CN113214208A - Hesperetin and isonicotinamide eutectic crystal, preparation method, composition and application thereof - Google Patents
Hesperetin and isonicotinamide eutectic crystal, preparation method, composition and application thereof Download PDFInfo
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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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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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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- 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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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses an hesperetin and isonicotinamide eutectic crystal, a preparation method, a composition and application thereof, belonging to the technical field of medicines. Specifically, the invention discloses a co-crystal formed by hesperetin and isonicotinamide, and the components of the co-crystalHas the sub-formula of (C)16H14O6)·(C6H6N2O); a preparation method of an hesperetin and isonicotinamide eutectic compound; application of hesperetin and isonicotinamide eutectic compound in preparation of anti-tumor, anti-oxidation, anti-inflammation and atherosclerosis disease and complication prevention medicines.
Description
Technical Field
The invention relates to an eutectic compound formed by hesperetin and isonicotinamide; a preparation method of an hesperetin and isonicotinamide eutectic compound; the hesperetin and isonicotinamide eutectic crystal is used as the effective component of the medicine and is applied to the preparation of the medicines for resisting tumors, oxidation and inflammation or preventing atherosclerosis 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]。
Isonicotinamide (the name of England:Isonicotinamide) is a common co-crystal former for pharmaceutical co-crystals[4]The structural formula is shown as b. Isonicotinamide as a co-crystal former, there are at present myricetin and isonicotinamide co-crystals[5]Zileuton co-crystal with isonicotinamide[6]Quercetin and isonicotinamide co-crystal[7]And the like.
Polymorphism studies on hesperetin: hesperetin which is discovered at present has two 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 isonicotinamide is found so far, and similar or conflicting research contents in aspects of substance form, combination ratio, preparation method, application and the like are also not found.
Disclosure of Invention
The invention discloses a novel solid substance which is different from hesperetin and isonicotinamide and is simply combined and applied by preparing hesperetin and isonicotinamide into an eutectic solid substance with specific non-covalent acting force, and further discovers the special advantages of the novel eutectic solid substance in preparation of the treatment of relevant diseases and complications such as tumor resistance, oxidation resistance, inflammation resistance, atherosclerosis prevention and the like.
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 isonicotinamide.
The second technical problem to be solved by the present invention is: provides a preparation method of a hesperetin and isonicotinamide eutectic compound.
The invention aims to solve the third technical problem: the pharmaceutical composition using the hesperetin and isonicotinamide eutectic crystal as the active pharmaceutical ingredient is provided, 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 isonicotinamide 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 isonicotinamide eutectic compound and mixed crystal solid matter thereof as raw materials of active ingredients of the medicine in preparing medicines for resisting tumor, oxidation and inflammation, preventing diseases and complications related to atherosclerosis and the like.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. morphological characteristics of a hesperetin and isonicotinamide eutectic crystal sample:
1.1 the hesperetin and isonicotinamide eutectic compound provided by the invention is a eutectic compound formed by combining hesperetin and isonicotinamide by non-covalent bonds, and the molar ratio of the hesperetin to the isonicotinamide is 1: 1.
1.2 the hesperetin and isonicotinamide eutectic crystal 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 (°) ord value
The diffraction peak relative intensity peak Height (Height%) or peak Area value (Area%) was determined to have the following characteristic peaks (table 1, fig. 1). The powder X-ray diffraction pattern data of the physical mixture of hesperetin and isonicotinamide are shown in figure 2 and table 2. The powder X-ray diffraction patterns of the hesperetin and isonicotinamide eutectic compound and the physical mixture of hesperetin and isonicotinamide have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, and the results show that the hesperetin and isonicotinamide eutectic compound and the physical mixture of hesperetin and isonicotinamide are different and identical.
