A Stable Pharmaceutical Composition Comprising Testosterone Undecanoate

Abstract

The present invention relates to an injectable composition of testosterone ester for the treatment of testosterone deficiency. Particularly, the present invention relates to a pharmaceutical composition comprising testosterone undecanoate, which is capable of increasing the convenience for use in injection with the low viscosity and injection force, and has improved stability.

Claims

1. An injectable composition for sustained release, comprising testosterone undecanoate as an active ingredient, characterized in that the injectable composition comprises sesame oil or safflower oil as oil, and benzyl benzoate as a solvent, and the injectable composition has a viscosity of 10 to 110 mPas at 4 to 30° C. when the viscosity is measured by the USP rotational rheometer method.

2. The injectable composition for sustained release according to claim 1, characterized in that when an injection force is measured at an injection rate of 12 mm/min using a 5-mL syringe of which an inner diameter is 0.47 inch and which is equipped with a 27G or 29G injection needle having a length of 0.5 inch, the injection force is 15 N or less when using the 27G injection needle and 40 N or less when using the 29G injection needle.

3. The injectable composition for sustained release according to claim 1, characterized in that a weight ratio of testosterone undecanoate to benzyl benzoate is 1:1 to 1:3.

4. The injectable composition for sustained release according to claim 1, characterized in that a weight ratio of testosterone undecanoate to the oil is 1:1 to 1:3.

5. The injectable composition for sustained release according to claim 1, characterized in that the injectable composition is administered every 4 to 16 weeks.

6. The injectable composition for sustained release according to claim 1, characterized in that the injectable composition contains 50% or more of the active ingredient when stored during 12 hours under an acidic condition of a 0.15 M to 0.25 M hydrochloric acid solution.

7. The injectable composition for sustained release according to claim 1, characterized in that the injectable composition is used for the prevention or treatment of hypogonadism.

8. The injectable composition for sustained release according to claim 1, characterized in that the injectable composition is formulated as an intramuscular injectable formulation.

Description

MODE FOR THE INVENTION

[0031] Hereinafter, the present invention will be described in more detail through Examples. However, the Examples are provided merely for helping in understanding the present invention, and the scope of the present invention is not limited by the following Examples.

EXAMPLES

Preparation of Compositions of Examples 1 to 9

[0032] According to the composition in Table 1, testosterone undecanoate (hereinafter, referred to as ‘TU’), castor oil, sesame oil, safflower oil, or benzyl benzoate (hereinafter, referred to as ‘BB’) were added and stirred at room temperature for 0.5 to 24 hours to prepare the compositions of Examples 1 to 9.

TABLE-US-00001 TABLE 1 (Unit: mg) Testosterone Castor Sesame Safflower Benzyl Example undecanoate oil oil oil benzoate 1 — 800 — — — 2 — — 800 — — 3 — — — 800 — 4 100 1,900 — — — 5 100 — 1,900 — — 6 100 — — 1,900 — 7 100 120 — — 200 8 100 — 120 — 200 9 100 — — 120 200

Test Example 1

[0033] Viscosity Measurement

[0034] The viscosities of the compositions of Examples 1 to 9 were measured by the following method.

[0035] 1) Viscosity measurement method: USP 42 <912> Rotational rheometer methods—Method IV. Parallel plate (or parallel disk) rheometers

[0036] 2) Diameter of disk of rheometer: 25 mm

[0037] 3) Distance to the upper disk: 1 mm

[0038] 4) Shear rate: 1 to 50 (1/s)

[0039] 5) Temperature: 4, 15, 25, and 30° C.

[0040] 6) Sample collection volume: 0.65 mL

[0041] The viscosity of Examples 1 to 3 comprising oil alone, measured by the above method, is shown in Table 2 below.

