Curcumin and alpha-lipoic acid co-amorphous substance as well as preparation method and application thereof

Abstract

The invention provides a curcumin and alpha-lipoic acid co-amorphous substance and a preparation method thereof. The curcumin and alpha-lipoic acid co-amorphous substance is prepared by mixing, melting or grinding curcumin and alpha-lipoic acid according to a certain proportion. The preparation method of the co-amorphous substance adopts a melting cooling method or a grinding method, and the melting cooling method comprises the following steps: mixing curcumin and alpha-lipoic acid, heating to 145-155 DEG C, melting, cooling with liquid nitrogen, and crushing to obtain the co-amorphous substance; the grinding method comprises the following steps: mixing curcumin and alpha-lipoic acid, and mechanically grinding at the frequency of 20-40Hz. The preparation method of the co-amorphous substance is simple and low in cost, and the prepared co-amorphous substance is good in stability, has the characteristic of quick release, and can be applied to the fields of medicines, foods and health-care products.

Description

Technical Field

[0001] The invention relates to the technical field of co-amorphous drug preparation, in particular to a co-amorphous product of curcumin and alpha-lipoic acid, and a preparation method and application of the co-amorphous product of curcumin and alpha-lipoic acid. Background Art

[0002] Curcumin (CUR) is a natural polyphenol compound extracted from ginger plants and exists in other herbs. It is a representative of natural products and is widely used in the pharmaceutical and food industries. Curcumin has strong antioxidant, anti-inflammatory, and anti-tumor biological activities. It has lipid-regulating, anti-viral, anti-infective, anti-coagulant, anti-liver fibrosis, and anti-atherosclerotic pharmacological activities. The chemical structure of curcumin is as follows (I), with the molecular formula C 21 H 20 O6; It belongs to the diketone compound, and the main chain is unsaturated aliphatic and aromatic groups.

[0003]

[0004] α-Lipoic acid (Alpha Lipoic Acid) is a naturally occurring multifunctional coenzyme that is both water-soluble and fat-soluble, and can assist the coenzyme in physiological metabolism that is beneficial to the body's immunity. α-Lipoic acid also has significant antioxidant effects. It is a vitamin-like compound that can eliminate free radicals that accelerate aging and cause disease. α-Lipoic acid has certain effects on the treatment of liver diseases, diabetes, HIV virus, tumors, nervous system degeneration, radiation damage, heavy metal poisoning, etc. The chemical structure of α-lipoic acid is as follows (II), and the molecular formula is C8H 14 O2S2 exists as a mixture of two structures: a closed-ring disulfide form and an open-chain reduced form, and these two forms are converted into each other through redox cycles.

[0005]

[0006] Although the combined use of curcumin and α-lipoic acid can protect the liver through a variety of synergistic mechanisms, thereby expanding the efficacy of curcumin and α-lipoic acid in anti-oxidation, anti-inflammation, detoxification, protection of liver cell membranes, anti-fibrosis, promotion of liver cell regeneration, regulation of lipid metabolism and anti-tumor, these synergistic effects can jointly improve the protective effect on the liver. However, the water solubility of these two compounds is poor. After being formulated into a pharmaceutical preparation, the physical and chemical stability of the two insoluble drugs, as well as the low water solubility and low dissolution rate problems, limit their clinical application. Summary of the invention

[0007] The purpose of the present invention is to overcome the defects of the prior art and provide a method for preparing a co-amorphous compound formed by curcumin and α-lipoic acid, which effectively improves the dissolution performance of curcumin and thus improves its bioavailability.

[0008] In order to achieve the above object, the present invention provides a co-amorphous material of curcumin and α-lipoic acid, wherein the co-amorphous material is made of curcumin and α-lipoic acid, and the molar ratio of curcumin to α-lipoic acid is 1: (0.5-4), preferably 1: (1-2).

[0009] Preferably, the molar ratio of curcumin to α-lipoic acid is 1:1.

[0010] Preferably, the molar ratio of curcumin to α-lipoic acid is 1:2.

[0011] As a further technical solution, the co-amorphous product formed by curcumin and α-lipoic acid is tested and confirmed by using a Bruker D8Advanced model X-ray powder diffractometer, which uses Cu-Kα irradiation The scanning range was from 3° to 40° in the 2θ interval at a scanning speed of 5° / min, and it was confirmed that the X-ray powder diffraction (PXRD) pattern of the co-amorphous material had no sharp diffraction peaks.

[0012] As a further technical solution, a differential scanning calorimetry (DSC) test of the co-amorphous compound formed by the curcumin and α-lipoic acid confirmed that the glass transition temperature of the co-amorphous compound ranged from 55°C to 60°C.

