CN113214209A - Hesperetin and carbamazepine eutectic compound, preparation method, composition and application thereof - Google Patents
Hesperetin and carbamazepine eutectic compound, preparation method, composition and application thereof Download PDFInfo
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- CN113214209A CN113214209A CN202010080013.XA CN202010080013A CN113214209A CN 113214209 A CN113214209 A CN 113214209A CN 202010080013 A CN202010080013 A CN 202010080013A CN 113214209 A CN113214209 A CN 113214209A
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- hesperetin
- carbamazepine
- crystal
- eutectic
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a hesperetin and carbamazepine eutectic compound, a preparation method, a composition and application thereof, and belongs to the technical field of medicines. Specifically, the invention discloses a co-crystal formed by hesperetin and carbamazepine, and the molecular formula of the co-crystal is (C)16H14O6)·(C15H12N2O); a preparation method of an hesperetin and carbamazepine eutectic compound; the hesperetin and carbamazepine eutectic compound is used as an effective component of a medicine, and is applied to preparing medicines for resisting tumors, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications.
Description
Technical Field
The invention relates to an eutectic compound formed by hesperetin and carbamazepine; a preparation method of an hesperetin and carbamazepine eutectic compound; the hesperetin and carbamazepine eutectic compound is used as an effective component of a medicine, and is applied to the preparation of medicines for resisting tumors, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression, atherosclerosis, arrhythmia diseases 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]。
Carbamazepine (British name: Carbamazepine) is a common calcium channel blocker with strong fat solubility, is a first choice medicament for clinically treating epilepsy, is commonly used for treating trigeminal neuralgia, manic depression, arrhythmia and other diseases, and has a structural formula shown as b. Some progress has been made in the study of co-crystals of carbamazepine, such as the co-crystal of carbamazepine and nicotinamide[4]Eutectic of carbamazepine and saccharin[5]Co-crystals of carbamazepine and aspirin[6]Eutectic compound of carbamazepine and 2-hydroxybenzoic acid[7]And so on.
Polymorphism studies on hesperetin: the hesperetin which is discovered at present hasTwo crystal form states[8-9]Wherein, the research crystal A is hesperetin containing one molecule of water, and the research crystal B is a crystal form without water. 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 and carbamazepine is found so far, and similar or conflicting research contents in aspects of substance form, combination ratio, preparation method, application and the like are not found.
Disclosure of Invention
The research of the invention is that hesperetin and carbamazepine are prepared into eutectic solid matter with specific non-covalent acting force, so that a new matter which is different from hesperetin and carbamazepine and is simply combined with the hesperetin and the carbamazepine is formed, and the special advantages of the novel eutectic solid matter in preparing the medicines for resisting tumors, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression, and preventing atherosclerosis, arrhythmia diseases and complications are further discovered.
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 existing state and the characterization mode of the co-crystal of hesperetin and carbamazepine.
The second technical problem to be solved by the present invention is: provides a preparation method of a hesperetin and carbamazepine eutectic compound.
The invention aims to solve the third technical problem: provides a pharmaceutical composition using the co-crystal of hesperetin and carbamazepine 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 hesperetin and carbamazepine eutectic compound which can improve the blood concentration in organisms to play the effective treatment role of the medicament due to the combination of the two eutectic compounds in the process of treating diseases.
The invention aims to solve the technical problems that: provides the application of the hesperetin and carbamazepine eutectic compound and the mixed crystal solid matter thereof as raw materials of active ingredients of the medicine in preparing the medicines for resisting tumors, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. morphological characteristics of a hesperetin and carbamazepine eutectic sample:
1.1 the hesperetin and carbamazepine eutectic compound provided by the invention is combined with non-covalent bonds to form a eutectic substance, and the molar ratio of the hesperetin to the carbamazepine is 1: 1.
1.2 the co-crystal of hesperetin and carbamazepine does not contain a crystallization solvent or a crystallization water component, and CuK is adopted when powder X-ray diffraction analysis is usedαWhen 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 and carbamazepine are shown in figure 2 and table 2. The powder X-ray diffraction patterns of the hesperetin and carbamazepine eutectic compound and the hesperetin and carbamazepine physical mixture are obviously different in the number of diffraction peaks, the positions of the diffraction peaks, the intensity of the diffraction peaks, the topological patterns of the diffraction peaks and the like, which indicates that the hesperetin and carbamazepine eutectic compound and the hesperetin and carbamazepine physical mixture are not the same or identical.
