Proliposomal testosterone undecanoate preparation

Abstract

The present invention relates to proliposomal powder dispersions of testosterone undecanoate (TU) and phospholipids, including dispersions of TU and dipalmitoylphosphatidylcholine (DPPC), wherein the weight / weight (w / w) ratio of TU:DPPC in the proliposomal powder dispersion is about 1:2; or TU and dimyristoylphosphatidylcholine (DMPC), wherein the weight / weight (w / w) ratio of TU:DMPC in the proliposomal powder dispersion is about 1:3; or TU and 1-myristoyl-2-palmitoylphosphatidylcholine (MPPC), wherein the weight / weight (w / w) ratio of TU:MPPC in the proliposomal powder dispersion is about 1:3.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Application No. 62 / 884,919, filed on August 9, 2019, which is incorporated herein in its entirety. Technical Field

[0003] The present invention relates to proliposomal powder dispersions of testosterone undecanoate and phospholipids, and improved bioavailability of testosterone undecanoate for oral administration. Technical Background

[0004] The goal of testosterone replacement therapy (TRT) is to restore low endogenous plasma levels of testosterone to normal physiological levels. Restoring normal physiological levels in patients can alleviate symptoms suggestive of hormone deficiency or, for some individuals, lead to a more masculine appearance and identity. A convenient form of TRT relies on oral administration of testosterone undecanoate (TU). However, the performance of currently marketed oral dosage forms of TU varies significantly, depending on when the dosage form is ingested by an individual relative to mealtime, see Yin et al. However, the following description shows that TU can be combined with a certain phospholipid in a specific ratio to form a proliposomal powder dispersion that can be incorporated into a dry, free-flowing powder that can form liposome-encapsulated TU that is easily absorbed. In addition, because the proliposomal preparation is a dry powder, unlike a liquid suspension of liposomes, it can be incorporated into an oral dosage form with an enteric coating to protect the preparation until it reaches the less harsh aqueous environment of the small intestine, where hydration of the proliposomal powder dispersion can occur to form liposomes that deliver TU to the intestinal epithelium. Summary of the invention

[0005] The present invention relates to a proliposomal powder dispersion of testosterone undecanoate (TU) and a phospholipid. For example, the proliposomal powder dispersion of the present invention may comprise TU and:

[0006] (A) dipalmitoylphosphatidylcholine (DPPC), wherein the weight / weight (w / w) ratio of TU:DPPC in the proliposomal powder dispersion is about 1:2; or

[0007] (B) dimyristoylphosphatidylcholine (DMPC), wherein the weight / weight (w / w) ratio of TU:DMPC in the proliposomal powder dispersion is about 1:3; or

[0008] (C) 1-myristoyl-2-palmitoylphosphatidylcholine (MPPC), wherein the weight / weight (w / w) ratio of TU:MPPC in the proliposomal powder dispersion is about 1:3.

[0009] The proliposomal powder dispersion of the present invention can also be included in a dosage form suitable for oral administration. In this regard, some oral dosage forms of the present invention also include mannitol. Thus, for example, the oral dosage form of the present invention can include:

[0010] (A) combining a proliposomal powder dispersion of TU and DPPC in a w / w ratio of about 1:2 with mannitol such that the w / w ratio of the proliposomal powder dispersion to mannitol is about 1:1.25; or

[0011] (B) combining a proliposomal powder dispersion of TU and DMPC in a w / w ratio of about 1:3 with mannitol such that the w / w ratio of the proliposomal powder dispersion to mannitol is about 1:1.25; or

[0012] (C) A proliposomal powder dispersion of TU and MPPC in a w / w ratio of about 1:3 was combined with mannitol such that the w / w ratio of the proliposomal powder dispersion to mannitol was about 1:1.25.

[0013] Furthermore, since the dosage form of the present invention may be suitable for oral administration, in some embodiments, the oral dosage form of the present invention may be in the form of a capsule or tablet, optionally an enteric-coated capsule.

[0014] The proliposomal powder dispersion and oral dosage form of the present invention can be used for treating the disease and the method for the disease of the endogenous testosterone related to low plasma level or caused by the endogenous testosterone of low plasma level of individual.Therefore, the proliposomal powder dispersion or oral dosage form of the present invention can be used in the method for the testosterone replacement therapy (TRT) of the individual in need.For example, the TRT method can, for example, treat the disease of the endogenous testosterone of low plasma level caused by injury, infection, testicular deficiency, chemotherapy, radiotherapy, genetic abnormality, hemochromatosis, pituitary dysfunction, inflammatory disease, drug side effect, chronic renal failure, cirrhosis, stress, alcoholism, obesity, Kallmann syndrome, male hypogonadism, testosterone deficiency syndrome (TDS) or any treatment before plasma testosterone level is 300ng / dL or lower disease or disease cause. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1The percentage content of TU released from the following proliposomal powder dispersion formulations containing TU in phosphate buffer (pH 6.8) over time is shown: TSX-011 (TU: DSPC = 1:2); TSX-048 (TU: DMPC = 1:3); TSX:049 (TU: DPPC = 1:2); TSX-056 (TU: MPPC = 1:3); and TSX-057 (TU: (DPPC + oleic acid) = 1:2). For TSX-011 and TSX-048, n = 3 / capsule formulation. For TSX-049, TSX-056 and TSX-057, n = 6 / capsule formulation.

[0016] Figure 2 The percentage of TU released from the following proliposomal powder dispersion formulations containing TU in capsules over time under simulated intestinal fluid fed conditions is shown: TSX-011 (TU: DSPC = 1:2); TSX-048 (TU: DMPC = 1:3); TSX:049 (TU: DPPC = 1:2); TSX-056 (TU: MPPC = 1:3); and TSX-057 (TU: DPPC + oleic acid = 1:2). n = 6 / capsule formulation.

[0017] Figure 3A Shown are plasma T levels in six fasted dogs after oral administration of a single dose of TSX-011 capsule (31.6 mg TU, TU:DSPC=1:2).

[0018] Figure 3B shows the change over time based on Figure 3A The average plasma T level for individual data points in .

[0019] Figure 4A Shows Figure 3A Plasma TU levels in six fasted dogs administered TSX-011 formulations as described in.

[0020] Figure 4B shows the change over time based on Figure 4A Mean plasma TU levels for individual data points in .