TABLE 1 powder X-ray diffraction peak data of hesperetin and isonicotinamide eutectic
TABLE 2 powder X-ray diffraction Peak data for physical mixtures of Hesperetin and Isoniacinamide
1.3 The hesperetin and isonicotinamide eutectic compound of the invention is analyzed by attenuated total reflection Fourier infrared spectroscopy, and is characterized in that 3423, 3213, 3162, 3022, 2970, 2950, 2895, 2843, 2543, 2176, 1776, 1765, 1759, 1746, 1697, 1629, 1596, 1561, 1537, 1472, 1456, 1445, 1438, 1407, 1335, 1305, 1294, 1267, 1251, 1219, 1201, 1186, 1167, 1138, 1128, 1113, 1058, 1024, 1013, 959, 917, 871, 858, 820, 802, 760, 733, 690, 656cm 656-1Is characterized by the existence of infrared spectrum characteristic peaks, wherein the infrared spectrum characteristicAllowable deviation of peak of. + -.2 cm-1(FIG. 3).
1.4 when the hesperetin and isonicotinamide eutectic compound is analyzed by a differential scanning calorimetry technology, 1 endothermic peak (figure 4) exists at 176 +/-3 ℃ in a DSC spectrum within the range of 30-250 ℃ when the heating rate is 10 ℃ per minute. DSC (differential scanning calorimetry) spectra of the hesperetin and isonicotinamide eutectic compound, the hesperetin and isonicotinamide have obvious differences in the quantity, position and the like of heat absorption/release peaks, and the results show that the hesperetin and isonicotinamide eutectic compound, the hesperetin and isonicotinamide raw materials are different and identical (figure 5).
2. The preparation method of the hesperetin and isonicotinamide eutectic compound is characterized by comprising the following steps:
2.1 the preparation method of the hesperetin and isonicotinamide eutectic compound related by the invention adopts a solvent suspension method, the hesperetin and isonicotinamide 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 isonicotinamide 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 isonicotinamide to the organic solvent within the range of 1mg/ml to 500 mg/ml.
2.2 the mixed solid matter containing the hesperetin and isonicotinamide eutectic mixture is prepared by mixing the hesperetin and isonicotinamide 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 the hesperetin and isonicotinamide eutectic mixture, and has the following characteristics of administration dosage and pharmaceutical preparation composition:
3.1 the pharmaceutical composition contains effective dose of hesperetin and isonicotinamide eutectic crystal and pharmaceutically acceptable carriers.
3.2 the daily dosage of the hesperetin and isonicotinamide eutectic compound 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 application of the hesperetin and isonicotinamide eutectic crystal in preparing the medicines for resisting tumors, oxidation and inflammation, preventing atherosclerosis and other related diseases and complications.
The invention relates to a pharmaceutical composition taking a hesperetin and isonicotinamide eutectic crystal as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The hesperetin and isonicotinamide eutectic crystal can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary agents to prepare any preparation formulation suitable for human or animal use. The content of the co-crystal of hesperetin and isonicotinamide is usually within the range of 10-90% by weight.
The hesperetin and isonicotinamide eutectic crystal 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 isonicotinamide eutectic compound and the mixed solid matter of the hesperetin and isonicotinamide 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 isonicotinamide co-crystal of the invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants and glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to prepare the administration unit into a capsule, the hesperetin and isonicotinamide eutectic mixture as an effective component 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 isonicotinamide eutectic crystal is 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 isonicotinamide eutectic mixture component tablets can also be used for preparing capsules of the hesperetin and isonicotinamide eutectic mixture.
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 isonicotinamide comprises the following steps:
the invention finds the application of the hesperetin and isonicotinamide eutectic compound in preparing and/or treating medicaments for resisting tumors, oxidation and inflammation, preventing atherosclerosis and other related 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 hesperetin and isonicotinamide co-crystal 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 isonicotinamide eutectic crystal can be taken alone or combined with other treatment medicines or symptomatic medicines. When the hesperetin and isonicotinamide eutectic crystal and other treatment medicines have synergistic effect, the dosage of the hesperetin and isonicotinamide eutectic crystal 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 isonicotinamide eutectic crystal has obvious advantages in the aspects of safety, stability, solubility, biological activity and the like.
The hesperetin and isonicotinamide eutectic crystal does not contain any crystallization solvent, and has good safety and patent medicine advantages.
