CN113214209B - Hesperetin and carbamazepine eutectic, preparation method, composition and application thereof - Google Patents
Hesperetin and carbamazepine eutectic, preparation method, composition and application thereof Download PDFInfo
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- CN113214209B CN113214209B CN202010080013.XA CN202010080013A CN113214209B CN 113214209 B CN113214209 B CN 113214209B CN 202010080013 A CN202010080013 A CN 202010080013A CN 113214209 B CN113214209 B CN 113214209B
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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Abstract
The invention discloses a hesperetin and carbamazepine eutectic, a preparation method, a composition and application thereof, and belongs to the technical field of medicines. Specifically, the invention discloses a eutectic substance formed by hesperetin and carbamazepine, which has a molecular formula of (C 16 H 14 O 6 )·(C 15 H 12 N 2 O); a preparation method of hesperetin and carbamazepine eutectic; the hesperetin and carbamazepine eutectic is used as the effective components of the medicine, and is applied to preparing the medicines for resisting tumor, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications.
Description
Technical Field
The invention relates to a eutectic substance formed by hesperetin and carbamazepine; a preparation method of hesperetin and carbamazepine eutectic; the hesperetin and carbamazepine eutectic is used as the effective components of the medicine and applied to the preparation of medicines for resisting tumor, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications; belongs to the technical field of medicines.
Background
Hesperetin is a dihydroflavonoid widely existing in citrus fruits, is a hydrolysate of hesperidin, has a structural formula shown as a, and has anti-tumor, antioxidant, antiinflammatory and atherosclerosis preventing effects [1-3] 。
Carbamazepine (English name: carbamazepine) is a common calcium channel blocker with strong lipid solubility, is the first medicament for clinically treating epilepsy, and is commonly used for treating trigeminal neuralgia, manic depression, arrhythmia and other diseases, and the structural formula is shown as b. Some progress has been made in the study of the co-crystals of carbamazepine, such as the co-crystals of carbamazepine with nicotinamide [4] Carbamazepine and saccharin co-crystals [5] Carbamazepine and aspirin co-crystal [6] Co-crystals of carbamazepine and 2-hydroxybenzoic acid [7] And the like.
Polymorphic studies on hesperetin: the hesperetin found at present has two crystal forms [8-9] Wherein, the form A is the hesperetin containing one molecule of water, and the form B is the crystal-free form. The two crystal forms have essential difference in material composition with the invention, and the hesperetin bulk drug used in the patent is in a crystal B form.
In summary, no study report on forming a eutectic of hesperetin and carbamazepine has been found so far, and no similar or conflicting study contents have been found in aspects of substance morphology, combination ratio, preparation method, application and the like.
Disclosure of Invention
According to the research, the hesperetin and carbamazepine are prepared into a eutectic solid substance with specific non-covalent acting force, so that a novel substance which is different from the hesperetin and carbamazepine and is simply combined is formed, and the special advantages of the novel eutectic solid substance in preparing anti-tumor, anti-oxidation, anti-inflammatory, anti-epileptic, trigeminal neuralgia, manic depression, atherosclerosis, arrhythmia diseases and complications are found.
The invention aims to solve the technical problems:
one of the technical problems to be solved by the invention is as follows: providing the existence state and characterization mode of the hesperetin and carbamazepine eutectic.
The second technical problem to be solved by the invention is: provides a preparation method of hesperetin and carbamazepine eutectic.
The third technical problem to be solved by the invention is: pharmaceutical compositions are provided which use a co-crystal of hesperetin and carbamazepine as the pharmaceutically active ingredient in an amount ranging from 10-1000mg per administration. The medicine composition comprises tablets, capsules, pills, injection, slow release or controlled release preparation medicines.
The invention aims to solve the fourth technical problem: provides the hesperetin and carbamazepine eutectic which can be combined to improve the blood concentration in organisms in the process of treating diseases so as to play a role in effectively treating the diseases.
The invention solves the technical problems: provides the application of using hesperetin and carbamazepine eutectic and mixed crystal solid matters thereof as raw materials of active pharmaceutical ingredients in preparing medicines for resisting tumors, oxidization, inflammation, epilepsy, trigeminal neuralgia and manic depression and preventing atherosclerosis, arrhythmia diseases and complications.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. hesperetin and carbamazepine eutectic sample morphological characteristics:
1.1 the invention relates to a eutectic substance of hesperetin and carbamazepine, wherein the hesperetin and the carbamazepine are combined by non-covalent bonds to form the eutectic substance, and the molar ratio of the hesperetin to the carbamazepine is 1:1.
