CN115120589B - Berberine-bicyclic alcohol co-amorphous complex, and preparation method and application thereof - Google Patents
Berberine-bicyclic alcohol co-amorphous complex, and preparation method and application thereof Download PDFInfo
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- CN115120589B CN115120589B CN202210767601.XA CN202210767601A CN115120589B CN 115120589 B CN115120589 B CN 115120589B CN 202210767601 A CN202210767601 A CN 202210767601A CN 115120589 B CN115120589 B CN 115120589B
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- berberine
- bicyclo
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- ethanol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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- A61P3/06—Antihyperlipidemics
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention relates to a berberine-bicyclo alcohol co-amorphous compound, a preparation method and application thereof, wherein the dissolution behavior of two drugs in the berberine-bicyclo alcohol co-amorphous compound is consistent; the preparation method of the co-amorphous complex comprises the following steps of (1) mixing berberine and dicyclo alcohol according to a molar ratio of 6:1-36; (2) The berberine-bicyclo alcohol co-amorphous complex is prepared by using a grinding method and a reduced pressure rotary evaporation method.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a berberine-bicyclo-ethanol co-amorphous complex, a preparation method and application thereof.
Background
Berberine (molecular formula: C) 20 H 18 NO 4 Molecular weight: 336.37 Is a quaternary ammonium alkaloid separated from rhizoma coptidis, and is a main effective component of rhizoma coptidis antibacterial. The clinical application is mainly non-prescription medicine for preventing and treating diarrhea. The berberine has broad antibacterial spectrum, and has antibacterial effect on various gram-positive and gram-negative bacteria in vitro, such as dysentery bacillus, tubercle bacillus, pneumococcus, typhoid bacillus, diphtheria bacillus, etc., wherein the berberine has strongest effect on dysentery bacillus, and almost no drug resistance and side effect.
In recent years, with the continuous and deep research, the application range of the compound preparation has been newly developed, and the compound preparation specifically comprises the following steps:
1. the berberine has remarkable effects in regulating blood sugar and lipid metabolism, resisting inflammation, reducing blood uric acid, resisting rheumatoid arthritis, inhibiting tumor cell proliferation, resisting virus, etc. Several basic and clinical evidence confirm that berberine is involved in glucose metabolism through a variety of mechanisms. Such as retinol binding protein-4 (retinol binding protein-4, RBP-4) and glucose transport factor-4 (glucose transporter 4, GLUT-4) mechanisms; increase expression of hepatocyte nuclear factor-4α (hepatocyte nuclear factor 4α, HNF-4α) and glucokinase activity; reverse phosphorylation of insulin receptor-1 Ser307 (insulin receptor 1Ser307, ISR-1Ser 307); up-regulating ISR expression, etc.
2. The lipid lowering function of berberine, the molecular mechanism involves up-regulating the level of low density lipoprotein receptor (low-density lipoprotein receptor, LDLR) mRNA, inhibiting the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (recombiant 3-hydroxy-3-methylglutaryl coenzyme Areductase, HMGCR) gene, increasing the expression of liver apolipoprotein E (Apo E) mRNA, activating the adenylate activator protein kinase (AMP-activated protein kinase, AMPK) pathway, cholesterol regulatory element binding protein-1C (sterol-regulatory element binding proteins C, SREBP-1C) and CCAAT enhancer binding protein-alpha (CCAAT enhancer binding protein alpha, C/EBP-alpha), oxidizing the enzyme proliferator-activated receptor-gamma (peroxisome proliferators-activated receptors gamma, PPAR-gamma), decreasing the transcriptional level of the subtilisin converting enzyme 9 (proprotein convertase subtilisin/kexin type 9, PCSK9) gene, etc 1,2 。
3. Berberine is also a promising candidate for multiple targets in the treatment of cardiovascular diseases. The cardiovascular pharmacological actions of berberine mainly comprise antiarrhythmic, vasodilating and lowering blood pressure, regulating lipid metabolism and antiatherosclerotic, antiplatelet and antithrombotic, antianaeus and ischemia protecting, antiangiogenic and anti-inflammatory and tumor angiogenesis inhibiting effects. Target cells for action include myocardial cells, vascular endothelial cells, vascular smooth muscleCells, platelets, blood mononuclear macrophages, and the like. Specific targets are mainly Ca2+ channel, K+ channel, M receptor, adenosine receptor, cholinesterase and angiotensin converting enzyme (angiotensin converting enzyme, ACE), etc 3 。
The berberine is yellow needle crystal, has extremely bitter taste, poor oral absorption and oral bioavailability of less than 5%. Improving bioavailability and taste is the key to increase the clinical applicability.
