CN115557924B - Baicalein inclusion compound eutectic crystal, traditional Chinese medicine composition, and preparation method and application thereof - Google Patents
Baicalein inclusion compound eutectic crystal, traditional Chinese medicine composition, and preparation method and application thereof Download PDFInfo
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- CN115557924B CN115557924B CN202211317227.XA CN202211317227A CN115557924B CN 115557924 B CN115557924 B CN 115557924B CN 202211317227 A CN202211317227 A CN 202211317227A CN 115557924 B CN115557924 B CN 115557924B
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- baicalein
- cyclodextrin
- crystal
- clathrate
- eutectic
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000000879 optical micrograph Methods 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Classifications
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- 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
- C07D311/30—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 not hydrogenated in the hetero ring, e.g. flavones
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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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
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- 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
- C07D311/40—Separation, e.g. from natural material; Purification
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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Abstract
The invention provides a baicalein inclusion compound eutectic, which comprises a eutectic ligand and a medicinal active ingredient included by the eutectic ligand; the active component of the medicine is baicalein, and the eutectic ligand is cyclodextrin. The inclusion compound eutectic formed by baicalein and cyclodextrin has better water solubility, better thermal stability and more definite crystal structure. In addition, the preparation method of the inclusion compound eutectic formed by baicalein and cyclodextrin can be realized by combining proper heating temperature through the method of preparing nanoparticles by a fusion solvent injection method and crystallizing by an anti-solvent method, and is simple and feasible, and convenient to popularize and apply.
Description
Technical Field
The invention relates to the fields of fine chemical engineering and application, in particular to a baicalein inclusion compound eutectic and traditional Chinese medicine composition, and a preparation method and application thereof.
Background
Baicalein is a flavonoid compound separated from radix Scutellariae, and is a xanthine oxidase inhibitor with molecular formula of C 15 H 10 O 5 The molecular weight was 270.24, and yellow needle crystals were used. Although pharmacological results show that baicalein has the effects of reducing cerebrovascular resistance, improving cerebral blood circulation, increasing cerebral blood flow, resisting platelet aggregation, resisting cancer, oxidization, bacteria, fat and inflammation, resisting HIV, the baicalein has the problems of poor water solubility, low oral bioavailability, strong first pass effect and the like, and the application of the baicalein to clinic is limited to a great extent. Conventional approaches have generally employed various nano-delivery techniques to increase the bioavailability of baicalein.
Cyclodextrins (CD) are a class of cyclic oligosaccharides produced from starch by the action of a glycosyltransferase, which is typically produced by certain species of the genus Bacillus. The cyclodextrin has a three-dimensional chiral cavity with an inner hydrophobic and an outer hydrophilic. The inner side of the cavity of the cyclodextrin structure is composed of two circles of hydrogen atoms and one circle of oxygen atoms of the glycosidic bond, which are under the shielding of the C-H bond, so that the inner cavity of the cyclodextrin is hydrophobic, and the outer side of the cyclodextrin molecule is hydrophilic due to the aggregation of hydroxyl groups. The cyclodextrin is composed of glucose, so that the cyclodextrin has the characteristics of no toxicity, no harm, no side effect, capability of being absorbed by human bodies and the like, has the general property of starch, can be used as a filler and a binder of medicines, and is widely applied to the fields of medicines, foods, chemical engineering, materials, environmental protection, analytical chemistry and the like.
Disclosure of Invention
Based on the above, the invention provides the baicalein inclusion compound eutectic which has better water solubility and better thermal stability, can improve the bioavailability, and has a definite crystal structure.
The invention is realized by the following technical scheme.
A baicalein inclusion compound co-crystal comprising a co-crystal ligand and a pharmaceutically active ingredient that is included by the co-crystal ligand; the active component of the medicine is baicalein, and the eutectic ligand is cyclodextrin.
In one embodiment, the cyclodextrin is gamma-cyclodextrin.
