Amorphous Venetoclax and pharmaceutic adjuvant solid dispersoid and preparation method thereof

Abstract

The invention relates to an amorphous Venetoclax and pharmaceutic adjuvant solid dispersoid and a preparation method thereof. The amorphous Venetoclax and pharmaceutic adjuvant solid dispersoid is prepared from Venetoclax and pharmaceutic adjuvants according to the weight ratio of 1:(0.1 to 100), wherein the Venetoclax is in an amorphous state; and in the X-ray powder diffraction spectrum of the solid dispersoid, no Venetoclax crystal feature peaks exist after the background peaks of the pharmaceutic adjuvants are eliminated. The Venetoclax and pharmaceutic adjuvant solid dispersoid provided by the invention has the advantages that the stability and the dispersibility are good; the dissolution rate of the Venetoclax is increased; the improvement of the bioavailability on the medicine preparation and the adsorption of the body on the medicine can be facilitated; and under the acceleration test conditions, high physical stability and chemical stability can be maintained. The preparationmethod of the amorphous Venetoclax and pharmaceutic adjuvant solid dispersoid has the advantages that the operation is simple; the cost is low; the reproducibility is high; the realization is easy; and the method is suitable for industrial production.

Description

technical field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a solid dispersion of amorphous Venetoclax and pharmaceutical auxiliary materials and a preparation method thereof. Background technique

[0002] Venetoclax, chemical name 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohex-1-yl]methyl]-1-piperazinyl]- N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrole[2,3-b ]pyridin-5-yloxy)-benzamide, whose trade name is Venclexta, is a kind of B-cell lymphoma 2 (BCL-2) inhibitor jointly developed by U.S. AbbVie and Swiss Roche, used for On April 11, 2016, it was approved by the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p gene mutation and who have received at least one treatment. Venclexta is the first B-cell lymphoma factor-2 inhibitor approved by the FDA. The FDA has previously granted it breakthrough drug designation,...

Examples

Embodiment 1

[0041] Add Venetoclax (5 g) and povidone K30 (10 g) into water (300 ml), heat to 60° C. and stir to dissolve. Dry the above solution with a JISL micro-spray dryer LSD-48, maintain the inlet temperature at 60°C and the outlet temperature at 50°C, collect the outlet material to obtain a white solid, and further vacuum-dry to obtain a solid dispersion of amorphous Venetoclax and povidone-K30 . X-ray powder diffraction pattern as figure 1 As shown, in the X-ray powder diffraction pattern of the solid dispersion, there is no characteristic peak of the Venetoclax crystal form after deducting the background peak of the pharmaceutical excipient.

Embodiment 2

[0043] Add Venetoclax (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) into water (10 ml), heat to 40°C and stir to dissolve. The above solution was freeze-dried to obtain a white solid, that is, a solid dispersion of amorphous Venetoclax and hydroxypropylmethylcellulose E50. In the X-ray powder diffraction pattern of the solid dispersion, there was no Venetoclax after deducting the background peaks of pharmaceutical excipients The characteristic peaks of the crystal form.

Embodiment 3

[0045] Venetoclax (1 g) and polyethylene glycol 8000 (50 g) were heated to melt, and rapidly cooled to room temperature with stirring to obtain a white solid. The above solid was pulverized to obtain a white powdery solid, i.e. a solid dispersion of amorphous Venetoclax and polyethylene glycol 8000. In the X-ray powder diffraction pattern of the solid dispersion, there was no Venetoclax crystal after deducting the background peak of pharmaceutical excipients. type of characteristic peaks.

technical field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a solid dispersion of amorphous Venetoclax and pharmaceutical auxiliary materials and a preparation method thereof. Background technique

[0002] Venetoclax, chemical name 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohex-1-yl]methyl]-1-piperazinyl]- N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrole[2,3-b ]pyridin-5-yloxy)-benzamide, whose trade name is Venclexta, is a kind of B-cell lymphoma 2 (BCL-2) inhibitor jointly developed by U.S. AbbVie and Swiss Roche, used for On April 11, 2016, it was approved by the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p gene mutation and who have received at least one treatment. Venclexta is the first B-cell lymphoma factor-2 inhibitor approved by the FDA. The FDA has previously granted it breakthrough drug designation,...

Examples

Embodiment 1

[0041] Add Venetoclax (5 g) and povidone K30 (10 g) into water (300 ml), heat to 60° C. and stir to dissolve. Dry the above solution with a JISL micro-spray dryer LSD-48, maintain the inlet temperature at 60°C and the outlet temperature at 50°C, collect the outlet material to obtain a white solid, and further vacuum-dry to obtain a solid dispersion of amorphous Venetoclax and povidone-K30 . X-ray powder diffraction pattern as figure 1 As shown, in the X-ray powder diffraction pattern of the solid dispersion, there is no characteristic peak of the Venetoclax crystal form after deducting the background peak of the pharmaceutical excipient.

Embodiment 2

[0043] Add Venetoclax (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) into water (10 ml), heat to 40°C and stir to dissolve. The above solution was freeze-dried to obtain a white solid, that is, a solid dispersion of amorphous Venetoclax and hydroxypropylmethylcellulose E50. In the X-ray powder diffraction pattern of the solid dispersion, there was no Venetoclax after deducting the background peaks of pharmaceutical excipients The characteristic peaks of the crystal form.

Embodiment 3

[0045] Venetoclax (1 g) and polyethylene glycol 8000 (50 g) were heated to melt, and rapidly cooled to room temperature with stirring to obtain a white solid. The above solid was pulverized to obtain a white powdery solid, i.e. a solid dispersion of amorphous Venetoclax and polyethylene glycol 8000. In the X-ray powder diffraction pattern of the solid dispersion, there was no Venetoclax crystal after deducting the background peak of pharmaceutical excipients. type of characteristic peaks.

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