CN115536654A - Berberine hesperetin salt crystal form, preparation method, composition and application thereof - Google Patents
Berberine hesperetin salt crystal form, preparation method, composition and application thereof Download PDFInfo
- Publication number
- CN115536654A CN115536654A CN202211151576.9A CN202211151576A CN115536654A CN 115536654 A CN115536654 A CN 115536654A CN 202211151576 A CN202211151576 A CN 202211151576A CN 115536654 A CN115536654 A CN 115536654A
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- CN
- China
- Prior art keywords
- hesperetin
- berberine
- salt
- crystal form
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940093265 berberine Drugs 0.000 title claims abstract description 131
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- -1 Berberine hesperetin salt Chemical class 0.000 title claims abstract description 121
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- AIONOLUJZLIMTK-AWEZNQCLSA-N hesperetin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-AWEZNQCLSA-N 0.000 claims abstract description 22
- AIONOLUJZLIMTK-UHFFFAOYSA-N hesperetin Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-UHFFFAOYSA-N 0.000 claims abstract description 19
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
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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 crystal form of berberine hesperetin salt, a preparation method thereof, a composition thereof and application thereof. Specifically, the invention discloses a solid state form of a crystal form of berberine hesperetin salt; a preparation method of a crystal form of berberine hesperetin salt; the crystal form of berberine hesperetin salt can be used as medicinal active ingredient for preventing and treating antibacterial, antiinflammatory, blood lipid reducing, blood glucose reducing, antivirus, cardiovascular disease and cerebrovascular disease, anticancer and anti-infective medicine. The crystal form of the berberine hesperetin salt formed by the invention has good stability, and can solve the problem of poor stability of commercially available berberine hydrochloride; the invention can realize the combined administration of two effective components with similar pharmacological actions of berberine and hesperetin; in addition, the method has the advantages of simple reaction conditions, good reproducibility, easy industrial production and good application and development prospects.
Description
Technical Field
The invention discloses a crystal form of berberine hesperetin salt, a preparation method, a composition and an application thereof; specifically, the invention discloses a solid state form of a crystal form of berberine hesperetin salt; a process for the preparation of a crystalline solid form of berberine hesperetin salt; the solid state form containing berberine hesperetin salt crystal form is used for preparing medicines for preventing and treating antibacterial, antiinflammatory, reducing blood lipid, lowering blood sugar, antivirus, cardiovascular disease and cerebrovascular disease, anticancer and anti-infection.
Background
The solid crystal forms of the drug mainly include polymorphism, hydrate, solvate, salt, eutectic and the like, the physicochemical properties of different solid forms of the same active ingredient, such as solubility, dissolution rate, stability and the like, may have great differences, and the physicochemical properties are different, which may affect the stability and absorption of the drug and further affect the curative effect of the drug. The search for suitable solid forms of drugs, which often exert the best therapeutic effect, has been the focus of research in pharmaceutics. Among them, the salt formation of ionizable drugs is one of the most effective means for improving the physicochemical properties thereof.
The combined administration can enhance the curative effect of the medicine and shorten the administration period of patients. Salification or co-crystallization of the drug and the drug is an important means for realizing combined medication, and is a research hotspot in the field of drug crystallization; in addition, the solid form of the medicament can be changed by salifying or eutectic implementation of combined medication, and the physicochemical properties of the medicament are improved.
Berberine hydrochloride (formula 1) is an isoquinoline alkaloid and is mainly used for clinically treating gastroenteritis and diarrhea caused by bacteria. In recent years, berberine is found to have good activities of resisting arrhythmia, resisting platelet aggregation, resisting cerebral ischemia, resisting tumor, reducing blood sugar, resisting virus, resisting inflammation and the like. Therefore, researchers have been working on the development of berberine drugs with new clinical indications. Berberine hydrochloride exists in four solid forms including anhydrate, monohydrate, dihydrate and tetrahydrate. The anhydrate and monohydrate are significantly hygroscopic and readily convert to the dihydrate at 12% humidity. Humidity above 70% will further induce the transition from dihydrate to tetrahydrate. Thus, commercially available berberine hydrochloride is usually a mixture of its dihydrate and tetrahydrate. Environmental changes may also promote changes in the solid state form of commercially available berberine hydrochloride, however, changes in the solid state form are detrimental to its clinical treatment.
