CN113214206B - Hesperetin and betaine eutectic substance B, preparation method, composition and application thereof - Google Patents
Hesperetin and betaine eutectic substance B, preparation method, composition and application thereof Download PDFInfo
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- CN113214206B CN113214206B CN202010080007.4A CN202010080007A CN113214206B CN 113214206 B CN113214206 B CN 113214206B CN 202010080007 A CN202010080007 A CN 202010080007A CN 113214206 B CN113214206 B CN 113214206B
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- hesperetin
- betaine
- crystal
- eutectic
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- 239000012071 phase Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
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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
- 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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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P35/00—Antineoplastic agents
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- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- C07C227/38—Separation; Purification; Stabilisation; Use of additives
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- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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Abstract
The invention discloses a hesperetin and betaine eutectic substance B, a preparation method, a composition and application thereof, and belongs to the technical field of medicines. Specifically, the invention discloses a eutectic substance B formed by hesperetin and betaine, and the molecular formula of the eutectic substance B is (C 16 H 14 O 6 )·(C 5 H 11 NO 2 ) The method comprises the steps of carrying out a first treatment on the surface of the A preparation method of a hesperetin and betaine eutectic substance B; the hesperetin and betaine eutectic substance B are used as the effective components of the medicine, and are applied to the preparation of medicines for resisting oxidation, resisting inflammation, treating cardiovascular and cerebrovascular diseases, treating epilepsy, treating liver and kidney injury, resisting tumor and nerve diseases and treating Alzheimer disease and complications.
Description
Technical Field
The invention relates to a eutectic substance B formed by hesperetin and betaine; a preparation method of a hesperetin and betaine eutectic substance B; the hesperetin and betaine eutectic substance B are used as the effective components of the medicine, and are applied to the preparation of medicines for resisting oxidation, resisting inflammation, treating cardiovascular and cerebrovascular diseases, treating epilepsy, treating liver and kidney injury, resisting tumor and nerve diseases and treating Alzheimer disease 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] 。
Betaine is a quaternary ammonium type water-soluble alkaloid extracted from fructus Lycii, has good physicochemical properties and biological functions, and is widely used in pharmaceutical, food, and additive fields, and has a structural formula shown in b. Betaine has antiinflammatory, anti-epileptic, liver and kidney injury improving, antitumor, nerve disease inhibiting, and Alzheimer disease treating effects [4-11] 。
Polymorphic studies on hesperetin: the hesperetin found at present has two crystal forms [12-13] Wherein, the crystal B is the hesperetin containing one molecule of water, and the crystal B is the crystal-free crystal. 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 the formation of the eutectic of the hesperetin and the betaine is found so far, and no similar or conflicting study contents are found in aspects of substance form, combination proportion, preparation method, application and the like.
Disclosure of Invention
According to the invention, the hesperetin-betaine is prepared into a eutectic solid substance with specific non-covalent acting force, so that a novel substance which is different from the hesperetin and the betaine and is simply combined is formed, and the special advantages of the novel eutectic solid substance in preparation of antioxidant, anti-inflammatory, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, antitumor, nerve diseases and treatment of Alzheimer's disease and other related diseases and complications are discovered.
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 betaine eutectic compound B.
The second technical problem to be solved by the invention is: provides a preparation method of a hesperetin and betaine eutectic substance B.
The third technical problem to be solved by the invention is: pharmaceutical compositions are provided which use hesperetin and betaine co-crystals B as pharmaceutically active ingredient in an amount in the range of 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 betaine eutectic compound B to play a role in effectively treating the diseases by improving the blood concentration in organisms due to the combination of the hesperetin and betaine eutectic compound B.
The invention solves the technical problems: provides the application of using the hesperetin and betaine eutectic substance B and mixed crystal solid substances thereof as raw materials of active ingredients of medicines in the preparation of medicines for resisting oxidation, inflammation, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumor and nerve diseases and treating Alzheimer disease diseases and complications.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. hesperetin and betaine eutectic B sample morphological characteristics:
1.1 the hesperetin and betaine eutectic substance B are combined by non-covalent bonds to form eutectic substances, and the molar ratio of the hesperetin to the betaine eutectic substance B is 1:1.
