CN110041326B - Eutectic compound of berberine hydrochloride and fumaric acid, preparation method, composition and application thereof - Google Patents
Eutectic compound of berberine hydrochloride and fumaric acid, preparation method, composition and application thereof Download PDFInfo
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- 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
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Abstract
The invention discloses a berberine hydrochloride and fumaric acid eutectic compound, a preparation method, a composition and application thereof. Specifically, the invention discloses a novel berberine hydrochloride and fumaric acid eutectic compound which takes berberine hydrochloride as a medicinal active ingredient and fumaric acid as an eutectic precursor; a preparation method of a berberine hydrochloride and fumaric acid eutectic compound; the berberine hydrochloride and fumaric acid eutectic crystal can be used as pharmaceutical active ingredient for preparing medicines for preventing and treating cardiovascular diseases, resisting virus, resisting cancer, reducing blood lipid, reducing blood glucose, resisting inflammation, resisting bacteria and resisting infection.
Description
Technical Field
The invention discloses a berberine hydrochloride and fumaric acid eutectic compound, a preparation method, a composition and application thereof. Specifically, the invention discloses an eutectic compound formed by berberine hydrochloride and fumaric acid; a preparation method of a berberine hydrochloride and fumaric acid eutectic compound; the berberine hydrochloride and fumaric acid eutectic crystal can be used as pharmaceutical active ingredient for preparing medicines for preventing and treating cardiovascular diseases, resisting virus, resisting cancer, reducing blood lipid, reducing blood glucose, resisting inflammation, resisting bacteria and resisting infection.
Background
The pharmaceutical co-crystal is a crystal formed by active drug molecules and a co-crystal ligand in a certain proportion through intermolecular non-covalent interaction force. The medicine can improve the physicochemical property and the clinical treatment effect on one hand by forming the eutectic crystal, and the eutectic crystal can enrich the crystal form on the other hand. For chemical imitation drugs, the research on eutectic compounds can break the patent protection of the original research and drug enterprises, and improve the innovation and market competitiveness of the drugs.
The invention adopts berberine hydrochloride as an active substance with the chemical name of 5, 6-dihydro-9, 10-dimethoxybenzo [ g]-1, 3-benzodioxole [5,6-a ]]Quinolizine hydrochloride with molecular formula C20H17NO4HCl with the structural formula shown as a. The eutectic ligand (crystal former) adopted in the invention is fumaric acid, and the molecular formula is C4H4O4The structural formula is shown as b.
a b
Berberine hydrochloride (Berberine hydrochloride) is a quinoline alkaloid hydrochloride, and is usually applied clinically in the form of solid preparations (mainly tablets). Physical and chemical properties record that berberine hydrochloride is yellow powder and slightly soluble in water. The reported crystal forms of the berberine hydrochloride are totally 6[1-4]. At present, no report about berberine hydrochloride eutectic exists.
Disclosure of Invention
One of the objects of the present invention is: provides a existence state and a representation mode of a berberine hydrochloride and fumaric acid eutectic compound.
The second object of the present invention is: provides a preparation method of berberine hydrochloride and fumaric acid eutectic compound.
The third object of the present invention is: provides a pure product containing the eutectic compound of berberine hydrochloride and fumaric acid, or a mixed solid substance containing the eutectic compound of berberine hydrochloride and fumaric acid in any non-zero proportion and a pharmaceutical composition thereof.
The fourth purpose of the invention is that: provides a pharmaceutical composition using berberine hydrochloride and fumaric acid eutectic crystal as pharmaceutical active ingredients, and the daily dosage of the berberine hydrochloride is within the range of 5-3000 mg. The pharmaceutical composition comprises tablets, capsules, pills, injection preparations and sustained-release or controlled-release preparation medicaments.
The fifth purpose of the invention is: provides an eutectic substance of berberine hydrochloride and fumaric acid, and has better stability and solubility compared with berberine hydrochloride.
