CN113214207A - Hesperetin and betaine eutectic compound A, preparation method, composition and application thereof - Google Patents
Hesperetin and betaine eutectic compound A, preparation method, composition and application thereof Download PDFInfo
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- CN113214207A CN113214207A CN202010080008.9A CN202010080008A CN113214207A CN 113214207 A CN113214207 A CN 113214207A CN 202010080008 A CN202010080008 A CN 202010080008A CN 113214207 A CN113214207 A CN 113214207A
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- Prior art keywords
- hesperetin
- betaine
- crystal
- eutectic compound
- preparation
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Abstract
The invention discloses a hesperetin and betaine eutectic crystal A, a preparation method, a composition and application thereof, and belongs to the technical field of medicines. Specifically, the invention discloses a co-crystal A formed by hesperetin and betaine, and the molecular formula of the co-crystal A is (C)16H14O6)·(C5H11NO2) (ii) a A preparation method of a hesperetin and betaine eutectic compound A; the hesperetin and betaine eutectic crystal A is used as an effective component of a medicine, and is applied to preparation of medicines for resisting oxidation, inflammation, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumors and nerve diseases and treating Alzheimer disease and complications.
Description
Technical Field
The invention relates to a co-crystal A formed by hesperetin-betaine; a preparation method of a hesperetin and betaine eutectic compound A; the hesperetin and betaine eutectic crystal A is used as an effective component of a medicine, and is applied to the preparation of medicines for resisting oxidation, inflammation, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumors and nerve diseases and treating Alzheimer disease and complications; belongs to the technical field of medicine.
Background
Hesperetin (Hesperetin) is flavanone compound widely existing in citrus fruits, is hesperidin hydrolysate, has a structural formula shown as a, and has effects of resisting tumor, oxidation and inflammation, and preventing atherosclerosis[1-3]。
Betaine (English name: Betaine) is a quaternary ammonium type water-soluble alkaloid extracted from Chinese wolfberry, has various good physicochemical properties and biological functions, is widely applied to a plurality of fields of pharmacy, food, additives and the like, and has a structural formula shown as b. The betaine has antiinflammatory, anti-epileptic, liver and kidney injury relieving, antitumor, nerve disease inhibiting, and Alzheimer disease treating effects[4-11]。
Polymorphism studies on hesperetin: hesperetin which is discovered at present has two crystal form states[12-13]Wherein the research crystal form A is orange containing one molecule of waterThe crystal B of the skin element is a non-aqueous crystal form. The two crystal forms of the hesperetin have essential difference with the invention in material composition, and the hesperetin raw material medicine used in the invention is crystal B.
In summary, no research report of forming a co-crystal of hesperetin-betaine is seen so far, and similar or conflicting research contents in aspects of substance form, combination ratio, preparation method, application and the like are not seen.
Disclosure of Invention
The invention prepares hesperetin-betaine into a eutectic solid substance with specific non-covalent acting force, thereby forming a new substance which is different from hesperetin and betaine and simple combined application of the hesperetin and the betaine, and further finds out the special advantages of the new eutectic solid substance in the preparation of the pharmaceutical composition for resisting oxidation, inflammation, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumors and nerve diseases and the treatment of related diseases and complications such as Alzheimer's disease.
The technical problems to be solved by the invention are as follows:
the invention aims to solve one of the technical problems that: provides the existence state and the characterization mode of the hesperetin and betaine eutectic compound A.
The second technical problem to be solved by the present invention is: provides a preparation method of a hesperetin and betaine eutectic compound A.
The invention aims to solve the third technical problem: provides a pharmaceutical composition using hesperetin and betaine eutectic compound A as a pharmaceutical active ingredient, and the dosage of each administration is within the range of 10-1000 mg. The medicine composition comprises tablets, capsules, pills, injection and sustained-release or controlled-release preparation medicines.
The fourth technical problem to be solved by the invention is: provides the effective treatment effect of the medicine by improving the blood concentration in organisms due to the combination of the hesperetin and the betaine eutectic compound A in the process of treating diseases.
The invention aims to solve the technical problems that: provides the application of the hesperetin and betaine eutectic compound A and mixed crystal solid substances thereof serving as raw materials of active ingredients of medicaments in the preparation of medicaments for resisting oxidation, inflammation, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumor and nerve diseases and treating Alzheimer disease and complications.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. the morphological characteristics of a sample A of the hesperetin and betaine eutectic compound are as follows:
1.1 the hesperetin and betaine eutectic compound A is combined by non-covalent bonds to form an eutectic substance, and the molar ratio of the hesperetin to the betaine is 1: 1.
