CN114014853B - Curcumin berberine eutectic crystal and pharmaceutical composition thereof - Google Patents

Curcumin berberine eutectic crystal and pharmaceutical composition thereof Download PDF

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CN114014853B
CN114014853B CN202111595341.4A CN202111595341A CN114014853B CN 114014853 B CN114014853 B CN 114014853B CN 202111595341 A CN202111595341 A CN 202111595341A CN 114014853 B CN114014853 B CN 114014853B
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crystal
curcumin
berberine
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CN114014853A (en
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广兵
占伟
阳泰
董韧涵
刘进
覃传军
黄胜
谢建
彭向阳
赖永新
许庆
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Chengdu Benuo Kecheng Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Organic Chemistry (AREA)
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Abstract

The invention belongs to the field of pharmacy, and particularly relates to curcumin berberine eutectic crystal and a medicinal composition thereof. The eutectic of the invention not only improves water solubility and moisture absorption stability, but also has obvious inhibition activity on human colon cancer cells HT-29, and simultaneously has obvious treatment effect on a mouse imiquiz Mo Teyin psoriasis model, and has good application prospect in the aspects of colon cancer and psoriasis treatment.

Description

Curcumin berberine eutectic crystal and pharmaceutical composition thereof
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to curcumin berberine eutectic crystal and a medicinal composition thereof.
Background
Berberine, also called berberine, is a quaternary ammonium alkaloid separated from rhizoma Coptidis, and is a main effective component of rhizoma Coptidis for resisting bacteria. Yellow needle-like crystals, bitter taste. The distribution in the plant kingdom is broad, and berberine is found in about 4 families, 10 genera. The salt of berberine hydrochloride, also called berberine hydrochloride, is isoquinoline alkaloid, is used as a heat-clearing and detoxicating and antibacterial medicament for clinical application, and is commonly used for treating bacillary dysentery, acute gastroenteritis, chronic cholecystitis, conjunctivitis, suppurative otitis media and other diseases, and has remarkable curative effects. Berberine hydrochloride is also found in many plants of the genus 10 of the family 4 such as berberidaceae.
Curcumin is a natural compound with good anti-inflammatory and anticancer properties. Curcumin is a diketone compound extracted from rhizome of some plants in Zingiberaceae and Araceae, and has chemical formula of C 21 H 20 O 6 . Wherein, the turmeric contains about 3% -6% of curcumin, which is a rare pigment with diketone structure in the plant kingdom. Curcumin is orange yellow crystal powder, has slightly bitter taste, is insoluble in water, and is mainly used for coloring sausage products, cans, marinated products and other products in food production. Curcumin has the effects of reducing blood lipid, resisting tumor, resisting inflammation, promoting bile flow, resisting oxidation, and the like, and scientists find that curcumin helps to treat drug-resistant tuberculosis.
Curcumin and berberine are natural product components with more research reports, chunying, inhibition effect research of curcumin and berberine on bile acid induced human colon cancer cell proliferation [ D ], tianjin: the university of Tianjin medical science, 2004 discloses that curcumin and berberine inhibit colon cancer cells in a concentration and time dependent mode, and is hopeful to develop into a new anticancer drug, but curcumin has poor water solubility and low oral bioavailability; berberine sold in the market has certain hygroscopicity, less definite crystal water proportion and the like, and the defects cause the effect of the two medicaments to be influenced when the two medicaments are used together.
Disclosure of Invention
In view of the shortcomings of the prior art, the present invention provides a co-crystal which is a pharmaceutical co-crystal of berberine, or a pharmaceutically acceptable salt thereof, or a derivative thereof, and curcumin or a derivative thereof; the molar ratio of the berberine or the pharmaceutically acceptable salt or the derivative thereof to the curcumin or the derivative thereof is 1-5: 1.
further, it is a pharmaceutical co-crystal of berberine hydrochloride and curcumin.
Further, the X-ray powder diffraction pattern of the co-crystal is at diffraction anglesThe angle represents at least 6.85+ -0.2 °, 8.86+ -0.2 °, 9.10+ -0.2 °, 17.20+ -0.2 °, 23.25+ -0.2 °,24.69 + -0.2 °, 25.55+ -0.2 °, 26.30+ -0.2 ° with characteristic peaks.