The sixth purpose of the invention is: the berberine hydrochloride and fumaric acid eutectic crystal can be used as effective component of medicine for preparing medicines for preventing and treating cardiovascular diseases, resisting virus, resisting cancer, reducing blood lipid, reducing blood glucose, resisting inflammation, resisting bacteria and resisting infection.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. the morphological characteristics of an eutectic sample of berberine hydrochloride and fumaric acid are as follows:
1.1 the invention relates to a berberine hydrochloride and fumaric acid eutectic compound, which is formed by berberine hydrochloride and fumaric acid in a molar ratio of 2: 1.
1.2 the co-crystal of berberine hydrochloride and fumaric acid shows triclinic symmetry when using single crystal X-ray diffraction analysis, the space group is P-1, and the unit cell parameter value is
72.26 ° for α, 85.40 ° for β, 88.99 ° for γ, unit cell volume
The molecular formula is (C)20H18NO4Cl)2·C4H4O4. Fig. 1 shows a three-dimensional structure diagram of a berberine hydrochloride and fumaric acid eutectic crystal, and fig. 2 shows a unit cell stacking diagram of the berberine hydrochloride and fumaric acid eutectic crystal.
1.3 Co-crystals of berberine hydrochloride and fumaric acid according to the invention, when analyzed by powder X-ray diffraction, CuK is usedαDiffraction peak position under irradiation test conditions: 2-Theta value (°) or d value
Diffraction peak relative intensity: the peak Height value (Height%) or peak Area value (Area%) had the following characteristics (table 1, fig. 3); the powder X-ray diffraction pattern and data of the physical mixture of berberine hydrochloride and fumaric acid are shown in Table 2 and FIG. 4. The powder X-ray diffraction patterns of the physical mixture of the berberine hydrochloride and fumaric acid eutectic compound and the berberine hydrochloride and fumaric acid have obvious differences in the number of diffraction peaks, the positions of the diffraction peaks, the intensities of the diffraction peaks, the topological patterns of the diffraction peaks and the like, which shows that the physical mixture of the berberine hydrochloride and fumaric acid eutectic compound and the physical mixture of the berberine hydrochloride and fumaric acid eutectic compound are not the same or the same.
TABLE 1 powder X-ray diffraction Peak values of eutectic mixture of berberine hydrochloride and fumaric acid
TABLE 2 powder X-ray diffraction peaks of physical mixtures of Berberine hydrochloride and fumaric acid
1.4 the eutectic compound of berberine hydrochloride and fumaric acid is analyzed by attenuated total reflection Fourier infrared spectroscopy, and is 3102, 2998, 2951, 2906, 2849, 2747, 2564, 2473, 2426, 1696, 1637, 1620, 1602, 1568, 1506, 1480, 1458, 1423, 1393, 1368, 1352, 1332, 1306, 1277, 1236、1215、1196、1144、1103、1057、1040、1007、994、974、957、940、916、889、872、856、835、779、769、754、737、713、664cm-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1(FIG. 5).
1.5 the eutectic compound of berberine hydrochloride and fumaric acid shows that 1 endothermic peak exists at 238 +/-3 ℃ in DSC chart when the temperature rise rate is 10 ℃ per minute when being analyzed by differential scanning calorimetry (figure 6). The DSC contrast map of berberine hydrochloride, fumaric acid and berberine hydrochloride and fumaric acid eutectic is shown in figure 7. DSC (differential scanning calorimetry) spectra of the berberine hydrochloride and fumaric acid eutectic compound and the berberine hydrochloride and fumaric acid have obvious differences in the quantity, position and the like of heat absorption/release peaks, and the berberine hydrochloride and the fumaric acid are proved to form a new substance.