Bicyclic alcohols (formula C) 19 H 18 O 9 Molecular weight: 390.34 Is an artificially synthesized I-type anti-inflammatory liver-protecting drug which is independently researched and developed by China and belongs to biphenyl structure derivatives. Can reduce transaminase increase caused by chronic hepatitis, effectively scavenge free radicals in cells to maintain structural integrity of biological membrane, and protect liver cell membrane and mitochondria 4 Has remarkable liver protecting effect and a certain anti-hepatitis virus activity 5,6 The traditional Chinese medicine composition is mainly used for treating viral hepatitis and other chronic liver diseases clinically, and has high safety.
The liver protection effect of the bicyclic alcohol mainly comprises two aspects, namely anti-inflammatory and anti-oxidative stress.
First, liver function damage is often accompanied by various degrees of inflammatory response, and bicyclic alcohols inhibit the expression and activity of various inflammatory mediators, including nuclear transcription factor- κB (nuclear factor-kappa B, NF- κB), interleukin-1β (interleukin-1β, IL-1β), interleukin-18 (interleukin-18, IL-18), tumor necrosis factor- α (tumor necrosis factor- α, TNF- α), transforming growth factor- β1 (transforming growth factor- β1, TGF- β1), and inducible nitric oxide synthase (inducible nitric oxide synthase, iNOS), etc 7-10 。
Second, oxidative stress is also the basis for causing liver disease. The scavenging ability of the organism to reactive oxygen species (reactive oxygen species, ROS) in pathological conditions is reduced, and excessive free radical accumulation can lead to oxidative stressBy excitation or oxygen stress, lipid peroxidation, intracellular protein and enzyme denaturation, DNA oxidative damage, etc. are generated in phospholipid in biological membrane 11 . The bicyclic alcohol can reduce the generation of ROS and Nitric Oxide (NO), thereby playing the pharmacological action of protecting liver.
Although berberine and bicyclo-ethanol have many similar pharmacological activities, and research shows that the two medicines are used together to have a synergistic effect, the two medicines have low bioavailability and the difference of release and absorption characteristics obviously limits the clinical use of the two medicines, so that the method for improving the bioavailability of berberine and bicyclo-ethanol and exerting the synergistic effect of the berberine and bicyclo-ethanol has great significance in clinic.
Co-amorphous drugs are monophasic amorphous binary systems with a single glass transition temperature formed by the combination of an active drug ingredient with other small molecule solid substances (drugs or excipients). It is used as a new solid form of medicine, can improve the physical and chemical properties of medicine such as solubility, dissolution rate, stability and bioavailability, and is a new way for medicine research and development 12 。
Based on this, the present invention has been proposed.
[ reference ]
1. Berberine regulates the metabolic mechanism of glycolipid research progress Liu Xiaoyan, liu Jian, gao Yu journal of the elderly in China 2016, 36 (8): 4117-4119.
2. Clinical research progress of berberine Wang Xiaogong, medical front, 2013, 27:380-381.
3. Berberine cardiovascular pharmacological research brief evaluation Wang Ruiguo, fang Taihui conference on national academy of Chinese medicine, 2007.
4. Antiviral and hepatocyte protective effects of Bicyclol and its mechanism of action Liu Gengtao, J.China New medicine 2001,10 (5): 325-327.
5. New developments in pharmacological mechanism of liver protection and anti-inflammatory with bicyclic alcohol are Wang Yuming, li Yan J.GI and liver diseases 2010,19 (7): 674-677.
6. Bicyclol clinical application expert consensus 2020 edition Xie, J. Le Cheng, J.Chi.In.Infection, 2020,14 (3): 177-185.
7. The effect of bicyclic alcohol on liver gene expression profile of mice with liver injury caused by Canavalia gladiata is described in Ind. Men, guo Jiang, li, et al, pharmaceutical journal 2008,43 (6): 596-600.
8.Bicyclol attenuates liver inflammation induced by infection of hepatitis c virus via repressing ros-mediated activation of MAPK/NF-κB signaling pathway.Li H,Li J R,Huang MH,et al.Frontiers in Pharmacology,2018,9,1438.
9. Effects of Bicyclol on inflammatory factors, gastrointestinal function and liver function in liver cirrhosis model rats Dong Li, wang Jian, gu Chenhong, et al medical clinical research 2017,34 (2): 234-236.
10.Bicyclol promotes toll-like 2receptor recruiting inosine 5′-monophosphate dehydrogenase II to exert its anti-inflammatory effect.Zhang Y W,Guo Y S,Bao X Q,et al.Journal of Asian Natural Products Research,2016,18(5):475-485.
11. Oxidative stress and liver protection Liu Yafeng journal of gastroenterology and liver science 2011, 20 (7): 594-597.
12. Co-amorphous drugs-novel single phase amorphous binary systems. Guo Huihui, miao Nana, li Tengfei, et al chemical evolution. 2014,26 (2): 478-486.
