阅读说明：本技术 一种共晶体及制备方法、包含共晶体的药物组合物及用途 (Co-crystal, preparation method thereof, pharmaceutical composition containing co-crystal and application thereof ) 是由 刘湖 于 2019-09-10 设计创作，主要内容包括：本发明公开了一种共晶体及制备方法、包含共晶体的药物组合物及用途。共晶体由姜黄素的氢化产物与有机酸类化合物、葡甲胺、2-羟基苯乙酮、4-胺基苯酚、(异)烟酰胺、甘露醇、或山梨醇中的任意一种制备而成,制备得到的该共晶体可以制备用于治疗癌症、消除炎症、治疗创伤、预防或治疗老年痴呆、防治骨质疏松和/或促进骨愈合、降血脂、治疗脂肪肝以及伴有高血脂症、糖尿病的相关代谢性综合征疾病或美容美白的药物。在实际应用中,发现姜黄素的氢化产物在共晶体药物中的生物利用度得到了明显提高,极大地扩展了其临床应用。(The invention discloses a cocrystal, a preparation method thereof, a pharmaceutical composition containing the cocrystal and application thereof. The eutectic is prepared from a hydrogenation product of curcumin and any one of an organic acid compound, meglumine, 2-hydroxyacetophenone, 4-aminophenol, (iso) nicotinamide, mannitol or sorbitol, and the prepared eutectic can be used for preparing medicines for treating cancers, eliminating inflammation, treating wounds, preventing or treating senile dementia, preventing and treating osteoporosis and/or promoting bone healing, reducing blood fat, treating fatty liver and related metabolic syndrome diseases accompanied by hyperlipidemia and diabetes or beautifying and whitening. In practical application, the bioavailability of the curcumin hydrogenated product in the cocrystal drug is obviously improved, and the clinical application of the curcumin hydrogenated product is greatly expanded.)

1. A eutectic is prepared from raw materials A and B, wherein the chemical structural formula of A is as follows:

R₁and R₂Is H or OCH₃，

B is any one of organic acid compounds, meglumine, 2-hydroxyacetophenone, 4-aminophenol, (iso) nicotinamide, mannitol or sorbitol.

2. Co-crystal according to claim 1, wherein the organic acid compound is selected from the group consisting of long chain fatty acid compounds, benzoic acid derivative compounds, organic diacid compounds and amino acid compounds.

3. Co-crystal according to claim 2, wherein the long chain fatty acid compound is selected from any one of caprylic acid, capric acid and lauric acid.

4. The co-crystal according to claim 2, wherein the benzoic acid derivative based compound is selected from any one of benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, m-hydroxybenzoic acid, phthalic acid, isophthalic acid, terephthalic acid, and trimesic acid.

5. Co-crystal according to claim 2, characterized in that the organic diacid like compound is selected from any of oxalic acid, succinic acid, glutaric acid, adipic acid, fumaric acid and maleic acid.

6. Co-crystal according to claim 2, wherein the amino acid compound is selected from any one of alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, glycine, asparagine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

7. A method of preparing a co-crystal according to any of claims 1 to 6, comprising

Mixing the raw materials A and B according to a molar ratio of 1: 1-2: 1, adding deionized water, uniformly stirring, heating to 60-80 ℃, and stirring for reaction for 1-3 hours;

filtering the reaction solution after the reaction is finished to obtain filtrate;

and standing the filtrate at room temperature for 60-72 h to precipitate a eutectic.

8. A pharmaceutical composition comprising a co-crystal prepared from the co-crystal of any one of claims 1-6 and a pharmaceutically acceptable additive.

9. The pharmaceutical composition comprising the co-crystal according to claim 8, wherein the pharmaceutical composition is in the form of any one of lyophilized powder, tablet, troche, capsule, soft capsule, granule, syrup, pellet, microsphere, pellet, aqua, oral liquid and paste.

10. Use of a co-crystal according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of cancer, for the elimination of inflammation, for the treatment of trauma, for the prevention or treatment of senile dementia, for the prevention and/or treatment of osteoporosis and/or for the promotion of bone healing, for the reduction of blood lipids, for the treatment of fatty liver and associated metabolic syndrome diseases with hyperlipidemia, diabetes, or for cosmetic whitening.

Technical Field

The invention relates to the technical field of medicines, in particular to a cocrystal and a preparation method thereof, a pharmaceutical composition containing the cocrystal and application of the cocrystal.