2. The preparation method of the eutectic compound and the mixed solid substance of the berberine hydrochloride and the fumaric acid is characterized in that:
2.1 the invention relates to a preparation method of a berberine hydrochloride and fumaric acid eutectic compound, which comprises the steps of feeding berberine hydrochloride and fumaric acid according to the molar ratio of 2:1, and preparing the berberine hydrochloride and fumaric acid eutectic compound by a mechanochemical method for controlling pressure and temperature. The mechanochemical method is preferably a liquid adding ball milling method, wherein the ball-to-material ratio of the liquid adding ball milling method is 1: 1-10: 1, and preferably 6: 1-10: 1; the ball milling speed is 20r/min to 400 r/min; the type of the added liquid is any one or more mixed solvents prepared by combining organic solvents in different proportions; the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane and cyclohexane; the liquid adding amount is 0.01-100 ml; the grinding time is 0.1 to 10 hours.
2.2 the invention relates to a preparation method of a berberine hydrochloride and fumaric acid eutectic compound, which comprises the steps of putting berberine hydrochloride and fumaric acid into a clean container according to the molar ratio of 2:1, adding an organic solvent to prepare a suspension, stirring at room temperature for 0.1-4 days, and carrying out solvent evaporation drying, filtering natural drying or filtering vacuum drying on the obtained suspension to obtain the berberine hydrochloride and fumaric acid eutectic compound. The organic solvent is preferably a mixed solvent prepared by combining any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane and cyclohexane in different proportions; keeping the solid-to-liquid ratio of the total mass of the berberine hydrochloride and the fumaric acid to the organic solvent within the range of 1mg/ml to 500 mg/ml.
2.3 the solid mixture of berberine hydrochloride and fumaric acid eutectic compound of the invention is prepared by mixing the berberine hydrochloride and fumaric acid eutectic compound components prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. The pharmaceutical preparation composition containing the berberine hydrochloride and fumaric acid eutectic components has the following administration dosage characteristics and pharmaceutical application:
3.1 the pharmaceutical composition of the invention contains berberine hydrochloride and fumaric acid eutectic compound and pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition of the invention comprises a mixed solid matter of berberine hydrochloride and fumaric acid eutectic compound and a pharmaceutically acceptable carrier.
3.3 in the pharmaceutical composition of the invention, the daily dose of berberine hydrochloride is within the range of 5-3000 mg.
3.4 the pharmaceutical composition is various tablets, capsules, pills, injection preparations, sustained release preparations or controlled release preparations.
3.5 the invention relates to the application of berberine hydrochloride and fumaric acid eutectic, mixed solid matter of berberine hydrochloride and fumaric acid eutectic or pharmaceutical composition in the preparation of drugs for preventing and treating cardiovascular diseases, resisting virus, cancer, reducing blood fat, reducing blood sugar, resisting inflammation, resisting bacteria and resisting infection.
The invention relates to a pharmaceutical composition taking berberine hydrochloride and fumaric acid eutectic crystal as active ingredients. The pharmaceutical composition may be prepared according to methods well known in the art. The berberine hydrochloride and fumaric acid eutectic composition can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary agents to prepare any dosage form suitable for human or animal use. The content of the berberine hydrochloride and fumaric acid eutectic compound in the pharmaceutical composition is within the range of 10-90% by weight.
The berberine hydrochloride and fumaric acid eutectic compound can be administrated in a unit dosage form, and the administration route can be intestinal tract or parenteral tract, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum and the like.
The administration form according to the invention is preferably a solid form. The solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.
The berberine hydrochloride and fumaric acid eutectic crystal can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
In order to form the co-crystal of berberine hydrochloride and fumaric acid into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants and glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to prepare the administration unit into a capsule, the berberine hydrochloride and fumaric acid eutectic crystal serving as the effective ingredients can be mixed with a diluent and a glidant, and the mixture is directly placed into a hard capsule or a soft capsule. Or the effective components of the berberine hydrochloride and fumaric acid eutectic crystal are firstly prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. Various diluents, binding agents, wetting agents, disintegrating agents and glidants used for preparing the berberine hydrochloride and fumaric acid eutectic mixture tablets can also be used for preparing capsules of the berberine hydrochloride and fumaric acid eutectic mixture.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug of the present invention can be administered by any known administration method.