Compared with hesperetin, the hesperetin and isonicotinamide eutectic crystal 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 acetate buffer solution (pH4.5), phosphate buffer solution (pH6.8), pure water (pH7.0) and the like (figure 6).
The hesperetin and isonicotinamide 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 hesperetin and isonicotinamide eutectic
FIG. 2 powder X-ray diffraction pattern of physical mixture of hesperetin and isonicotinamide
FIG. 3 shows an infrared absorption spectrum of an eutectic compound of hesperetin and isonicotinamide
FIG. 4 Differential Scanning Calorimetry (DSC) spectrum of co-crystal of hesperetin and isonicotinamide
FIG. 5 Differential Scanning Calorimetry (DSC) spectrum of eutectic mixture of hesperetin and isonicotinamide and raw material
FIG. 6 solubility curves of samples under different conditions
FIG. 7 stability chart of hesperetin and isonicotinamide eutectic crystal
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 isonicotinamide eutectic compound 1
Taking a proper amount of hesperetin and isonicotinamide, wherein the molar ratio of the hesperetin to the isonicotinamide 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 isonicotinamide eutectic crystal, and the diffraction pattern of the hesperetin and isonicotinamide eutectic crystal is consistent with that of a figure 1.
TABLE 3 preparation of Co-crystals of hesperetin and Isoniacinamide 1 example
Example 2
In-vitro dissolution and release characteristics of hesperetin and isonicotinamide eutectic crystal
The solubility characteristics of the hesperetin and isonicotinamide eutectic compound and the hesperetin raw material drug in three solution systems of pure water, 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 behavior of the hesperetin and isonicotinamide eutectic compound in an acetate buffer solution, a phosphate buffer solution and a pure water system is superior to that of a hesperetin raw material, and the hesperetin and isonicotinamide eutectic compound is particularly characterized in that the hesperetin and isonicotinamide eutectic compound has a faster dissolving rate and a higher dissolving amount, is easy to be absorbed more quickly to reach effective blood concentration, the total absorption amount is also obviously increased, particularly the dissolving amount in the acetate buffer solution is about 2 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 isonicotinamide 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 isonicotinamide eutectic
High-temperature test: placing a sample of the hesperetin and isonicotinamide eutectic crystal 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 isonicotinamide eutectic is stable under a high-temperature influence factor test.
High humidity test: placing a hesperetin and isonicotinamide eutectic crystal sample in an open clean surface dish, standing for 10 days at 25 ℃ under the condition of relative humidity of 90% +/-5%, and sampling on days 0, 5 and 10. And (3) performing powder X-ray diffraction analysis on the sample obtained at the sampling point, wherein the result shows that the hesperetin and isonicotinamide eutectic compound is stable under the high-humidity condition.
And (3) illumination test: placing the hesperetin and isonicotinamide eutectic crystal 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 (3) performing powder X-ray diffraction analysis on the sample obtained at the sampling point, wherein the result shows that the hesperetin and isonicotinamide eutectic compound 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 isonicotinamide eutectic crystal 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 co-crystal of hesperetin and isonicotinamide
The method for preparing the pure bulk drug of the co-crystal product of hesperetin and isonicotinamide 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 isonicotinamide eutectic crystal 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 6:
preparation formula of pharmaceutical tablet combined by hesperetin and isonicotinamide eutectic compound
The method for preparing the pure bulk drug of the co-crystal product of hesperetin and isonicotinamide 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 an hesperetin and isonicotinamide eutectic crystal 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 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 isonicotinamide eutectic crystal
The method for preparing the hesperetin and isonicotinamide 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 isonicotinamide eutectic substance raw material medicine with a plurality of excipient auxiliary materials uniformly without using a granulating step, sieving, and directly encapsulating to obtain the finished product.
Example 5
Administration dosage of the combined drug of the hesperetin and isonicotinamide eutectic compound 1 (tablet):
the pharmaceutical composition is prepared and developed by using a hesperetin and isonicotinamide eutectic sample as a pharmaceutical active ingredient, and is characterized in that the hesperetin and isonicotinamide eutectic 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 3 times a day per 1 tablet or 300mg tablets 1 time a day per 1 tablet.