Formula 1: molecular structural formula of berberine hydrochloride
Hesperetin (formula 2) is mainly derived from young fruit of Citrus of Rutaceae, and has antibacterial, antiinflammatory, antioxidant, antitumor, anti-fibrosis, anti-Alzheimer's disease, blood lipid reducing and cardiovascular protecting effects.
Formula 2: molecular structural formula of hesperetin
In view of the hope of improving the physicochemical property of the modified berberine salt, the invention solves the problem of poor stability of the market-sold form by synthesizing the berberine hesperetin salt; in addition, the berberine and the hesperetin have a plurality of similar pharmacological actions, and the combination of the berberine and the hesperetin can better play the treatment effect of the berberine and the hesperetin; therefore, the aims of simultaneously improving the stability of the berberine and the drug combination can be achieved by synthesizing the crystal form of the berberine hesperetin salt; the research of the literature finds that no report of the crystal form of the berberine hesperetin salt still exists at present, so that the development of the crystal form of the berberine hesperetin salt has important significance and good application prospect.
Disclosure of Invention
One of the objects of the present invention is: provides the existence state and the representation mode of the crystal form of the berberine hesperetin salt.
The second purpose of the invention is that: provides a preparation method of a crystal form of berberine hesperetin salt.
The third purpose of the invention is: provides a pure product containing the berberine hesperetin salt crystal form, or a mixed solid substance containing the berberine hesperetin salt crystal form with the proportion of 1-99 percent, and a pharmaceutical composition thereof.
The fourth purpose of the invention is: provides a pharmaceutical composition using the berberine hesperetin salt crystal form as a pharmaceutical active ingredient, wherein the daily dosage of the berberine hesperetin salt crystal form is within the range of 20-5000 mg. The pharmaceutical composition comprises tablets, capsules, injection preparations, pills and sustained-release or controlled-release preparation medicaments.
The fifth purpose of the invention is: provides a crystal form substance of berberine hesperetin salt, which is obviously superior to berberine hydrochloride in stability.
The sixth purpose of the invention is: the crystal form of berberine hesperetin salt is used as effective component of medicine for preparing medicines for preventing and treating antibacterial, antiinflammatory, blood lipid reducing, blood glucose reducing, antivirus, cardiovascular disease and cerebrovascular disease, anticancer and anti-infective medicine.
In order to achieve the purpose, the invention adopts the technical scheme that:
1. the morphological characteristics of the berberine hesperetin salt crystal type sample are as follows:
1.1 the crystal form of berberine hesperetin salt related by the invention is salt formed by berberine and hesperetin by non-covalent bond according to the molar ratio of 1:1.
1.2 the crystal form of berberine hesperetin salt related by the invention is represented as monoclinic system when the single crystal X-ray diffraction analysis is used for 100K, and the space group isP21/nUnit cell parameters a/a =14.734 (2), b/a =12.548 (2), c/a =16.591 (2), α/° = γ/° =90, β/° 108.45 (2), V =2909.7 (4)/a 3 Z =4, molecular formula: c 20 H 18 NO 4 ·C 16 H 13 O 6 。
1.3 Berberine hesperetin salt crystal form related to the invention, when powder X-ray diffraction analysis is used, cu is adoptedKαWhen the radiation experiment condition is adopted, the diffraction peak positions are mainly located at the degrees of 6.2 +/-0.2, 7.6 +/-0.2, 9.3 +/-0.2, 11.1 +/-0.2, 11.8 +/-0.2, 12.5 +/-0.2, 12.9 +/-0.2, 13.9 +/-0.2, 14.3 +/-0.2, 15.3 +/-0.2, 16.7 +/-0.2, 18.1 +/-0.2, 18.4 +/-0.2, 19.2 +/-0.2, 19.7 +/-0.2, 20.1 +/-0.2, 20.4 +/-0.2, 20.9 +/-0, 21.9 +/-0.2, 22.0 +/-0.2, 22.7, 25 +/-0.0, 25 +/-0.2, 25.0, 25 +/-0.2, 25.1 +/-0.2, 25.2, 25 +/-0.2, 25.2, 25.1 +/-0.2, 25.2, 25.0.2.