Disclosure of Invention
The invention firstly relates to a preparation method of berberine-bicyclo alcohol co-amorphous complex, which is characterized by comprising the following steps,
(1) The berberine and the bicyclo-ethanol are mixed according to the mol ratio of 6:1-36, preferably, the mol ratio of 4:1-16, more preferably, the mol ratio of 2:1-4, most preferably, the mol ratio of 2:1 to 2;
(2) The berberine-bicyclo alcohol co-amorphous complex is prepared by using a grinding method and a reduced pressure rotary evaporation method. The grinding method comprises the following steps:
using a high-speed ball mill, and performing dry grinding in 45% RH at room temperature, wherein the grinding frequency is 20-30Hz, the dry grinding time is 20-60 minutes, and the grinding is performed until the particle size is 8 mu m;
the step parameters of the decompression rotary evaporation method are as follows:
dissolving berberine and bicyclo-ethanol in organic solvent to obtain clear solution, removing organic solvent by rotary evaporation under reduced pressure at 35-60deg.C, and vacuum drying; the organic solvent is methanol, ethanol, isopropanol or a mixed solvent thereof, preferably ethanol; the temperature of the reduced pressure rotary evaporation is preferably 45-55 ℃;
the berberine is berberine or pharmaceutically acceptable salt thereof; the pharmaceutically acceptable salt is a salt formed by berberine and inorganic acid or organic acid, wherein the inorganic acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid; the organic acid includes, but is not limited to, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, phthalic acid, or p-toluenesulfonic acid; preferably, the berberine is berberine hydrochloride.
The dicyclo alcohol compound is dicyclo alcohol or a derivative thereof; the bicyclo alcohol derivative is bicyclo alcohol and the derivative metabolized into bicyclo alcohol in vivo, and the bicyclo alcohol derivative comprises, but is not limited to, bifendate, bicyclo alcohol amino acid ester, bicyclo alcohol glycoside compound, bicyclo alcohol-glutathione conjugate and bicyclo alcohol-leucinamide; preferably, the bicyclo-ethanol has the structural formula:
the invention also relates to the berberine-bicyclo alcohol co-amorphous complex prepared by the method; the dissolution behavior of the two drugs in the berberine-bicyclo alcohol co-amorphous complex is consistent; specifically, the berberine has a dissolution rate of more than 70% in 6 hours and the bicyclol has a dissolution rate of more than 40% in 6 hours; the dissolution rate is measured by a pharmacopoeia method.
The X-ray diffraction pattern of the berberine-bicyclo alcohol co-amorphous compound has no characteristic diffraction peaks of berberine and bicyclo alcohol;
the infrared spectrum properties of the berberine-bicyclo alcohol co-amorphous compound after being pressed by KBr are as follows:
(1) At 3600-3600cm -1 No characteristic absorption peak of berberine and bicyclo alcohol;
(2) At 1703.0cm -1 The c=o characteristic peak at the point disappeared;
(3) In 3065, 3014, 2942, 2844, 1770, 1695, 1638, 1601, 1567, 1506, 1480, 1458, 1385, 1361, 1340, 1272, 1233, 1211, 1181, 1162, 1127, 1098, 1062, 1034, 994, 972, 935, 910, 859, 819, 788, 763, 739, 729, 647, 627, 588, 567, 535, 503, 461, 438, 424cm -1 There is an infrared spectrum characteristic peak.
Wherein the allowable deviation of the characteristic peak of the infrared spectrum is +/-2 cm -1 。
The berberine-bicyclo alcohol co-amorphous complex is determined by a differential scanning calorimetric analysis method, and has no characteristic melting peak of berberine and bicyclo alcohol.
The invention also relates to a medicine or a medicine composition containing the berberine-bicyclo alcohol co-amorphous complex, which contains the berberine-bicyclo alcohol co-amorphous complex with a therapeutically effective dose and a pharmaceutically acceptable excipient.
The dosage form of the medicament or the pharmaceutical composition can be a liquid dosage form, a solid dosage form or a semisolid dosage form;
the liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and multiple emulsions), suspensions, injections (including water injections, powder injections and infusion solutions), and the like;
the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays;
the semisolid dosage form may be an ointment, gel, paste, or the like.
The invention also relates to application of the berberine-bicyclo alcohol co-amorphous complex in preparing medicines for preventing or treating metabolic diseases.
The metabolic diseases comprise blood lipid metabolic disorder, obesity and fatty liver disease;
the blood lipid metabolic disorder comprises high-low density lipoprotein-cholesterol, high total cholesterol, high triglyceride or low-high density lipoprotein-cholesterol;
the obesity is weight gain and body fat rate increase;
the fatty liver disease is liver tissue Triglyceride (TG) increase, liver index increase, liver lipid rate increase, serum glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) increase, and liver inflammatory factor increase.