TABLE 1 powder X-ray diffraction Peak data of Co-crystals of hesperetin and carbamazepine
TABLE 2 powder X-ray diffraction Peak data for physical mixtures of hesperetin and carbamazepine
1.3A hesperetin/carbamazepine cocrystal of the present invention is analyzed by attenuated total reflection 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-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1(FIG. 3).
1.4 when the hesperetin and carbamazepine eutectic compound is analyzed by using a differential scanning calorimetry technology, 1 endothermic peak (shown in figure 4) exists at 176 +/-3 ℃ in a DSC spectrum at the temperature rise rate of 10 ℃ per minute within the range of 30-250 ℃. DSC (differential pressure curves) spectra of the hesperetin and carbamazepine eutectic product, the hesperetin and the carbamazepine have obvious differences in the quantity, the position and the like of heat absorption/release peaks, and show that the hesperetin and carbamazepine eutectic product is different from hesperetin and carbamazepine raw materials and is also different from the hesperetin and the carbamazepine raw materials (figure 5).
2. The preparation method of the hesperetin and carbamazepine eutectic compound is characterized by comprising the following steps:
2.1 the preparation method of the hesperetin and carbamazepine eutectic compound related by the invention adopts a solvent suspension method, the hesperetin and the carbamazepine are mixed according to the molar ratio of 1:1, an organic solvent is added, the stirring speed is 20 r/min-400 r/min under the condition of room temperature, the stirring is carried out for 1 hour-96 hours, and the obtained suspension is subjected to solvent evaporation drying, filtering natural drying or filtering vacuum drying to obtain the hesperetin and carbamazepine eutectic compound. The organic solvent is preferably a mixed solvent prepared by combining any one or more of methanol, ethanol, acetonitrile, acetone, ethyl acetate, dioxane, normal hexane and cyclohexane in different proportions; keeping the solid-to-liquid ratio of the total mass of the hesperetin and the carbamazepine to the organic solvent within the range of 1mg/ml to 500 mg/ml.
2.2 the mixed solid matter containing the hesperetin and carbamazepine eutectic mixture is prepared by mixing the hesperetin and carbamazepine eutectic mixture prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. Contains the components of a co-crystal substance of hesperetin and carbamazepine, and has the characteristics of administration dosage and pharmaceutical preparation composition:
3.1 the pharmaceutical composition contains effective dose of hesperetin and carbamazepine eutectic crystal and pharmaceutically acceptable carriers.
3.2 the daily dosage of the pharmaceutical composition related to the invention is 10 mg-1000 mg of the hesperetin and carbamazepine eutectic mixture.
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 carbamazepine eutectic compound is applied to preparing medicaments for resisting tumors, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications.
The invention relates to a pharmaceutical composition taking a hesperetin and carbamazepine eutectic crystal as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The co-crystal of hesperetin and carbamazepine 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 composition of the co-crystal of hesperetin and carbamazepine is usually within the range of 10-90% by weight.
The hesperetin and carbamazepine eutectic compound can be administrated in a unit dosage form, and the administration route can be intestinal tract or parenteral tract, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, 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 carbamazepine eutectic compound and the mixed solid matter of the hesperetin and the carbamazepine eutectic compound 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 carbamazepine cocrystal of the present invention into tablets, various excipients known in the art, including diluents, binders, wetting agents, disintegrants, lubricants, glidants, can be widely used. 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-carbamazepine eutectic compound 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 components of the hesperetin and carbamazepine eutectic crystal are firstly prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. Various diluents, adhesives, wetting agents, disintegrating agents and glidants for preparing the hesperetin and carbamazepine cocrystal ingredient tablets can also be used for preparing capsules of the hesperetin and carbamazepine cocrystal.
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 containing hesperetin and carbamazepine comprises the following steps:
the invention finds the application of the co-crystal of hesperetin and carbamazepine in preparing and/or treating medicaments for resisting tumors, resisting oxidation, resisting inflammation, epilepsy, trigeminal neuralgia and manic depression and preventing atherosclerosis, arrhythmia diseases 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 co-crystal of hesperetin and carbamazepine 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 carbamazepine eutectic crystal can be taken alone or combined with other treatment medicines or symptomatic medicines. When the hesperetin and carbamazepine eutectic compound has synergistic effect with other treatment medicines, the dosage of the hesperetin and carbamazepine eutectic compound 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 carbamazepine eutectic crystal has obvious advantages in the aspects of safety, solubility, stability, biological activity and the like.
The hesperetin and carbamazepine eutectic compound does not contain any crystallization solvent, and has good safety and patent medicine advantages.