Background

Curcumin is the main component of Curcuma rhizome, has effects of resisting oxidation, resisting tumor, reducing blood lipid, reducing blood glucose, resisting ulcer, protecting liver, resisting myocardial ischemia, resisting depression, resisting bacteria, diminishing inflammation, resisting virus and resisting fungi, and can be used for treating cancer, diabetes, coronary atherosclerotic heart disease, arthritis, Alzheimer disease (Alzheimer disease) and other chronic diseases.

The tetrahydrocurcumin, the tetrahydrodemethoxycurcumin and the tetrahydrobisdemethoxycurcumin are hydrogenation products of curcumin, have pharmacological actions similar to that of the curcumin, have stronger pharmacological activities of resisting cancer, resisting oxidation, eliminating free radicals, reducing blood sugar, reducing blood fat and the like through research, and have better treatment effects on related diseases such as metabolic syndrome, obesity type 2 diabetes, hypertension, insulin resistance syndrome and the like through the tetrahydrocurcumin. A large number of experimental results show that the biological activity of the curcumin-containing compound is superior to that of curcumin.

However, in practical application, the bioavailability of tetrahydrocurcumin (SHCUR) and its derivatives tetrahydrodemethoxycurcumin (SHDMCUR) and tetrahydrobisdemethoxycurcumin (SHDDMCUR) is found to be very low, which greatly limits the clinical application.

Disclosure of Invention

The object of the present invention is to provide a co-crystal and a preparation method, a pharmaceutical composition comprising the co-crystal and use thereof, thereby solving the aforementioned problems in the prior art.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the invention provides a eutectic which is prepared from raw materials A and B, wherein the chemical structural formula of A is as follows:

R₁and R₂Is H or OCH₃，

B is any one of organic acid compounds, meglumine, 2-hydroxyacetophenone, 4-aminophenol, (iso) nicotinamide, mannitol or sorbitol.

Preferably, the organic acid compound is selected from long-chain fatty acid compounds, benzoic acid derivative compounds, organic diacid compounds and amino acid compounds.

Preferably, the long-chain fatty acid compound is selected from any one of caprylic acid, capric acid and lauric acid.

Preferably, the benzoic acid derivative compound is selected from any one of benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, m-hydroxybenzoic acid, phthalic acid, isophthalic acid, terephthalic acid and trimesic acid.

Preferably, the organic diacid compound is selected from any one of oxalic acid, succinic acid, glutaric acid, adipic acid, fumaric acid and maleic acid.

Preferably, the amino acid compound is selected from any one of alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, glycine, asparagine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

In another aspect of the invention, a method for preparing a co-crystal is provided, comprising

Mixing the raw materials A and B according to a molar ratio of 1: 1-2: 1, adding deionized water, uniformly stirring, heating to 60-80 ℃, and stirring for reaction for 1-3 hours;

filtering the reaction solution after the reaction is finished to obtain filtrate;

and standing the filtrate at room temperature for 60-72 h to precipitate a eutectic.

In a third aspect, the invention provides a pharmaceutical composition comprising a co-crystal, prepared from the above co-crystal and a pharmaceutically acceptable additive.

Preferably, the dosage form of the pharmaceutical composition is any one of freeze-dried powder, tablets, buccal tablets, capsules, soft capsules, granules, syrup, micro-pills, microspheres, pellets, aqueous solution, oral liquid and paste.

In a fourth aspect, the invention provides a use of the co-crystal in preparing a medicament for treating cancer, eliminating inflammation, treating trauma, preventing or treating senile dementia, preventing and treating osteoporosis and/or promoting bone healing, reducing blood lipid, treating fatty liver, and associated metabolic syndrome diseases accompanied by hyperlipidemia and diabetes, or beautifying and whitening.

The invention has the beneficial effects that: the eutectic crystal is prepared from any one of a hydrogenation product of curcumin, an organic acid compound, meglumine, 2-hydroxyacetophenone, 4-aminophenol, (iso) nicotinamide, mannitol or sorbitol, and can be used for preparing a medicament for treating cancer, eliminating inflammation, treating trauma, preventing or treating senile dementia, preventing and treating osteoporosis and/or promoting bone healing, reducing blood fat, treating fatty liver, treating hyperlipidemia and diabetes-related metabolic syndrome diseases or beautifying and whitening. In practical application, the bioavailability of the curcumin hydrogenated product in the cocrystal drug is obviously improved, and the clinical application of the curcumin hydrogenated product is greatly expanded.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below. It should be understood that the detailed description and specific examples, while indicating the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.