The administration dosage of the pharmaceutical composition of the berberine hydrochloride and fumaric acid eutectic compound can be widely changed according to the nature and severity of diseases to be prevented or treated, individual conditions of patients or animals, administration routes, dosage forms and the like. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The berberine hydrochloride and fumaric acid eutectic crystal or the composition can be taken alone or combined with other treatment medicines or symptomatic medicines. When the berberine hydrochloride and fumaric acid eutectic compound has synergistic effect with other therapeutic drugs, the dosage of the eutectic compound is adjusted according to actual conditions.
4. The invention has the beneficial technical effects that: the berberine hydrochloride and fumaric acid eutectic compound has the advantages of safety, stability and solubility.
4.1 the eutectic compound of berberine hydrochloride and fumaric acid does not contain any crystallization solvent, and the adopted eutectic precursor is safe to human bodies and has good safety and patent medicine advantages.
4.2 the eutectic crystal of berberine hydrochloride and fumaric acid is stable under the conditions of high temperature, high humidity, illumination and 8T pressure, does not generate crystal transformation phenomenon and has the advantage of stable patent medicine.
4.3 the eutectic compound of berberine hydrochloride and fumaric acid shows better solubility advantage than berberine hydrochloride in 4 common solvent systems.
Drawings
FIG. 1 is a three-dimensional structure diagram of co-crystal of berberine hydrochloride and fumaric acid
FIG. 2 is a unit cell stacking diagram of a co-crystal of berberine hydrochloride and fumaric acid
FIG. 3 is an experimental powder X-ray diffraction pattern of a co-crystal of berberine hydrochloride and fumaric acid
FIG. 4 powder X-ray diffraction Pattern of physical mixture of Berberine hydrochloride and fumaric acid
FIG. 5 is an infrared absorption spectrum of an eutectic compound of berberine hydrochloride and fumaric acid
FIG. 6 Differential Scanning Calorimetry (DSC) spectrum of eutectic compound of berberine hydrochloride and fumaric acid
FIG. 7 Differential Scanning Calorimetry (DSC) chart of eutectic compound of berberine hydrochloride and fumaric acid and raw materials
FIG. 8 is an influence factor experimental chart of co-crystal of berberine hydrochloride and fumaric acid (a: berberine hydrochloride influence factor chart; b: co-crystal of berberine hydrochloride and fumaric acid influence factor chart)
FIG. 9 is a solubility curve of co-crystal of berberine hydrochloride and fumaric acid in 4 solvent systems
Detailed Description
The following examples are given to better illustrate the technical aspects of the present invention, but the present invention is not limited thereto.
Example 1
The preparation method of the berberine hydrochloride and fumaric acid eutectic compound comprises the following steps:
according to the table shown below, taking a proper amount of berberine hydrochloride and fumaric acid according to the molar ratio of 2:1, putting the mixture into a mortar, adding a proper amount of organic solvent, and manually grinding for a proper time. Powder X-ray diffraction analysis is carried out on the berberine hydrochloride and the sample, and the diffraction pattern is consistent with that of figure 3, which shows that the obtained sample is an eutectic compound of berberine hydrochloride and fumaric acid.
The preparation method of the berberine hydrochloride and fumaric acid eutectic compound 2:
according to the table shown below, taking a proper amount of berberine hydrochloride and fumaric acid according to a molar ratio of 2:1, putting the mixture into a ball milling tank, adding a proper amount of organic solvent, selecting a proper ball-material ratio, setting a proper rotating speed, and grinding for a proper time. Powder X-ray diffraction analysis is carried out on the berberine hydrochloride and the sample, and the diffraction pattern is consistent with that of figure 3, which shows that the obtained sample is an eutectic compound of berberine hydrochloride and fumaric acid.