The beneficial effects of the invention include:
1. the berberine hydrochloride and the bicyclo-ethanol are prepared into the berberine-bicyclo-ethanol co-amorphous compound by a non-chemical synthesis method, the amorphous compound can obviously improve the dissolution rate of the berberine and the bicyclo-ethanol, realize the synchronous release of the two medicines and increase the synergistic pharmacological effect of the two medicines in preventing or treating metabolic related diseases;
2. in the high-fat diet-induced golden-yellow mice model of hyperlipidemia and fatty liver disease, the co-amorphous substance can reduce weight gain, blood lipid level, liver function and triglyceride content of model animals, and in addition, the levels of glutamic pyruvic transaminase (ALT) and glutamic oxaloacetic transaminase (AST) of the livers of the model animals are obviously reduced (P is less than 0.05).
Drawings
FIG. 1, DSC of berberine.
FIG. 2 shows DSC of bicyclic alcohol.
FIG. 3 DSC of physical mixtures of berberine and bicyclo-alcohols.
FIG. 4 DSC of berberine-bicyclo-ethanol co-amorphous.
FIG. 5, powder X-ray diffraction pattern of berberine.
FIG. 6, powder X-ray diffraction pattern of bicyclic alcohol.
FIG. 7 powder X-ray diffraction pattern of berberine-bicyclo-ethanol co-amorphous material.
FIG. 8, infrared spectrum of berberine.
FIG. 9, IR spectrum of dicyclo alcohol.
FIG. 10, infrared spectra of physical mixtures of berberine and bicyclo-alcohols.
FIG. 11, infrared spectra of berberine-bicyclo-ethanol co-amorphous material.
FIG. 12, cumulative dissolution profiles of berberine and bicyclo-ethanol in water for physical mixtures and co-amorphous forms.
FIG. 13, physical mixture and co-amorphous, drug time profile of berberine in plasma of C57 mice given by gavage.
Fig. 14, physical mixture and co-amorphous, time profile of the administration of the bicyclic alcohol in plasma by gavage to C57 mice.
Figure 15, comparison of body weight changes in experimental animals of different dosing groups.
Figure 16, epididymal fat weight comparison of experimental animals of different dosing groups.
Fig. 17, comparison of liver triglyceride levels in experimental animals of different dosing groups.
Figure 18, comparison of total cholesterol levels in plasma of experimental animals from different dosing groups.
FIG. 19 comparison of the plasma low density lipoprotein-cholesterol levels of experimental animals in different dosing groups.
FIG. 20, comparison of triglyceride levels in plasma of experimental animals of different dosing groups.
FIG. 21 comparison of plasma glutamic pyruvic transaminase levels of experimental animals of different administration groups
FIG. 22 comparison of plasma glutamic-oxaloacetic transaminase levels of experimental animals of different dosing groups.
FIG. 23 shows the results of oil red staining of liver tissue sections of experimental animals.
FIG. 24 shows the results of HE staining of liver tissue sections of experimental animals.
Detailed Description
Material and apparatus
The berberine hydrochloride is purchased from Nanjing Zelang biological Co., ltd, and the purity is more than or equal to 97%; the berberine used in the following examples is berberine hydrochloride;
bicyclic alcohols were purchased from Shanghai Qiam analytical technology Co., ltd, chemically pure, purity 98%;
KBr was purchased from Shanghai Ala Biochemical technologies Co., ltd., and was spectrally pure with a purity of 99%;
c57 mice, syrian golden yellow mice were all purchased from Beijing Vitolihua laboratory animal technologies Co., ltd;
high fat diet feed (feed number H10141) was purchased from the biological sciences company of versham, beijing.
EXAMPLE 1 preparation method 1 of berberine-bicyclic alcohol Co-amorphous Complex
The berberine and the bicyclo-ethanol are weighed according to the mol ratio of 1:0.5, placed in a high-speed ball mill at room temperature (45%RH), and are ground for 20 minutes at 20Hz, and then are ground to the particle size of 8 mu m.
EXAMPLE 2 preparation method 2 of berberine-bicyclic alcohol Co-amorphous Complex
The berberine and the bicyclol are weighed according to the mol ratio of 1:1, placed in a high-speed ball mill at room temperature (45%RH), and subjected to dry grinding for 60 minutes, wherein the grinding frequency is 30 Hz.
EXAMPLE 3 preparation method 3 of berberine-bicyclic alcohol Co-amorphous Complex
The berberine and the bicyclol are weighed according to the mol ratio of 1:1, dissolved in absolute ethanol to obtain clear solution, the solvent is removed by rotary evaporation under reduced pressure at 55 ℃, and the solution is dried in vacuum.
EXAMPLE 4 DSC determination of berberine-Bicyclol Co-amorphous Complex
The berberine-bicyclo alcohol co-amorphous complex prepared in example 3 was taken, 2-5mg of the sample was precisely weighed and placed in an aluminum crucible, while an empty crucible of the same type was used as a reference. The shielding gas is nitrogen with the purity of 99 percent and the flow rate of 60ml/min. The sample was scanned at a rate of 10 ℃/min over a scan range of 25-280 ℃.
FIGS. 1-4 are DSC spectra of berberine, bicyclo-ethanol, physical mixture of berberine and bicyclo-ethanol, and co-amorphous of berberine and bicyclo-ethanol.