1.2 the present invention relates to a co-crystal B of hesperetin and betaine, which contains no crystallization solvent or crystallization water component, and which uses CuK when powder X-ray diffraction analysis is used 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-betaine starting materials are shown in fig. 2, table 2. The powder X-ray diffraction patterns of the physical mixtures of the hesperetin and betaine eutectic B and the hesperetin-betaine raw material 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 physical mixtures of the hesperetin and betaine eutectic B and the hesperetin-betaine raw material are neither identical nor equivalent.
Table 1 peak X-ray diffraction of hesperetin and betaine co-crystals B
TABLE 2 powder X-ray diffraction peaks for physical Hesperetin-betaine mixing
1.3 hesperetin and betaine co-crystals B according to the invention are obtained by analysis by attenuated total reflection Fourier infrared spectrometry at 3455, 3045, 2992, 2954, 2905, 2844, 2696, 2611, 2321, 2252, 2230, 2208, 2107, 1999, 1877, 1820, 1778, 1766, 1620, 1594, 1582, 1530, 1492, 1456, 1436, 1414, 1398, 1383, 1348, 1321, 1292, 1275, 1258, 1235, 1195, 1184, 1159, 1130, 1090, 1059, 1026, 1012, 979, 965, 934, 904, 894, 865, 830, 800, 761, 745, 712, 680, 660cm -1 There is an infrared spectrum characteristic peak, wherein infrared lightPermissible deviation of spectrum characteristic peak is + -2 cm -1 (FIG. 3).
1.4 the hesperetin and betaine co-crystal B according to claim 1, characterized by the fact that when analyzed using differential scanning calorimetry, it exhibits 1 endothermic peak at 141 ℃ ± 3 ℃ in the DSC profile at a rate of 10 ℃ per minute, in the range of 30-250 ℃ (fig. 4). The DSC spectra of the hesperetin and betaine eutectic B and hesperetin and betaine all have obvious differences in the number, position and the like of the absorption/release peaks, which indicates that the hesperetin and betaine eutectic B are neither identical nor equivalent to the hesperetin and betaine raw materials (fig. 5).
2. The preparation method of the hesperetin and betaine eutectic substance B is characterized in that:
2.1A solvent suspension method is adopted in the preparation method of the hesperetin and betaine eutectic substance B, the hesperetin and betaine are mixed according to a molar ratio of 1:1, an organic solvent is added, the room temperature is reached, the stirring speed of a stirrer is 20 r/min-400 r/min, the stirring is carried out for 1 hour-96 hours, and the obtained suspension is subjected to solvent evaporation drying, natural drying by filtration or vacuum drying by filtration, so that the hesperetin and betaine eutectic substance B is prepared. The organic solvent is preferably acetonitrile; the solid-liquid ratio of the total mass of the hesperetin and the betaine to the organic solvent is kept within the range of 1mg/ml to 500 mg/ml.
2.2 the mixed solid substance of the hesperetin and betaine eutectic substance B is prepared by mixing the components of the hesperetin and betaine eutectic substance B prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. Comprises the component B of the eutectics of the hesperetin and the betaine, the administration dosage and the characteristics of the pharmaceutical preparation composition:
3.1 pharmaceutical compositions according to the invention comprise an effective dose of hesperetin and betaine co-crystals B and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition related by the invention has the dose of hesperetin and betaine eutectic substance B 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 hesperetin and betaine eutectic substance B related to the invention is applied to the preparation of various medicines for preventing or treating oxidation resistance, anti-inflammatory, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, tumor resistance, nerve diseases and Alzheimer disease and complications.
The invention relates to a pharmaceutical composition taking the hesperetin and betaine eutectic substance B 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 betaine co-crystals B of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The composition of the hesperetin and betaine co-crystal B according to the invention is generally in the range of 10-90% by weight.
The hesperetin and betaine co-crystal B can be administered in 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, eye, lung and respiratory tract, skin, vagina, rectum and the like.