TABLE-US-00002 TABLE 2 (Unit: mPas, Temperature: 4° C.) Comparison in viscosity of oil Example 1 Example 2 Example 3 (Castor oil) (Sesame oil) (Safflower oil) 3,791 154 129

[0042] As shown in Table 2 above, it was confirmed that the viscosity of Example 2 (sesame oil) and Example 3 (safflower oil) exhibited the values of 154 mPas and 129 mPas, respectively, while the viscosity of Example 1 (castor oil) exhibited the value of 3,791 mPas, which was remarkably higher by 20 times or more than those of Examples 2 and 3.

[0043] The viscosity of Examples 4 to 6 in which testosterone undecanoate and oil were comprised, measured by the above method, is shown in Table 3 below.

TABLE-US-00003 TABLE 3 (Unit: mPas, Temperature: 4° C.) Comparison in viscosity of a composition (TU + oil) Example 4 Example 5 Example 6 (TU + (TU + (TU + Castor oil) Sesame oil) Safflower oil) 3,822 220 149

[0044] As shown in Table 3 above, it can be seen that the viscosity of Example 5 (TU+sesame oil) and Example 6 (TU+safflower oil) exhibited the values of 220 mPas and 149 mPas, respectively, which were increased as compared to that of Examples 2 and 3 comprising oil alone.

[0045] Further, it was confirmed that the viscosity of Example 4 (TU+castor oil) exhibited the value of 3,822 mPas, which was remarkably higher than those of Examples 5 and 6.

[0046] The viscosity of Examples 7 to 9 in which testosterone undecanoate (TU), oil, and benzyl benzoate (BB) were comprised, measured by the above method, are shown in Tables 4 to 6 below.

TABLE-US-00004 TABLE 4 (Unit: mPas) Example 7 (TU + Castor oil + BB) Shear rate Temperature (1/s) 4° C. 15° C. 25° C. 30° C. 1 216 106 64 48 2 216 103 63 47 4 218 102 62 47 6 218 102 62 48 11 218 102 61 48 18 217 101 60 47 30 217 99 59 46 50 216 98 58 45 Average 217 102 61 47

TABLE-US-00005 TABLE 5 (Unit: mPas) Example 8 (TU + Sesame oil + BB) Shear rate Temperature (1/s) 4° C. 15° C. 25° C. 30° C. 1 97 57 36 30 2 94 54 36 29 4 93 53 34 28 6 93 52 34 28 11 91 50 33 28 18 90 49 32 27 30 89 47 31 25 50 88 46 30 24 Average 92 51 33 27

TABLE-US-00006 TABLE 6 (Unit: mPas) Example 9 (TU + Safflower oil + BB) Shear rate Temperature (1/s) 4° C. 15° C. 25° C. 30° C. 1 85 51 33 29 2 84 49 33 27 4 86 48 32 27 6 86 48 32 27 11 86 48 32 27 18 85 47 31 26 30 84 46 30 25 50 83 45 29 24 Average 85 48 32 26

[0047] As shown in Tables 5 and 6 above, it was confirmed that Example 8 (TU+sesame oil+BB) and Example 9 (TU+safflower oil+BB) exhibited the lower viscosity than those of Examples 2 and 3 comprising oil alone or Examples 5 and 6 comprising testosterone undecanoate and oil.

[0048] Further, as shown in Table 4 above, it was confirmed that Example 7 (TU+castor oil+BB) exhibited the lower viscosity than that of Example 1 comprising oil alone or Example 4 comprising testosterone undecanoate and oil, but exhibited the high viscosity of 216 mPas or more at 4° C.

[0049] It was also confirmed that Examples 8 and 9 maintained a low viscosity even under a wide range of a temperature condition as compared to Example 7, which results in easily applying and using as an injectable formulation.

Test Example 2

[0050] Injection Force Measurement

[0051] A 5-mL syringe of which inner diameter is 0.47 inch was filled with the compositions of Examples 7 to 9 by 2.5 cm and equipped with a 0.5-inch-long 27G or 29G needle. The syringe was mounted on a MultiTest-dV device manufactured by Mecmesin. The Basic Force Gauge 200 manufactured by Mecmesin was used to measure the injection force (Newton, N) at an interval of 5 to 15 mm while pushing the composition at a rate of 12 mm/min. The results thereof are shown in Table 7 below.