[0021] Figure 5A Shown are plasma T levels in six fasted dogs after oral administration of a single dose of TSX-057 capsules (22 mg TU, TU:(DPPC+oleic acid)=1:2).

[0022] Figure 5B shows the change over time based on Figure 5A The average plasma T level for individual data points in .

[0023] Fig. 6AShows Figure 5A Plasma TU levels in six fasted dogs administered TSX-057 formulations as described in.

[0024] Figure 6B shows the change over time based on Figure 5A Mean plasma TU levels for individual data points in .

[0025] Fig. 7A Shown are plasma T levels in six fasted dogs after oral administration of a single dose of TSX-056 capsules (16.6 mg TU, TU:MPPC=1:3).

[0026] Figure 7B shows the change over time based on Fig. 7A The average plasma T level for individual data points in .

[0027] Fig. 8A Shows Fig. 7A Plasma TU levels in six fasted dogs administered TSX-056 formulations as described in.

[0028] Figure 8B shows the change over time based on Fig. 7A Mean plasma TU levels for individual data points in .

[0029] Fig.9A Shown are plasma T levels in six fasted dogs after oral administration of a single dose of TSX-048 capsules (24.1 mg TU, TU:DMPC=1:3).

[0030] Fig. 9B shows the change over time based on Fig.9A The average plasma T level for individual data points in .

[0031] Fig. 10A Shows Fig.9A Plasma TU levels in six fasted dogs administered TSX-048 formulations as described in

[0032] Fig. 10B shows the change over time based on Fig.9A Mean plasma TU levels for individual data points in .

[0033] Fig.11A Shown are plasma T levels in six fasted dogs after oral administration of a single dose of TSX-049 capsules (22.81 mg TU, TU:DPPC=1:2).

[0034] Fig. 11B shows the change over time based on Fig.11A The average plasma T level for individual data points in .

[0035] Fig. 12A Shows Fig.11A Plasma TU levels in six fasted dogs administered TSX-049 formulations as described in.

[0036] Fig. 12B shows the change over time based on Fig.11A Mean plasma TU levels for individual data points.

[0037] Fig.13 The AUC (ng h / dL) of T over a 24-hour period following oral administration of a single dose of TSX-011 capsule (31.6 mg TU, TU: DSPC = 1:2); TSX-057 capsule (22 mg TU, TU: (DPPC + oleic acid) = 1:2); TSX-056 capsule (16.6 mg TU, TU: MPPC = 1:3); TSX-048 capsule (24.1 mg TU, TU: DMPC = 1:3); and TSX-049 capsule (22.81 mg TU, TU: DPPC = 1:2) to fasted female dogs are shown, respectively (n = 6).

[0038] Fig.14 Shows Fig.13 AUC (ng h / dL) of TU in dogs over a 24-hour period is shown.

[0039] Fig.15 Shows Fig.13 The dogs described had a C of T in a 24-hour period 平均 (ng / dL).

[0040] Fig.16 Shows Fig.13 C of TU in dogs described over a 24-hour period 平均 (ng / dL).

[0041] Fig.17 Shows Fig.13 AUC (ng h / dL) of DHT in dogs over a 24 hour period is depicted.

[0042] Fig.18 Shows Fig.13 AUC (ng h / dL) of DHTU in dogs over a 24-hour period is depicted.

[0043] Fig.19AShown are mean plasma T levels over a 24-hour period following oral administration of a single dose of TSX-011 capsules (31.6 mg TU, TU: DSPC = 1:2); TSX-057 capsules (22 mg TU, TU: (DPPC + oleic acid) = 1:2); TSX-056 capsules (16.6 mg TU, TU: MPPC = 1:3); TSX-048 capsules (24.1 mg TU, TU: DMPC = 1:3); and TSX-049 capsules (22.81 mg TU, TU: DPPC = 1:2) to fasted female dogs, (n = 6).

[0044] Fig.19B Shows Fig.19A Mean plasma T levels of , which have been normalized to TSX-011 and data obtained from dog 1F1 have been excluded, (n=5).

[0045] Fig. 20 Shown are mean plasma testosterone levels in female dogs studied following oral administration of TSX-049 and TSX-011, respectively.

[0046] Fig.21A Shown are mean plasma testosterone levels in male dogs over 24 hours following oral administration of low dose TU formulations in TSX-011 capsules (low dose = 94.8 mg TU, TU: DSPC ratio = 1:2) or TSX-049 capsules (low dose = 60 mg, TU: DPPC ratio = 1:2) twice daily (BID) under fed conditions.

[0047] Fig. 21B Shown are mean plasma testosterone levels in male dogs over 24 hours following twice daily oral administration of a medium dose TU formulation in TSX-011 capsules (medium dose = 189.6 mg TU, ratio of TU: DSPC = 1:2) or TSX-049 capsules (low dose = 120 mg, ratio of TU: DPPC = 1:2) under fed conditions.

[0048] Fig. 21C Shown are mean plasma testosterone levels in male dogs over 24 hours following twice daily oral administration of high dose TU formulations in TSX-011 capsules (high dose = 284.4 mg TU, ratio of TU: DSPC = 1:2) or TSX-049 capsules (high dose = 240 mg, ratio of TU: DPPC = 1:2) under fed conditions.

[0049] Fig.22AShown are mean AUC (ng h / dL) levels of T in fed male dogs over a 24-hour period following twice daily administration of low, medium or high doses of TU formulations in TSX-011 capsules (TU:DSPC=1:2) or TSX-049 capsules (TU:DPPC=1:2) (n=6 for TSX-011; n=10 for TSX-049).

[0050] Fig. 22B Shows Fig.21A The mean C of the dogs studied is described in 最大 (ng h / dL) level.

[0051] Fig.23A Shown are mean plasma T concentrations over 24 hours, baseline plasma T concentrations, and pre-dose plasma T concentrations for male dogs used in the multi-day dose escalation study described in Example 14.

[0052] Fig. 23B Shown are mean plasma T concentrations over 24 hours, baseline plasma T concentrations, and ESO plasma T concentrations for male dogs used in the multi-day dose escalation study described in Example 14.

[0053] Fig.23C Shown are mean plasma T concentrations over 24 hours on the first day (D1) of dosing with 30 mg / BID TSX-049 in male dogs used in the multi-day dose escalation study described in Example 14.

