JP-2022513635-A5 -

Dates

Publication Date

20221202

Application Date

20191122

Description

In a separate rat study, the level of CRV431 distributed in the liver relative to the blood was measured (see Figure 8). In this study, Sprague Dawley rats (n=6) were orally administered 30 mg/kg of 1/3/3/2/9 (Vitamin E/Maisine® CC/Propylene Glycol/Ethanol/Cremophor® RH40 (w/w/w/w/w)) CRV431 SMEDDS (50 mg/ml) for 7 days. A fixed amount of whole blood and liver homogenate were analyzed by LC-ESI-MS 12 hours after the final administration. The level of CRV431 distributed in the liver (10 μg/g tissue) was found to be 6.5 times higher than the level in the whole blood fraction. Error bars represent the mean ± standard deviation. Another aspect of the present invention may be as follows: [1] CRV431: (CRV431) Alternatively, a self-microemulsifying drug delivery system (SMEDDS) containing a pharmaceutically acceptable salt thereof. [2] The self-microemulsifying drug delivery system according to [1], comprising Cremophor® RH40. [3] A self-microemulsifying drug delivery system according to [1] or [2], comprising ethanol. [4] A self-microemulsifying drug delivery system according to any one of [1] to [3] above, comprising Transcutol®. [5] A self-microemulsifying drug delivery system according to any one of [1] to [4], comprising propylene glycol. [6] A self-microemulsifying drug delivery system according to any one of the above items [1] to [5], comprising Maisine® CC. [7] A self-microemulsifying drug delivery system according to any one of the above items [1] to [6], comprising vitamin E. [8] A self-microemulsifying drug delivery system according to any one of [1] to [7] above, comprising vitamin E, Maisine® CC, propylene glycol, Transcutol®, ethanol, and Cremophor® RH40 in a mass ratio of 1/1/5/5/2.4/4 or 1/1.5/2.5/5/2.4/5. [9] A self-microemulsifying drug delivery system according to any one of the above items [1] to [8], comprising CRV431 at a concentration of approximately 10 mg/mL to approximately 90 mg/mL. [10] A self-microemulsifying drug delivery system according to any one of the above items [1] to [9], comprising CRV431 at a concentration of approximately 90 mg/mL. [11] (a) CRV431 at concentrations of approximately 10 mg/mL to approximately 90 mg/mL: (CRV431) (b) Vitamin E, (c) Maisine (registered trademark) CC, (d) Propylene glycol, (e) Transcutol®, (f) Ethanol, and A pharmaceutical composition comprising (g) Cremophor® RH40, wherein vitamin E, Maisine® CC, propylene glycol, Transcutol®, ethanol, and Cremophor® RH40 are present in mass ratios of approximately (0.75-1.5)/(0.5-2)/(2-5)/(2-5)/(2-2.4)/(4-8). [12] A method for treating a disease in a subject requiring the same, comprising administering to the subject a therapeutically effective amount of a self-microemulsifying drug delivery system (SMEDDS) described in any one of [1] to [10] or a therapeutically effective amount of a pharmaceutical composition described in [11]. [13] A method for preventing a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a self-microemulsifying drug delivery system (SMEDDS) described in any one of [1] to [10] above, or a therapeutically effective amount of a pharmaceutical composition described in [11] above. [14] A self-microemulsifying drug delivery system (SMEDDS) according to any one of items [1] to [10] above, or a pharmaceutical composition according to item [11] above, for the treatment or prevention of a disease in a subject. [15] Use of a therapeutically effective amount of a self-microemulsifying drug delivery system (SMEDDS) according to any one of items [1] to [10] above, or the pharmaceutical composition according to item [11] above, in the manufacture of a pharmaceutical for the treatment or prevention of a disease in a subject. [16] The method according to any one of the above [12] to [13], the SMEDDS or pharmaceutical composition described in [14], or the use described in [15], wherein the disease is a severe liver disease. [17] The method according to any one of the above [12] to [13], the SMEDDS or pharmaceutical composition according to the above [14], or the use according to the above [15], wherein the disease is hepatitis B (HBV), hepatic fibrosis, or hepatocellular carcinoma. [18] The method according to any one of the above [12] to [13], the SMEDDS or pharmaceutical composition described in [14], or the use described in [15], wherein the disease is hepatitis B (HBV). [19] The method according to any one of the above [12] to [13], the SMEDDS or pharmaceutical composition described in [14], or the use described in [15], wherein the disease is hepatic fibrosis. [20] The method according to any one of the above [12] to [13], the SMEDDS or pharmaceutical composition described in [14], or the use described in [15], wherein the disease is hepatocellular carcinoma. [21] The method, SMEDDS, pharmaceutical composition, or use according to any one of the above [12] to [20], wherein the area under the curve (AUC) of a graph plotting the concent