Further, the X-ray powder diffraction pattern of the co-crystal is at diffraction anglesThe angle is at least 6.85+ -0.2 °, 8.86+ -0.2 °, 9.10+ -0.2 °, 13.76+ -0.2 °, 17.20+ -0.2 °, 18.13+ -0.2 °, 19.41+ -0.2 °, 21.14+ -0.2 °, 23.25+ -0.2 °, 23.66+ -0.2 °,24.69 + -0.2 °, 25.55+ -0.2 °, 26.30+ -0.2 °, 27.04+ -0.2 °, 27.43+ -0.2 °,29.08 + -0.2 °.
Further, the X-ray powder diffraction pattern of the co-crystal is at diffraction anglesThe angles represent characteristic peaks at least at 6.85.+ -. 0.2 °, 7.92.+ -. 0.2 °, 8.86.+ -. 0.2 °, 9.10.+ -. 0.2 °, 12.24.+ -. 0.2 °, 13.76.+ -. 0.2 °, 14.11.+ -. 0.2 °, 14.51.+ -. 0.2 °, 17.20.+ -. 0.2 °, 18.13.+ -. 0.2 °, 18.57.+ -. 0.2 °, 19.44.+ -. 0.2 °, 21.14.+ -. 0.2 °, 23.25.+ -. 0.2 °, 23.66.+ -. 0.2 °, 24.69..2 °, 25.55.+ -. 0.2 °, 26.30.+ -. 0.2 °, 27.04.+ -. 0.2 °, 27.43.+ -. 0.2 °, 29.08.+ -. 0.2 °.
Further, the molecular molar ratio of the curcumin to the berberine hydrochloride is 1:1.
The invention also provides a preparation method of the eutectic, which comprises the following steps:
1) Mixing curcumin and berberine hydrochloride, adding solvent, stirring, and filtering to obtain solid;
2) Taking solid, adding solvent for recrystallization to obtain eutectic.
Further, the solvent is an alcohol or an aqueous solution containing an alcohol, preferably 95 ethanol.
The invention also provides application of the co-crystal in preparing a medicament for treating cancer.
Further, the medicament is a medicament for treating colon cancer.
The invention also provides application of the co-crystal in preparing a medicament for preventing and/or treating skin diseases.
Further, the medicament is a medicament for preventing and/or treating psoriasis.
The invention finally provides a pharmaceutical composition for preventing and/or treating cancer or psoriasis, which is a preparation prepared by taking the eutectic as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the preparation is a tablet, capsule, suspension, injection, ointment or patch.
The curcumin berberine hydrochloride eutectic has good water solubility and moisture absorption stability, is obviously superior to berberine hydrochloride, curcumin and a composition thereof in inhibiting human colon cancer cells HT-29, has obvious treatment effect on a mouse imiquiz Mo Teyin psoriasis model, and has wide application prospect in colon cancer and psoriasis treatment.
Drug co-crystals are new crystalline solids formed by the forces of two or more drug molecules through hydrogen bonding, etc. Co-crystal studies have shown that not all drug molecules can form co-crystals, and that not all co-crystals have suitable patentability. In addition, it is also difficult to predict whether the co-crystal formed between the drug molecules, and the mechanical mixture between the drug molecules have non-obvious physicochemical properties, and whether there is a non-obvious biological effect. Thus, developing a co-crystal that is drug-resistant and has unexpected biological effects remains a major challenge.
However, the inventor finds that the berberine hydrochloride and the curcumin not only can form a eutectic, but also can greatly change the physical and chemical properties of the eutectic relative to a mechanical mixture, such as obviously improving the solubility, reducing the hygroscopicity and unexpectedly improving the pharmacological activity of the components.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a graph showing the weight change of each group of mice in test example 4.
Fig. 2 is a graph showing the overall score of skin lesions for each group of mice in test example 4.
FIG. 3 is a graph showing the scale scores of mice in each group of test example 4.
FIG. 4 is a graph showing the skin thickening scores of each group of mice in test example 4.