In one embodiment, the X-ray powder diffraction pattern of the baicalein/gamma cyclodextrin inclusion compound co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
3.74 ° ± 0.5 °, 6.41 ° ± 0.5 °, 7.37 ° ± 0.5 °, 9.18 ° ± 0.5 °, 10.48 ° ± 0.5 °, 11.42 ° ± 0.5 °, 12.00 ° ± 0.5 °, 14.15 ° ± 0.5 °, 14.89 ° ± 0.5 °, 15.79 ° ± 0.5 °, 16.65 ° ± 0.5 °, 19.19 ° ± 0.5 °, 20.29 ° ± 0.5 °, 21.13 ° ± 0.5 °, 21.81 ° ± 0.5 °, 22.48 ° ± 0.5 °, 24.49 ° ± 0.5 °, 26.78 ° ± 0.5 ° and 34.96 ° ± 0.5 °.
In one embodiment, the X-ray powder diffraction pattern of the baicalein/gamma cyclodextrin inclusion compound co-crystal is substantially as shown in FIG. 5.
In one embodiment, the baicalein/gamma cyclodextrin inclusion compound co-crystal has a melting point of 280 ℃ ± 5 ℃.
In one embodiment, the baicalein inclusion compound eutectic comprises 12-13% by mass of baicalein.
The invention also provides a preparation method of the baicalein inclusion compound eutectic, which comprises the following steps:
mixing baicalein with a first solvent to prepare a baicalein solution;
mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;
heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the baicalein solution to prepare a mixed solution;
cooling the mixed solution, standing and collecting precipitated solid;
wherein the first solvent is a water-miscible organic solvent.
In one embodiment, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.
In one embodiment, the volume ratio of the first solvent to water in the mixed solution is 3 (7-60).
In one embodiment, the molar ratio of the baicalein to the cyclodextrin in the mixed solution is 1 (1-20).
In one embodiment, the process of adding the baicalein solution satisfies one or more of the following conditions:
(1) The adding time is controlled to be 0.5 to 30 minutes according to 1 to 3mL of baicalein solution;
(2) The aqueous cyclodextrin solution is stirred at a speed of 100rpm to 1000rpm.
The invention also provides a traditional Chinese medicine composition, which comprises the baicalein inclusion compound eutectic and a carrier or an auxiliary material.
The invention also provides application of the baicalein inclusion compound eutectic crystal or the traditional Chinese medicine composition in preparing chemical preparations, medicines or foods.
Compared with the prior art, the baicalein inclusion compound eutectic has the following beneficial effects:
according to the invention, the inclusion compound eutectic formed by baicalein and cyclodextrin is obtained through research and preparation. Compared with the traditional inclusion compound, the inclusion compound eutectic formed by the baicalein and the cyclodextrin has better water solubility, and the oral bioavailability of the baicalein is also improved; meanwhile, compared with baicalein, the melting point of the inclusion compound eutectic is obviously increased, which indicates that the thermal stability of the baicalein/gamma cyclodextrin inclusion compound eutectic is improved. In addition, inclusion eutectic also has a more definite crystal structure. Unlike the conventional eutectic preparation process in which crystal is formed through hydrogen bond, electrostatic effect, etc. between active medicine component and eutectic ligand, the inclusion compound eutectic of the present invention has the feature of cyclodextrin and baicalein forming inclusion compound, and the two are assembled into inclusion compound eutectic with main and auxiliary body to raise the water solubility of baicalein.
Furthermore, the preparation method of the inclusion compound eutectic formed by baicalein and cyclodextrin can be realized by combining proper heating temperature through the method of preparing nanoparticles by a fusion solvent injection method and crystallizing by an anti-solvent method, and is simple and feasible, and convenient to popularize and apply.