[0054] Fig.23D Shown are mean plasma T concentrations over 24 hours on day 5 (D5) of dosing with 30 mg / BID TSX-049 in male dogs used in the multi-day dose escalation study described in Example 14.

[0055] Fig.23E Shown are mean plasma T concentrations over 24 hours on the first day (D1) of dosing with 60 mg / BID TSX-049 in male dogs used in the multi-day dose escalation study described in Example 14.

[0056] Fig.23F Shown are mean plasma T concentrations over 24 hours on day 5 (D5) of dosing with 60 mg / BID TSX-049 in male dogs used in the multi-day dose escalation study described in Example 14.

[0057] Figure 23G Shown are mean plasma T concentrations over 24 hours on the first day (D1) of dosing with 120 mg / BID TSX-049 in male dogs used in the multi-day dose escalation study described in Example 14.

[0058] Fig.23H Shown are mean plasma T concentrations over 24 hours on day 5 (D5) of dosing with 120 mg / BID TSX-049 in male dogs used in the multi-day dose escalation study described in Example 14.

[0059] Fig.24A The mean AUC of T for each time point and TU dose in the multi-day dose escalation study described in Example 14 is shown. 0-t最后 .

[0060] Fig. 24B The mean AUC of DHT for each time point and TU dose in the multi-day dose escalation study described in Example 14 is shown. 0-t最后 .

[0061] Fig.24C The mean AUC of TU for each time point and TU dose in the multi-day dose escalation study described in Example 14 is shown. 0-t最后 .

[0062] Fig.24D The mean AUC of DHTU for each time point and TU dose in the multi-day dose escalation study described in Example 14 is shown. 0-t最后 .

[0063] Fig.25A The mean C values ​​for each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 .

[0064] Fig.25B The mean C values ​​of DHT at each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 .

[0065] Fig.25C The mean C values ​​of TU for each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 .

[0066] Fig.25D The mean C values ​​of DHTU for each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 .

[0067] Fig.26A The mean t values ​​for each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 .

[0068] Fig.26BThe mean t values ​​for DHT at each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 .

[0069] Fig.26C The mean t values ​​of TU for each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 .

[0070] Fig.26D The mean t values ​​of DHTU for each time point and TU dose in the multi-day dose escalation study described in Example 14 are shown. 最大 . DETAILED DESCRIPTION

[0071] The present invention is disclosed in the following description according to embodiments related to proliposomal powder dispersions of testosterone undecanoate (TU) and phospholipids, as well as dosage forms comprising such dispersions and methods of treating diseases or conditions associated with or caused by low plasma levels of endogenous testosterone. A "proliposomal powder dispersion" of TU and phospholipids is a mixture in which TU and phospholipids are dispersed with each other. The proliposomal powder dispersions of the present invention form liposomes when in contact with water or an aqueous solution (e.g., including fluids of the gastrointestinal tract).

[0072] As described herein, testosterone undecanoate is a synthetic androstane steroid, which is 17β-testosterone undecanoate. The phospholipid component of the proliposomal powder dispersion of the present invention preferably refers to dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC) or 1-myristoyl-2-palmitoylphosphatidylcholine (MPPC). In some embodiments of the present invention, the proliposomal powder dispersion comprises TU in a dispersion containing DPPC, wherein the weight / weight (w / w) ratio of TU to DPPC (i.e., TU: DPPC) is about 1:2. In other embodiments of the present invention, the proliposomal powder dispersion comprises TU in a dispersion containing DMPC, wherein the w / w ratio of TU to DMPC (i.e., TU: DMPC) is about 1:3. However, in other embodiments of the present invention, the proliposomal powder dispersion comprises TU in a dispersion containing MPPC, wherein the w / w ratio of TU to MPPC (i.e., TU: MPPC) is about 1:3. As used herein, the term "about" provides flexibility for the w / w ratio of the proliposomal powder dispersion of the present invention by indicating that a specific ratio between ingredients can be "a little less" or "a little more" than stated. For example, "a little less" or "a little more" can indicate a variance of 10% or less. Thus, in some proliposomal powder dispersions of the invention, wherein the w / w ratio of TU to DPPC is about 1:2, the ratio of TU:DPPC can be (0.9:2), (0.91:2), (0.92:2), (0.93:2), (0.94:2), (0.95:2), (0.96:2), (0.97:2), (0.98:2), (0.99:2), (1:2), (1.01:2), (1.02:2), (1.03:2), (1.04:2), (1.05:2), (1.06:2), (1.07:2), (1.08:2), (1.09:2), (1.10:2), (1:19:2), (1:10:2), (1:11:2). (1:1.97), (1:1.96), (1:1.95), (1:1.94), (1:1.93), (1:1.92), (1:1.91), (1:1.90), (1:1.89), (1:1.88), (1:1.87), (1:1.86), (1:1.85), (1:1.84), (1:1.83), (1:1.82), (1:1.81), (1:1.80), (1:2.01), (1:2.02), (1:2.03), (1:2.04), (1:2.05), (1:2.06), (1:2.07), (1:2.08), (1:2.09), (1:2.19), (1:2.2) or any ratio therebetween.Similarly, in other proliposomal powder dispersions of the present invention, wherein the w / w ratio of TU to DMPC is about 1:3, the ratio of TU:DMPC can be (0.9:3), (0.91:3), (0.92:3), (0.93:3), (0.94:3), (0.95:3), (0.96:3), (0.97:3), (0.98:3), (0.99:3, (1:3), (1.01:3), (1.02:3), (1.03:3), )、(1.04:3)、(1.05:3)、(1.06:3)、(1.07:3)、(1.08:3)、(1.09:3)、(1.10:3)、(1:2.99)、(1:2.98)、(1:2.97)、(1:2.96)、(1:2.95)、(1:2.94)、(1:2.93)、(1:2.92)、(1:2.91)、(1:2.90)、(1:2.89)、(1:2.88)、(1:2 .87)、(1:2.86)、(1:2.85)、(1:2.84)、(1:2.83)、(1:2.82)、(1:2.81)、(1:2.80)、(1:2.79)、(1:2.78)、(1:2.77)、(1:2.76)、(1:2.75)、(1:2.74)、(1:2.73)、(1:2.72)、(1:2.71)、(1:2.70)、(1:3.01)、(1:3.02)、( 1:3.03), (1:3.04), (1:3.05), (1:3.06), (1:3.07), (1:3.08), (1:3.09), (1:3.19), (1:3.2), (1:3.21), (1:3.22), (1:3.23), (1:3.24), (1:3.25), (1:3.26), (1:3.27), (1:3.28), (1:3.29), (1:3.3), or any proportion thereof.However, in other proliposomal powder dispersions of the present invention, wherein the w / w ratio of TU to MPPC is about 1:3, the ratio of TU:MPPC may be (0.9:3), (0.91:3), (0.92:3), (0.93:3), (0.94:3), (0.95:3), (0.96:3), (0.97:3), (0.98:3), (0.99:3), (1:3), (1.01:3), (1.02:3), (1.03:3), )、(1.04:3)、(1.05:3)、(1.06:3)、(1.07:3)、(1.08:3)、(1.09:3)、(1.10:3)、(1:2.99)、(1:2.98)、(1:2.97)、(1:2.96)、(1:2.95)、(1:2.94)、(1:2.93)、(1:2.92)、(1:2.91)、(1:2.90)、(1:2.89)、(1:2.88)、(1:2 .87)、(1:2.86)、(1:2.85)、(1:2.84)、(1:2.83)、(1:2.82)、(1:2.81)、(1:2.80)、(1:2.79)、(1:2.78)、(1:2.77)、(1:2.76)、(1:2.75)、(1:2.74)、(1:2.73)、(1:2.72)、(1:2.71)、(1:2.70)、(1:3.01)、(1:3.02)、 (1:3.03), (1:3.04), (1:3.05), (1:3.06), (1:3.07), (1:3.08), (1:3.09), (1:3.19), (1:3.2), (1:3.21), (1:3.22), (1:3.23), (1:3.24), (1:3.25), (1:3.26), (1:3.27), (1:3.28), (1:3.29), (1:3.3) or any ratio therebetween.

