Crystal forms of scutellarin aglycone and preparation thereof
Inventors
Wang, Zeren • Xu, Jun • Wang, Minghui • ZHU, Zhaoyun • WANG, Jingkun • MEI, Shuangxi • SUN, Wenqiang • Cui, Tao
Assignees
Hlk Pharmaceuticals Co Ltd • YUNNAN INSTITUTE OF MATERIA MEDICA
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Publication Number
US-10172824-B2
Publication Date
2019-01-08
Expiration Date
Abstract
The invention belongs to the field of medicine and chemical industry, and particularly relates to multiple crystal forms of scutellarin aglycone and preparation thereof. The invention also relates to use of said crystal forms of scutellarin aglycone in the manufacture of a medicament for preventing and/or treating a cardiovascular or cerebrovascular disease, rheumatic arthritis or stroke sequelae, etc. The crystal forms of scutellarin aglycone according to the invention have good stability, and can solve the problems concerning poor oral absorption and low bioavailability of scutellarin.
Core Innovation
The invention relates to crystalline forms of scutellarin aglycone, including crystal form E. Crystal form E is defined by an X-ray powder diffraction pattern with main characteristic absorption peaks at about 2b8 positions of 9.6b10.2 0, 14.0b10.2 0, 15.3b10.2 0, 17.8b10.2 0, and 26.6b10.2 0, as determined using CuadKb1 radiation. Additional characterization for crystal form E is described via further XRPD peak positions and thermal behavior determined by DSC.
The disclosure further defines crystal form E by quantitative thermal properties, including a melting point determined by differential scanning calorimetry. Crystal form E is also described as an anhydrous substance. The partial content additionally describes that crystal forms Ae28093I of scutellarin aglycone are characterized by XRPD main peak 2b8 values (CuadKb1) together with corresponding DSC thermal properties and purity levels, and it includes a related crystal form for an ammonium salt hydrate.
The disclosure provides preparation and interconversion context for producing and obtaining specific crystalline forms, and it includes a pharmaceutical use framework. A downstream framework is described for preventing or treating cardiovascular disease, cerebrovascular disease, rheumatic arthritis, and stroke sequelae, including cerebral infarction. The partial content specifically mentions an MCAO rat model study for scutellarin aglycone (crystal form A) showing improved nerve function impairment scores and reduced cerebral infarction area.
Claims Coverage
The independent claim identified in the partial content is directed to a single crystalline material identity: crystal form E of scutellarin aglycone defined by a specific XRPD peak set measured by CuadKb1 radiation. Dependent claims add further XRPD peak positions, a DSC melting point constraint, an anhydrous material state, a preparation approach involving heating and natural cooling, and a therapeutic method for cerebral infarction by administration.
Crystal form E with XRPD main characteristic absorption peaks
Crystal form E of scutellarin aglycone having an X-ray powder diffraction pattern with main characteristic absorption peaks at least at about 2b8 positions 9.6b10.2 0, 14.0b10.2 0, 15.3b10.2 0, 17.8b10.2 0 and 26.6b10.2 0, as determined using CuadKb1 radiation.
Additional XRPD characteristic absorption peaks for crystal form E
Crystal form E having an XRPD pattern that further includes one or more characteristic absorption peaks at about 2b8 selected from 10.2b10.2 0, 10.9b10.2 0, 16.1b10.2 0, 19.3b10.2 0, 21.2b10.2 0, 28.5b10.2 0, 29.8b10.2 0, 31.1b10.2 0 (and others), as determined using CuadKb1 radiation.
DSC melting point of crystal form E
Crystal form E of the claimed material having a melting point of about 364.0b13.0b0C as determined by differential scanning calorimetry.
Preparation method by heating and natural cooling to obtain crystal form E
A method for preparing crystal form E comprising heating scutellarin aglycone solid to 250e28093350b0C and then naturally cooling it to room temperature to obtain crystal form E.
Anhydrous crystal form E
Crystal form E is an anhydrous substance.
Treatment of cerebral infarction by administering crystal form E
A method for treating cerebral infarction comprising administering to a subject in need thereof a therapeutically effective amount of the crystal form E according to claim 1.
Across the independent and dependent claims in the partial content, crystal form E is defined by a specific XRPD peak set using CuadKb1 radiation, refined by additional XRPD peaks and a DSC melting point, characterized as an anhydrous substance, and positioned for treating cerebral infarction through administration of a therapeutically effective amount.
Stated Advantages
Improved nerve function impairment scores (described for scutellarin aglycone crystal form A in an MCAO rat model study).
Reduced cerebral infarction area (described for scutellarin aglycone crystal form A in an MCAO rat model study).
Documented Applications
Preventing or treating cardiovascular disease.
Preventing or treating cerebrovascular disease.
Preventing or treating rheumatic arthritis.
Preventing or treating stroke sequelae.
Treating cerebral infarction by administering crystal form E to a subject in need thereof.
MCAO rat model application for scutellarin aglycone (crystal form A), with outcomes including nerve function impairment scores and cerebral infarction area assessed.
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