[0013] As a further technical solution, the infrared absorption spectrum (IR) test of the co-amorphous compound formed by the curcumin and α-lipoic acid confirms that the infrared absorption spectrum of the co-amorphous compound is at least 3381 cm -1 、2952cm -1 、1652cm -1 、1580cm -1 、1512cm -1 、1460cm -1 、1421cm -1 、1284cm -1 、1124cm -1 、1029cm -1 、964cm -1 There is an absorption peak at.

[0014] The invention also provides a method for preparing the curcumin and alpha-lipoic acid co-amorphous product. The co-amorphous product is prepared by a melt cooling method or a grinding method.

[0015] The melt cooling method comprises: mixing the curcumin and α-lipoic acid in a molar ratio, heating to 145° C. to 155° C. to melt, heating time being 5 to 15 minutes, then cooling with liquid nitrogen, and pulverizing to obtain the co-amorphous product.

[0016] The grinding method comprises: mixing the curcumin and α-lipoic acid in a molar ratio, and mechanically grinding the mixture with a ball mill at a frequency of 20 Hz to 40 Hz for 60 to 120 minutes to obtain the co-amorphous product.

[0017] In addition, the co-amorphous compound formed by the curcumin and α-lipoic acid of the present invention can be used as an auxiliary material in an optional health product, medicine, food, cosmetic or feed in an acceptable amount.

[0018] Use of the composition of curcumin and α-lipoic acid in health products, foods, cosmetics, medicines or feeds; or use of the co-amorphous product formed by curcumin and α-lipoic acid in health products, foods, cosmetics, medicines or feeds.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. The present invention provides a co-amorphous substance of curcumin and α-lipoic acid. Compared with the water-insoluble curcumin crystalline powder raw material itself, the co-amorphous substance has a co-amorphous solution concentration of 9.2 times that of the curcumin raw material in a pH 2.0 buffer solution at 5 min; the co-amorphous solution concentration is 5 times that of the curcumin raw material in a pH 4.5 buffer solution at 5 min, which effectively improves the dissolution and dissolution properties of curcumin, thereby improving its bioavailability. By making curcumin co-amorphous, the interaction force between curcumin molecules is weak, and no large energy is required to destroy its lattice structure, so the molecule is more soluble in water. In addition, by forming a co-amorphous substance with α-lipoic acid, it is in a high-energy state, which can reduce the glass transition temperature of the system, making it more stable, and the synergistic effect between the components will reduce the possibility of molecular recrystallization.

[0021] 2. The preparation method of the co-amorphous material of curcumin and α-lipoic acid provided by the present invention forms a co-amorphous material by a melt cooling method or a grinding method. The solubility and dissolution rate of curcumin in the co-amorphous material are significantly improved compared with the raw material drug. The co-amorphous material has good activity and also exhibits a certain synergistic effect.

[0022] 3. The preparation method of the co-amorphous material is simple and low in cost. The prepared co-amorphous material has good stability and the characteristics of rapid release, and is suitable for the fields of health products, food, cosmetics, medicine or feed. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is an X-ray powder diffraction (PXRD) pattern of the co-amorphous product of curcumin and α-lipoic acid of the present invention;

[0024] Figure 2 is a differential scanning calorimetry (DSC) diagram of a co-amorphous product of curcumin and α-lipoic acid of the present invention;

[0025] Figure 3 It is an infrared absorption spectrum (IR) of the amorphous compound of curcumin and α-lipoic acid of the present invention;

[0026] Figure 4 The PXRD overlay of the curcumin and α-lipoic acid co-amorphous product of the present invention in an accelerated stability test;

[0027] Figure 5 The dissolution curves of the curcumin and α-lipoic acid co-amorphous product and the curcumin raw material in a pH 2.0 buffer solution of the present invention;

[0028] Figure 6 The present invention discloses a dissolution curve of the curcumin and alpha-lipoic acid co-amorphous product and the curcumin raw material in a pH 4.5 buffer solution. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments, so that those skilled in the art can fully understand the technical content of the present invention. It should be understood that the following embodiments are used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art according to the above content of the present invention belong to the scope of protection of the present invention. The specific process parameters of the following examples are also only an example in a suitable range, that is, those skilled in the art can make a selection within a suitable range according to the description herein, and are not limited to the specific values ​​​​exemplified below.

[0030] The invention provides a co-amorphous material of curcumin and alpha-lipoic acid, wherein the co-amorphous material is prepared from curcumin and alpha-lipoic acid, and the molar ratio of curcumin to alpha-lipoic acid is 1:(0.5-4), preferably 1:(1-2); more preferably the molar ratio of curcumin to alpha-lipoic acid is 1:1; more preferably the molar ratio of curcumin to alpha-lipoic acid is 1:2.