As is shown in the figures,
(1) The berberine has two endothermic peaks at 92.2 ℃ and 195.8 ℃ respectively;
(2) The bicyclic alcohol had an endothermic peak at 139.6 ℃;
(3) The physical mixture of berberine and bicyclo-ethanol shows the addition of the endothermic peaks of the two medicines;
(4) The berberine-bicyclo alcohol co-amorphous material has no obvious endothermic peak.
EXAMPLE 5 determination of the Properties of the berberine-Bicyclol Co-amorphous Complex by X-ray powder diffraction
An appropriate amount of each sample was taken out in an aluminum sample cell to prepare an analytical sample, which was then subjected to X-ray powder diffraction. Measurement conditions: cuKa targets as the x-ray sources; voltage: 40kV, current: 35mA, scan range is 3 <2 theta <40 deg.. FIGS. 5-7 are X-ray powder diffraction patterns of berberine, bicyclo-ethanol, and berberine-bicyclo-ethanol co-amorphous material (example 3).
As can be seen from the figures of the drawing,
(1) The berberine and the bicyclol have a plurality of sharp diffraction peaks;
(2) The berberine-bicyclo-ethanol co-amorphous material has no obvious diffraction peak, which indicates the amorphous state of the berberine-bicyclo-ethanol co-amorphous material.
Example 6 IR Spectroscopy of berberine-Bicyclol Co-amorphous Complex
The samples (berberine-bicyclo alcohol co-amorphous complex from example 3) were taken and mixed with KBr powder and tableted. The scanning range is 400-4000cm -1 . FIGS. 8-11 are IR spectra of berberine, bicyclo-ethanol, physical mixture of berberine and bicyclo-ethanol, and co-amorphous material of berberine and bicyclo-ethanol.
As can be seen from the figures of the drawing,
(1) The spectrogram of the physical mixture of berberine and bicyclo-ethanol is a simple superposition of the peak shapes of bicyclo-ethanol and berberine;
(2) In infrared spectrum of berberine-bicyclo alcohol co-amorphous material, 3442cm -1 The free vibration peak of OH at 1703.0cm disappeared -1 The c=o characteristic peak at the point disappeared.
Example 7 cumulative dissolution Curve measurement
Berberine assay chromatographic conditions:
chromatographic column: kromasil C18 column (150 mm. Times.4.6 mm,5 μm);
mobile phase: acetonitrile-0.05 mol/L sodium dihydrogen phosphate (ph=3 adjusted with phosphoric acid) (28:72);
flow rate: 1.0ml/min; column temperature: room temperature (25 ℃); detection wavelength: 345nm; sample injection amount: 10 mu L.
Bicyclic alcohol assay chromatographic conditions:
chromatographic column: agilent ZORBAX Eclipse XDB C18 column (4.6X250 mm,5 μm);
mobile phase: methanol-water-glacial acetic acid (48:52:1);
column temperature: 30 ℃; detection wavelength: 287nm; flow rate: 1 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the Sample injection amount: 10 mu L.
Taking each sample to be processed according to the regulation of relevant paddles in the appendices of 2015 edition of Chinese pharmacopoeia, wherein the rotating speed is 100+/-1 r/min, the water bath temperature is 37 ℃, and the dissolution medium is: the dosage of water is equivalent to 16mg of berberine, 20mg of bicyclol, 2ml of water is sampled in 0.25,0.5,1,2,3,5,6,8, 10 and 12 hours, 2ml of water is filtered through a 0.45um filter membrane, and 2ml of dissolution medium at the same temperature is supplemented, 1ml of filtrate is taken, and the accumulated dissolution amount is measured by adopting the HPLC method after the mobile phase is diluted.
FIG. 12 is a graph showing the cumulative elution profile of berberine and bicyclo-ethanol in each sample. As can be seen from the figures of the drawing,
(1) The berberine in the physical mixture can be dissolved out for 80% in 15 minutes, and the bicyclo alcohol can be dissolved out for only 5% in 24 hours;
(2) The berberine-bicyclo alcohol co-amorphous material (example 3) delays the berberine dissolution rate to 78% after 6 hours; meanwhile, the dissolution rate of the bicyclic alcohol is obviously increased, the cumulative dissolution rate of the bicyclic alcohol is increased to 40.2% after 6 hours, and the dissolution behaviors of the two medicines are consistent.
The dissolution behavior of the berberine-bicyclo alcohol co-amorphous substance and the physical mixture of the two medicines are obviously different, which is likely to be beneficial to the synergistic action of the two medicines.
EXAMPLE 8 time-of-drug Curve of berberine in plasma
Berberine assay chromatographic conditions:
chromatographic column: shim-pack XR-ODS II column (3 mm. Times.75 mm,2.3 μm);
internal standard (Internal standard, IS): palmatine hydrochloride;
column temperature: 30 ℃; sample injection amount: 10. Mu.L;
mobile phase: gradient elution (0-4 min,85% A+15% B;5-6min,20% A+80% B) was performed with 0.5% aqueous formic acid solution and B acetonitrile; flow rate: 0.5mL/min.