[0073] The proliposome powder dispersion of the present invention can be prepared by methods known in the art, including the general method for preparing proliposome powder dispersion disclosed in PCT patent application publication number WO 2002 / 085304, WO 2013 / 170012, WO 2017 / 120586 and WO 2017 / 120592, all of which are incorporated herein in their entirety. The homogenization step can be carried out at a temperature higher than the Tc / Tg of phospholipids under high pressure. In some embodiments of the present invention, the average particle size of the proliposome powder dispersion can be reduced by grinding, passing the powder through a sieve or any other suitable technology. For example, the particles in the proliposome powder dispersion can be but not required to have a powder size ranging from about 10 to 200 meshes, 20 to 120 meshes, or 40 to 60 meshes or 60 to 80 meshes. In other embodiments of the present invention, high pressure homogenization can be used for the homogenization step to produce a proliposome powder suspension having an average particle size (Z average) less than 200 nanometers (nm). Thus, some proliposomal powder dispersions of the invention have an average particle size of about 200 nm, 199 nm, 198 nm, 197 nm, 196 nm, 195 nm, 194 nm, 193 nm, 192 nm, 191 nm, 190 nm, 189 nm, 188 nm, 187 nm, 186 nm, 185 nm, 184 nm, 183 nm, 182 nm, 181 nm, 180 nm, 179 nm, 178 nm, 177 nm, 176 nm, 175 nm, 174 nm, 173 nm, 172 nm, 171 nm, 170 nm, or any size therebetween.

[0074] As mentioned above, the present invention also relates to dosage forms comprising the proliposomal powder dispersions of the present invention. More particularly, the dosage forms of the present invention are generally suitable for oral administration and can therefore be referred to as "oral dosage forms". In some embodiments of the present invention, the proliposomal powder dispersion component of the oral dosage form is mixed with (usually with) mannitol.

[0075] Therefore, in an oral dosage form according to the present invention, wherein the proliposomal powder dispersion comprises TU and DPPC in a w / w ratio of about 1:2, the proliposomal dispersion is a mixture containing mannitol, wherein the w / w ratio of the proliposomal powder dispersion to mannitol is about 1:1.25. Therefore, consistent with the definition of “about”, as described above with respect to the components of TU and phospholipids, the ratio of the proliposomal powder dispersion to mannitol in the above-mentioned oral dosage form can be (0.9:1.25), (0.91:1.25), (0.92:1.25), (0.93:1.25), (0.94:1.25), (0.95:1.25), (0.96:1.25), (0.97:1.25), (0.98:1.25), (0.99:1.25), (1:1.25), (1.01:1.25), (1.02:1.25), (1.03:1.25), (1.04:1.25), (1.05:1.25), (1.06:1.25), (1.07:1 .25), (1.08:1.25), (1.09:1.25), (1.10:1.25), (1:1.24), (1:1.23), (1:1.22), (1:1.21), (1:1.20), (1:1.19), (1:1.18), (1:1.17), (1:1.16), (1:1.15), (1:1.14), (1:1.13), (1:1.26), (1:1.27), (1:1.28), (1:1.29), (1:1.30), (1:1.31), (1:1.32), (1:1.33), (1:1.34), (1:1.35), (1:1.36), (1:1.37) or any ratio therebetween.

[0076] In some other oral dosage forms of the present invention, wherein the proliposomal powder dispersion comprises TU and DMPC in a w / w ratio of about 1:3 w / w ratio, the proliposomal powder dispersion is mixed with mannitol in a w / w ratio of about 1:1.25. Therefore, in the above-mentioned oral dosage form, the ratio of the proliposomal powder dispersion to mannitol can be (0.9:1.25), (0.91:1.25), (0.92:1.25), (0.93:1.25), (0.94:1.25), (0.95:1.25), (0.96:1.25), (0.97:1.25), (0.98:1.25), (0.99:1.25), (1:1.25), (1.01:1.25), (1.02:1.25), (1.03:1.25), (1.04:1.25), (1.05:1.25), (1.06:1.25), (1.07:1.25), (1.08:1.25). (1:1.8), (1.09:1.25), (1.10:1.25), (1:1.24), (1:1.23), (1:1.22), (1:1.21), (1:1.20), (1:1.19), (1:1.18), (1:1.17), (1:1.16), (1:1.15), (1:1.14), (1:1.13), (1:1.26), (1:1.27), (1:1.28), (1:1.29), (1:1.30) (1:1.31) (1:1.32) (1:1.33) (1:1.34) (1:1.35) (1:1.36) (1:1.37) or any ratio therebetween.