1.2 the hesperetin and betaine eutectic crystal A does not contain a crystallization solvent or a crystallization water component, and when powder X-ray diffraction analysis is used, CuK is adoptedαWhen irradiated under experimental conditions, the diffraction peak positions are shown as follows: 2-Theta value (°) or d value
The diffraction peak relative intensity peak Height (Height%) or peak Area value (Area%) was as follows (table 1, fig. 1). The powder X-ray diffraction pattern data of the physical mixture of hesperetin-betaine raw material is shown in figure 2 and table 2. The powder X-ray diffraction pattern of the physical mixture of the hesperetin and betaine eutectic A and the hesperetin-betaine raw material has obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, and shows that the physical mixture of the hesperetin and betaine eutectic A and the hesperetin-betaine raw material is neither the same nor the same.
TABLE 1 powder X-ray diffraction Peak of hesperetin and betaine cocrystal A
TABLE 2 Hesperetin-betaine physically blended powder X-ray diffraction peaks
1.3 Thehesperetin and betaine eutectic compound A, when analyzed by attenuated total reflection Fourier infrared spectroscopy, has characteristic peaks of infrared spectra at 3056, 2973, 2846, 2752, 2619, 2167, 2015, 1723, 1711, 1641, 1634, 1607, 1594, 1533, 1516, 1488, 1473, 1459, 1447, 1434, 1426, 1397, 1388, 1336, 1305, 1280, 1269, 1244, 1221, 1185, 1176, 1161, 1133, 1089, 1065, 1025, 1012, 978, 968, 935, 896, 863, 838, 830, 812, 781, 762, 744, 713, 658cm-1, wherein the allowable deviation of the characteristic peaks of the infrared spectra is +/-2 cm-1-1(FIG. 3).
1.4 Hesperetin-betaine eutectic compound A according to claim 1, wherein when analyzed by differential scanning calorimetry, it is shown that 1 endothermic peak (fig. 4) exists at 187 ℃ ± 3 ℃ in a DSC spectrum at a temperature rise rate of 10 ℃ per minute within a range of 30-250 ℃. DSC (differential scanning calorimetry) spectra of the hesperetin and betaine eutectic compound A, the hesperetin and the betaine are obviously different in the quantity, the position and the like of heat absorption/release peaks, and show that the hesperetin and betaine eutectic compound A is not identical or identical to the hesperetin and the betaine raw materials (figure 5).
2. The preparation method of the hesperetin and betaine eutectic compound A is characterized by comprising the following steps:
2.1 the preparation method of the hesperetin and betaine eutectic compound A related by the invention adopts a solvent suspension method, the hesperetin and the betaine are mixed according to the molar ratio of 1:1, an organic solvent is added, the mixture is stirred for 1 to 96 hours at room temperature and the stirring speed of a stirrer of 20 to 400r/min, and the obtained suspension is subjected to solvent evaporation drying, filtering natural drying or filtering vacuum drying to prepare the hesperetin and betaine eutectic compound A. The organic solvent is preferably a mixed solvent prepared by combining any one or more of methanol, ethanol, ethyl acetate, dioxane, normal propyl alcohol and isopropanol in different proportions; keeping the solid-liquid ratio of the total mass of the hesperetin-betaine to the organic solvent within the range of 1mg/ml to 500 mg/ml.
2.2 the mixed solid matter of hesperetin and betaine eutectic compound A of the invention is prepared by mixing the component A of the hesperetin and betaine eutectic compound prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. Contains a hesperetin and betaine eutectic compound A component, and is characterized by comprising the following components in percentage by weight:
3.1 the pharmaceutical composition contains effective dose of hesperetin and betaine eutectic compound A and a pharmaceutically acceptable carrier.
3.2 the daily dosage of the hesperetin and betaine eutectic compound A of the pharmaceutical composition is within the range of 10 mg-1000 mg.
3.3 the pharmaceutical composition is in the form of tablets, capsules, pills, injections, sustained release preparations or controlled release preparations.
3.4 the hesperetin and betaine eutectic compound A related by the invention is applied to the preparation of various medicaments for preventing or treating oxidation resistance, inflammation resistance, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumor resistance, neurological diseases, Alzheimer's disease and other diseases and complications.