1.2 the present invention relates to a eutectic compound of hesperetin and carbamazepine, which contains no crystallization solvent or water componentWhen powder X-ray diffraction analysis is used, cuK is employed α Under radiation experimental conditions, the diffraction peak positions are shown as follows: 2-Theta value (°) or d valueThe diffraction peak has a solid matter (table 1, fig. 1) having the following characteristic peak with respect to the peak Height value (Height%) or the peak Area value (Area%). Powder X-ray diffraction pattern data for the physical mixture of hesperetin and carbamazepine are shown in fig. 2, table 2. The powder X-ray diffraction patterns of the hesperetin and carbamazepine eutectic and the physical mixture of hesperetin and carbamazepine have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, which indicates that the hesperetin and the carbamazepine eutectic and the physical mixture of hesperetin and carbamazepine are neither identical nor equivalent.
TABLE 1 powder X-ray diffraction peak data for hesperetin and carbamazepine co-crystals
TABLE 2 powder X-ray diffraction peak data for physical mixtures of hesperetin and carbamazepine
1.3 hesperetin and carbamazepine co-crystals according to the invention are analyzed by attenuated total reflection Fourier IR spectroscopy at 3430, 3348, 3206, 3057, 3025, 2969, 2941, 2845, 2605, 2252, 2155, 2053, 1969, 1677, 1644, 1604, 1583, 1514, 1491, 1447, 1418, 1401, 1386, 1343, 1289, 1273, 1237, 1220, 1193, 1160, 1132, 1114, 1080, 1067, 1042, 1028, 1016, 985, 971, 957, 878, 867, 860, 841, 827, 801, 789, 772, 764, 741, 716, 663cm -1 There is an infrared spectrum characteristic peak, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 (FIG. 3).
1.4 the hesperetin and carbamazepine co-crystals according to the present invention have 1 endothermic peak at 176 ℃ + -3 ℃ in the DSC profile when analyzed by differential scanning calorimetry at a temperature rise rate of 10 ℃ per minute in the range of 30-250 ℃ (FIG. 4). The DSC spectra of hesperetin and carbamazepine co-crystals and hesperetin, carbamazepine have obvious differences in the number, position and the like of absorption/release peaks, which indicates that the hesperetin and carbamazepine co-crystals are neither identical nor equivalent to hesperetin and carbamazepine raw materials (fig. 5).
2. The preparation method of the hesperetin and carbamazepine eutectic is characterized in that:
2.1A solvent suspension method is adopted in the preparation method of the hesperetin and carbamazepine eutectic, the hesperetin and the carbamazepine are mixed according to the mol ratio of 1:1, an organic solvent is added, the stirring speed is 20 r/min-400 r/min under the room temperature condition, the stirring is carried out for 1 hour-96 hours, and the obtained suspension is dried through solvent evaporation, natural drying through filtration or vacuum drying through filtration, so that the hesperetin and carbamazepine eutectic is obtained. The organic solvent is preferably selected from any one or more of methanol, ethanol, acetonitrile, acetone, ethyl acetate, dioxane, n-hexane and cyclohexane, and is prepared by combining the mixed solvents in different proportions; the solid-liquid ratio of the total mass of the hesperetin and the carbamazepine to the organic solvent is kept within the range of 1mg/ml-500 mg/ml.
2.2 the mixed solid substance containing the hesperetin and carbamazepine eutectic is prepared by mixing the hesperetin and carbamazepine eutectic prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. Comprises the components of the hesperetin and carbamazepine eutectic, the administration dose characteristics and the pharmaceutical preparation composition characteristics:
3.1 pharmaceutical compositions according to the invention comprise an effective dose of hesperetin in co-crystals with carbamazepine and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition related by the invention has the dose of hesperetin and carbamazepine eutectic in the range of 10 mg-1000 mg per day.
3.3 the pharmaceutical composition of the invention is in the form of tablet, capsule, pill, injection, sustained release preparation or controlled release preparation.
3.4 the application of the hesperetin and carbamazepine eutectic in preparing the medicines for resisting tumor, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications.
The invention relates to a pharmaceutical composition taking hesperetin and carbamazepine eutectic as active ingredients. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be made by combining the hesperetin and carbamazepine co-crystals of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The hesperetin and carbamazepine co-crystals of the invention typically have a composition in the range of 10-90% by weight.