[0077] However, in another oral dosage form of the present invention, wherein the proliposomal powder comprises TU and MPPC in a w / w ratio of about 1:3 w / w ratio, the proliposomal powder dispersion is mixed with mannitol in a w / w ratio of about 1:1.25. Therefore, in the above oral dosage form, the ratio of the proliposomal powder dispersion to mannitol can be (0.9:1.25), (0.91:1.25), (0.92:1.25), (0.93:1.25), (0.94:1.25), (0.95:1.25), (0.96:1.25), (0.97:1.25), (0.98:1.25), (0.99:1.25), (1:1.25), (1.01:1.25), (1.02:1.25), (1.03:1.25), (1.04:1.25), (1.05:1.25), (1.06:1.25), (1.07:1.25), (1.08:1.25). 25), (1.09:1.25), (1.10:1.25), (1:1.24), (1:1.23), (1:1.22), (1:1.21), (1:1.20), (1:1.19), (1:1.18), (1:1.17), (1:1.16), (1:1.15), (1:1.14), (1:1.13), (1:1.26), (1:1.27), (1:1.28), (1:1.29), (1:1.30), (1:1.31), (1:1.32), (1:1.33), (1:1.34), (1:1.35), (1:1.36), (1:1.37) or any ratio therebetween.

[0078] The oral dosage form of the present invention can be a tablet or a capsule. Generally, the oral dosage form according to the present invention is a capsule. The capsule can be a soft capsule or a hard capsule. More particularly, the capsule material of the oral dosage form of the present invention is preferably, but not limited to, plant-derived hydroxypropyl methylcellulose (HPMC). For example, the capsule made of animal-derived gelatin or the capsule size of the oral dosage form of the present invention can be any size sufficient to contain its proliposome powder dispersion and excipient components. For example, the size of the capsule can be 5, 4, 3, 2, 1, 0, 0E, 00, 000, 13, 12, 12e1, 11, 10, 7 or Su07. Use any suitable technology to fill the capsule.

[0079] The filled capsules can be coated with an enteric coating. The enteric coating protects the oral dosage form of the present invention from the harsh acidic environment of the stomach, thereby delaying the release of the proliposomal powder dispersion until the dosage form reaches the small intestine. Upon contact with the small intestinal fluid, the proliposomal powder dispersion is hydrated, resulting in the formation of liposomes, and absorption of TU by the small intestinal epithelium or lymphatic system or both. Any coating imparted to the oral dosage form of the present invention is of sufficient thickness so that the entire coating does not dissolve in the gastrointestinal fluid. In some embodiments of the present invention, the enteric coating material of the oral dosage form comprises a methacrylic acid copolymer. More particularly, the enteric coating of the oral dosage form of the present invention is an aqueous dispersion of an anionic polymer having methacrylic acid as a functional group, similar to that used as The enteric coating of the oral dosage form of the present invention may further include a plasticizer (eg, triethyl citrate), an anti-adherent (eg, talc), and a diluent.

[0080] As described above, the proliposomal powder dispersion and oral dosage form of the present invention can be used to treat a method for a disease or condition associated with or caused by low plasma levels of endogenous testosterone in an individual. Low endogenous testosterone refers to subphysiological testosterone levels. In humans, low plasma levels of endogenous testosterone are generally considered to be 300 ng / dL (testosterone / plasma) or lower. Thus, the oral dosage forms of the invention can be used to therapeutically increase a subject's testosterone plasma concentration to at least 300 ng / dL, at least 350 ng / dL, at least 400 ng / dL, at least 450 ng / dL, at least 500 ng / dL, at least 550 ng / dL, at least 600 ng / dL, at least 650 ng / dL, at least 700 ng / dL, at least 750 ng / dL, at least 800 ng / dL, at least 850 ng / dL, at least 900 ng / dL, at least 950 ng / dL, at least 1000 ng / dL, at least 1050 ng / dL, or any plasma testosterone level therebetween. Administration of some oral dosage forms of the invention to a subject in need thereof increases the plasma level to any of the above plasma levels within 5 hours after administration, under fasting or fed conditions.

[0081] In some methods, the method for treating individuality of the present invention to improve testosterone of low endogenous level can be referred to as testosterone replacement therapy (TRT).The example of the disease and illness that can be treated by using the oral dosage form of the present invention includes but is not limited to can be by damage, infection, testicular loss, chemotherapy, radiotherapy, genetic abnormality, hemochromatosis, pituitary dysfunction, inflammatory diseases, drug side effects, chronic renal failure, liver cirrhosis, stress, alcoholism, obesity, Kallmann syndrome, idiopathic gonadotropin deficiency, Klinefelter syndrome, pituitary hypothalamic injury caused by tumor, osteoporosis, diabetes, chronic heart failure, chemotherapy, hemochromatosis, renal failure, AIDS, sarcoidosis, Kallmann syndrome, androgen receptor defect, 5-α reductase deficiency, myotonic dystrophy, cryptorchidism, mumps orchitis, aging, fertility without testicular syndrome and the result of pituitary disorder cause low endogenous testosterone level.Another kind of illness related to the testosterone illness of low endogenous plasma level is male hypogonadism, and this illness can also be referred to as testosterone deficiency syndrome (TDS). Hypogonadism is caused by the inability of the testicles to produce adequate androgens.

[0082] The individual of low-level circulating testosterone can experience the symptom of the change such as (but not limited to) fatigue, erectile dysfunction and body composition.The reason of low endogenous testosterone level can be primary (genetic abnormality, Kallmann syndrome) or secondary (hypothalamic or pituitary defect), but usually presents as the same symptom.In elderly patients, elderly male androgen deficiency (ADAM) is the important reason of secondary hypogonadism, because testosterone level gradually declines after 40 years old.The patient of hypogonadism not only has change in sexual function and body composition, but also has change in cognition and metabolism.No matter the cause of disease, the hypogonadism patient with symptomatic and significant clinical change in test value is the candidate for treatment.