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products. The preparation process of the tablet, capsule, suspension, injection, ointment and patch prepared from the eutectic of the invention is mature, and the preparation process is finished by referring to the conventional method in the prior art.
EXAMPLE 1 preparation of Co-crystals I-1 according to the invention
10.0 g of berberine hydrochloride hydrate and 9.9 g of curcumin are taken in a 250 ml single-mouth bottle, mixed with 100 ml of 95 ethanol, stirred at room temperature overnight and filtered to obtain yellow solid. Recrystallizing the solid with 95 ethanol to obtain yellow crystals, namely the eutectic I-1; the structural characteristics of the eutectic I-1 are as follows:
1 HNMR(400MHz，DMSO-d6)δ：9.89(s，1H)，9.69(d，J＝2.4Hz，2H)，8.94(s，1H)，8.20(d，J＝9.2Hz，1H)，8.00(d，J＝9.1Hz，1H)，7.80(s，1H)，7.55(s，1H)，7.52(s，1H)，7.32(d，J＝2.0Hz，2H)，7.14(dd，J＝8.3，1.9Hz，2H)，7.09(s，1H)，6.83(d，J＝8.1Hz，2H)，6.77(s，1H)，6.73(s，1H)，6.17(s，2H)，6.05(s，1H)，4.93(t，J＝6.4Hz，2H)，4.09(s，3H)，4.07(s，3H)，3.83(s，6H)，3.20(t，J＝6.3Hz，2H)。
powder X-ray diffraction pattern at diffraction anglesThe angle is expressed in: peaks at 6.85, 7.92, 8.86, 9.10, 12.24, 13.76, 14.11, 14.51, 17.20, 18.13, 18.57, 19.44, 21.14, 23.25, 23.66, 24.69, 25.55, 26.30, 27.04, 27.43, 29.08, 30.15 with an error of + -0.2 deg..
EXAMPLE 2 preparation of pharmaceutical tablet composition of Co-crystal I-1 of the present invention
The formula comprises the following components: co-crystal I-1 1 weight parts, lactose 0.1-0.3 weight parts, starch 0.4-0.2 weight parts, sodium carboxymethyl starch 0.008-0.014 weight parts, proper amount of povidone K30, magnesium stearate 0.01-0.05 weight parts and 40% ethanol 0.5 weight parts prepared in example 1;
preparing into tablets according to the proportion, and obtaining the co-crystal I-1 medicinal tablet of the invention, wherein each tablet contains co-crystal I-150-1500 mg.
EXAMPLE 3 preparation of pharmaceutical cream composition of Co-crystal I-1 of the invention
The formula comprises the following components: co-crystals I-1 1 parts by weight prepared in example 1, 99 parts by weight of an oil-in-water type cream base;
weighing the raw materials according to the proportion, and stirring the eutectic I-1 and the cream matrix for 20 minutes at 80 ℃ until the mixture is uniform, wherein the eutectic content in the cream is 1%.
The beneficial effects of the invention are further illustrated by the following experimental examples:
experimental example 1 Water solubility test of Co-crystals I-1 of the present invention
3 parts of purified water were taken 1 ml each, and an appropriate amount of co-crystal I-1 prepared in example 1 of the present invention and curcumin were added at room temperature each until there were significant solid particles insoluble in purified water. The solution was allowed to stand at room temperature for 10 minutes, and the supernatants were tested and compared for solubility. Solubility records are as follows in table 1:
TABLE 1 Co-crystal I-1 Water solubility of the invention
Compounds of formula (I) Solubility (g/100 g)
I-1 0.1
Curcumin <0.01
The results show that the co-crystal of the invention significantly improves the water solubility, which is more than 10 times that of curcumin.
Experimental example 2 hygroscopicity test of Co-crystal I-1 of the present invention
Taking a proper amount of the eutectic I-1 and a proper amount of commercial berberine hydrochloride dihydrate, placing the mixture under the condition of 40 ℃/75% RH, and detecting the change of moisture contained in the mixture after one week, wherein the results are recorded in the following table 2:
TABLE 2 Co-crystal hygroscopicity of the invention
Compounds of formula (I) Moisture (%)
I-1 0.6
Berberine hydrochloride dihydrate 10
Experimental results show that the water content of the commercial berberine hydrochloride dihydrate is increased by 10% when the commercial berberine hydrochloride dihydrate is placed for one week at 40 ℃/75%, and the water content of the eutectic is increased by 0.6%, so that the eutectic has higher stability.