Drawings
FIG. 1 is a schematic diagram of a preparation process of baicalein inclusion compound eutectic crystal;
FIG. 2 is an optical micrograph (scale: 50 μm) of a baicalein-baicalein inclusion compound co-crystal provided by the invention;
FIG. 3 is an H-NMR spectrum of baicalein, gamma-cyclodextrin and baicalein/gamma-cyclodextrin inclusion compound eutectic provided by the invention;
FIG. 4 is an infrared spectrum of baicalein, gamma-cyclodextrin and baicalein/gamma-cyclodextrin inclusion compound eutectic provided by the invention;
FIG. 5 is a graph of XPRD of baicalein, gamma-cyclodextrin and baicalein/gamma-cyclodextrin inclusion compound co-crystals (angle 2 θ (°) on the abscissa and intensity on the ordinate) provided by the present invention;
FIG. 6 shows DSC spectra (abscissa is temperature (. Degree. C.), and ordinate is heat flow rate (W/g)) of baicalein, gamma-cyclodextrin and baicalein/gamma-cyclodextrin inclusion compound eutectic provided by the invention.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. The drawings illustrate preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise. In the description of the present invention, the meaning of "several" means at least one, such as one, two, etc., unless specifically defined otherwise.
The words "preferably," "more preferably," and the like in the present invention refer to embodiments of the invention that may provide certain benefits in some instances. However, other embodiments may be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values for the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
All percentages, fractions and ratios are calculated on the total mass of the composition of the invention, unless otherwise indicated. All of the mass of the ingredients listed, unless otherwise indicated, are given to the active substance content and therefore they do not include solvents or by-products that may be included in commercially available materials. The term "mass percent" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless indicated otherwise. All formulations and tests herein take place in an environment of 25 ℃, unless otherwise indicated. The terms "comprising," "including," "containing," "having," or other variations thereof herein are intended to cover a non-closed inclusion, without distinguishing between them. The term "comprising" means that other steps and ingredients may be added that do not affect the end result. The compositions and methods/processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as additional or optional ingredients, components, steps, or limitations of any of the embodiments described herein. The terms "efficacy," "performance," "effect," "efficacy" are not differentiated herein.
By "pharmaceutically acceptable" is meant those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to patients and commensurate with a reasonable benefit/risk ratio.
"pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and/or pharmacological effect in vivo or in vitro, and often provides a beneficial effect. The range of physiological and/or pharmacological actions of the "drug" in vivo is not particularly limited, and may be systemic or local. The activity of the "drug" is not particularly limited, and may be an active substance capable of interacting with other substances or an inert substance which does not interact with other substances.
The dosage form and the mode of administration of the compound of the present invention or the pharmaceutical composition thereof are not particularly limited.
Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Such as suspensions, may contain suspending agents as, for example, particularly ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. Is prepared by mixing the active ingredient under aseptic condition with pharmaceutically acceptable carrier and any preservative, buffer or propellant as required.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The invention provides a baicalein inclusion compound eutectic, which comprises a eutectic ligand and a medicinal active ingredient included by the eutectic ligand; the active component of the medicine is baicalein, and the eutectic ligand is cyclodextrin.
In one specific example, the cyclodextrin is gamma-cyclodextrin.
In a specific example, the X-ray powder diffraction pattern of the baicalein/gamma cyclodextrin inclusion compound co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
3.74 ° ± 0.5 °, 6.41 ° ± 0.5 °, 7.37 ° ± 0.5 °, 9.18 ° ± 0.5 °, 10.48 ° ± 0.5 °, 11.42 ° ± 0.5 °, 12.00 ° ± 0.5 °, 14.15 ° ± 0.5 °, 14.89 ° ± 0.5 °, 15.79 ° ± 0.5 °, 16.65 ° ± 0.5 °, 19.19 ° ± 0.5 °, 20.29 ° ± 0.5 °, 21.13 ° ± 0.5 °, 21.81 ° ± 0.5 °, 22.48 ° ± 0.5 °, 24.49 ° ± 0.5 °, 26.78 ° ± 0.5 ° and 34.96 ° ± 0.5 °.