[0083] Some oral dosage forms of the present invention can be administered to deliver, for example, 96 to 1580 mg / day, which is equivalent to about 60.75 to 1000 mg of testosterone / day. In certain embodiments of the present invention, the daily TU dosage that can be administered to an adult via the oral dosage form of the present invention is about 95 mgTU / 60 kg body weight, about 192 mg / 60 kg body weight, about 384 mg / 60 kg body weight, about 768 mg / 60 kg body weight, about 1152 mg / 60 kg body weight, or any dosage therebetween.

[0084] Example

[0085] Example 1

[0086] In vitro testing of TU proliposomal powder dispersion candidate formulations: TU release in phosphate buffer (pH 6.8). The percentage of TU released in phosphate buffer (pH 6.8) was determined over time for the following encapsulated TU proliposomal powder dispersion formulations: TSX-011; TSX-048; TSX:049; TSX-056; and TSX-057. For TSX-011 and TSX-048, n=3. For TSX-049, TSX-056 and TSX-057, n=6. The ingredients of each test formulation are described in Table 1. For solubility testing, one capsule was added, each to 250 mL of 0.2 M sodium phosphate tribasic containing 1% w / v SLS. The final concentration of SLS in the compounding medium was 0.25% w / v. The pH of the medium was adjusted to 6.8 using 2N HCl or 2N NaOH, and the dissolution conditions were maintained at 37 ± 0.5 ° C for 4 hours at a speed of 75 RPM. Aliquots of samples were collected at 0, 15, 30, 60, 90, 120 and 240 minutes, filtered using a 5μ glass fiber filter, and then estimated using high pressure liquid chromatography (HPLC). HPLC analysis was performed using a gradient method. The mobile phase consisted of water and acetonitrile as follows: (90% water + 10% acetonitrile) 0 minutes; (4% water + 96% acetonitrile) 2 minutes; (4% water + 96% acetonitrile) 15 minutes. Separation was achieved on a C18; 150 × 4.6mm (5μm) (Ace) column. The flow rate of the mobile phase was set to 1.4mL / min. The temperature of the column was maintained at 40°C at the same time. The total run time was 15 minutes and the injection volume was 35μl. Testosterone was detected using a UV detector at a maximum absorbance of 243nm. The retention time of testosterone was found to be approximately 10 minutes. The method was able to resolve testosterone undecanoate and all other excipients. Solubility data are shown in Figure 1 As reported.

[0087] Table 1 Composition of candidate formulations

[0088]

[0089]

[0090] Example 2

[0091] In vitro testing of candidate TU proliposomal powder dispersion formulations: release of TU in simulated intestinal fluid fed conditions. The percentage of TU released in 0.1N HCl solution was determined over time for the following encapsulated TU proliposomal powder dispersion formulations: TSX-011; TSX-048; TSX:049; TSX-056; and TSX-057. n=6 for each formulation. The ingredients of each test formulation are described in Table 1. The 0.1N HCl dissolution medium simulates the fed state in small intestinal fluid. Dissolution of each capsule was performed in 750 mL of 0.1N HCl and maintained at 37±0.5°C at 75 RPM for 4 hours. Aliquots were collected at 0, 15, 30, 60, 90, 120 and 240 minutes and filtered using a 5μ glass fiber filter and then estimated using HPLC as described in Example 1. Solubility data are shown in Table 1. Figure 2 As reported.

[0092] Example 3

[0093] The single-dose study design was used to evaluate the dose response rate in female dogs. The dose response rate of dogs for TSX-011; TSX-048; TSX:049; TSX-056 and TSX-057 was evaluated. Each formulation was orally administered to female beagle dogs under fasting conditions. The components of the administered formulations are described in Table 1. For the study, the dogs were fasted overnight and dosed the next morning (1 capsule / formulation / dog was administered orally). The formulation dose of each formulation was standardized based on the body weight of each dog (administered formulation mg / body weight kg). See Table 2.

[0094] Table 2 Standardized formulation dosage for dogs (administered per kg body weight)

[0095]

[0096] Blood samples were collected from each dog by jugular vein puncture 1 hour before oral administration, and then at 2, 4, 6, 8, 12, 15, 18, 21 and 24 hours after administration.

[0097] Example 4

[0098] As described in Example 3, plasma T and TU levels were determined in blood samples obtained from fasting dogs following administration of a single dose of TSX-011. Figure 3A and 4A Plasma T and TU levels are shown separately for each dog over time. Figure 3B and 4B Mean plasma T and TU levels over time are shown. Mean plasma T levels 最大 (h) is 12±7.82. The average C of T level最大 (ng / dL) is 135±176.

[0099] Example 5

[0100] As described in Example 3, plasma T and TU levels were determined in blood samples obtained from fasting dogs following administration of a single dose of TSX-057. Figure 5A and 6A Plasma T and TU levels are shown separately for each dog over time. Figure 5B and 6B Mean plasma T and TU levels over time are shown. Mean plasma T levels 最大 (h) is 3.33±2.42. The average C of T level 最大 (ng / dL) is 307±251.

[0101] Example 6

[0102] As described in Example 3, plasma T and TU levels were determined in blood samples obtained from fasting dogs following administration of a single dose of TSX-056. Fig. 7A and 8A Plasma T and TU levels are shown separately for each dog over time. Figure 7B and 8B Mean plasma T and TU levels over time are shown. Mean plasma T levels 最大 (h) is 3.33±1.33. The average C of T level 最大 (ng / dL) is 306.6±251.16.

[0103] Example 7

[0104] As described in Example 3, plasma T and TU levels were determined in blood samples obtained from fasting dogs following administration of a single dose of TSX-048. Fig.9A and 10A Plasma T and TU levels are shown separately for each dog over time. Fig. 9B and 10B Mean plasma T and TU levels over time are shown. Mean plasma T levels 最大 (h) is 2.67±1.63. The average C level of T 最大 (ng / dL) is 727±539.

[0105] Example 8

[0106] As described in Example 3, plasma T and TU levels were determined in blood samples obtained from fasting dogs following administration of a single dose of TSX-048. Fig.11A and 12APlasma T and TU levels are shown separately for each dog over time. Fig. 11B and 12B Mean plasma T and TU levels over time are shown. Mean plasma T levels 最大 (h) is 4.83±5.23. The average C level of T 最大 (ng / dL) is 461±226.