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 betaine eutectic substance B and the hesperetin and betaine eutectic substance B can be prepared into common preparations, and also can be prepared into sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the preparation of the hesperetin and betaine co-crystals B according to the invention as tablets, various excipients known in the art can 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 and betaine eutectic substance B of the invention as active ingredients can be mixed with a diluent and a glidant, and the mixture can be directly placed into a hard capsule or a soft capsule. The active ingredient of the hesperetin and betaine eutectic substance B can be firstly prepared into particles or pellets with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used for preparing the tablet of the component B of the hesperetin and betaine eutectic substance can also be used for preparing the capsule of the hesperetin and betaine eutectic substance B.
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 B comprising hesperetin and betaine:
the invention discovers the application of the hesperetin and betaine eutectic compound B in preparing and/or treating antioxidant, anti-inflammatory, cardiovascular and cerebrovascular diseases, epilepsy, liver and kidney injury, anti-tumor, nerve diseases and Alzheimer disease 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 betaine co-crystal B according to 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 administration route and 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 betaine eutectic compound B can be taken alone or combined with other therapeutic drugs or symptomatic drugs. When the hesperetin and betaine eutectic B and other therapeutic drugs have synergistic effect, the dosage of the hesperetin and betaine eutectic B is adjusted according to the actual situation.
The technical scheme of the invention has the following beneficial technical effects:
compared with the prior art, the hesperetin has obvious advantages in the aspects of safety, stability, solubility, biological activity and the like.
The hesperetin and betaine eutectic substance B does not contain any crystallization solvent, and has good safety patent medicine advantage.
The hesperetin and betaine eutectic substance B has unexpected solubility advantages compared with the hesperetin, and is specifically expressed in the following steps: significant solubility and dissolution rate advantages were exhibited in pure water (ph 7.0) dissolution systems (fig. 6).
The hesperetin and betaine eutectic substance B according to the present invention can exist stably under high temperature (60 ℃) and illumination (4500 lx.+ -. 500 lx) conditions (FIG. 7).
Drawings
FIG. 1 powder X-ray diffraction pattern of hesperetin and betaine co-crystal B
FIG. 2 powder X-ray diffraction pattern of physical mixture of hesperetin and betaine co-crystal B
FIG. 3 is an infrared absorption spectrum of a eutectic B of hesperetin and betaine
FIG. 4 differential scanning calorimetric profile of hesperetin and betaine co-crystal B
FIG. 5 differential scanning calorimetric profile of hesperetin and betaine co-crystals B and raw materials
FIG. 6 dissolution profile of hesperetin and betaine co-crystals B
FIG. 7 stability profile of hesperetin and betaine co-crystals B
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 betaine eutectic B
Taking proper amount of hesperetin and betaine, adding the samples into a proper container by adopting a solvent suspension method at room temperature, adding proper amount of organic solvent, stirring for 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 is consistent with fig. 1, showing that the obtained sample is hesperetin and betaine eutectic B.
TABLE 3 preparation of hesperetin and betaine Co-crystals, method 1 concrete examples
Example 2
In vitro dissolution and release characteristics of hesperetin-betaine
The solubility characteristics of the hesperetin and betaine eutectic B and the hesperetin bulk drug in an aqueous solution system are examined. The method is characterized in that experiments are carried out by referring to the general oral solid preparation dissolution test technical guidelines, and the dissolution percentage is calculated by adopting a high-efficiency 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: nail armorAlcohol-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 betaine eutectic in pure water is superior to that of hesperetin, the hesperetin and betaine eutectic has a faster dissolution rate and a higher dissolution amount, the hesperetin and betaine eutectic is easy to be absorbed more quickly to reach the effective blood concentration, the absorption total amount of the hesperetin and betaine eutectic is obviously increased, the equilibrium dissolution amount of the hesperetin and betaine eutectic is about 1.5 times that of the hesperetin, but the dissolution rate is obviously improved, the maximum dissolution amount of the hesperetin and betaine eutectic can be basically reached in 90min, compared with the hesperetin raw material, the hesperetin and betaine eutectic is shortened by nearly 5 times, and the disease treatment effect of the medicine can be better realized; the solubility curve of the hesperetin and betaine eutectic has a stable release platform, and can ensure that the stable blood concentration is maintained in the disease treatment process.