1.4 the crystal form of the berberine hesperetin salt is mainly 3063 + -5, 3016 + -5, 2955 + -5, 2930 + -5, 2905 + -5, 2834 + -5, 1636 + -5, 1560 + -5, 1523 + -5, 1506 + -5, 1482 + -5, 1457 + -5, 1451 + -5, 1435 + -5, 1383 + -5, 1350 + -5, 1337 + -5, 1314 + -5, 1259 + -5, 1229 + -5, 1175 + -5, 1134 + -5, 1099 + -5, 1079 + -5, 1059 + -5, 1026 + -5, 865 + -5, 805 + -5, 762 + -5 and 541 + -5 cm -1 There exists a characteristic peak of infrared spectrum.
1.5 when the crystal form of the berberine hesperetin salt related by the invention is analyzed by using a differential scanning calorimetry technology, 1 endothermic peak exists at 213 +/-5 ℃ in a DSC chart when the temperature rise rate is 10 ℃ per minute.
2. The preparation method of the crystal form and the mixed solid matter of the berberine hesperetin salt is characterized in that:
2.1 the berberine hesperetin salt crystal form related to the invention is prepared by taking 8-hydroxy-dihydroberberine (formula 3) and hesperetin as raw materials, placing the raw materials in a mixed solvent of water and an organic solvent according to a molar ratio of 1.5 to 1. The organic solvent is methanol, ethanol, N-propanol, isopropanol, N-butanol, ethylene glycol, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-dimethylacetamide or N, N-dimethylformamide; the ratio of the total mass of the 8-hydroxy-dihydroberberine and the hesperetin to the dosage of the solvent is 1g: (1 to 200) ml.
Formula 3: molecular structural formula of 8-hydroxy-dihydroberberine
2.2 the mixed solid matter containing the crystal form of the berberine hesperetin salt of the invention is prepared by mixing the crystal form component of the berberine hesperetin salt 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 crystal form component of the berberine hesperetin salt, the administration dosage characteristics and the pharmaceutical application are as follows:
3.1 the pharmaceutical composition contains the crystal form of the berberine hesperetin salt and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition of the invention contains berberine hesperetin salt crystal form mixed solid matter and a pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition of the invention has the daily dosage of the crystal form of the berberine hesperetin salt within the range of 20-5000 mg.
3.4 the pharmaceutical composition of the present invention is characterized in that the pharmaceutical composition is various tablets, capsules, injections, pills, sustained release preparations or controlled release preparations.
3.5 the invention relates to the application of berberine hesperetin salt crystal form, mixed solid matter of berberine hesperetin salt crystal form or pharmaceutical composition in the preparation of drugs for preventing and treating bacteria, inflammation, blood fat and blood sugar, virus and cardiovascular and cerebrovascular diseases, cancer and infection.
The invention relates to a pharmaceutical composition taking the crystal form of berberine hesperetin salt of the invention as an active component. The pharmaceutical composition may be prepared according to methods well known in the art. The crystal form component of the berberine hesperetin salt can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary agents to prepare any preparation formulation suitable for human or animal use.
The content of the berberine hesperetin salt crystal form in the pharmaceutical composition is within the range of 1-99% by weight.
The berberine hesperetin salt crystal form can be administrated in a unit dosage form, and the administration route can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, lung, 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, etc.
The berberine hesperetin salt crystal form can be prepared into a common preparation, a slow release preparation, a controlled release preparation, a targeted preparation and various particle drug delivery systems. In order to form the berberine hesperetin salt crystal form of the present invention into tablets, various excipients well known in the art can be widely used, including diluents, wetting agents, binders, disintegrants, lubricants, glidants. The diluent can be dextrin, starch, sucrose, lactose, glucose, sorbitol, mannitol, xylitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, etc.; the humectant can be water, ethanol, etc.; the binder can be dextrin, starch slurry, syrup, glucose solution, mel, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be microcrystalline cellulose, dry starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, 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 capsules, the effective component of the berberine hesperetin salt crystal form can be mixed with a diluent and a glidant, and the mixture is directly placed into hard capsules or soft capsules. Or the effective component of the crystal form of the berberine hesperetin salt of the invention can be prepared into granules or pellets with diluent, adhesive and 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 hesperetin salt crystal form tablets can also be used for preparing capsules of the berberine hesperetin salt crystal form tablets. 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 berberine hesperetin salt crystal pharmaceutical composition can be widely changed according to the nature and severity of diseases to be prevented and 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 crystal form or the composition of the berberine hesperetin salt can be taken alone or combined with other treatment medicines or symptomatic medicines. When the crystal form of the berberine hesperetin salt of the invention has synergistic effect with other therapeutic drugs, the dosage of the crystal form of the berberine hesperetin salt of the invention is adjusted according to actual conditions.