[0031] The preparation method of the co-amorphous substance of curcumin and α-lipoic acid of the present invention adopts a melt cooling method or a grinding method; the melt cooling method is: mixing curcumin and α-lipoic acid in a molar ratio, heating to 145°C to 155°C to melt, the heating time is 5 to 15 minutes, then cooling with liquid nitrogen, and crushing to obtain a co-amorphous substance. The grinding method is: mixing curcumin and α-lipoic acid in a molar ratio, using a ball mill to mechanically grind at a frequency of 20Hz to 40Hz for 60 to 120min to obtain a co-amorphous substance. The relevant proof experiment is specifically described as follows.

[0032] Reagents and instruments:

[0033] The X-ray powder diffraction (PXRD) patterns used in the embodiments of the present invention were obtained using a Bruker D8 Advanced X-ray powder diffractometer, which uses Cu-Kα irradiation. The scanning range was from 3° to 40° in the 2θ interval, and the scanning speed was 5° / min.

[0034] Differential Scanning Calorimetry (DSC) instrument: DSC Q2000 differential scanning calorimeter. Nitrogen flow rate: 50 mL / min; Heating rate: 10°C / min.

[0035] Infrared absorption spectroscopy (IR) instrument, using ThermoFisher NicoletTM iS50 FT-IR infrared spectrometer. Scanning range: 4000-400cm -1 ; Resolution: 2cm -1 .

[0036] The micro-dissolution apparatus used was Mini-IDR micro-dissolution apparatus.

[0037] High performance liquid chromatography was performed using Agilent Technologies 1260 high performance liquid chromatograph.

[0038] Embodiment 1:

[0039] Weigh 184 mg of curcumin (0.5 mmol) and 103 mg of α-lipoic acid (0.5 mmol), add to a stainless steel cup and mix, melt in an oil bath heated to 150° C. for 10 min, immediately place in a liquid nitrogen cooling zone, put into a desiccator and wait for it to return to room temperature, take it out, grind it into fine powder with a mortar, and store it in a desiccator to obtain a co-amorphous product of curcumin and α-lipoic acid.

[0040] Embodiment 2:

[0041] Weigh 184 mg of curcumin (0.5 mmol) and 103 mg of α-lipoic acid (0.5 mmol), add to a stainless steel cup and mix, melt in an oil bath heated to 145° C. for 15 min, immediately place in a liquid nitrogen cooling zone, put into a desiccator and wait for it to return to room temperature, take it out, grind it into fine powder with a mortar, and store it in a desiccator to obtain a co-amorphous product of curcumin and α-lipoic acid.

[0042] Embodiment 3:

[0043] Weigh 368 mg of curcumin (1 mmol) and 206 mg of α-lipoic acid (1 mmol), add to a stainless steel cup and mix, melt in an oil bath heated to 155° C. for 5 min, immediately place in a liquid nitrogen cooling zone, put into a desiccator and wait for it to return to room temperature, take it out, grind it into fine powder with a mortar, and store it in a desiccator to obtain a co-amorphous product of curcumin and α-lipoic acid.

[0044] Embodiment 4:

[0045] 368 mg of curcumin (1 mmol) and 206 mg of α-lipoic acid (1 mmol) were weighed and placed in a 25 mL ball mill, and ball milled at 40 Hz for 1 hour. The ball milled sample was vacuum dried and characterized by X-ray powder diffraction to determine that it was a co-amorphous product of curcumin and α-lipoic acid. The X-ray powder diffraction pattern is as follows Figure 1 shown.

[0046] Embodiment 5:

[0047] 184 mg of curcumin (0.5 mmol) and 206 mg of α-lipoic acid (1 mmol) were weighed and placed in a 25 mL ball mill, and ball milled at a frequency of 40 Hz for 1 hour. The ball-milled sample was vacuum dried and characterized by X-ray powder diffraction to determine that it was a co-amorphous product of curcumin and α-lipoic acid.

[0048] Embodiment 6:

[0049] 736 mg of curcumin (2 mmol) and 206 mg of α-lipoic acid (1 mmol) were weighed and placed in a 25 mL ball mill, and ball milled at a frequency of 40 Hz for 2 hours. The ball-milled sample was vacuum dried and characterized by X-ray powder diffraction to determine that it was a co-amorphous product of curcumin and α-lipoic acid.

[0050] Embodiment 7:

[0051] 368 mg of curcumin (1 mmol) and 824 mg of α-lipoic acid (4 mmol) were weighed and put into a 25 mL ball mill, and ball milled at a frequency of 40 Hz for 2 hours. The ball-milled sample was vacuum dried and characterized by X-ray powder diffraction to determine that it was a co-amorphous product of curcumin and α-lipoic acid.

[0052] Test Example 1:

[0053] The co-amorphous material in Example 4 was subjected to a stability test.