Example 3
Stability advantage of hesperetin and betaine co-crystal B
High temperature test: samples of the hesperetin and betaine co-crystals B 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 betaine eutectic B are stable under a high-temperature influence factor test.
Illumination test: samples of the hesperetin and betaine co-crystals B were placed in open clean dishes, placed in a light box with fluorescent lamps, placed for 10 days at an illuminance of 4500 lx.+ -. 500lx, and sampled on days 0, 5 and 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 betaine eutectic B are stable under the illumination 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 products of hesperetin and betaine eutectic substance B 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 drug content of 10-500 mg of each tablet is prepared according to a certain proportion, and the formulation proportion of the tablet is shown in table 5:
table 5 preparation formulation of hesperetin and betaine co-crystal B combination pharmaceutical tablet
The method for preparing the pure material medicine of the hesperetin and betaine eutectic substance B 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 pure products of hesperetin and betaine eutectic substance B 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 drug content 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 6:
preparation formula of table 6 hesperetin and betaine eutectic compound pharmaceutical tablet
The method for preparing the pure material medicine of the hesperetin and betaine eutectic substance B 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 substances of a hesperetin and betaine eutectic substance B 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 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 betaine eutectic compound B pharmaceutical capsule preparation
The method for preparing the tablet preparation from the hesperetin and betaine eutectic substance B bulk drugs 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 betaine eutectic substance B with excipient adjuvants, sieving, and directly encapsulating.
Example 5
Dose 1 (tablet) of hesperetin and betaine co-crystal B combination:
the preparation and development of the pharmaceutical composition using the sample of the hesperetin and betaine eutectic B as the active ingredients is characterized in that the hesperetin and betaine eutectic B are used as the active ingredients of the medicine, the daily administration dosage is 300mg, and the pharmaceutical composition can be prepared into 100mg common tablets of 3 times per time or 1 time per day or 300mg tablets of 1 time per time.
Dose 2 (capsule) of hesperetin and betaine co-crystal B combination:
the preparation and development of the pharmaceutical composition are carried out by taking a sample of the hesperetin and betaine eutectic substance B as the active ingredients, and the pharmaceutical composition is characterized in that the hesperetin and betaine eutectic substance B is taken as the active ingredients of the medicine, the daily administration dosage is 500mg, and the pharmaceutical composition can be respectively prepared into 250mg capsules for 2 times per time or 1 capsule for 1 time per time.
Problems to be described: the pharmaceutical composition of the hesperetin and betaine eutectic B 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 plasma concentration differences between the crystalline forms also result in a suitable daily dosage range of 0.002-20mg/kg body weight, preferably 0.01-10mg/kg body weight, of the hesperetin and betaine co-crystal B ingredients of the present invention. When in use, different total dosage schemes of the active ingredients of the hesperetin and betaine eutectic substance B are formulated according to the actual requirements of prevention and treatment under different conditions, and the administration can be completed in a mode of multiple times or one time.
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]Chen W,Zhang X,Li J,et a1.Efficacy of osmoprotectants on prevention and treatment of routine dry eye[J].Invest Ophthalmol Vis Sci,2013,54(9):6287-6297.
[5]Zheng P,Liu J,Mai S,et a1.Regulation of signal transducer and activator of transcription 3and apoptotic pathways by betaine attenuates isoproterenol—induced acute myocardial injury in rats[J].Hum Exp Toxicol.2014(1):1-10.
[6] Wang Hui, wang Shuxiang, cui Guoli, etc., effect of betaine on the expression of the hippocampal GFAP, glycine and glycine receptor in penta-tetrazate [ J ], journal of pathophysiology, 2013, 29 (9): 1657-1661.
[7]Fan CY,Wang MX,Ge CX,et a1.Betaine supplementation Ppteets against high-fructose-induced renal injury in rats[J].J Nutr Biochem,2014,25(3):1-10.
[8]Zhang W,Wang LW,Wang LK,et a1.Betaine protects against high-fat-diet-induced liver injury by inhibition of high-mobility group box 1 and Toll-like receptor 4 expression in rats.Dig Dis Sci, 2013,58(11):3198-3206.