In a specific example, the X-ray powder diffraction pattern of the baicalein/gamma cyclodextrin inclusion compound co-crystal is substantially as shown in figure 5.
In one specific example, the differential scanning calorimetric curve of baicalein/gamma cyclodextrin inclusion compound co-crystals is substantially as shown in fig. 6.
In a specific example, the baicalein-gamma cyclodextrin inclusion compound eutectic has a melting point of 280 ℃ ± 5 ℃.
It will be appreciated that the baicalein/gamma cyclodextrin inclusion compound eutectic has a melting point of 275 ℃, 276 ℃, 277 ℃, 278 ℃, 279 ℃, 280 ℃, 281 ℃, 282 ℃, 283 ℃, 284 ℃, 285 ℃.
In a specific example, the baicalein inclusion compound eutectic comprises 12-13% by mass of baicalein.
It is understood that in the present invention, the mass percentage of baicalein in the baicalein clathrate co-crystal includes, but is not limited to, 12%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13%.
In a specific example, the baicalein inclusion compound eutectic crystals are in the form of a block.
In a specific example, the baicalein inclusion compound has a eutectic size of 10 μm to 20 μm.
With reference to fig. 1, the invention also provides a preparation method of the baicalein inclusion compound eutectic, which comprises the following steps:
mixing baicalein with a first solvent to prepare a baicalein solution;
mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;
heating cyclodextrin water solution to 30-60 deg.c, and adding baicalein solution to prepare mixed solution;
cooling the mixed solution, standing, and collecting precipitated solid;
wherein the first solvent is a water-miscible organic solvent.
The first solvent is used as solvent of baicalein, and can be used as diluent and delivery medium of medicine. After the baicalein solution is injected into the cyclodextrin aqueous solution, the solvent can be quickly combined with water molecules, so that the dispersion of the baicalein in the water and the formation of inclusion compound eutectic are promoted; on the other hand, the organic solvent can be used as a poor solvent of cyclodextrin to promote the precipitation of inclusion compound eutectic from the solution.
In a specific example, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.
In a specific example, the volume ratio of the first solvent to water in the mixed solution is 3 (7 to 60).
It is understood that in the present invention, the volume ratio of the first solvent to water in the mixed liquor includes, but is not limited to, 3:7, 3:8, 3:9, 3:10, 3:11, 3:12, 3:13, 3:14, 3:15, 3:20, 3:25, 3:30, 3:35, 3:40, 3:45, 3:50, 3:55, 3:60.
More specifically, a fixed volume of baicalein solution is injected into cyclodextrin water solution, and the ratio of organic solvent to water is controlled within a certain range, such as methanol: water=1:20-3:7; ethanol: water=1:20-3:7; acetonitrile: water=1:20-3:7; acetone: water=1:20-3:7; isopropanol: water=1:20-3:7; ethylene glycol water=1:20-3:7, and when the baicalein solvent is insufficient, the blank solvent can be used for supplementing the ratio of the solvent to the water.
In a specific example, the molar ratio of baicalein to cyclodextrin in the mixed solution is 1 (1-20).
It will be appreciated that in the present invention, the molar ratio of baicalein to cyclodextrin in the mixed liquor includes, but is not limited to, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20.
In a specific example, the concentration of baicalein in the baicalein solution is 1mg/mL to 5mg/mL.
It is understood that in the present invention, the concentration of baicalein in the baicalein solution includes, but is not limited to, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL.