Preparation method of berberine hydrochloride and fumaric acid eutectic compound 3:
according to the table shown in the following, taking a proper amount of berberine hydrochloride and fumaric acid according to the molar ratio of 2:1, putting the mixture into a clean container, adding a proper amount of organic solvent, stirring for a proper time at room temperature, evaporating and drying the obtained suspension solvent, filtering and naturally drying or filtering and vacuum drying. Powder X-ray diffraction analysis is carried out on the berberine hydrochloride and the sample, and the diffraction pattern is consistent with that of figure 3, which shows that the obtained sample is an eutectic compound of berberine hydrochloride and fumaric acid.
Example 2
The stability characteristics of the berberine hydrochloride and fumaric acid eutectic compound are as follows:
high-temperature test: placing berberine hydrochloride and fumaric acid eutectic crystal samples in an open clean surface dish, standing at 60 deg.C for 10 days, and sampling on day 0, day 5 and day 10. Powder X-ray diffraction analysis is carried out on the sample obtained at the sampling point, and the result shows that berberine hydrochloride, berberine hydrochloride and fumaric acid eutectic are stable under a high-temperature influence factor test.
High humidity test: placing berberine hydrochloride, berberine hydrochloride and fumaric acid eutectic crystal samples in an open clean surface dish, standing at 25 ℃ under the condition of relative humidity of 90% +/-5% for 10 days, and sampling on the 0 th day, the 5 th day and the 10 th day. Powder X-ray diffraction analysis is carried out on the sample obtained at the sampling point, and the result shows that berberine hydrochloride is unstable under high humidity conditions, and the eutectic compound of berberine hydrochloride and fumaric acid is stable under the conditions.
And (3) illumination test: placing berberine hydrochloride, berberine hydrochloride and fumaric acid eutectic crystal samples in an open clean surface dish, placing in an illumination box equipped with a fluorescent lamp, placing for 10 days under the condition that the illumination is 4500lx +/-500 lx, and sampling on day 0, day 5 and day 10. Powder X-ray diffraction analysis is carried out on the sample obtained from the sampling point, and the result shows that berberine hydrochloride, berberine hydrochloride and fumaric acid eutectic are stable under the test of illumination influence factors.
And (3) pressure test: weighing 100mg of berberine hydrochloride and fumaric acid eutectic samples respectively, tabletting and sampling under the conditions of 2T, 4T and 8T. Grinding, sieving with a 100-mesh sieve, and measuring with a powder X-ray diffractometer, wherein the result shows that berberine hydrochloride, berberine hydrochloride and fumaric acid eutectic are stable under pressure test.
Example 3
The solubility characteristics of the berberine hydrochloride and fumaric acid eutectic and berberine hydrochloride bulk drug in 4 solvent systems are as follows: selection of vehicle system: firstly, referring to a solvent system adopted by a dissolution determination method in an appendix of pharmacopoeia; secondly, the pH values of digestive juice of different organs in the organism are referred; 4 vehicle systems were set up according to the 2 references above: 0.1N hydrochloric acid solution with pH value of 1.0; acetate buffer with pH 4.5; phosphate buffer at pH 6.8; an aqueous solution. According to the determination of the general oral solid preparation dissolution test technical guideline, a model independent similarity factor (f2) method is adopted for dissolution curve comparison, the similarity of dissolution curves of berberine hydrochloride and fumaric acid eutectic samples in 4 solvent systems is compared through calculation of f2 values, when the f2 value is higher than 50, the two curves are considered to be similar, and when the f2 value is lower than 50, the two curves are considered to be different. The experiment takes berberine hydrochloride samples as reference, and the value of the model independent similarity factor f2 is calculated. The content of berberine hydrochloride is measured at 345nm wavelength by high performance liquid chromatography, and the content of berberine hydrochloride is calculated by external standard method. And respectively drawing a dissolution curve by taking the time as an abscissa and the dissolution percentage as an ordinate. The data are shown in the following table:
TABLE 3 Co-crystals of berberine hydrochloride with fumaric acid (YSXBJ-FDXES) and berberine hydrochloride (YSXBJ)
Dissolution profile data in 4 vehicles
Experimental data show that the dissolving behavior of the co-crystal of berberine hydrochloride and fumaric acid in water, hydrochloric acid, acetate and phosphate systems is superior to that of berberine hydrochloride, and the co-crystal of berberine hydrochloride and fumaric acid is embodied in that the co-crystal of berberine hydrochloride and fumaric acid has a faster dissolving rate, is easy to be rapidly absorbed to reach an effective blood concentration, and realizes the disease treatment effect of the medicament; the solubility curve of the berberine hydrochloride and fumaric acid eutectic compound has a stable release platform, and can ensure that the stable blood concentration is kept in the disease treatment process.