The hesperetin and carbamazepine co-crystals of the present invention can be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory tract, skin, vaginal, rectal, etc.
The administration form of the present invention is preferably a solid dosage form. The solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and spray.
The mixed solid substance of the hesperetin and carbamazepine eutectic substance and the mixed solid substance of the hesperetin and the carbamazepine eutectic substance can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various particle administration systems.
For the preparation of the hesperetin and carbamazepine co-crystals of the present invention into tablets, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, 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 bilayer and multilayer tablets.
In order to prepare the administration unit into a capsule, the hesperetin-carbamazepine eutectic of the present invention as an active ingredient may be mixed with a diluent and a glidant, and the mixture may be directly placed into a hard capsule or a soft capsule. The active ingredients of the hesperetin and carbamazepine eutectic compound of the invention can be prepared into particles or pellets by mixing with a diluent, a binder and a disintegrating agent, and then placed into hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants and glidants used for preparing the tablets of the present invention of the eutectic substance of hesperetin and carbamazepine can also be used for preparing the capsules of the present invention of the eutectic substance of hesperetin and carbamazepine.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
4. Use of a co-crystal comprising hesperetin and carbamazepine:
the invention discovers the application of the hesperetin and carbamazepine eutectic in preparing and/or treating anti-tumor, antioxidant, anti-inflammatory, epileptic, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The administration amount of hesperetin and carbamazepine co-crystals of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The hesperetin and carbamazepine cocrystal can be taken alone or combined with other therapeutic drugs or symptomatic drugs. When the hesperetin and carbamazepine eutectic of the invention have synergistic effect with other therapeutic drugs, the dosage of the hesperetin and carbamazepine eutectic should be adjusted according to the actual situation.
The technical scheme of the invention has the following beneficial technical effects:
compared with the hesperetin in the prior art, the hesperetin has obvious advantages in the aspects of safety, solubility, stability, bioactivity and the like.
The hesperetin and carbamazepine eutectic does not contain any crystallization solvent, and has good safety patent medicine advantages.
Compared with the hesperetin, the hesperetin and carbamazepine eutectic compound has unexpected solubility advantages, and is specifically characterized in that: the dissolution system showed remarkable advantages of solubility and dissolution rate in a hydrochloride buffer (ph 1.2), an acetate buffer (ph 4.5), a phosphate buffer (ph 6.8), pure water (ph 7.0) and the like (fig. 6).
The hesperetin and carbamazepine eutectic compound can exist stably under the conditions of high temperature (60 ℃), high humidity (25 ℃), relative humidity (90% +/-5%) and illumination (4500 lx+/-500 lx), and has good stability and advantages of patent medicine (figure 7).
Drawings
FIG. 1 powder X-ray diffraction pattern of hesperetin and carbamazepine co-crystals
FIG. 2 powder X-ray diffraction pattern of physical mixture of hesperetin and carbamazepine
FIG. 3 is an infrared absorption spectrum of hesperetin and carbamazepine co-crystals
FIG. 4 differential scanning calorimetric profile of hesperetin and carbamazepine co-crystals
FIG. 5 differential scanning calorimetric profile of hesperetin and carbamazepine co-crystals and starting material
FIG. 6 solubility curves of samples under different conditions
FIG. 7 stability profile of hesperetin and carbamazepine co-crystals
Detailed Description
The following examples are given for better illustration of the technical solution of the present invention, but the present invention is not limited thereto.
Example 1
Preparation method 1 of hesperetin and carbamazepine eutectic
Taking a proper amount of hesperetin and carbamazepine, 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, wherein the condition parameters are shown in Table 3. Powder X-ray diffraction analysis was performed on the sample, and the diffraction pattern thereof was identical to that of fig. 1, indicating that the obtained sample was a eutectic of hesperetin and carbamazepine.
TABLE 3 preparation of hesperetin and carbamazepine Co-crystals specific examples of method 1
Example 2
In vitro dissolution and release characteristics of hesperetin and carbamazepine eutectic
The solubility characteristics of the hesperetin and carbamazepine eutectic and hesperetin bulk drug in a solution system with pure water, pH value of 1.2, pH value of 4.5 and pH value of 6.8 are examined. The experiment is carried out by referring to the common oral solid preparation dissolution test technical guidelines. The dissolution percentage is calculated by a high performance liquid phase method and an external standard method. Dissolution curves were drawn with time on the abscissa and percent dissolution on the ordinate, respectively (fig. 6). The data are shown in Table 4.
