a pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 10 w / v %.

3. 2. The pharmaceutical composition according to claim 1, wherein enavogliflozin or a pharmaceutically acceptable salt thereof is present at a concentration of 0.3 to 8 w / v %.

4. 2. The pharmaceutical composition according to claim 1, wherein enavogliflozin or a pharmaceutically acceptable salt thereof is present at a concentration of 0.5 to 5 w / v %.

5. 2. The pharmaceutical composition according to claim 1, wherein the combination of polysorbate and polyoxyl 40 stearate is at a concentration of 1 to 15 w / v %.

6. 2. The pharmaceutical composition according to claim 1, wherein the combination of polysorbate and polyoxyl 40 stearate is at a concentration of 4 to 10 w / v %.

7. 2. The pharmaceutical composition according to claim 1, wherein the weight ratio of polysorbate to polyoxyl 40 stearate is 1:1-10.

8. 2. The pharmaceutical composition according to claim 1, wherein the weight ratio of polysorbate to polyoxyl 40 stearate is 1:2-8.

9. The pharmaceutical composition according to claim 1, which forms nanomicelles having an average particle size of 1 to 500 nm.

10. The pharmaceutical composition according to claim 1, which forms nanomicelles having an average particle size of 5 to 50 nm.

11. The pharmaceutical composition according to any one of claims 1 to 10, further comprising one or more additives selected from the group consisting of permeation enhancers, osmolality adjusters, and pH adjusters.

12. 12. The pharmaceutical composition of claim 11, wherein the permeation enhancer is D-α-tocopheryl polyethylene glycol succinate.

13. 12. The pharmaceutical composition of claim 11, wherein the osmolality adjusting agent is glycerin.

14. The pharmaceutical composition according to claim 13, having an osmotic pressure of 230 to 350 mOsmol / kg.

15. 12. The pharmaceutical composition of claim 11, having a pH of from pH 6.0 to pH 7.

5.

16. an aqueous medium comprising: 0.5 to 5 w / v % enavogliflozin or a pharmaceutically acceptable salt thereof; 4 to 10 w / v % of a combination of polysorbate and polyoxyl 40 stearate; 0.1 to 0.5 w / v % D-α-tocopheryl polyethylene glycol succinate; 0.5 to 6 w / v % glycerin; and a pH adjuster; The pharmaceutical composition according to claim 1, which forms nanomicelles having an average particle size of 5 to 50 nm.

17. 17. The pharmaceutical composition according to claim 16, wherein the weight ratio of polysorbate to polyoxyl 40 stearate is 1:2-8.

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