Example 4
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined drug tablet is characterized in that a berberine hydrochloride and fumaric acid eutectic compound and a plurality of excipients are used as auxiliary material components for preparing the combined drug tablet, tablet samples containing 5-500 mg of eutectic are prepared according to a certain proportion, and the formula proportion of the tablet is given in a table 4:
TABLE 4 preparation of pharmaceutical tablet containing berberine hydrochloride and fumaric acid
The method for preparing the tablet preparation by taking the berberine hydrochloride and fumaric acid eutectic compound as the raw material medicaments comprises the following steps: mixing several excipients with the raw materials, and directly tabletting; or mixing the auxiliary materials, granulating by a dry method, uniformly mixing with the raw material medicines, and tabletting to obtain the traditional Chinese medicine.
Method for the preparation of a combined pharmaceutical preparation 2 (tablet):
a preparation method of a combined drug tablet is characterized in that berberine hydrochloride and fumaric acid eutectic are used, a plurality of excipients are used as auxiliary material components for preparing the combined drug tablet, tablet samples containing 5-500 mg of eutectic are prepared according to a certain proportion, and the formula proportion of the tablet is given in table 5:
TABLE 5 preparation formula of pharmaceutical tablet of berberine hydrochloride and fumaric acid eutectic composition
The method for preparing the tablet preparation by taking the berberine hydrochloride and fumaric acid eutectic compound as the raw material medicaments comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into soft material, sieving, granulating, oven drying, sieving, grading, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Method for preparing a combined pharmaceutical preparation 3 (capsule):
a preparation method of a combined medicine capsule is characterized in that a berberine hydrochloride and fumaric acid eutectic compound is used as a raw material medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine capsule, a capsule sample with the medicine content of 5-500 mg is prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 6:
TABLE 6 bulk drug and adjuvant formulation of berberine hydrochloride and fumaric acid eutectic compound combined drug capsule preparation
The method for preparing the capsule by taking the berberine hydrochloride and fumaric acid eutectic as raw material medicaments comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing berberine hydrochloride and fumaric acid with several excipient adjuvants, sieving, and directly encapsulating without granulating.
Example 5
The administration dosage of the berberine hydrochloride and fumaric acid eutectic compound combined medicine is 1 (tablet):
the pharmaceutical composition prepared and developed by using the berberine hydrochloride and fumaric acid eutectic compound as the active pharmaceutical ingredients is characterized in that the berberine hydrochloride and fumaric acid eutectic compound is used as the active pharmaceutical ingredients, the daily administration dosage is 900mg, and the pharmaceutical composition can be respectively prepared into 3 tablets each time 3 times a day, 100mg common tablets or 1 tablet each time 3 times a day, 300mg tablets.
The administration dosage of the berberine hydrochloride and fumaric acid eutectic compound combined medicine is 2 (capsules):
the pharmaceutical composition prepared and developed by using the berberine hydrochloride and fumaric acid eutectic compound as the active pharmaceutical ingredients is characterized in that the berberine hydrochloride and fumaric acid eutectic compound is used as the active pharmaceutical ingredients, the daily administration dosage is 1200mg, and the pharmaceutical composition can be respectively prepared into 4 capsules of 100mg 3 times a day each time or 4 capsules of 150mg 2 times a day each time.