[0107] Example 9

[0108] Based on the 24-hour, single-dose, fasted dog studies described in Examples 3-8, the AUC (ng h / dL) of T and TU was determined for TSX-011; TSX-048; TSX:049; TSX-056 and TSX-057. The AUC data are Fig.13 and 14 Table 3 contains the AUC values ​​for T for each formulation and individual dogs in the study. The AUC values ​​for T and TU for TSX-048 were the highest among the formulations tested; however, the AUC values ​​for TSX-049 were also good but showed lower variability. The composition of the TSX-057 formulation included the components of TSX-049 plus oleic acid. The AUC values ​​for TSX-057 showed that the addition of oleic acid did not result in a significant improvement. These studies also showed that the AUC values ​​for TU were approximately 25%-33% of the AUC values ​​for T, thus indicating good absorption of TU.

[0109] Table 3

[0110]

[0111] ANOVA: Based on the geometric mean, there were no differences between all formulations. However, animal 1F1 was virtually a non-responder to all formulations. If this was excluded, then there were significant differences between formulations with respect to AUC.

[0112] Example 10

[0113] Based on the 24-hour, single-dose, fasted dog studies described in Examples 3-8, the steady-state mean concentrations of T and TU for TSX-011; TSX-048; TSX:049; TSX-056 and TSX-057 were determined. 平均 (ng / dL). 平均 The data in Fig.15 and 16 TSX-048 showed the highest T C 平均 , however, TSX-049 showed good T C with lower variability 平均 .

[0114] Embodiment 11

[0115] Based on the 24-hour, single-dose, fasted dog studies described in Examples 3-8, the AUC (ngh / dL) of dihydrotestosterone (DHT) and dihydrotestosterone undecanoate (DHTU) were determined for TSX-011; TSX-048; TSX:049; TSX-056 and TSX-057. The AUC data are Fig.17 and 18 The AUC levels of DHT and DHTU were found to correspond to those of T and TU, indicating the maintenance of the T / DHT and TU / DHTU ratios. All T / DHT and TU / DHTU ratios were also within the guidance of the U.S. Food and Drug Administration (FDA) of ≤20. See Table 4.

[0116] Table 4 AUC and C 最大 T:DHT ratio

[0117]

[0118]

[0119] Table 5 compares and summarizes the pharmacokinetic parameters of DHT and DHTU and T and TU reported in Examples 3-11 for TSX-011; TSX-048; TSX:049; TSX-056 and TSX-057.

[0120] Table 5

[0121]

[0122]

[0123] Table 6 contains the pharmacokinetic parameters determined by normalizing the parameters in Table 3 to the administered dose of TSX-011. Overall, these data indicate that the testosterone PK level of TSX-049 is dominant among the tested formulations, an observation that is carried forward to Fig. 20 , which compares mean plasma testosterone levels in a dog study following oral administration of TSX-049 and TSX-011, respectively.

[0124] Table 6 AUC and C normalized to TSX-011 formulation dose 最大 (n=5)

[0125]

[0126] C of the test preparation 最大The coefficient of variation (CV%) values ​​for AUC (0-24 hours) and AUC (0-24 hours) indicate that differences between formulations are evident after dose normalization to TSX-011 and exclusion of non-responder animal 1F1. The lower CV% indicates lower variation in absorption within each formulation. Of the formulations tested, TSX-049 and TSX-057 showed the lowest CV%. See Table 7 for CV% values ​​determined using results from 6 animals in the study and Table 8 for CV% determined excluding dog 1F1.

[0127] Table 7 AUC and C 最大 CV% (n=6)

[0128]

[0129]

[0130] Table 8 AUC and C 最大 CV% (n=5)

[0131]

[0132] Example 12

[0133] Based on the bioavailability data reported in Tables 3 and 6, the relative in vivo bioavailability of testosterone for each formulation was determined relative to the bioavailability data determined for TSX-011 in the fasted dog studies described in Examples 3-8, following administration of a single dose of TSX-011, TSX-048, TSX-049, TSX-056 and TSX-057, excluding data obtained for dog 1F1. See Table 9.

[0134] Table 9

[0135]

[0136] Embodiment 13

[0137] Comparison of testosterone PK parameters in male dogs: TSX-011 vs TSX-049. Considering its performance advantages in Examples 1-12, the TSX-049 formulation (TU: DPPC = 1: 2) was selected for further pharmacokinetic (PK) studies in male beagle dogs with respect to bioavailability and dose response. In these studies, TSX-049 was compared with TSX-011 (TU: DSPC = 1: 2). The TSX-011 formulation is described and characterized in PCT Application Publication No. WO 2017 / 120592, which is incorporated by reference. The dosage forms of TSX-011 and TSX-049 used in these studies are described in Table 10.

[0138] Table 10

[0139]

[0140] For the study, the dogs were fasted overnight and dosed in the fed state the next morning by providing food to the dogs immediately after oral dosing (and allowing access to food for 2 hours). Approximately 8 hours later, the second dose was again orally administered, and the dogs were then allowed immediate access to food (allowing access to food for an additional 2 hours). Thus, dosing was performed twice a day. The dogs were administered low, medium or high doses of TU over a 24-hour period. For TSX-011, the daily low TU dose administered to 6 dogs was 94.8 mg, the medium dose was 189.4 mg, and the high dose was 284.4 mg. For TSX-049, the daily low TU dose administered to 10 dogs was 60 mg, the medium dose was 120 mg, and the high dose was 240 mg.

[0141] Doses were normalized based on each dog's body weight (administered TU mg / kg body weight). Table 11 summarizes the mean normalized doses and relative TU dose differences for the low, mid, and high doses of the TSX-011 and TSX-049 groups.

[0142] Table 11

[0143]

[0144]

[0145] Blood samples were collected from each dog by jugular vein puncture 1 hour before oral administration of the formulation, and then 2, 4, 6, 8, 12, 15, 18, 21 and 24 hours after administration, and plasma was collected. PK analysis of plasma samples included calculation of AUC (ng h / dL) and C 最大 (ng h / dL) level. AUC and C 最大 Data in Fig.22A -B and Table 12 show.

[0146] Table 12

[0147]

[0148] The relative testosterone bioavailability for each dose of TSX-011 and TSX-049 was also determined and is reported in Table 13. TSX-049 demonstrated higher bioavailability and a significantly higher dose response in non-hypogonadal male dogs compared to TSX-011.