Compared with hesperetin, the hesperetin and carbamazepine eutectic compound provided by the invention has unexpected solubility advantage, and is specifically represented as follows: the dissolution system shows obvious advantages of solubility and dissolution rate in hydrochloride buffer solution (pH1.2), acetate buffer solution (pH4.5), phosphate buffer solution (pH6.8), pure water (pH7.0) and the like (FIG. 6).
The hesperetin and carbamazepine eutectic crystal can stably exist under the conditions of high temperature (60 ℃), high humidity (25 ℃), relative humidity (90% +/-5%) and illumination (4500lx +/-500 lx), and has good stability and patent medicine advantages (figure 7).
Drawings
FIG. 1 powder X-ray diffraction pattern of co-crystal of hesperetin and carbamazepine
FIG. 2 powder X-ray diffraction Pattern of a physical mixture of hesperetin and carbamazepine
FIG. 3 is an infrared absorption spectrum of a co-crystal of hesperetin and carbamazepine
FIG. 4 differential scanning calorimetry thermogram of hesperetin and carbamazepine eutectic
FIG. 5 Differential Scanning Calorimetry (DSC) spectrum of eutectic mixture of hesperetin and carbamazepine and raw material
FIG. 6 solubility curves of samples under different conditions
FIG. 7 stability chart of hesperetin and carbamazepine eutectic mixture
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 carbamazepine eutectic compound 1
Taking a proper amount of hesperetin and carbamazepine, wherein the molar ratio of the hesperetin to the carbamazepine 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 carbamazepine eutectic crystal, and the diffraction pattern of the hesperetin and carbamazepine eutectic crystal is consistent with that of a figure 1.
TABLE 3 preparation of Co-crystals of hesperetin and carbamazepine 1
Example 2
In-vitro dissolution release characteristic of hesperetin and carbamazepine eutectic substance
The solubility characteristics of the hesperetin and carbamazepine eutectic compound and the hesperetin raw material 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 according to the technical guidance principle of dissolution test of common oral solid preparations. The percentage of dissolution was calculated by the HPLC method and by the 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 behaviors of the co-crystal of hesperetin and carbamazepine in a hydrochloride buffer solution, an acetate buffer solution, a phosphate buffer solution and a pure water system are all superior to those of a raw material of hesperetin, and the dissolution is particularly characterized in that the co-crystal of hesperetin and carbamazepine has higher dissolving rate and higher dissolving amount, is easy to absorb more quickly to reach 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 co-crystal of hesperetin and carbamazepine 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 carbamazepine eutectic crystal
High-temperature test: placing a sample of the co-crystal of hesperetin and carbamazepine 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 from the sampling point, and the result shows that the hesperetin and carbamazepine eutectic compound is stable under a high-temperature influence factor test.
High humidity test: the hesperetin and carbamazepine eutectic crystal sample is placed in an open clean surface dish, is placed for 10 days at 25 ℃ under the condition that the relative humidity is 90% +/-5%, and is sampled 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 from the sampling point, and the result shows that the hesperetin and carbamazepine eutectic is stable under the high-humidity condition.
And (3) illumination test: placing a hesperetin and carbamazepine eutectic crystal sample in an open clean surface dish, placing the sample in an illumination box 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. Powder X-ray diffraction analysis is carried out on the sample obtained from the sampling point, and the result shows that the hesperetin and carbamazepine eutectic is stable under the high-humidity 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 pure products of a hesperetin and carbamazepine eutectic compound are used as raw material drugs of the 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 pharmaceutical tablet containing hesperetin and carbamazepine eutectic mixture
The method for preparing the pure bulk drug of the co-crystal product of hesperetin and carbamazepine 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 carbamazepine eutectic compound is used as a raw drug of a combined drug, a plurality of excipients are used as auxiliary 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 6:
preparation formula of pharmaceutical tablet combined by hesperetin and carbamazepine eutectic compound
The method for preparing the pure bulk drug of the co-crystal product of hesperetin and carbamazepine 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 pure products of hesperetin and carbamazepine eutectic crystal are used as raw material medicines 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 table 7 hesperetin and carbamazepine eutectic compound
The method for preparing the hesperetin and carbamazepine eutectic crude drug 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 hesperetin and carbamazepine eutectic crude drug with a plurality of excipient auxiliary materials without using a granulation step, sieving, and directly encapsulating to obtain the pharmaceutical composition.