Mass spectrometry conditions for berberine:
ion source: electrospray ionization (ESI); IS:5500V; temperature: 550 ℃; CUR:20V; CE:35V; DP:50V; CAD: media;
the detection mode is as follows: a positive ion mode; ion pairs were monitored: BBR m/z 398.2/308.2, IS m/z 392.1/312.1.
The experimental method comprises the following steps:
(1) The physical mixture of berberine and bicyclo-ethanol is respectively and parenterally administered to 60C 57 mice (example 3) (dosage: berberine/bicyclo-ethanol: 100/100 mg/kg);
(2) Two groups of 5 mice were sacrificed at 0.25,0.5,1,3,6, 12, 24h after dosing, 500ul of blood was collected, placed in EP tubes containing 1% heparin sodium, and centrifuged at 3000rpm at 4 ℃ for 10min;
(3) Taking 100 mu L of plasma in a 1.5mL EP tube, sequentially adding 10 mu L of internal standard solution, 50 mu L of 0.6M NaOH solution and 1.25mL of anhydrous diethyl ether, and vortex shaking for 10min at 2500 r/min;
(4) Centrifuging at 12000rpm and 4deg.C for 10min, collecting upper diethyl ether 500 μL to new EP tube, blow drying in nitrogen blower at 40deg.C, and re-dissolving 100 μL of 20% acetonitrile water solution;
(5) Vortex shaking and centrifugation were repeated and 80 μl of the supernatant was taken into a sample vial containing an inner cannula for analysis.
FIG. 13 shows the drug-time curves of berberine in each sample. From the figure, berberine-bicyclo-ethanolSmall in co-amorphous material The bioavailability of berberine is consistent with the physical mixture of the two medicines。
EXAMPLE 9 time to drug Curve of Bicyclol in plasma
Bicyclic alcohol assay chromatographic conditions:
chromatographic column: zorbax C18 column (3.5 μm, 2.1X100 mm, agilent, USA) equipped with 0.5 μm in-line filter (Upchurch Scientific Ltd.);
the mobile phase was acetonitrile (0.1% formic acid)/water (0.1% formic acid) =45: 55,
flow rate: 0.2mL/min; the sample loading was 5. Mu.L.
Mass spectrometry conditions for bicyclic alcohols:
ion source: electrospray ionization (ESI); IS:3600V; sheath Gas Pressure:35; aux Gas Pressure:15; capillary Temperature:350 ℃; collision Pressure:1.5; cation mode detection, scanning mode is selective reaction detection (SIM), and detection reaction is: m/z 413.1 (bicyclol), m/z 441.1 (internal standard).
FIG. 14 is a graph showing the drug-time profile of bicyclic alcohol in each sample. From the figure, berberine-bicyclo-ethanolCo-amorphous material of double The bioavailability of the cyclitol is significantly higher than that of the physical mixture of berberine and the bicyclic alcohol。
EXAMPLE 10 treatment of hyperlipidemia and Metabolic fatty liver disease with berberine-Bicyclol Co-amorphous Complex
The model of hyperlipidemia and metabolic fatty liver disease was established by feeding syrian golden yellow mice with high fat diet (H10141, beijing verruca biotechnology, inc.). The effect of berberine-bicyclo alcohol co-amorphous complex in treating hyperlipidemia and fatty liver disease related to metabolism is examined.
1. Design of experiment
(1) The syrian golden yellow rats (8 weeks old) were randomly divided into 4 groups of 8 animals each
1) Blank control (normal diet);
2) Model group (high fat diet);
3) Physical mixture of berberine and bicyclol (high fat diet + physical mixture of berberine and bicyclol);
4) Berberine-bicyclo-ethanol co-amorphous material group (high fat diet + berberine-bicyclo-ethanol co-amorphous material).
The animals in the above groups were administered by gastric lavage, and the rats in the control group and the model group were given 10mL/kg/d distilled water.
The physical mixture of berberine and bicyclo-ethanol and the total amorphous substance of berberine and bicyclo-ethanol have dosage of 100mg/kg/d and 100mg/kg/d (corresponding to the molar ratio of 1:1 of example 3), and are administered 1 time a day for 8 weeks.
During the experiment, the body weight of the animals was recorded weekly, after the end of administration, 1ml of 20% chloral hydrate was injected intraperitoneally after the completion of orbital blood collection to anesthetize the animals, and the liver and epididymal adipose tissues were taken for preservation. An automatic biochemical analyzer is used for measuring the biochemical index of blood.