4. The invention has the beneficial technical effects that:
4.1 the crystal form of the berberine hesperetin salt of the invention has good stability, does not generate phase change under the conditions of high temperature, high humidity and illumination, and is more stable as a medicine raw material in the preparation production and storage processes.
4.2 the crystal form of the berberine hesperetin salt does not contain any crystallization solvent, and has good safety and patent medicine advantages.
4.3 The invention realizes the co-crystallization of the berberine and the hesperetin which have similar pharmacological effects through a crystallization technology, and is more convenient for combined medication of patients.
4.4 the preparation method of the berberine hesperetin salt crystal form of the invention is simple and easy to implement, has mild and easily controlled conditions, good reproducibility, easy realization of large-scale industrial production, low production cost and great commercial application value.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of a crystal form of berberine hesperetin salt;
FIG. 2 is a crystal structure diagram of a crystal form of berberine hesperetin salt;
FIG. 3 is a unit cell stacking diagram of a crystal form of berberine hesperetin salt;
FIG. 4 thermal analysis (TG-DSC) diagram of the hesperetin salt crystal form of berberine;
FIG. 5 is an Infrared (IR) spectrum of a crystal form of berberine hesperetin salt;
figure 6 experimental spectrum of influence factors of crystal form of berberine hesperetin salt.
Detailed Description
The technical features of the present invention are further illustrated by the following specific embodiments and the accompanying drawings, which are intended to enable persons skilled in the relevant art to understand the present invention and to implement the present invention, but not to limit the protection scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, but these equivalents also fall within the scope of the present invention defined by the appended claims.
The instrument and the method for detecting the crystal structure and the properties of the crystal form of the berberine hesperetin salt are as follows:
single crystal diffraction characterization: bruker APEX-II D8X-ray single crystal diffractometer usingSHELXTLAndOLEXcarrying out structural analysis and correction; using Mercury andOLEXthe software obtains a structure map.
Powder X-ray diffraction (PXRD) characterization: the instrument comprises the following steps: bruker D8 Advance, cu KαRadiation, power 40kV,40mA; detection conditions are as follows: the scanning range 2 theta is 5-50 degrees, the scanning speed is 4 degrees/min, and the testing temperature is 20 degrees.
Thermal analysis (TG-DSC) characterization: the instrument comprises the following steps: the detection conditions of ZCT-B DSC/TGA of Beijing Gaokou instruments Ltd are as follows: placing the sample in an open crucible, and raising the temperature: 10 ℃/min, temperature range: 40 to 240 ℃.
Fourier Infrared (IR) characterization: the instrument comprises the following steps: fourier transform Infrared Spectroscopy (Thermo Fisher, inc., nicolet Nexus IS5, ATR method, USA); detection conditions are as follows: the scanning wave band is 4000-500 cm -1 Resolution ratio: 5cm -1 。
Influence factor experiment: placing the crystal form sample of the berberine hesperetin salt in a clean surface dish with an opening, respectively placing the sample in an environment of 90% +/-5% (25 ℃) or 4500lx + -500 lx (25 ℃) for 10 days for sampling, and testing by using IR.
Example 1
The preparation method of the berberine hesperetin salt crystal type sample 1 comprises the following steps:
weighing 8-hydroxy-dihydroberberine and hesperetin with a molar ratio of 1:1, adding into acetone-water (with a volume ratio of 1:1), heating to 60 ℃, clarifying the solution, filtering, standing at normal temperature, filtering after 48h of complete precipitation, and drying to obtain yellow solid powder which is a crystal form of berberine hesperetin salt; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the hesperetin to the solvent is 1.
The preparation method of the berberine hesperetin salt crystal type sample 2 comprises the following steps:
weighing 8-hydroxy-dihydroberberine and hesperetin with a molar ratio of 1:1, adding the weighed materials into N, N-dimethylacetamide-water (with a volume ratio of 4:1), heating to 45 ℃, clarifying the solution, filtering, taking out, standing at normal temperature, filtering after 72h is completely separated out, and drying to obtain yellow solid powder which is a crystal form of berberine hesperetin salt; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the hesperetin to the solvent is 1.