The invention relates to a pharmaceutical composition taking hesperetin and betaine eutectic compound A as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The hesperetin and betaine eutectic compound A 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 component A of the hesperetin and betaine eutectic crystal is usually in the range of 10-90% by weight.
The hesperetin and betaine eutectic crystal A can be administered 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, eyes, 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 hesperetin and betaine eutectic compound A and the mixed solid matter of the hesperetin and betaine eutectic compound A can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various particle drug delivery systems.
In order to prepare the hesperetin and betaine eutectic compound A into tablets, various excipients well known in the art can be widely used, and comprise 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 hesperetin and betaine eutectic compound A serving as an effective ingredient 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 component of the hesperetin and betaine eutectic compound A can be 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, adhesives, wetting agents, disintegrating agents and glidants for preparing the hesperetin and betaine eutectic A ingredient tablet can also be used for preparing the hesperetin and betaine eutectic A capsule.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
4. The application of the eutectic compound A containing hesperetin and betaine comprises the following steps:
the invention finds the application of the hesperetin and betaine eutectic compound A in preparing and/or treating anti-oxidation, anti-inflammation, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, anti-tumor and nerve diseases and medicaments for treating Alzheimer disease and complications.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The administration dosage of the hesperetin and betaine eutectic compound A 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 hesperetin and betaine eutectic crystal A can be taken alone or combined with other treatment medicines or symptomatic medicines. When the hesperetin and betaine eutectic compound A has synergistic effect with other therapeutic drugs, the dosage of the hesperetin and betaine eutectic compound A is adjusted according to actual conditions.
The technical scheme of the invention has the following beneficial technical effects:
compared with hesperetin in the prior art, the hesperetin and betaine eutectic compound A has obvious advantages in the aspects of safety, stability, solubility, bioactivity and the like.
The hesperetin and betaine eutectic compound A does not contain any crystallization solvent, and has good safety and patent medicine advantages.
Compared with hesperetin, the hesperetin and betaine eutectic compound A provided by the invention has an unexpected solubility advantage, and is specifically represented as follows: the compound shows remarkable advantages of solubility and dissolution rate in dissolution systems such as hydrochloride buffer (pH1.2), acetate buffer (pH4.5), phosphate buffer (pH6.8) and the like (figure 6).
The hesperetin and betaine eutectic compound A can stably exist under the conditions of high temperature (60 ℃) and illumination (4500lx +/-500 lx), and has good stability and patent medicine advantages (figure 7).
Drawings
FIG. 1 powder X-ray diffraction pattern of hesperetin and betaine eutectic compound A
FIG. 2 powder X-ray diffraction pattern of physical mixture of hesperetin and betaine eutectic A
FIG. 3 shows an infrared absorption spectrum of hesperetin and betaine eutectic compound A
FIG. 4 Differential Scanning Calorimetry (DSC) spectrum of hesperetin and betaine eutectic compound A
FIG. 5 Differential Scanning Calorimetry (DSC) spectrum of hesperetin and betaine eutectic compound A and raw material
FIG. 6 dissolution curve map of hesperetin and betaine eutectic compound A sample
FIG. 7 stability chart of hesperetin and betaine eutectic compound A
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
Preparation method of hesperetin and betaine eutectic compound A
Taking a proper amount of hesperetin and betaine, wherein the molar ratio of the hesperetin to the betaine is 1:1, adding a sample into a proper container by adopting a solvent suspension method at room temperature, 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, and the condition parameters are shown in table 3. Powder X-ray diffraction analysis is carried out on the hesperetin and betaine eutectic compound A, and the diffraction pattern of the hesperetin and betaine eutectic compound A is consistent with that of a figure 1.
TABLE 3 preparation of Co-crystals of hesperetin and betaine A method 1 embodiment
Example 2
In vitro dissolution and release characteristics of hesperetin-betaine
The solubility characteristics of the hesperetin and betaine eutectic compound A, the bulk drug and the hesperetin in a solution system with the pH value of 1.2, the pH value of 4.5 and the pH value of 6.8 are examined. The dissolution percentage is determined by referring to the technical guidance principle of dissolution test of common oral solid preparations, and the dissolution percentage is calculated by a high performance liquid chromatography and an external standard method. Dissolution curves were respectively plotted with time as abscissa and% dissolution as ordinate (fig. 6). The data are shown in Table 4.