Example 5
Administration dose 1 (tablet) of the combined drug of hesperetin and carbamazepine cocrystal:
the pharmaceutical composition is prepared and developed by using a hesperetin and carbamazepine eutectic sample as a pharmaceutical active ingredient, and is characterized in that the hesperetin and carbamazepine eutectic is used as the pharmaceutical active ingredient, the daily administration dose 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 combined drug of the hesperetin and carbamazepine eutectic compound is 2 (capsules):
the pharmaceutical composition is prepared and developed by using a hesperetin and carbamazepine eutectic sample as a pharmaceutical active ingredient, and is characterized in that the hesperetin and carbamazepine eutectic is used as the pharmaceutical active ingredient, the daily administration dose is 500mg, and 250mg capsules can be prepared respectively by 2 times a day and 1 capsule each time, or 500mg capsules can be prepared by 1 time a day and 1 capsule each time.
Problems to be explained are: the pharmaceutical composition of the co-crystal of hesperetin and carbamazepine 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 composition of the co-crystal of hesperetin and carbamazepine used in the invention is 0.002-20mg/kg of body weight, and preferably 0.01-10mg/kg of body weight. When in use, different hesperetin and carbamazepine eutectic compound effective component total dosage schemes are made according to different actual requirements of prevention and treatment of different conditions, and the total dosage schemes 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]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.31.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 (12)
1. The co-crystal of hesperetin and carbamazepine is characterized in that the hesperetin and the carbamazepine form the co-crystal by non-covalent bonds according to the molar ratio of 1: 1.
2. The co-crystal of hesperetin and carbamazepine according to claim 1, characterized in that CuK is used when using powder X-ray diffraction analysisαDiffraction 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 of hesperetin and carbamazepine according to claim 1, which has been analyzed by attenuated total reflection 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, 764, 741, 716, 663cm-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1。
4. The co-crystal of hesperetin and carbamazepine according to claim 1, characterized in that when analyzed by differential scanning calorimetry, it shows that 1 endothermic peak exists at 176 ℃ ± 3 ℃ in a DSC spectrum when the temperature rise rate is 10 ℃ per minute within the range of 30-250 ℃.
5. A preparation method of the co-crystal of hesperetin and carbamazepine as defined in any one of claims 1 to 4, characterized in that the hesperetin and carbamazepine are fed according to a molar ratio of 1:1, and the co-crystal of hesperetin and carbamazepine is prepared by a chemical method of solvent suspension.
6. The process of claim 5, said solvent suspension process, wherein the solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, acetone, acetonitrile, dioxane, n-hexane, cyclohexane; the stirring speed 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 carbamazepine eutectic compound.
7. A mixed solid substance containing co-crystals of hesperetin and carbamazepine, characterized in that the amount of co-crystals of hesperetin and carbamazepine according to any one of claims 1 to 4 is 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 containing an effective dose of a co-crystal of hesperetin and carbamazepine according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising an effective amount of a mixed solid substance of hesperetin and carbamazepine co-crystal of claim 7 and a pharmaceutically acceptable carrier.
10. Pharmaceutical composition according to claim 8 or 9, characterized in that the daily dosage of the co-crystal of hesperetin and carbamazepine 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. Use of the co-crystal of hesperetin and carbamazepine according to any one of claims 1 to 4 or of the mixed solid substance containing hesperetin and carbamazepine according to claim 7 or of the pharmaceutical composition according to claim 8 or 9 for the preparation of an antitumor, antioxidant, anti-inflammatory, antiepileptic, anti-trigeminal neuralgia, antimanic depression, atherosclerosis prevention, antiarrhythmic diseases and complications.
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| CN114524769A (en) * | 2022-02-14 | 2022-05-24 | 中国药科大学 | Celecoxib-carbamazepine eutectic, preparation method, pharmaceutical composition and application |
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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 |
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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 |
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| 刘胜;侯静美;龚俊波;: "在线过程分析技术在抗生素等药物结晶中的应用", 中国抗生素杂志, no. 11 * |
| 黄雨婷;徐嘉;迟宗良;范孟雪;秦昆明;蔡挺;蔡宝昌;: "药物共晶筛选技术的研究进展", 国际药学研究杂志, no. 04 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114524769A (en) * | 2022-02-14 | 2022-05-24 | 中国药科大学 | Celecoxib-carbamazepine eutectic, preparation method, pharmaceutical composition and application |
| CN114524769B (en) * | 2022-02-14 | 2023-10-24 | 中国药科大学 | Celecoxib-carbamazepine eutectic, preparation method, pharmaceutical composition and application |
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