2. Influence of berberine-bicyclic alcohol coform on body weight of experimental animal
The body weight of the syrian golden yellow mice was recorded weekly during the experiment and the body weight changes are shown in figure 15. From the figure, it can be seen that the high fat diet significantly increased the body weight of the syrian golden-yellow rats compared to the normal diet. The body weight of the physical mixture of berberine and bicyclo-ethanol group was not significantly different from that of the model group, but the body weight increase was lower than that of the model group. The berberine-bicyclo alcohol co-amorphous material is effective in reducing weight gain caused by high fat diet, and the weight reduction degree is more remarkable than physical mixture of berberine and bicyclo alcohol. ( * : blank VS model group; #: co-amorphous object VS model group )
3. Influence of berberine-bicyclic alcohol co-amorphous substance on weight of epididymal fat of experimental animal
The results of epididymal fat weight are shown in fig. 16 and table 1.
TABLE 1 epididymal fat weight after administration
As a result of this, it can be seen that,
(1) The epididymal fat weight of the high-fat diet model animal is significantly increased compared to the blank group;
(2) Compared with the model group, the epididymal fat weight of the physical mixture group of berberine and bicyclo-ethanol is not different from that of the model group;
(3) The berberine-bicyclo alcohol co-amorphous substance effectively reverses the weight increase of epididymal fat caused by high-fat diet.
4. Influence of berberine bicyclic alcohol co-amorphous substance on liver triglyceride content of experimental animal
The results of the liver triglyceride content measurement are shown in fig. 17 and table 2.
TABLE 2 liver triglyceride content after administration
As a result of this, it can be seen that,
(1) Triglyceride in liver of animal with high fat diet model is obviously increased compared with blank group;
(2) The physical mixture group has the effect of reducing the content of liver triglyceride, but has no obvious difference with the model composition;
(3) The co-amorphous material is effective in reducing the increase in liver triglyceride content caused by high fat diet to a degree more pronounced than physical mixture of berberine and bicyclo-ethanol.
5. Influence of berberine-bicyclic alcohol co-amorphous substance on blood lipid of experimental animal
The detection of blood lipid is mainly aimed at the content of total cholesterol, low density lipoprotein-cholesterol and triglyceride in blood plasma.
The results of plasma total cholesterol levels are shown in fig. 18 and table 3.
TABLE 3 plasma Total cholesterol levels after dosing
The plasma low density lipoprotein-cholesterol levels are shown in figure 19 and table 4.
TABLE 4 plasma Low Density lipoprotein-cholesterol levels after dosing
The results of plasma triglyceride levels are shown in figure 20 and table 5.
TABLE 5 plasma triglyceride levels after dosing
As a result of this, it can be seen that,
(1) The blood fat of the animal with the high-fat diet model is obviously increased;
(2) The physical mixture group has a certain function of reducing blood fat;
(3) The co-amorphous material is effective in reducing the elevated blood lipids caused by a high fat diet to a degree that is more pronounced than the physical mixture.
The results of the above-mentioned experiments show that,the berberine-bicyclo alcohol co-amorphous substance has effects of reducing body weight, lowering liver index and epididymis Fat index, triglyceride in liver, and effect of reducing blood lipid, and the effects are superior to physical mixture of berberine and bicyclo-ethanol。
6. Modification of liver function of experimental animals by berberine-bicyclic alcohol co-amorphous substance
FIG. 21, table 6 shows a comparison of glutamate pyruvate transaminase (ALT) levels in groups of golden yellow mice after the end of the intervention.
TABLE 6 level of alanine Aminotransferase (ALT) after administration
As a result, it was found that,
(1) ALT levels were significantly elevated in model group compared to the placebo group
(2) The co-amorphous significantly reduced ALT levels caused by high fat diets compared to the model group, and to a greater extent than the physical mixture.
FIG. 22 and Table 7 are comparisons of levels of glutamate oxaloacetate transaminase (AST) in groups of golden yellow mice after the end of the intervention.
TABLE 7 glutamic-oxaloacetic transaminase (AST) levels after administration
As a result, it was found that,
(1) AST levels were significantly elevated in animals from the model group compared to the placebo group;
(2) The co-amorphous significantly reduced AST levels caused by the high fat diet compared to the model group, and to a greater extent than the physical blend.
Fig. 23 shows the results of oil red staining of liver tissue sections of experimental animals, and the results can be seen:
(1) Compared with the blank control group, the lipid deposition in liver tissues of the high-fat diet group is obviously increased;
(2) The liver oil red staining of the mice in the group of the co-amorphous substances is obviously reduced, and the liver lipid deposition is reduced;
the dry medicine has the advantages of inhibiting the deposition of neutral fat such as triglyceride in the liver, improving liver steatosis, and improving liver tissue degeneration to a degree obviously stronger than that of a berberine and dicyclo alcohol physical mixture group.
Fig. 24 shows the results of HE staining of liver tissue sections of experimental animals, and the results can be seen:
(1) The liver cells of the mice in the blank control group have normal morphological structure and no lipid vacuoles;
(2) The high-fat diet can cause abnormal morphological structure of liver tissue, diffuse lipid vacuoles can be seen, and liver cells become obviously large;
(3) Compared with a high-fat diet group, the dry prognosis of the berberine-bicyclo alcohol co-amorphous substance is obviously improved, and the degree of improving hepatic tissue degeneration is obviously stronger than that of a physical mixture group of berberine and bicyclo alcohol.