Problems to be explained are: the pharmaceutical composition of the berberine hydrochloride and fumaric acid cocrystal has many factors on the administration dosage of the effective components, such as: the age and the body surface area of patients are different, and the administration route, the administration frequency and the treatment purpose are different, so that the dosage of each administration is different; the difference of absorption and blood concentration existing among samples also causes that the suitable dosage range of the eutectic composition of berberine hydrochloride and fumaric acid used in each time is 0.1-50mg/kg body weight, preferably 5-30mg/kg body weight. When in use, different total dosage schemes of the effective components of the berberine hydrochloride and fumaric acid eutectic compound are made according to different actual requirements of treatment on different conditions, and the administration can be completed in a mode of multiple times or one time.
Reference to the literature
[1]BENSON M.KARIUKI.Five Salts of Berberine.Acta Cryst.1995,C51,1234-1240.
[2] Luyang, du guanhua, zhonhaohui, shi li, populus gium, berberine hydrochloride crystal D type substance, preparation method and its pharmaceutical composition and use, publication No: 103421002A.
[3] Berberine hydrochloride crystal E type substance, preparation method and pharmaceutical composition and use thereof, Duguanhua, Lvyang, Zhonhaohui, Zhang Heng ai, Zhang Li, Berberine hydrochloride crystal E type substance, publication No: 103421001A.
[4] Duguanhua, Lvyang, Zhonghaohui, Chengnian, Yangyijing, Berberine hydrochloride crystal F substance, preparation method, pharmaceutical composition and use thereof, publication (Notification) No. 103421000A.
Claims (18)
1. An eutectic compound of berberine hydrochloride and fumaric acid is characterized in that the eutectic compound is formed by the berberine hydrochloride and the fumaric acid according to the molar ratio of 2: 1; using CuK when powder X-ray diffraction analysis is usedαDiffraction peak position under irradiation test conditions: 2-Theta value or d value,Diffraction peak relative intensity: the peak height or peak area values have the following characteristics:
2. the co-crystal of berberine hydrochloride and fumaric acid as claimed in claim 1, which shows triclinic symmetry when analyzed by single crystal X-ray diffraction, space group is P-1, and unit cell parameter value is
72.26 ° for α, 85.40 ° for β, 88.99 ° for γ, unit cell volume
The molecular formula is (C)20H18NO4Cl)2·C4H4O4。
3. The co-crystal of berberine hydrochloride and fumaric acid as claimed in claim 1, characterized in that when analyzed by attenuated total reflection Fourier infrared spectroscopy, it has a spectrum of 3102, 2998, 2951, 2906, 2849, 2747, 2564, 2473, 2426, 1696, 1637, 1620, 1602, 1568, 1506, 1480, 1458, 1423, 1393, 1368, 1352, 1332, 1306, 1277, 1236, 1215, 1196, 1144, 1103, 1057, 1040, 1007, 994, 974, 957, 940, 916, 889, 872, 856, 835, 779, 769, 754, 737, 713, 664cm-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1。
4. The co-crystal of berberine hydrochloride and fumaric acid according to claim 1, characterized in that when analyzed by differential scanning calorimetry, it shows that there are 1 endothermic peak at 238 ℃ ± 3 ℃ in the DSC spectrum when the temperature rise rate is 10 ℃ per minute.
5. The method for preparing the berberine hydrochloride and fumaric acid eutectic compound according to any one of claims 1 to 4, wherein the berberine hydrochloride and fumaric acid eutectic compound is prepared by a mechanochemical method with controlled pressure and temperature according to the feeding of the berberine hydrochloride and the fumaric acid according to the molar ratio of 2: 1.