In a specific example, the concentration of cyclodextrin in the aqueous cyclodextrin solution is 3mg/mL to 50mg/mL. More specifically, in the aqueous solution of gamma-cyclodextrin, the concentration of gamma-cyclodextrin is 3 mg/mL-30 mg/mL. It will be appreciated that in the present invention, the concentration of gamma-cyclodextrin in the aqueous gamma-cyclodextrin solution includes, but is not limited to, 3mg/mL, 5mg/mL, 7mg/mL, 10mg/mL, 11mg/mL, 12mg/mL, 13mg/mL, 14mg/mL, 15mg/mL, 16mg/mL, 17mg/mL, 18mg/mL, 19mg/mL, 20mg/mL, 25mg/mL, 30mg/mL. Preferably, the concentration of gamma-cyclodextrin in the aqueous gamma-cyclodextrin solution is 7mg/mL.
In a specific example, in the process of adding the baicalein solution, the adding time is controlled to be 0.5-30 min according to 1-3 mL of the baicalein solution.
It will be appreciated that in the present invention, in the process of adding baicalein solution, the time of controlling the addition includes, but is not limited to, 0.5min, 0.6min, 0.7min, 0.8min, 1min, 1.2min, 1.4min, 1.5min, 1.6min, 1.7min, 1.8min, 1.9min, 2min, 2.1min, 2.2min, 2.3min, 2.4min, 2.5min, 3min, 4min, 5min, 6min, 7min, 8min, 10min, 15min, 20min, 25min, 30min based on 1mL to 3mL of the baicalein solution. Preferably, the addition time is controlled to be 3 minutes.
In a specific example, during the addition of the baicalein solution, the aqueous cyclodextrin solution is stirred at a rotational speed of 100rpm to 1000rpm.
It is understood that in the present invention, the rotational speed of stirring the aqueous cyclodextrin solution during the addition of the baicalein solution includes, but is not limited to, 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, 800rpm, 900rpm, 1000rpm.
In a specific example, the mixture is cooled to 4-30 ℃.
In one specific example, the mixture is left to stand for 4 to 72 hours.
In a specific example, the method further comprises the following steps after collecting the precipitated solid:
filtering the precipitated solid, washing the solid for 1 to 3 times by using ice water or precooled crystallization solvent, and collecting white solid; and then the white solid is dried for 1 to 24 hours at the temperature of between 30 and 60 ℃.
The invention also provides a traditional Chinese medicine composition, which comprises the baicalein inclusion compound eutectic and a carrier or an auxiliary material.
In a specific example, the carrier or adjuvant is a pharmaceutically acceptable carrier or pharmaceutically acceptable adjuvant.
The invention also provides the baicalein inclusion compound eutectic crystal, or the application of the traditional Chinese medicine composition in preparing chemical preparations, medicines or foods.
The baicalein clathrate eutectic crystal and the preparation method thereof of the present invention are described in further detail below with reference to specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides a baicalein inclusion compound eutectic crystal, which is prepared by the following specific steps:
(1) Preparing gamma-cyclodextrin water solution and baicalein solution respectively. Wherein the solvent of baicalein is methanol, the concentration of which is 2mg/mL, and the concentration of gamma-cyclodextrin is 15mg/mL.
(2) Heating the cyclodextrin aqueous solution to 50 ℃; under stirring at 100rpm, 1mL of baicalein solution was poured into 7mL of cyclodextrin aqueous solution, the addition time was controlled to be 1 minute, 2mL of methanol was additionally added, and stirring was continued for 0.5 minute.
(3) Stopping heating and stirring, and cooling the mixed solution of baicalein and cyclodextrin to 20 ℃; standing for 12 hours until the crystals in the solution are completely separated out.
(4) Suction filtration to obtain white solid, washing 3 times with water at 4 ℃; and then drying the product at 40 ℃ for 48 hours to obtain the inclusion eutectic of the white powder, which is formed by baicalein and cyclodextrin. The yield of the product is 75 percent calculated by baicalein.
Comparative example 1
This comparative example provides a preparation method for attempting to prepare gamma-cyclodextrin crystals, specifically as follows:
(1) An aqueous solution of gamma-cyclodextrin was prepared, wherein the concentration of gamma-cyclodextrin was 15mg/mL.