Experimental example 3 test of inhibitory Activity of Co-crystal I-1 of the present invention on proliferation of colorectal cancer HT29 cells
The human colon cancer cells HT-29 in the logarithmic growth phase are respectively collected, counted, the cells are resuspended by using a complete culture medium, the cell concentration is adjusted to 20 cells/mu L, the human colon cancer cell suspension is obtained, a 96-well plate is inoculated, and 100 mu L of cell suspension is added to each well. Cells were incubated at 37℃with 100% relative humidity, 5% CO 2 After 24 hours of incubation in the incubator, the test compounds were diluted with medium to the corresponding working concentrations set and added to the cells at 25 μl/well. The final concentration of the compound was varied from 0nM to 400nM, 4-fold gradient dilution, for a total of 10 concentration points. After addition of the compounds to be treated, the cells were subjected to 37℃with 100% relative humidity and 5% CO 2 Incubate in incubator for 72 hours. The medium was aspirated and 100. Mu.L of fresh medium containing 10% CCK-8 was added to each well, incubated in an incubator at 37℃for 2-4 hours, absorbance at 450nm was measured on SpectraMaxM5 Microplate Reader with gentle shaking, absorbance at 650nm was used as a reference, and the inhibitory activity IC of the test compound against human colon cancer cells HT-29 was measured 50 The results are shown in Table 3:
TABLE 3 inhibitory Activity of Co-crystals I-1 of the invention on human colon cancer cells HT-29
Note that: the berberine hydrochloride and curcumin in the combined group are mixed in an equimolar ratio, namely, 1 mol of berberine hydrochloride and 1 mol of curcumin are mixed, and the mixture is regarded as 1 mol of mixture.
Experimental results show that the inhibition effect of the eutectic I-1 on human colon cancer cells HT-29 is obvious compared with berberine hydrochloride and curcumin and the composition thereof, and the compound has good inhibition effect on colon cancer cells and can be used for preventing and treating colon cancer.
Experimental example 4 therapeutic Effect of Co-crystal I-1 of the invention on mouse imiquiz Mo Teyin psoriasis model
BALB/c female mice at 5-6 weeks, after one week of adaptive feeding, were randomly divided into 6 groups, which were blank group, model group, co-crystal I-1 group (co-crystal prepared in example 1), oil-in-water cream matrix group, positive control budesonide group, curcumin group, respectively; the blank group was shaved only, and the remaining groups were given 62.5mg of 5% imiquimod daily in the morning, except that the model group was not given other treatments, and the co-crystal I-1 group was given 50mg of 1% co-crystal I-1 cream daily in the afternoon, the matrix group was given 50mg of an oil-in-water cream matrix, the budesonide group was given 60mg of 0.05% budesonide cream, and the curcumin group was given 50mg of 0.5% curcumin cream for a total of 7 days. The mice were evaluated for body weight, skin loss, scale, and degree of thickening over 7 days, and the results were as described in fig. 1-4.
Experimental results show that compared with the cream matrix, the budesonide group and the curcumin group, the co-crystal I-1 has better treatment effect on the mouse imiquiz Mo Teyin psoriasis model, wherein the overall skin damage score, the scale score and the skin thickening score are obviously lower than those of the cream matrix, the positive compounds of budesonide and curcumin, so that the co-crystal has obvious effect on treating psoriasis.
In conclusion, the eutectic of the invention not only improves water solubility and moisture absorption stability, but also has obvious inhibitory activity on human colon cancer cells HT-29, and has obvious therapeutic effect on mice imiquidone Mo Teyin psoriasis model, and has wide application prospect in colon cancer and psoriasis treatment.

Claims (14)

1. A co-crystal, characterized in that: the berberine is a pharmaceutical co-crystal of berberine or pharmaceutically acceptable salt thereof and curcumin; the molar ratio of the berberine or the pharmaceutically acceptable salt thereof to the curcumin is 1:1.