Detection conditions are as follows: the detection system comprises: align 1200, column: agilent Eclipse XDB-C18 (4.6X 150mm,5 μm); mobile phase: methanol-water (70:30, v/v); flow rate: 1 mL. min-1(ii) a Column temperature: 30 ℃; detection wavelength: hesperetin: 280 nm; sample introduction amount: 10 μ l.
TABLE 4 dissolution Curve data
The experimental data show that the dissolving behavior of the hesperetin and betaine eutectic compound in a hydrochloride buffer solution, an acetate buffer solution and a phosphate buffer solution system is superior to that of hesperetin, and the dissolution behavior is embodied in that the hesperetin and betaine eutectic compound has a faster dissolving rate and a higher dissolving amount, is easy to be absorbed more quickly to reach an effective blood concentration, the total absorption amount is also obviously increased, the dissolving amount is about 1.5 times of that of hesperetin, and the disease treatment effect of the medicine can be better realized; the solubility curve of the hesperetin and betaine eutectic compound has a stable release platform, and can ensure that the stable blood concentration is kept in the disease treatment process.
Example 3
Stability advantage of hesperetin and betaine eutectic compound A
High-temperature test: placing a sample of the hesperetin and betaine eutectic compound A in an open clean surface dish, placing the sample at the temperature of 60 ℃ 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 the hesperetin and betaine eutectic compound A is stable under a high-temperature influence factor test.
And (3) illumination test: placing a hesperetin and betaine eutectic compound A sample in an open clean surface dish, placing the sample in an illumination box provided with a fluorescent lamp for 10 days under the condition that the illumination is 4500lx +/-500 lx, and sampling on the 0 th day, the 5 th day and the 10 th day. And performing powder X-ray diffraction analysis on the sample obtained at the sampling point, wherein the result shows that the hesperetin and betaine eutectic compound A is stable under the illumination condition. (FIG. 7)
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 pure hesperetin and betaine eutectic compound A is used as a raw material drug of a combined drug, a plurality of excipients are used as auxiliary material components for preparing the combined drug tablet, a tablet sample with the drug content of 10-500 mg is prepared according to a certain proportion, and the formula proportion of the tablet is given in a table 5:
TABLE 5 preparation formula of hesperetin and betaine eutectic compound A combined pharmaceutical tablet
The method for preparing the pure bulk drug of the hesperetin and betaine eutectic substance A substance into the tablet preparation 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 a pure hesperetin and betaine eutectic compound A is used as a raw material drug of a combined drug, a plurality of excipients are used as auxiliary material components for preparing the combined drug tablet, a tablet sample with the drug content of 10-500 mg is prepared according to a certain proportion, and the formula proportion of the tablet is given in Table 6:
preparation formula of pharmaceutical tablet containing hesperetin and betaine eutectic compound A
The method for preparing the pure bulk drug of the hesperetin and betaine eutectic substance A substance 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 for preparing a combined pharmaceutical preparation 3 (capsule):
a preparation method of a combined medicine capsule is characterized in that a pure hesperetin and betaine eutectic substance A substance is used as a raw material medicine of a 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 10-500 mg is prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 7:
bulk drug and auxiliary material formula of combined drug capsule preparation of surface 7 hesperetin and betaine eutectic compound A
The method for preparing the hesperetin and betaine eutectic A raw material medicine 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 wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the hesperetin and betaine eutectic substance A material raw material medicine with a plurality of excipient auxiliary materials uniformly without using a granulation step, sieving, and directly encapsulating to obtain the hesperetin and betaine eutectic substance A capsule.
Example 5
Administration dose 1 (tablet) of hesperetin and betaine eutectic compound a combined medicine:
the pharmaceutical composition is prepared and developed by using a sample of the hesperetin and betaine eutectic compound A as a pharmaceutical active ingredient, and is characterized in that the hesperetin and betaine eutectic compound A is used as the pharmaceutical active ingredient, the daily administration dosage is 300mg, and the pharmaceutical composition can be respectively prepared into 100mg common tablets which are taken 3 times a day and 1 tablet each time, or 300mg tablets which are taken 1 time a day and 1 tablet each time.