The preparation method of the berberine hesperetin salt crystal type sample 3 comprises the following steps:
weighing 8-hydroxy-dihydroberberine and hesperetin with a molar ratio of 1.5 to 1.5, adding the mixture into acetonitrile-water (in a volume ratio of 2:1), heating to 50 ℃, clarifying the solution, filtering, standing at normal temperature, filtering and drying after 72 hours of complete precipitation to obtain yellow solid powder which is a crystal form of the berberine hesperetin salt; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the hesperetin to the solvent is 1.
The preparation method of the berberine hesperetin salt crystal type sample 4 comprises the following steps:
weighing 8-hydroxy-dihydroberberine and hesperetin in a molar ratio of 1:2, adding the weighed materials into acetone-water (in a volume ratio of 2:1), stirring at 30 ℃ for 10 h, filtering, and drying at 40 ℃ to obtain yellow solid powder which is a crystal form of berberine hesperetin salt; wherein the mass-volume ratio of the total mass of the 8-hydroxy-dihydroberberine and the hesperetin to the solvent is 1.
When tested in 100K, the prepared berberine hesperetin salt crystal belongs to a monoclinic system, and the space group isP21/nUnit cell parameters a/A =14.734 (2), b/A =12.548 (2), c/A =16.591 (2), α/° = γ/° =90, β/° =108.45 (2), 2909.7 (4)/A 3 Z =4, formula: c 20 H 18 NO 4 ·C 16 H 13 O 6 。
The X-ray diagram positions of the powder are represented by 2 theta angles at 6.2 +/-0.2 degrees, 7.6 +/-0.2 degrees, 9.3 +/-0.2 degrees, 11.1 +/-0.2 degrees, 11.8 +/-0.2 degrees, 12.5 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.3 +/-0.2 degrees, 16.7 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.4 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.1 +/-0.2 degrees, the main diffraction peaks are shown at 20.4 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.7 +/-0.2 degrees, 23.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.2 +/-0.2 degrees, 24.9 +/-0.2 degrees, 25.2 +/-0.2 degrees, 26.0 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.0 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.0 +/-0.2 degrees, 37.3 +/-0.2 degrees and 39.0 +/-0.2 degrees.
The crystal form of the berberine hesperetin salt prepared by the preparation method 1 is tested, and the test result is shown in figures 1-5. Figure 1 is a PXRD pattern for the crystal form of the berberine hesperetin salt. FIG. 2 is a crystal structure diagram of the hesperetin salt crystal form of berberine; figure 3 is a unit cell stacking diagram of a crystal form of berberine hesperetin salt. The crystallographic parameters are shown in table 1.
Table 1: crystallographic parameters of crystal form of berberine hesperetin salt
FIG. 4 is TG and DSC spectra of the hesperetin salt crystal form of berberine; analyzed using differential scanning calorimetry, it appears that there are 1 endothermic peak at 213 ℃ 5 ℃ in the DSC profile when the temperature rise rate is 10 ℃ per minute.
FIG. 5 shows characteristic peak position (cm) of infrared spectrum of crystal form of berberine hesperetin -1 ) 3063 + -5, 3016 + -5, 2955 + -5, 2930 + -5, 2905 + -5, 2834 + -5, 1636 + -5, 1560 + -5, 1523 + -5, 1506 + -5, 1482 + -5, 1457 + -5, 1451 + -5, 1435 + -5, 1383 + -5, 1350 + -5, 1337 + -5, 1314 + -5, 1259 + -5, 1229 + -5, 1175 + -5, 1134 + -5, 1099 + -5, 1079 + -5, 1059 + -5, 1026 + -5, 865 + -5, 805 + -5, 762 + -5, 541 + -5 cm + -5 -1 There exists a characteristic peak of infrared spectrum.
Example 2
The stability characteristics of the crystal form of the berberine hesperetin salt are as follows:
high-temperature test: placing the berberine hesperetin salt crystal form sample in an open clean surface dish, placing the sample at the temperature of 60 ℃ for 10 days, sampling and carrying out IR analysis, wherein the spectrum is consistent with the graph 5, and the result shows that the berberine hesperetin salt crystal form is stable under a high-temperature influence factor test.
High humidity test: placing the berberine hesperetin salt crystal type sample in a clean surface dish with an opening, placing the sample for 10 days under the condition of humidity of 90% +/-5% (25 ℃), sampling and carrying out IR analysis, wherein the spectrum is consistent with the graph 5, and the result shows that the berberine hesperetin salt crystal form is stable under a high-humidity influence factor test.