TABLE-US-00007 TABLE 7 (Unit: N) Example 7 Example 8 Example 9 (TU + (TV + (TU + Castor Sesame Safflower oil + oil + oil + BB) BB) BB) 27G injection needle 20.0 10.8 10.3 29G injection needle 53.7 29.6 29.6

[0052] As shown in Table 7 above, Example 8 comprising sesame oil and Example 9 comprising safflower oil exhibited the injection force lower than that of Example 7 comprising castor oil.

[0053] Therefore, it can be seen that since the composition comprising sesame oil or safflower oil may be injected with low injection force, it is easily injected using a thin injection needle, and may increase the convenience for use in injection.

Test Example 3

Stability Experiment on Compositions of Examples 4 to 6 Through Forced Degradation Test

[0054] A stability test was performed on Examples 4 to 6, which were a composition comprising testosterone undecanoate and oil, under an acidic, basic, oxidative, or thermal condition using the following experimental method.

[0055] 1) 0.1 mL of each of Examples 4 to 6 was put into a 20-mL flask adding 3 mL of methanol, and mixing.

[0056] 2) 6 mL of each of 0.05 M aqueous hydrochloric acid solution (acidic condition), a 0.05 M aqueous sodium hydroxide solution (basic condition), or a 0.5% aqueous hydrogen peroxide solution (oxidative condition) was put into the solution obtained in step 1), mixed, and stored at room temperature for 12 hours.

[0057] 3) 6 mL of a 0.5% aqueous hydrogen peroxide solution was put into the solution obtained in step 1), and stored at 80° C. for 30 minutes, and then at room temperature for 12 hours (oxidative and thermal conditions).

[0058] 4) Each of the solutions obtained in steps 2) and 3) was taken, followed by analyzing the content of testosterone undecanoate using HPLC.

[0059] The HPLC experimental conditions were as follows.

[0060] Detector: UV-VIS spectrophotometer (measurement wavelength: 240 nm)

[0061] Column: Kromasil C-18 (4.6 mm×250 mm, 5 um)

[0062] Flow rate: 1.5 mL/min

[0063] Injection volume: 20 uL

[0064] Mobile phase: acetonitrile/distilled water (95/5, v/v)

[0065] The analysis results are shown in Table 8 below.

TABLE-US-00008 TABLE 8 Example 4 Example 5 Example 6 12 hours 12 hours 12 hours Initial later Initial later Initial later Acidic 100% 33% 100% 61% 100% 59% condition Basic 100% 50% 100% 54% 100% 49% condition Oxidative 100% 41% 100% 63% 100% 55% condition Oxidative 100% 41% 100% 58% 100% 54% and thermal conditions

[0066] As shown in Table 8 above, it was confirmed under the acidic condition that Example 5 (TU+sesame oil) and Example 6 (TU+safflower oil) contained 61% and 59% of testosterone undecanoate, respectively, while Example 4 (TU+castor oil) contained 33% of testosterone undecanoate. As such, it can be seen that testosterone undecanoate in Example 4 comprising castor oil was very unstable under the acidic condition as compared to that of Example 5 or 6 comprising sesame oil or safflower oil.

[0067] It was confirmed under the oxidative condition and oxidative/thermal conditions that Example 5 (TU+sesame oil) and Example 6 (TU+safflower oil) contained 50% or more of testosterone undecanoate, while Example 4 (TU+castor oil) contained 41% of testosterone undecanoate. Accordingly, it can be seen that testosterone undecanoate in Example 4 comprising castor oil was unstable under the oxidative condition and oxidative/thermal conditions as compared to that of Example 5 or 6 comprising sesame oil or safflower oil.

[0068] In sum, it can be seen that Example 5 (TU+sesame oil) and Example 6 (TU+safflower oil) were stable under all the acidic, oxidative, and thermal conditions.

