US-12617781-B2 - Utidelone semi-hydrated single crystal and preparation method therefor and use thereof

US12617781B2US 12617781 B2US12617781 B2US 12617781B2US-12617781-B2

Abstract

A polycrystal form of Utidelone, particularly relating to a semi-hydrated crystal form (A) of Utidelone, a preparation method therefor and a use of crystal Utidelone in preparation of a pharmaceutical composition, especially the use in preparation of a pharmaceutical composition for inhibiting tumor growth and treating solid tumors of mammals, especially human. The provided crystal form is stable and resistant to high temperature and high humidity, and the preparation method is diversified and simple, and is suitable for industrialized production of new medicines.

Inventors

Li Tang
Rixiang KONG
Rongguo Qiu

Assignees

BEIJING BIOSTAR PHARMACEUTICALS CO., LTD.
CHENGDU BIOSTAR PHARMACEUTICALS, LTD.

Dates

Publication Date: 20260505
Application Date: 20210408
Priority Date: 20200408

Claims (8)

1 . Utidelone semihydrate crystal (A), which is single crystal, and the asymmetric structure unit is composed of four Utidelone molecules (crystallographically independent 1) and two water molecules to form the semihydrate crystal form.
2 . A pharmaceutical composition comprising the crystal according to claim 1 and a pharmaceutically acceptable excipient.
3 . The pharmaceutical composition according to claim 2 , wherein the B pharmaceutical composition is used for treating a solid tumor in mammal.
4 . A method of treating a solid tumor in mammal, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 2 .
5 . The method according to claim 4 , wherein the solid tumor is selected from the group consisting of breast cancer, lung cancer, colon cancer, gastrointestinal tumors, gynecological tumors, head and neck squamous cell carcinoma, esophageal cancer, pancreatic cancer, bile duct cancer, skin cancer, brain cancer and liver cancer.
6 . A pharmaceutical composition, which is obtained by utilizing the crystal according to claim 1 and a pharmaceutically acceptable excipient.
7 . The pharmaceutical composition according to claim 3 , wherein the mammal is a human.
8 . The method according to claim 5 , wherein the gastrointestinal tumor is a stomach cancer and the gynecological tumor is selected from ovarian cancer and cervical cancer.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is the U.S. national phase of International Patent Application No. PCT/CN2021/085903, filed on Apr. 8, 2021, which claims priority to Chinese Patent Application No. 202010282801.7, filed on Apr. 8, 2020, the disclosures of which are incorporated herein by reference in their entirety. TECHNICAL FIELD The present invention relates to 4S, 7R, 8S, 9S, 13Z, 16S-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[E-1-methyl-2-(2-methyl)-1,3-thiazol-4-yl)-prop-1-en-2-yl]-hexadecoxetan-13-en-2,6-one lactone (i.e. Utidelone) semihydrate crystal and its preparation method and use for preparing a pharmaceutical composition, especially use for preparing an antitumor drug. BACKGROUND ART Utidelone is an epothilone compound. Epothilone is a class of 16-membered macrolide natural cytotoxic compounds produced by the metabolism of microbial Myxobacteria. It has a similar mechanism of action to paclitaxel and has obvious antitumor activity. They both induce the polymerization of tubulin to form a hyperstable state, inhibit microtubule depolymerization, hinder mitosis, prevent tumor cell reproduction, and thus lead to apoptosis. Epothilone shows strong antitumor activity in p-glycoprotein expressing multidrug-resistant tumor cell lines, and has better water solubility than paclitaxel. Epothilone is superior to paclitaxel in many aspects and is considered to be a updated product of paclitaxel. As a member of epothilone family, Utidelone is chemically named 4S, 7R, 8S, 9S, 13Z, 16S-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[E-1-methyl-2-(2-methyl)-1,3-thiazol-4-yl)-prop-1-en-2-yl]-hexadecoxetan-13-en-2,6-one lactone with the following structural formula: Utidelone may be used to treat solid tumors including breast cancer, lung cancer, colon cancer, gastrointestinal tumors such as stomach cancer, gynecological tumors such as ovarian cancer and cervical cancer, head and neck squamous cell carcinoma, esophageal cancer, pancreatic cancer, bile duct cancer, skin cancer, brain cancer and liver cancer. Different crystal forms of a API may have significant differences in hygroscopicity, stability, and bioavailability, which may affect the efficacy of the drug. It is crucial to find a suitable crystal form for the development of a pharmaceutical composition of Utidelone. So far, no related crystal forms of Utidelone have been reported. SUMMARY In one aspect, the present invention provides a crystal form of Utidelone with extremely high stability. The present invention provides a single crystal of Utidelone, which is Utidelone semihydrate crystal (crystal form A). The X-ray diffraction pattern is shown in FIG. 1, the DSC is shown in FIG. 6, and the single crystal diffraction pattern is shown in FIG. 8. In another aspect, the present invention provides a method for preparing Utidelone semihydrate crystal. The preparation method includes dissolving Utidelone in a solvent, standing or stirring at 2-25° C., and then crystallizing. The solvent is a mixture of n-heptane and tetrahydrofuran or a mixture of dichloromethane and n-heptane. Single crystal with high purity may be obtained from the mixed solvent. In an embodiment, the preparation method is described as follows: weigh 3.0 mg of Utidelone compound as an initial sample into a 3 mL glass bottle, add 0.2 mL of the mixed solvent listed in Table 1 below, swirl and sonicate appropriately, complete dissolution of the solid sample was then observed. Subsequently, the above-mentioned 3 mL glass bottle was capped and sealed, and allowed to stand at room temperature. After 5 days, white needle-like solids or flaky crystal were precipitated. According to XRPD detection, the crystal form of the compound prepared by this preparation method is Utidelone semihydrate crystal, that is, a crystal form of Utidelone semihydrate in which 4 Utidelone molecules and 2 water molecules are contained. The X-ray powder diffraction pattern of the crystal form A is basically the same as that in FIG. 1. Through the X-ray diffraction analysis, the Utidelone semihydrate crystal of the present invention is a single flaky crystal, and single crystal X-ray diffraction pattern shows that the crystal belongs to triclinic system, P1 space group, and its unit cell parameters are: {a=6.37029(4)Å, b=14.67305(10)Å, c=29.54548(12)Å, α=81.3294(4°), β=86.3641(4°), γ=86.6019(5°), V=2721.14(3)Å3} □ and Z value is 4. The experimental details relating to the crystal structure, analysis of the results, and the refinement parameters for Utidelone semihydrate crystal are listed in Table 2. The crystal structure is an asymmetric structural unit, and the asymmetric structural unit of the crystal is composed of four Utidelone molecules (crystallographically independent) and two water molecules, which indicates that the crystal is the semihydrate of Utidelone compound. The single crystal data have successfully confirmed the stereochemical structure of Utidelone. The absolute configuration of the chi