Detection conditions: the detection system comprises: align 1200, column: agilent Eclipse XDB-C18 (4.6X105 mm,5 μm); mobile phase: methanol-water (70:30, v/v); flow rate: 1 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the Column temperature: 30 ℃; detection wavelength: hesperetin: 280nm; sample injection amount: 10 μl.
TABLE 4 dissolution profile data
The experimental data show that the dissolution behavior of the hesperetin and carbamazepine eutectic in a hydrochloride buffer solution, an acetate buffer solution, a phosphate buffer solution and a pure water system is superior to that of the hesperetin raw material, and the specific characteristics are that the hesperetin and carbamazepine eutectic has a faster dissolution rate and a higher dissolution amount, is easy to be absorbed more rapidly to reach the effective blood concentration, the absorption total amount is obviously increased, the dissolution amount is about 1.5 times of that of the hesperetin, and the disease treatment effect of the medicine can be better realized; the solubility curve of the hesperetin and carbamazepine eutectic has a stable release platform, and can ensure that the stable blood concentration can be maintained in the disease treatment process.
Example 3
Stability advantage of hesperetin and carbamazepine co-crystals
High temperature test: samples of hesperetin and carbamazepine cocrystals were placed in open clean dishes, left at 60 ℃ for 10 days, and sampled on day 0, day 5, and day 10. Powder X-ray diffraction analysis is carried out on the sample obtained by the sampling point, and the result shows that the hesperetin and carbamazepine eutectic is stable under a high-temperature influence factor test.
High humidity test: samples of hesperetin and carbamazepine co-crystals were placed in open clean petri dishes, left at 25 ℃ for 10 days at 90% ± 5% relative humidity, and sampled on day 0, day 5, and day 10. Powder X-ray diffraction analysis is carried out on the sample obtained by the sampling point, and the result shows that the hesperetin and carbamazepine eutectic is stable under the high-humidity condition.
Illumination test: the samples of the hesperetin and carbamazepine cocrystal were placed in an open clean petri dish, placed in an illumination box equipped with a fluorescent lamp, placed for 10 days at an illuminance of 4500 lx.+ -. 500lx, and sampled on day 0, day 5, and day 10. Powder X-ray diffraction analysis is carried out on the sample obtained by the sampling point, and the result shows that the hesperetin and carbamazepine eutectic is stable under the high-humidity condition. (FIG. 7)
Example 4
Preparation method of combination pharmaceutical formulation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that pure hesperetin and carbamazepine eutectic 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 tablet, a tablet sample with the dosage of 10-500 mg of each tablet is prepared according to a certain proportion, and the formula proportion of the tablet is shown in table 5:
table 5 preparation formulation of hesperetin and carbamazepine co-crystal combination pharmaceutical tablet
The method for preparing the pure product bulk drug of the hesperetin and carbamazepine eutectic into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, and tabletting directly; or mixing the auxiliary materials, granulating by a dry method, uniformly mixing with the raw materials, and tabletting.
Preparation method of combination pharmaceutical formulation 2 (tablet):
a preparation method of a combined medicine tablet is characterized in that hesperetin and carbamazepine eutectic pure products are used as raw material medicines of the combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, a tablet sample with the dosage of 10-500 mg of each tablet is prepared according to a certain proportion, and the formula proportion of the tablet is given in table 6:
table 6 preparation formulation of hesperetin and carbamazepine co-crystal compound pharmaceutical tablet
The method for preparing the pure product bulk drug of the hesperetin and carbamazepine eutectic into the tablet preparation comprises the following steps: mixing several excipients and raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into soft material, sieving, granulating, oven drying, sieving, granulating, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Preparation method 3 of the combined pharmaceutical preparation (capsule):
a preparation method of a combined medicine capsule is characterized in that pure hesperetin and carbamazepine eutectic 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 dosage of 10-500 mg is prepared according to a certain proportion, and the formula proportion of the capsule is shown in a table 7:
table 7 raw material medicine and auxiliary material formula of hesperetin and carbamazepine eutectic compound medicine capsule preparation
The method for preparing the hesperetin and carbamazepine eutectic bulk drug into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into wet granule, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing hesperetin and carbamazepine eutectic crude drug with excipient adjuvants, sieving, and directly encapsulating.