The administration dosage of the hesperetin and betaine eutectic compound A combined medicine is 2 (capsules):
the pharmaceutical composition is prepared and developed by using a sample of the hesperetin and betaine eutectic compound A as a pharmaceutical active ingredient, and is characterized in that the hesperetin and betaine eutectic compound A is used as the pharmaceutical active ingredient, the daily administration dose is 500mg, and 250mg capsules can be prepared into 1 capsule 2 times a day each time or 500mg capsules can be prepared into 1 capsule 1 time a day each time.
Problems to be explained are: the pharmaceutical composition of the hesperetin and betaine eutectic compound A has many factors on the administration dosage of the effective components, such as: the use for prevention and treatment varies with the daily dosage; 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 crystal form samples also causes that the daily proper dosage range of the component A of the hesperetin and betaine eutectic compound is 0.002-20mg/kg of body weight, and preferably 0.01-10mg/kg of body weight. When in use, different hesperetin and betaine eutectic A active ingredient total dosage schemes are formulated according to different actual requirements for preventing and treating different conditions, and the total dosage can be completed in a multi-time or one-time administration mode.
Reference to the literature
[1] Research progress of protective action and mechanism of cardiovascular system by Liu Zhengbing, Gongxitabin, hesperidin and hesperetin [ J ], southeast national defense medicine, 2017, 19 (5): 504-507.
[2] General research overview of values of the anti-tumor drugs of the tourmaline, the Huajuhua and the hesperetin [ J ], Chinese national folk medicine, 2017, 26 (9): 66-71.
[3] Among the zhou shujun, yuhui, maliying, etc., studies on the radical scavenging activity of hesperidin and hesperetin [ J ], report of traditional Chinese medicine and pharmacology, 2013, 41 (1): 66-67.
[4]Chen W,Zhang X,Li J,et a1.Efficacy of osmoprotectants on prevention and treatment of routine dry eye[J].Invest Ophthalmol Vis Sci,2013,54(9):6287-6297.
[5]Zheng P,Liu J,Mai S,et a1.Regulation of signal transducer and activator of transcription 3and apoptotic pathways by betaine attenuates isoproterenol—induced acute myocardial injury in rats[J].Hum Exp Toxicol.2014(1):1-10.
[6] Wanghui, wangshuxin, zuisingli, etc., influence of betaine on hippocampal GFAP, glycine and glycine receptor expression in rats with epilepsy induced by pentanitrogen [ J ], journal of chinese pathophysiology, 2013, 29 (9): 1657-1661.
[7]Fan CY,Wang MX,Ge CX,et al.Betaine supplementation Ppteets against high-fructose-induced renal injury in rats[J].J Nutr Biochem,2014,25(3):1-10.
[8]Zhang W,Wang LW,Wang LK,et a1.Betaine protects against high-fat-diet-induced liver injury by inhibition of high-mobility group box 1and Toll-like receptor 4expression in rats.Dig Dis Sci, 2013,58(11):3198-3206.
[9]Ying J,Rahbar MH,Hallman DM,et a1.Associations between dietary intake of choline and betaine and lung cancer risk,PLoS One,2013,8(2):e54561.
[10]Imbard A,Benoist JF,Blom HJ.Neural tube defects，folie acid and methylation,Int J Environ Res Public Health,2013,10(9):4352-4389.
[11]Chai GS,JiangX,Ni ZF,et a1.Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine.J Neurochem,2013,124(3):388-396.
[12]Shin W,Kim S,Chun KS.Structure of(R,S)-Hesperetin Monohydrate.Acta Crystallogr Sect C: Cryst Struct Commun,1987,43(5):904-911.
[13]Fujii S,Yamagata Y,Jin GZ,et al.Novel Molecular Conformation of(R,S)-Hesperetin in Anhydrous Crystal.Chem.Pharm.Bull.1994,42(5):1143-1145。
Claims (12)
1. A hesperetin and betaine eutectic compound A is characterized in that the hesperetin and betaine form the eutectic compound A in a non-covalent bond mode according to a 1:1 molar ratio.