The administration dosage of the combined drug of the hesperetin and isonicotinamide eutectic compound is 2 (capsules):
the pharmaceutical composition is prepared and developed by using a hesperetin and isonicotinamide eutectic crystal sample as a pharmaceutical active ingredient, and is characterized in that the hesperetin and isonicotinamide eutectic crystal is used as the pharmaceutical active ingredient, the daily administration dose is 500mg, and the pharmaceutical composition can be respectively prepared into capsules of 1 capsule of 250mg 2 times a day each time or capsules of 500mg 1 time a day each time.
Problems to be explained are: the pharmaceutical composition of the co-crystal of hesperetin and isonicotinamide has many influences 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 hesperetin and isonicotinamide eutectic composition 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 isonicotinamide eutectic compound effective component total dosage schemes are made according to different actual requirements of prevention and treatment, and the total dosage can be completed in a mode of multiple times or one time of administration.
Reference to the literature
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[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]Lynch M B,Lawrence S E,Nolan M.Predicting Nucleation of Isonicotinamide from the Solvent –Solute Interactions of Isonicotinamide in Common Organic Solvents.J.Phys.Chem.A.2018,122, 3301-3312.
[5] Chinese patent CN 103819440B
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Claims (12)
1. An hesperetin and isonicotinamide eutectic compound is characterized in that the hesperetin and isonicotinamide form the eutectic compound in a non-covalent bond according to a molar ratio of 1: 1.
2. The co-crystal of hesperetin and isonicotinamide 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. according toThe co-crystal of hesperetin and isonicotinamide as claimed in claim 1, which is characterized by having a structure of 3423, 3213, 3162, 3022, 2970, 2950, 2895, 2843, 2543, 2176, 1776, 1765, 1759, 1746, 1697, 1629, 1596, 1561, 1537, 1472, 1456, 1445, 1438, 1407, 1401, 1335, 1305, 1294, 1267, 1251, 1219, 1201, 1186, 1167, 1138, 1128, 1113, 1083, 1058, 1024, 1013, 959, 917, 871, 858, 820, 802, 760, 733, 690, 664, 656cm 656-1Has 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 isonicotinamide as claimed in claim 1, wherein 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. The preparation method of the co-crystal of hesperetin and isonicotinamide as claimed in any one of claims 1 to 4, characterized in that the hesperetin and isonicotinamide are fed according to a molar ratio of 1:1, and the co-crystal of hesperetin and isonicotinamide 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 selected from one or more 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 carrying out solvent evaporation drying, filtering and natural drying or filtering and vacuum drying on the obtained suspension to obtain the hesperetin and isonicotinamide eutectic.
7. A mixed solid substance containing a co-crystal of hesperetin and isonicotinamide 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% of the co-crystal of hesperetin and isonicotinamide according to any one of claims 1 to 4.
8. A pharmaceutical composition, characterized by comprising an effective amount of a co-crystal of hesperetin and isonicotinamide 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 isonicotinamide co-crystals as claimed in 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-crystals of hesperetin and isonicotinamide is in the range of 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 isonicotinamide according to any one of claims 1 to 4 or of the mixed solid substance containing the co-crystal of hesperetin and isonicotinamide according to claim 7 or of the pharmaceutical composition according to claim 8 or 9 for the preparation of a medicament for the antitumor, antioxidant, anti-inflammatory or prevention of atherosclerotic diseases and complications.
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| CN114634474A (en) * | 2022-03-03 | 2022-06-17 | 广西中医药大学 | Eutectic compound of dihydromyricetin and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008153945A2 (en) * | 2007-06-06 | 2008-12-18 | University Of South Florida | Nutraceutical co-crystal compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008153945A2 (en) * | 2007-06-06 | 2008-12-18 | University Of South Florida | Nutraceutical co-crystal compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114634474A (en) * | 2022-03-03 | 2022-06-17 | 广西中医药大学 | Eutectic compound of dihydromyricetin and preparation method thereof |
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