2. the co-crystal of claim 1, wherein: it is a pharmaceutical co-crystal of berberine hydrochloride and curcumin.
3. A co-crystal as claimed in claim 2, wherein: the X-ray powder diffraction pattern of the co-crystal has characteristic peaks at diffraction angles of 2, namely 6.85+/-0.2 degrees, 8.86+/-0.2 degrees, 9.10+/-0.2 degrees, 17.20+/-0.2 degrees, 23.25+/-0.2 degrees, 24.69 +/-0.2 degrees, 25.55+/-0.2 degrees and 26.30+/-0.2 degrees.
4. A co-crystal as claimed in claim 2, wherein: the X-ray powder diffraction pattern of the co-crystal is expressed as diffraction angle 2, and has characteristic peaks at 6.85+/-0.2 degrees, 8.86+/-0.2 degrees, 9.10+/-0.2 degrees, 13.76+/-0.2 degrees, 17.20+/-0.2 degrees, 18.13+/-0.2 degrees, 19.41+/-0.2 degrees, 21.14+/-0.2 degrees, 23.25+/-0.2 degrees, 23.66+/-0.2 degrees, 24.69 +/-0.2 degrees, 25.55+/-0.2 degrees, 26.30+/-0.2 degrees, 27.04+/-0.2 degrees, 27.43+/-0.2 degrees and 29.08 +/-0.2 degrees.
5. A co-crystal as claimed in claim 2, wherein: the X-ray powder diffraction pattern of the co-crystal has characteristic peaks at diffraction angles of 2-up to 6.85+ -0.2 °, 7.92+ -0.2 °, 8.86+ -0.2 °, 9.10+ -0.2 °, 12.24+ -0.2 °, 13.76+ -0.2 °, 14.11+ -0.2 °, 14.51+ -0.2 °, 17.20+ -0.2 °, 18.13+ -0.2 °, 18.57+ -0.2 °, 19.44+ -0.2 °, 21.14+ -0.2 °, 23.25+ -0.2 °, 23.66+ -0.2 °,24.69 + -0.2 °, 25.55+ -0.2 °, 26.30+ -0.2 °, 27.04+ -0.2 °, 27.43+ -0.2 °,29.08 + -0.2 °, and 30.15+ -0.2 °.
6. A method of preparing the co-crystal of claim 1, comprising:
1) Mixing curcumin and berberine hydrochloride, adding solvent, stirring, and filtering to obtain solid;
2) Taking solid, adding solvent for recrystallization to obtain eutectic.
7. The method of manufacturing according to claim 6, wherein: the solvent is alcohol or alcohol-containing water solution.
8. The method of manufacturing according to claim 6, wherein: the solvent is 95 ethanol.
9. Use of the co-crystal of claims 1-5 in the manufacture of a medicament for the treatment of cancer.
10. The use according to claim 9, characterized in that: the medicine is used for treating colon cancer.
11. Use of the co-crystal according to claims 1-5 for the preparation of a medicament for the prevention and/or treatment of dermatological disorders.
12. The use according to claim 10, characterized in that: the medicament is a medicament for preventing and/or treating psoriasis.
13. A pharmaceutical composition for preventing and/or treating cancer or psoriasis, which is a preparation prepared by adding pharmaceutically acceptable auxiliary materials into the co-crystal of claim 1 as an active ingredient.
14. The pharmaceutical composition of claim 13, wherein: the preparation is tablet, capsule, suspension, injection, ointment or patch.
CN202111595341.4A 2021-12-23 2021-12-23 Curcumin berberine eutectic crystal and pharmaceutical composition thereof Active CN114014853B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566317A (en) * 2016-01-13 2016-05-11 北京宜生堂医药科技研究有限公司 Compound and preparation method thereof
CN111888485A (en) * 2020-08-13 2020-11-06 中国药科大学 Co-crystal-like-alkaline protein drug compound and preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566317A (en) * 2016-01-13 2016-05-11 北京宜生堂医药科技研究有限公司 Compound and preparation method thereof
CN111888485A (en) * 2020-08-13 2020-11-06 中国药科大学 Co-crystal-like-alkaline protein drug compound and preparation method and application thereof

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