2. Hesperetin-betaine cocrystal form A according to claim 1, wherein CuK is used when powder X-ray diffraction analysis is usedαDiffraction peak position under irradiation test conditions: 2-Theta value (°) or d value
And diffraction peak relative intensity: the peak Height value (Height%) or peak Area value (Area%) has the following characteristics:
3. the co-crystal a of hesperetin and betaine according to claim 1, which is analyzed by attenuated total reflection fourier infrared spectroscopy at 3056, 2973, 2846, 2752, 2619, 2167, 2015, 1723, 1711, 1641, 1634, 1607, 1594, 1533, 1516, 1488, 1473, 1459, 1447, 1434, 1426, 1397, 1388, 1336, 1305, 1280, 1269, 1244, 1221, 1185, 1176, 1161, 1133, 1089, 1065, 1025, 1012, 978, 968, 955, 935, 896, 863, 838, 830, 812, 781, 762, 744, 713, cm 658, and/or 1268, and/or 46, and/or 48, and/or 658, and/or relates to a, of these, and a, and a method, each of these compounds, and a, each of these compounds, and a, each of these compounds, and a, are obtained by using attenuated total reflection, and a, respectively, and a, respectively, and a method, respectively, and a method, and a, respectively, and a, respectively, and a, respectively, and a, respectively, and a, respectively, and a, and-1has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1。
4. The hesperetin-betaine eutectic crystal A according to claim 1, wherein 1 endothermic peak is present at 187 ℃ ± 3 ℃ in a DSC spectrum when analyzed by a Differential Scanning Calorimetry (DSC) technique, wherein the temperature rise rate is 10 ℃ per minute.
5. The preparation method of the hesperetin-betaine eutectic compound A as claimed in any one of claims 1 to 4, characterized in that the hesperetin and betaine are fed according to a molar ratio of 1:1, and the hesperetin-betaine eutectic compound A is prepared by a chemical method of solvent suspension.
6. The preparation method according to claim 5, wherein the solvent in the solvent suspension method is one or more selected from the group consisting of methanol, ethanol, ethyl acetate, dioxane, n-propanol and isopropanol; the stirring speed of the stirrer is 20 r/min-400 r/min; stirring for 1-96 hours, and carrying out solvent evaporation drying, filtering and natural drying or filtering and vacuum drying on the obtained suspension to obtain the hesperetin and betaine eutectic compound A.
7. A mixed solid containing hesperetin and betaine co-crystal A, characterized by containing hesperetin and betaine co-crystal A according to any one of claims 1 to 4 in an amount of 1 to 99.9%, preferably 10 to 99.9%, more preferably 50 to 99.9%, most preferably 85 to 99.9%.
8. A pharmaceutical composition, characterized by comprising an effective amount of hesperetin co-crystal A according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising an effective amount of the hesperetin/betaine co-crystal A mixed solid substance of claim 7 and a pharmaceutically acceptable carrier.
10. Pharmaceutical composition according to claim 8 or 9, characterized in that the daily dosage of hesperetin in association with betaine co-crystal a is in the range 10mg to 1000 mg.
11. Pharmaceutical composition according to claim 8 or 9, characterized in that the pharmaceutical composition is in the form of tablets, capsules, pills, powder injections, sustained release formulations or controlled release formulations.
12. The use of the hesperetin and betaine co-crystal A according to any one of claims 1-4 or the pharmaceutical composition according to claim 8 or 9 as a pharmaceutical active ingredient in the preparation of drugs for resisting oxidation, inflammation, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumors and neurological diseases, and treating Alzheimer's disease and complications.
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| CN106924239A (en) * | 2017-03-06 | 2017-07-07 | 龚* | Hesperetin is used to prepare the purposes of the medicine for preventing and treating diabetes |
| CN107226784A (en) * | 2017-03-31 | 2017-10-03 | 华南理工大学 | The method that super-critical anti-solvent granulating technique prepares paracetamol and glycine betaine eutectic |
| CN110183338A (en) * | 2019-05-28 | 2019-08-30 | 山东省分析测试中心 | A kind of thiocarbamide glycine betaine eutectic and the preparation method and application thereof |
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| CN106924239A (en) * | 2017-03-06 | 2017-07-07 | 龚* | Hesperetin is used to prepare the purposes of the medicine for preventing and treating diabetes |
| CN107226784A (en) * | 2017-03-31 | 2017-10-03 | 华南理工大学 | The method that super-critical anti-solvent granulating technique prepares paracetamol and glycine betaine eutectic |
| CN110183338A (en) * | 2019-05-28 | 2019-08-30 | 山东省分析测试中心 | A kind of thiocarbamide glycine betaine eutectic and the preparation method and application thereof |
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| CN115650941A (en) * | 2022-10-28 | 2023-01-31 | 广西中医药大学 | Hesperetin-berberine hydrochloride pharmaceutical co-crystal, and application and preparation method thereof |
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