Example 5
Dose 1 (tablet) of hesperetin and carbamazepine co-crystal combination:
the pharmaceutical composition is characterized in that the hesperetin and carbamazepine eutectic is used as the active ingredients of the medicines, the daily administration dosage is 300mg, and the pharmaceutical composition can be prepared into 100-mg common tablets of 3 times per time or 1 time per day or 300-mg tablets of 1 time per time.
Dose 2 (capsule) of hesperetin and carbamazepine co-crystal combination drug:
the preparation and development of the pharmaceutical composition using the hesperetin and carbamazepine eutectic sample as the pharmaceutical active ingredients is characterized in that the hesperetin and carbamazepine eutectic is used as the pharmaceutical active ingredients, the daily administration dosage is 500mg, and the pharmaceutical composition can be prepared into 250mg capsules for 2 times a day/1 granule/time or 500mg capsules for 1 time a day/1 granule/time respectively.
Problems to be described: the pharmaceutical composition of hesperetin and carbamazepine co-crystal has a plurality of factors on the administration dosage of the active ingredients, such as: the different uses for prevention and treatment cause different daily dosage; the different nature and severity of the illness cause the different daily dosage of the medicine; the sex, age and body surface area of patients are different, and the administration route, the administration times and the treatment purpose are different, so that the daily administration dosage is different; in addition, the presence of absorption and blood concentration differences between the crystalline samples also result in a suitable daily dosage range of 0.002-20mg/kg body weight, preferably 0.01-10mg/kg body weight, for the hesperetin and carbamazepine co-crystals used in the present invention. When in use, different total dosage schemes of the active ingredients of the hesperetin and carbamazepine eutectic should be formulated according to the actual requirements of prevention and treatment under different conditions, and the administration can be completed in multiple or one administration modes.
Reference to the literature
[1] Liu Zhengbing, gong Jianbin, development of the protective effect and mechanism of hesperidin and hesperetin on the cardiovascular system [ J ], southeast national defense medicine, 2017, 19 (5): 504-507.
[2] Dan Linlin, zhou Juhua, hesperetin anti-tumor pharmaceutical value study profile [ J ], chinese ethnic medicine, 2017, 26 (9): 66-71.
[3] Shujun, in the sub-benefit, ma Liying, etc., study of hesperidin and hesperetin scavenging free radical activity [ J ], chinese medical report, 2013, 41 (1): 66-67.
[4]Buanz ABM.,Parkinson GN,and Gaisford S.Characterizati on of Carbamazepine-Nicatinamide Cocrystal Polymorphs with Rapid Heating DSC and XRPD.Cryst.Growth&Des.,2011,11,1177-1181.
[5]Childs SL,Wood PA,Hornedo NR,et al.Analysis of 50Crystal Structures Containing Carbamazepine Using the Materials Module of Mercury CSD.Cryst.Growth&Des.,2009,9(4),1869-1888.
[6]Vishweshwar P,McMahon JA,Oliveira M,et al.The Predictably Elusive Form II of Aspirin.J.Am.Chem.Soc.,2005,127,16802-16803.
[7]McMahon JA,Bis JA,Vishweshwar P,et al.Crystal engineering of the composition of pharmaceutical phases.3 1 .Primary amide supramolecular heterosynthons and their role in the design of pharmaceutical co-crystals.Z.Kristallogr.2005,220,340–350.
[8]Shin W,Kim S,Chun KS.Structure of(R,S)-Hesperetin Monohydrate.Acta Crystallogr.,Sect.C:Cryst.Struct.Commun.,1987,43(5):904-911.