As a result, the berberine-bicyclo alcohol co-amorphous substance can effectively prevent and treat hyperlipidemia and metabolic fatty liver Disease of the patient。
Finally, it should be noted that the above embodiments are only for helping the person skilled in the art to understand the essence of the present invention, and are not intended to limit the protection scope of the present invention.
Claims (9)
1. A method for preparing a berberine-bicyclo-ethanol co-amorphous complex, which is characterized by comprising the following steps:
(1) The molar ratio of berberine to bicyclo-ethanol is 2:1 to 2;
(2) The berberine-bicyclo alcohol co-amorphous complex is prepared by using a grinding method or a reduced pressure rotary evaporation method.
2. The method of claim 1, wherein the step of determining the position of the substrate comprises,
the grinding method comprises the following steps: using a high-speed ball mill, and performing dry grinding in 45% RH at room temperature, wherein the grinding frequency is 20-30Hz, the dry grinding time is 20-60 minutes, and the grinding is performed until the particle size is 8 mu m;
the step parameters of the decompression rotary evaporation method are as follows: dissolving berberine and bicyclo-ethanol in organic solvent to obtain clear solution, removing organic solvent by rotary evaporation under reduced pressure at 35-60deg.C, and vacuum drying; the organic solvent is ethanol; the temperature of the reduced pressure rotary evaporation is 45-55 ℃.
3. A method according to claim 1 or 2, characterized in that,
the berberine is berberine or pharmaceutically acceptable salt thereof; the pharmaceutically acceptable salt is berberine hydrochloride,
the structural formula of the bicyclic alcohol is as follows:
4. a berberine-bicyclo-ethanol co-amorphous complex prepared by the method of any one of claims 1-3.
5. The berberine-bicyclo alcohol co-amorphous complex according to claim 4, wherein the dissolution behavior of the two drugs in the berberine-bicyclo alcohol co-amorphous complex is consistent; wherein the berberine has a dissolution rate of more than 70% in 6 hours; the dissolution of the bicyclo alcohol is more than 40% in 6 hours; the dissolution rate is measured by a pharmacopoeia method.
6. The berberine-bicyclo-ethanol co-amorphous complex according to claim 4 or 5,
(1) The X-ray diffraction pattern of the berberine-bicyclo alcohol co-amorphous compound has no characteristic diffraction peaks of berberine and bicyclo alcohol;
or (2) the infrared spectrum property of the berberine-bicyclo alcohol co-amorphous complex after being tabletted by KBr is as follows:
1) At 3600-3600cm -1 No characteristic absorption peak of berberine and bicyclo alcohol;
2) At 1703.0cm -1 The c=o characteristic peak at the point disappeared;
3) In 3065, 3014, 2942, 2844, 1770, 1695, 1638, 1601, 1567, 1506, 1480, 1458, 1385, 1361, 1340, 1272, 1233, 1211, 1181, 1162, 1127, 1098, 1062, 1034, 994, 972, 935, 910, 859, 819, 788, 763, 739, 729, 647, 627, 588, 567, 535, 503, 461, 438, 424cm -1 An infrared spectrum characteristic peak exists at the position;
or (3) the berberine-bicyclo alcohol co-amorphous complex is determined by a differential scanning calorimetric analysis method, and has no characteristic melting peak of berberine and bicyclo alcohol.
7. A medicament or pharmaceutical composition comprising the berberine-bicyclo-ethanol co-amorphous complex according to any one of claims 4-6, comprising a therapeutically effective amount of the berberine-bicyclo-ethanol co-amorphous complex, and a pharmaceutically acceptable excipient.
8. The medicament or pharmaceutical composition according to claim 7, wherein the dosage form of the medicament or pharmaceutical composition is a liquid dosage form, a solid dosage form or a semi-solid dosage form;
the liquid dosage forms are true solutions, colloidal solutions, emulsions, and suspensions;
the solid dosage forms are tablets, granules, powder, micropills, dripping pills, suppositories, films and patches;
the semisolid dosage form is an ointment, a gel, a paste.
9. Use of the berberine-bicyclo-ethanol co-amorphous complex according to any one of claims 4-6 for the preparation of a medicament for the prevention or treatment of metabolic diseases including dyslipidemia, obesity, fatty liver disease;
the blood lipid metabolic disorder comprises high-low density lipoprotein-cholesterol, high total cholesterol, high triglyceride or low-high density lipoprotein-cholesterol;
the obesity is weight gain and body fat rate increase;
the fatty liver disease is liver tissue triglyceride increase, liver index increase, liver lipid rate increase, serum glutamic pyruvic transaminase increase, glutamic oxaloacetic transaminase increase and liver inflammatory factor increase.
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