And (3) illumination test: placing the berberine hesperetin salt crystal form sample in an open clean surface dish, placing for 10 days under the condition of 4500lx +/-500 lx (25 ℃) of illumination, sampling and carrying out IR analysis, wherein the spectrum is consistent with the graph 5, and the result shows that the berberine hesperetin salt crystal form is stable under the illumination influence factor test.
Example 3
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that a pure crystal form product of berberine hesperetin salt or mixed crystal solid matter containing 1% -99% of the crystal form of the berberine hesperetin salt is used as raw material medicine of the combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, tablet samples with the medicine content of 20-500mg are prepared according to a certain proportion, and the formula proportion of the tablet is given in a table 2:
TABLE 2 preparation formula of crystal form tablet of berberine hesperetin salt
The method for preparing the pure crystal form of the berberine hesperetin salt or the mixed crystal raw material medicine containing 1 to 99 percent of the berberine hesperetin salt crystal form into the tablet preparation 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 2 of preparation of the combined pharmaceutical preparation (capsule):
a preparation method of a combined medicine capsule is characterized in that a pure crystal form product of berberine hesperetin salt or a mixed crystal solid matter containing 1% -99% of berberine hesperetin salt crystal form is used as a raw material medicine of the combined 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 20-500mg is prepared according to a certain proportion, and the proportion of the formula of the capsule is given in a table 3:
TABLE 3 bulk drug and adjuvant formula of berberine hesperetin salt crystal type combined drug capsule preparation
The method for preparing the pure berberine hesperetin salt crystal form or the mixed crystal raw material medicine containing 1-99% of the berberine hesperetin salt crystal form into the capsule preparation 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 1-99% of the berberine hesperetin salt crystal-type raw material medicine with a plurality of excipient auxiliary materials without using a granulating step, sieving, and directly encapsulating to obtain the capsule.
Example 4
The administration dosage of the berberine hesperetin salt crystal type combined medicine is 1 (tablet):
the pharmaceutical composition prepared and developed by using the berberine hesperetin salt crystal form as the active pharmaceutical ingredient is characterized in that the berberine hesperetin salt crystal form is used as the active pharmaceutical ingredient, the daily administration dose is 900mg, and the pharmaceutical composition can be respectively prepared into 3 common tablets of 100mg 3 times a day each time and 1 common tablet of 300mg 3 times a day each time.
The administration dosage of the crystal form of the berberine hesperetin salt 2 (capsule):
the medicine composition prepared and developed by using the berberine hesperetin salt crystal form sample as the active ingredient of the medicine is characterized in that the berberine hesperetin salt crystal form is used as the active ingredient of the medicine, the daily administration dosage is 900mg, and 100mg capsules of 3 capsules of each time and 300mg capsules of 1 capsule of 3 capsules of each time are respectively prepared.
Problems to be explained are: the berberine hesperetin salt crystal type pharmaceutical composition provided by the invention has many factors on the administration dosage of the effective components, such as: the application of the composition for preventing and treating the diseases is different, so that the daily dosage is different; the nature and severity of the disease cause different daily doses; the difference of sex, age, body surface area of patients, administration route, administration frequency and treatment purpose causes the difference of daily dosage; in addition, the difference of absorption and blood concentration existing among samples also causes that the daily proper dosage range of the invention when using the berberine hesperetin salt crystal form is 0.3-70mg/kg body weight, preferably 5-30mg/kg body weight. When in use, different total dosage schemes of the berberine hesperetin salt crystal form active ingredients are formulated according to the actual requirements of different situations for prevention and treatment, and the total dosage schemes can be completed in a multi-time or one-time administration mode.
Claims (13)
1. A crystal form of berberine hesperetin salt is characterized in that berberine and hesperetin form a salt crystal form according to a 1:1 molar ratio.