[9]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 (14)
1. A eutectic of hesperetin and carbamazepine is characterized in that the eutectic is formed by the hesperetin and the carbamazepine in a non-covalent bond mode according to a molar ratio of 1:1, and CuK is adopted when powder X-ray diffraction analysis is used α Diffraction peak position under radiation experimental conditions: 2-Theta value (°) or d valueAnd diffraction peak relative intensity: peak Height value (Height%) or peak Area value (Area%)The method has the following characteristics:
2. the co-crystal of hesperetin and carbamazepine according to claim 1, wherein when analyzed using attenuated total reflectance fourier infrared spectroscopy, at 3430, 3348, 3206, 3057, 3025, 2969, 2941, 2845, 2605, 2252, 2155, 2053, 1969, 1677, 1644, 1604, 1583, 1514, 1491, 1447, 1418, 1401, 1386, 1343, 1289, 1273, 1237, 1220, 1193, 1160, 1132, 1114, 1080, 1067, 1042, 1028, 1016, 985, 971, 957, 878, 867, 860, 841, 827, 801, 789, 772, 764, 741, 716, 663cm -1 There is an infrared spectrum characteristic peak, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
3. The co-crystal of hesperetin and carbamazepine according to claim 1, characterized in that it exhibits 1 endothermic peak at 176 ℃ ± 3 ℃ in its DSC profile when analyzed using differential scanning calorimetric technique, at a temperature rise rate of 10 ℃ per minute, in the range of 30-250 ℃.
4. A method for preparing a co-crystal of hesperetin and carbamazepine according to any one of claims 1-3, wherein the hesperetin and carbamazepine are fed in a molar ratio of 1:1, and the co-crystal of hesperetin and carbamazepine is prepared by a chemical method of solvent suspension.
5. The method according to claim 4, wherein the solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane; the stirring speed is 20 r/min-400 r/min; stirring for 1-96 hours, and evaporating and drying the obtained suspension by solvent, filtering and naturally drying or filtering and vacuum drying to obtain the hesperetin and carbamazepine eutectic.
6. A mixed solid material comprising hesperetin and carbamazepine co-crystals, characterized in that the amount of hesperetin and carbamazepine co-crystals according to any of claims 1-3 is 1-99.9%.
7. A mixed solid material comprising hesperetin and carbamazepine co-crystals, characterized in that the amount of hesperetin and carbamazepine co-crystals according to any of claims 1-3 is 10-99.9%.
8. A mixed solid material comprising hesperetin and carbamazepine co-crystals, characterized in that the amount of hesperetin and carbamazepine co-crystals according to any of claims 1-3 is 50-99.9%.
9. A mixed solid material comprising hesperetin and carbamazepine co-crystals, characterized in that the amount of hesperetin and carbamazepine co-crystals according to any of claims 1-3 is 85-99.9%.
10. A pharmaceutical composition comprising an effective amount of the hesperetin and carbamazepine co-crystal according to any of claims 1 to 3 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising an effective amount of a mixed solid substance of hesperetin and carbamazepine co-crystals according to any of claims 6 to 9 and a pharmaceutically acceptable carrier.
12. Pharmaceutical composition according to claim 10 or 11, characterized in that the daily dosage of hesperetin and carbamazepine co-crystals is in the range of 10mg to 1000 mg.
13. Pharmaceutical composition according to claim 10 or 11, characterized in that the dosage form of the pharmaceutical composition is a tablet, capsule, pill, powder injection, slow release formulation or controlled release formulation.
14. Use of the hesperetin and carbamazepine co-crystals according to any of claims 1-3 or the mixed solid substance comprising hesperetin and carbamazepine co-crystals according to any of claims 6-9 or the pharmaceutical composition according to claim 10 or 11 for the preparation of an anti-tumor, anti-oxidant, anti-inflammatory, anti-epileptic, anti-trigeminal neuralgia, anti-manic depression, anti-atherosclerosis, anti-arrhythmic diseases and complications drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1721613A1 (en) * | 2005-05-13 | 2006-11-15 | Mewicon med. wiss. Beratung GmbH | Hesperidin for the treatment of epilepsy, migraine, schizophrenia, depression and drug abuse |
| WO2008108639A1 (en) * | 2007-03-08 | 2008-09-12 | Avantium Holding B.V. | Co-crystalline forms of carbamazepine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1721613A1 (en) * | 2005-05-13 | 2006-11-15 | Mewicon med. wiss. Beratung GmbH | Hesperidin for the treatment of epilepsy, migraine, schizophrenia, depression and drug abuse |
| WO2008108639A1 (en) * | 2007-03-08 | 2008-09-12 | Avantium Holding B.V. | Co-crystalline forms of carbamazepine |
Non-Patent Citations (2)
| Title |
|---|
| 在线过程分析技术在抗生素等药物结晶中的应用;刘胜;侯静美;龚俊波;;中国抗生素杂志(11) * |
| 药物共晶筛选技术的研究进展;黄雨婷;徐嘉;迟宗良;范孟雪;秦昆明;蔡挺;蔡宝昌;;国际药学研究杂志(04) * |
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