[0149] Table 13

[0150] Research preparation Dosage (mg) / day Relative bioavailability (F) Low dose TSX-049 vs TSX-011 60vs94.8 1.93 Medium dose TSX-049 vs TSX-011 120vs189.6 1.37 High dose TSX-049 vs TSX-011 240vs284.4 1.21

[0151] Embodiment 14

[0152] Dose escalation study of multi-day TSX-049 testosterone undecanoate (TU) in male beagle dogs. In order to evaluate the pharmacokinetics of TSX-049 formulations during extended time courses and at multiple daily TU doses, a 40-day dose escalation study was performed using 10 non-hypogonadal male beagle dogs. In the first 7 days of the study, no TSX-049 formulation was administered. On the 8th day of the study, TSX-049 was orally administered to the dogs daily to deliver 30 mg of TU BID for 10 days. On the 18th day of the study, the daily TU dose was increased to 60 mg BID and maintained for the next 10 days. On the 28th day of the study, the daily TU dose was increased to 120 mg BID and maintained until the 38th day of the study. The TSX-049 capsules administered in this study are described in Table 10. Since each capsule contains a 30 mg dose of TU, ​​multiple TSX-049 capsules are administered in the amount of the desired daily dose required to be achieved.

[0153] Blood samples were collected from dogs on Day 1 (pre-dose baseline); Day 8 (30 mg dosing D1); Day 12 (30 mg BID dosing D5); Day 18 (60 mg BID dosing D1); Day 22 (60 mg BID dosing D5); Day 27 (120 mg BID dosing D1); Day 32 (120 mg BID dosing D5); Days 39-40 (end of study (EOS)). On the days prior to the blood draw time points, the dogs were fasted overnight and dosed in the fed state the next morning by providing food to the dogs immediately after oral dosing (and then allowing access to food for 2 hours). Approximately 8 hours later, the second dose was administered orally again, followed by immediate access to food (allowing access to food for an additional 2 hours). The exception to the above protocol was that TSX-049 was not administered to the dogs on Day 1 of the study when the pre-dose plasma testosterone baseline level was determined. Blood was drawn by jugular venipuncture at 0, 2, 4, 6, 8, 12, 15, 18, 21, and 24 hours. Plasma was subjected to pharmacokinetic analysis to determine the plasma levels, AUC, C 最大 and t 最大 parameter. Fig.23A Mean baseline plasma T concentrations over 24 hours on day 1 of the study are shown. Fig. 23B Mean baseline plasma T concentrations over 24 hours at the end of study (EOS) on study day 39 or 40 are shown. End of study baselines were lower than pre-dose baselines as expected, as this is consistent with a negative feedback effect on endogenous T levels. Fig.23C-H shows the mean plasma T concentrations over 24 hours at D1 and D5 time points for daily TU doses of 60 mg, 120 mg, and 240 mg. Tables 14 and Figures 23C-23D The AUC parameters for T during the course of the study were summarized and indicate that the 30 mg / BID TU dose (60 mg daily) was not sufficient to elevate endogenous 'T' levels. Plasma concentration data from the D1 and D5 time points of the 120 mg / BID (240 mg daily) phase of this study indicate that this dose was sufficient to overcome endogenous 'T' levels. In fact, when doses exceeded 60 mg, C 最大 Increases with increasing dose (see Fig.25A ). The 120 mg dose showed a strong increase in exposure, especially later in the day. This is consistent with t 最大 The median extension (see Fig.26A ) and lymphatic absorption of TU. In addition, the AUC of DHT remained relatively constant with TU administration via TSX-049 (see Fig. 24B ), which is a gratifying finding. It was also observed that the AUC of TU increased in a nearly dose-proportional manner at all 3 doses (see Fig.24C ), an observation that suggests TU is not subject to negative feedback. The levels of the undecanoic acid form in plasma are also significantly higher than those of the unbound component ( Figures 24A-24D ), although DHTU tends to decrease with increasing TU doses and repeated administration of the same dose. Fig.24D .

[0154] Table 14 AUC of T plasma levels 0-t最后 (ng h / dL)

[0155]

[0156]

[0157] *AUC (0-18h)

[0158] Table 15 C 最大 ng / dL

[0159]

[0160] About t 最大 Parameters, observed T and DHT t 最大 There is a similar trend between the values. Fig.26A and 26B . In TU and DHTU 最大 Similar similarities are observed in the trends. Fig.26C and 26D .

[0161] Table 16 t 最大 h

[0162]

Claims

1. A proliposomal powder dispersion comprising testosterone undecanoate (TU) and dipalmitoylphosphatidylcholine (DPPC), wherein the weight / weight (w / w) ratio of TU:DPPC in the proliposomal powder dispersion is (0.9-1.1):(1.8-2.2).

2. An oral dosage form comprising the proliposome powder dispersion according to claim 1.

3. The oral dosage form according to claim 2, further comprising mannitol, wherein: The proliposomal powder dispersion comprises TU and DPPC in a w / w ratio of (0.9-1.1):(1.8-2.2), and the w / w ratio of the proliposomal powder dispersion to mannitol is (0.9-1.1):(1.13-1.37).

4. The oral dosage form of claim 2, wherein the oral dosage form comprises an enteric coated capsule.

5. The oral dosage form according to claim 4, wherein the enteric coating capsule material comprises plant-derived hydroxypropyl methylcellulose (HPMC).

6. The oral dosage form according to claim 4 or 5, wherein the enteric coating material comprises a methacrylic acid copolymer.

7. Use of the oral dosage form according to any one of claims 2 to 6 for the preparation of a medicament for treating a disease of low endogenous testosterone levels in plasma, for testosterone replacement therapy (TRT) in an individual in need thereof.

8. Use according to claim 7, wherein the low endogenous level of testosterone is caused by injury, infection, testicular loss, chemotherapy, radiation therapy, genetic abnormalities, hemochromatosis, pituitary dysfunction, inflammatory diseases, drug side effects, chronic renal failure, cirrhosis, stress, alcoholism, obesity, Kallmann syndrome, male hypogonadism or testosterone deficiency syndrome (TDS).

9. The use according to claim 7 or 8, wherein the plasma testosterone level before treatment is 300 ng / dL or lower.

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