2. The crystal form of berberine hesperetin salt according to claim 1, wherein the basic structural unit is composed of 1 berberine cation and 1 hesperetin anion, under the test condition of 100K, the crystal form of berberine hesperetin salt belongs to monoclinic system, and the space group isP21/nUnit cell parameters a/a =14.734 (2), b/a =12.548 (2), c/a =16.591 (2), α/a = γ/a =90, β/a =108.45 (2), V =2909.7 (4)/a 3 Z =4, formula: c 20 H 18 NO 4 ·C 16 H 13 O 6 。
3. The crystalline form of the hesperetin salt according to claim 1, characterized in that the powder X-ray pattern positions are represented at angles of 2 θ at 6.2 ± 0.2 °, 7.6 ± 0.2 °, 9.3 ± 0.2 °, 11.1 ± 0.2 °, 11.8 ± 0.2 °, 12.5 ± 0.2 °, 12.9 ± 0.2 °,13.9 ± 0.2 °, 14.3 ± 0.2 °, 15.3 ± 0.2 °, 16.7 ± 0.2 °, 18.1 ± 0.2 °, 18.4 ± 0.2 °, 18.2 ± 0.2 °, 19.2 ± 0.2 °, 19.7 ± 0.2 °, 20.1 ± 0.2 °, 20.4 ± 0.2 °, 20.0 ± 0.2 °, 20.1 ± 0.2 °, 20.0.2 °, 20.9 ± 0.0 °, 21.9 ± 0.0.0 °, 25.2 ± 0.25.2 °, 25.0.1 ± 0 °, 25.2 ° 0.2 ° and 25.0.25 ± 0.2 ° 2 ° as ± 0.2 ° or 25.2 ° of the peaks.
4. The crystalline form of berberine hesperetin salt according to claim 1, characterized in that it has a spectrum of 3063 ± 5, 3016 ± 5, 2955 ± 5, 2930 ± 5, 2905 ± 5, 2834 ± 5, 1636 ± 5, 1560 ± 5, 1523 ± 5, 1506 ± 5, 1482 ± 5, 1457 ± 5, 1451 ± 5, 1435 ± 5, 1383 ± 5, 1350 ± 5, 1337 ± 5, 1314 ± 5, 1259 ± 5, 1229 ± 5, 1175 ± 5, 1134 ± 5, 1099 ± 5, 1079 ± 5, 1059 ± 5, 1026 ± 5, 865 ± 5, 805 ± 5, 762 ± 5, 541 ± 5cm when analyzed by infrared spectroscopy -1 There exists a characteristic peak of infrared spectrum.
5. The crystalline form of berberine hesperetin salt according to claim 1, characterized in that it exhibits 1 endothermic peak at 213 ± 5 ℃ in a DSC diagram at a temperature rise rate of 10 ℃ per minute, when analyzed using differential scanning calorimetry.
6. The crystalline form of the berberine hesperetin salt according to any one of claims 1-5, which is prepared by putting 8-hydroxy-dihydroberberine and hesperetin as raw materials into a mixed solvent of water and an organic solvent according to a molar ratio of 1.5 to 1, stirring or dissolving at 20 to 70 ℃, volatilizing or dissolving the solvent, cooling and recrystallizing, and finally filtering and drying.
7. A preparation method of a crystal form of berberine hesperetin salt is characterized in that the organic solvent is methanol, ethanol, N-propanol, isopropanol, N-butanol, ethylene glycol, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N-dimethylacetamide or N, N-dimethylformamide; the ratio of the total mass of the 8-hydroxy-dihydroberberine and the hesperetin to the dosage of the solvent is 1g: (1 to 200) ml.
8. A mixed crystal form solid substance of a crystal form of berberine hesperetin salt is characterized by containing the crystal form of berberine hesperetin salt of any one of claims 1-5 in an amount of 1-99%, preferably 20-99%.
9. A pharmaceutical composition, characterized by comprising an effective amount of the solid substance of the crystalline form of berberine hesperetin salt as described in claims 1-5 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition, which is characterized by comprising an effective dose of the mixed crystal solid matter of the berberine hesperetin salt crystal form as defined in claim 8 and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition according to any one of claims 9 or 10, wherein the daily dose of the crystalline form of berberine hesperetin salt is in the range of 20-5000 mg.
12. The pharmaceutical composition according to any one of claims 9 or 10, wherein the pharmaceutical composition is in the form of a tablet, a capsule, an injectable formulation, a pill, a sustained release formulation or a controlled release formulation.
13. Use of the crystalline form of berberine hesperetin salt according to claims 1-5 or the pharmaceutical composition according to claims 9 or 10 for the preparation of a medicament for the prevention and treatment of antibacterial, anti-inflammatory, hypolipidemic, hypoglycemic, antiviral, cardiovascular and cerebrovascular diseases, anticancer and anti-infective.
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