[9]Ying J,Rahbar MH,Hallman DM,et a1.Associations between dietary intake of choline and betaine and lung cancer risk,PLoS One,2013,8(2):e54561.
[10]Imbard A,Benoist JF,Blom HJ.Neural tube defects，folie acid and methylation,Int J Environ Res Public Health,2013,10(9):4352-4389.
[11]Chai GS,JiangX,Ni ZF,et a1.Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine.J Neurochem,2013,124(3):388-396.
[12]Shin W,Kim S,Chun KS.Structure of(R,S)-Hesperetin Monohydrate.Acta Crystallogr Sect C:Cryst Struct Commun,1987,43(5):904-911.
[13]Fujii S,Yamagata Y,Jin GZ,et al.Novel Molecular Conformation of(R,S)-Hesperetin in Anhydrous Crystal.Chem.Pharm.Bull.1994,42(5):1143-1145。
Claims (14)
1. A eutectic substance B of hesperetin and betaine is characterized in that the eutectic substance B is formed by the hesperetin and the betaine 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: the peak Height value Height% or the peak Area value Area% has the following characteristics:
2. the hesperetin and betaine co-crystal B according to claim 1, characterized in that when analyzed using attenuated total reflection fourier infrared spectroscopy, at 3455, 3045, 2992, 2954, 2905, 2844, 2696, 2611, 2321, 2252, 2230, 2208, 2107, 1999, 1877, 1820, 1778, 1766, 1620, 1594, 1582, 1530, 1492, 1456, 1436, 1414, 1398, 1383, 1348, 1321, 1292, 1275, 1258, 1235, 1195, 1184, 1159, 1130, 1090, 1059, 1026, 1012, 979, 965, 934, 904, 894, 865, 830, 800, 761, 745, 712, 680, 660cm -1 There is an infrared spectrum characteristic peak, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
3. The hesperetin and betaine co-crystal B according to claim 1, characterized in that it exhibits 1 endothermic peak at 141 ℃ ± 3 ℃ in the DSC profile when analyzed using differential scanning calorimetry, at a temperature rise rate of 10 ℃ per minute, in the range of 30-250 ℃.
4. A method for preparing a hesperetin and betaine eutectic substance B according to any one of claims 1-3, characterized in that the hesperetin and betaine are fed according to a molar ratio of 1:1, and the hesperetin and betaine eutectic substance B is prepared by adopting a chemical method of solvent suspension.
5. The method of claim 4, wherein the solvent is acetonitrile; the stirring rotating speed of the stirrer 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 betaine eutectic substance B.
6. A mixed solid material comprising hesperetin and betaine co-crystal B, characterized in that the amount of hesperetin and betaine co-crystal B according to any of claims 1-3 is 1-99.9%.
7. A mixed solid material comprising hesperetin and betaine eutectic B, wherein the amount of hesperetin and betaine eutectic B is 10-99.9% according to any of claims 1-3.
8. A mixed solid material comprising hesperetin and betaine co-crystal B, characterized in that the amount of hesperetin and betaine co-crystal B according to any of claims 1-3 is 50-99.9%.
9. A mixed solid material comprising hesperetin and betaine co-crystal B, characterized in that the amount of hesperetin and betaine co-crystal B according to any of claims 1-3 is 85-99.9%.
10. A pharmaceutical composition comprising an effective amount of the hesperetin and betaine co-crystal B 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 material of hesperetin and betaine co-crystal B 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 dose of hesperetin and betaine co-crystal B 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 a pharmaceutical combination of hesperetin as claimed in any of claims 1 to 3 and betaine co-crystal B or as claimed in claim 10 or 11 as a pharmaceutically active ingredient for the preparation of a medicament for the antioxidant, anti-inflammatory, anti-cardiovascular and cerebrovascular diseases, anti-epileptic, anti-hepatic and renal injury, anti-tumour, anti-neurological diseases and for the treatment of alzheimer's disease and complications.
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| 黄雨婷等.药物共晶筛选技术的研究进展.国际药学研究杂志.2016,第43卷(第4期),第682-688页. * |
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