[0054] About 50 mg of the co-amorphous sample was weighed into a single-layer aluminum-plastic package and placed in an accelerated stability chamber (40°C / 75% RH). Samples were taken at 2 weeks, 4 weeks, 8 weeks and 12 weeks, and the physical stability of the powder sample was tested by PXRD. The results are shown in Figure 2. Figure 4 As shown, after 12 weeks, the sample is still amorphous and has good physical stability.

[0055] Test Example 2:

[0056] The dissolution properties of the curcumin and α-lipoic acid raw materials and the curcumin and α-lipoic acid co-amorphous obtained in Example 3 in different buffer media were compared.

[0057] Weigh about 20 mg (in terms of curcumin) of the curcumin raw material and the co-amorphous product, add 15 mL of pH 2.0 and pH 4.5 buffer (containing 0.5% soil temperature), and perform a powder dissolution experiment at 37 ° C, 50 rpm / min. Sampling is performed at 5, 10, 15, 30, 45, 60, 90 and 120 min, respectively. After centrifugation, take 400 μL of supernatant, dilute with 400 μL of methanol, and detect the concentration by HPLC.

[0058] Liquid phase detection method:

[0059] Instrument: Agilent 1260 series high performance liquid chromatograph

[0060] Test conditions: Chromatographic column: Agilent Zorbax Eclipse Plus C18 chromatographic column (5μm, 150mm×4.6mm); wavelength: 430nm; column temperature: 35℃; injection volume: 10μL; flow rate: 1.0mL / min; mobile phase: composed of 4% glacial acetic acid aqueous solution (eluent A) and acetonitrile (eluent B), the mobile phase ratio is 52:48 (v / v), isocratic elution.

[0061] The experimental results are as follows Figure 5 and Figure 6 As shown in the figure, the dissolution performance of the co-amorphous substance in pH 2.0 and pH 4.5 buffer solutions was significantly improved, wherein in pH 2.0 buffer solution, the concentration of the co-amorphous substance solution was 9.2 times that of the curcumin raw material at 5 min; in pH 4.5 buffer solution, the concentration of the co-amorphous substance solution was 5 times that of the curcumin raw material at 5 min.

[0062] It should be pointed out that the above preferred embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A co-amorphous product of curcumin and α-lipoic acid, characterized in that: The co-amorphous material is prepared from curcumin and alpha-lipoic acid, and the molar ratio of curcumin to alpha-lipoic acid is 1:(0.5-4).

2. The amorphous substance of curcumin and alpha-lipoic acid according to claim 1, characterized in that: The X-ray diffraction pattern of the co-amorphous powder has no sharp diffraction peaks.

3. The amorphous substance of curcumin and α-lipoic acid according to claim 1, characterized in that: The glass transition temperature of the co-amorphous material ranges from 55°C to 60°C.

4. The amorphous substance of curcumin and α-lipoic acid according to claim 1, characterized in that: The infrared absorption spectrum of the co-amorphous material is at least 3381 cm -1 、2952cm -1 、1652cm -1 、1580cm -1 、1512cm -1 、1460cm -1 、1421cm -1 、1284cm -1 、1124cm -1 、1029cm -1 、964cm -1 There is an absorption peak at.

5. The amorphous substance of curcumin and α-lipoic acid according to any one of claims 1 to 4, characterized in that: The molar ratio of curcumin to α-lipoic acid in the co-amorphous material is 1:(1-2).

6. The method for preparing amorphous product of curcumin and α-lipoic acid according to claim 1, characterized in that: The preparation method of the co-amorphous material adopts a melt cooling method or a grinding method.

7. The method for preparing amorphous product of curcumin and α-lipoic acid according to claim 6, characterized in that: The melt cooling method comprises: mixing the curcumin and α-lipoic acid in a molar ratio, heating to 145° C. to 155° C. to melt, heating time being 5 to 15 minutes, then cooling with liquid nitrogen, and pulverizing to obtain the co-amorphous product.

8. The method for preparing amorphous product of curcumin and α-lipoic acid according to claim 6, characterized in that: The grinding method comprises: mixing the curcumin and α-lipoic acid in a molar ratio, and mechanically grinding the mixture with a ball mill at a frequency of 20 Hz to 40 Hz for 60 to 120 minutes to obtain the co-amorphous product.

9. The use of the amorphous product of curcumin and α-lipoic acid according to any one of claims 1 to 5, characterized in that: The co-amorphous substance is used as an auxiliary material in health products, medicines, foods, cosmetics or feeds in an acceptable amount.

10. The use of the amorphous product of curcumin and α-lipoic acid according to any one of claims 1 to 5, characterized in that: Use of the composition of curcumin and α-lipoic acid in health products, foods, cosmetics, medicines or feeds; or use of the co-amorphous product formed by curcumin and α-lipoic acid in health products, foods, cosmetics, medicines or feeds.

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