Test Example 4

Stability Experiment on Compositions of Examples 7 to 9 Through Forced Degradation Test

[0069] A stability test was performed on Examples 7 to 9, which were a composition comprising testosterone undecanoate, oil, and benzyl benzoate (solvent), under an acidic, basic, oxidative, or thermal condition using the following experimental method.

[0070] 1) 0.1 mL of each of Examples 7 to 9 was put into a 20-mL flask adding 3 mL of methanol, and mixing.

[0071] 2) 6 mL of a 0.25 M aqueous hydrochloric acid solution was put into the solution obtained in step 1), mixed, and then stored at room temperature for 12 hours (acidic condition).

[0072] 3) 6 mL of a 0.25 M aqueous sodium hydroxide solution was put into the solution obtained in step 1), mixed, and then stored at room temperature for 12 hours (basic condition).

[0073] 4) 6 mL of a 2.5% aqueous hydrogen peroxide solution was put into the solution obtained in step 1), mixed, and then stored at room temperature for 12 hours (oxidative condition).

[0074] 5) 6 mL of a 2.5% aqueous hydrogen peroxide solution was put into the solution obtained in step 1) and stored at 80° C. for 30 minutes, and then at room temperature for 12 hours (oxidative and thermal condition).

[0075] 6) Each of the solutions in 2) to 5) was taken, followed by analyzing the content of testosterone undecanoate using HPLC.

[0076] The HPLC experimental conditions were as follows.

[0077] Detector: UV-VIS spectrophotometer (measurement wavelength: 240 nm)

[0078] Column: Kromasil C-18 (4.6 mm×250 mm, 5 um)

[0079] Flow rate: 1.5 mL/min

[0080] Injection volume: 20 uL

[0081] Mobile phase: acetonitrile/distilled water (95/5, v/v)

[0082] The analysis results are shown in Table 9 below.

TABLE-US-00009 TABLE 9 Example 7 Example 8 Example 9 12 hours 12 hours 12 hours Initial later Initial later Initial later Acidic 100% 36% 100% 62% 100% 69% condition Basic 100% 24% 100% 35% 100% 33% condition Oxidative 100% 45% 100% 61% 100% 66% condition Oxidative 100% 47% 100% 62% 100% 59% and thermal conditions

[0083] As shown in Table 9 above, it was confirmed under the acidic condition that Example 8 (TU+sesame oil+BB) and Example 9 (TU+safflower oil+BB) contained 62% and 69% of testosterone undecanoate, respectively, while Example 7 (TU+castor oil+BB) contained 36% of testosterone undecanoate. As such, it can be seen that testosterone undecanoate in Example 7 comprising castor oil was very unstable under the acidic condition as compared to that of Example 8 or 9 comprising sesame oil or safflower oil.

[0084] It was confirmed under the oxidative condition and oxidative/thermal conditions that Example 8 (TU+sesame oil+BB) and Example 9 (TU+safflower oil+BB) contained 50% or more of testosterone undecanoate while Example 7 (TU+castor oil+BB) contained 45% and 47% of testosterone, respectively. Thus, it can be seen that testosterone undecanoate in Example 7 comprising castor oil was very unstable under the oxidative condition and oxidative/thermal conditions as compared to that of Example 8 or 9 comprising sesame oil or safflower oil.

[0085] It was confirmed under the basic condition that 35% and 33% of testosterone undecanoate were detected in Example 8 (TU+sesame oil+BB) and Example 9 (TU+safflower oil+BB), respectively, while in Example 7 (TU+castor oil+BB), 24% of testosterone undecanoate was detected. As such, it can be seen that testosterone undecanoate in Example 7 comprising castor oil was very unstable under the basic condition as compared to that Example 8 or 9 comprising sesame oil or safflower oil.

[0086] In sum, it can be seen that Example 8 (TU+sesame oil+BB) and Example 9 (TU+safflower oil+BB) were stable under all the acidic, basic, oxidative, and thermal conditions as compared to Example 7 (TU+castor oil+BB).