6. The preparation method according to claim 5, wherein the mechanochemical method is selected from a liquid adding ball milling method, wherein the ball-to-material ratio of the liquid adding ball milling method is 1: 1-10: 1; the ball milling speed is 20r/min to 400 r/min; the type of the organic solvent added with liquid is any one or more mixed solvents prepared by combining in different proportions; the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane and cyclohexane; the liquid adding amount is 0.01-100 ml; the grinding time is 0.1 to 10 hours.
7. The preparation method according to claim 5, wherein the mechanochemical method is selected from a liquid adding ball milling method, wherein the ball-to-material ratio of the liquid adding ball milling method is 6: 1-10: 1; the ball milling speed is 20r/min to 400 r/min; the type of the organic solvent added with liquid is any one or more mixed solvents prepared by combining in different proportions; the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane and cyclohexane; the liquid adding amount is 0.01-100 ml; the grinding time is 0.1 to 10 hours.
8. The method for preparing the co-crystal of berberine hydrochloride and fumaric acid as claimed in any one of claims 1-4, wherein the berberine hydrochloride and fumaric acid are put into a clean container according to the molar ratio of 2:1, an organic solvent is added to prepare a suspension, the suspension is stirred at room temperature for 0.1-4 days, and the obtained suspension is subjected to solvent evaporation drying, filtering natural drying or filtering vacuum drying to obtain the co-crystal of berberine hydrochloride and fumaric acid.
9. The method for preparing the co-crystal of berberine hydrochloride and fumaric acid according to claim 7, wherein the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane and cyclohexane; keeping the solid-to-liquid ratio of the total mass of the berberine hydrochloride and the fumaric acid to the organic solvent within the range of 1mg/ml to 500 mg/ml.
10. A mixed solid matter of berberine hydrochloride and fumaric acid eutectic compound, characterized in that the berberine hydrochloride and fumaric acid eutectic compound of any one of claims 1-4 is contained in an amount of 1-99.9%.
11. A mixed solid matter of berberine hydrochloride and fumaric acid eutectic compound, characterized in that, the content of berberine hydrochloride and fumaric acid eutectic compound in any claim 1-4 is 10-99.9%.
12. A mixed solid matter of berberine hydrochloride and fumaric acid eutectic compound, characterized in that, the content of berberine hydrochloride and fumaric acid eutectic compound in any claim 1-4 is 50-99.9%.
13. A mixed solid matter of berberine hydrochloride and fumaric acid eutectic compound, characterized in that, the content of berberine hydrochloride and fumaric acid eutectic compound in any claim 1-4 is 85-99.9%.
14. A pharmaceutical composition comprising an effective amount of a co-crystal of berberine hydrochloride and fumaric acid according to any one of claims 1-4 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition, comprising an effective amount of the berberine hydrochloride and fumaric acid co-crystal mixture solid substance of claim 10 and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition according to any one of claims 14 or 15, wherein the daily dose of berberine hydrochloride is in the range of 5-3000 mg.
17. Pharmaceutical composition according to any one of claims 14 or 15, characterized in that the pharmaceutical composition is in the form of a tablet, capsule, pill, injectable preparation, sustained release preparation or controlled release preparation.
18. Use of the co-crystal of berberine hydrochloride and fumaric acid according to any one of claims 1-4 or the mixed solid substance of berberine hydrochloride and fumaric acid according to any one of claims 11-13 or the pharmaceutical composition according to any one of claims 14 or 15 for preparing the drugs for preventing and treating cardiovascular diseases, resisting cancer, reducing blood sugar, resisting inflammation and resisting infection.
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| CN112624918B (en) * | 2020-12-18 | 2022-02-11 | 深圳市萱嘉生物科技有限公司 | Eutectic of azelaic acid and organic base as well as preparation method and application thereof |
| CN113956250B (en) * | 2021-10-21 | 2023-07-14 | 上海工程技术大学 | Berberine hydrochloride pharmaceutical co-crystal and preparation method and application thereof |
| CN113999225A (en) * | 2021-11-29 | 2022-02-01 | 东南大学成贤学院 | Vinpocetine eutectic compound and preparation method thereof |
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