(2) The cyclodextrin aqueous solution was heated to 50 ℃.
(3) Stopping heating, and cooling the cyclodextrin water solution to 20 ℃; after 12 hours, no solid precipitated.
Characterization of the baicalein clathrate eutectic prepared in example 1 includes crystal morphology, H-NMR, infrared spectrum, X-ray powder diffraction (XRD) and Differential Scanning Calorimeter (DSC), and the characterization results are specifically as follows:
(1) Crystal morphology
The inclusion compound eutectic prepared in the above example 1 is placed on a glass slide, and the morphology of each sample is observed and recorded under an optical microscope (10×20); another 1mL of baicalein in methanol (3 mg/mL) was dispersed in 10mL of water, and after stirring, a drop of the solution was placed on a slide glass as a control. The results are shown in FIG. 2: the baicalein is dissolved by a good solvent and then injected into water, needle-shaped crystals can be rapidly precipitated in the water, and the water-miscible solvent is taken as a medium, so that the medicine can be promoted to exist in a single-molecule state in the water, and the formation of inclusion compounds can be effectively promoted. Compared with baicalein control, inclusion compound eutectic formed by baicalein and gamma-cyclodextrin has definite crystal habit: the pale yellow crystals are about 10 μm to about 20. Mu.m.
(2)H-NMR
D for eutectic inclusion compound prepared in the above example 1 by using baicalein and gamma-cyclodextrin 6 Hydrogen spectra were determined after DMSO dissolution and the results are shown in figure 3. The H-NMR data of the inclusion compound eutectic simultaneously contain signals of baicalein and gamma-cyclodextrin, and the fact that the crystal consists of two components is proved.
(3) Infrared spectrum
The infrared spectra of baicalein, cyclodextrin and clathrate eutectic prepared in the above example 1 are shown in figure 4. Wherein baicalein has a characteristic peak of 475.65cm -1 、527.05cm -1 、575.36cm -1 、641.81cm -1 、702.43cm -1 、759.83cm -1 、845.06cm -1 、937.48cm -1 、997.56cm -1 、1022.10cm -1 、1048.68cm -1 、1076.02cm -1 、1104.04cm -1 、1154.69cm -1 、1299.97cm -1 、1335.09cm -1 、1367.83cm -1 、1412.60cm -1 、1448.28cm -1 、1468.88cm -1 、1587.55cm -1 、1615.81cm -1 、1661.99cm -1 The infrared spectrum of the inclusion compound eutectic formed by the baicalein and the gamma-cyclodextrin is consistent with the cyclodextrin as a whole, so that the inclusion compound formed by the medicine and the cyclodextrin is shown, and the characteristic peak of the baicalein in the structure is covered by the cyclodextrin.
(4)XRD
The XPRD of the inclusion compound eutectic prepared in the above example 1 is shown in figure 5. Wherein the XRD diffraction peaks of the inclusion compound co-crystals prepared in example 1 above were 3.74 °, 6.41 °, 7.37 °, 9.18 °, 10.48 °, 11.42 °, 12.00 °, 14.15 °, 14.89 °, 15.79 °, 16.65 °, 19.19 °, 20.29 °, 21.13 °, 21.81 °, 22.48 °, 24.49 °, 26.78 ° and 34.96 °, the characteristic diffraction peaks of the crystal XPRD were completely different from γ -cyclodextrin, indicating that a new crystal form was not formed, and HNMR results showed that the crystal comprised both cyclodextrin and baicalein, and thus could be determined as a baicalein/γ -cyclodextrin co-crystal.
(5)DSC
DSC (temperature rise rate of DSC measurement is 10K/min) of baicalein, gamma-cyclodextrin and clathrate compound eutectic prepared in the embodiment 1, and a graph is shown in figure 6. The melting point of baicalein is 267 ℃, the melting point of the inclusion compound eutectic is 280 ℃ after the baicalein and the gamma-cyclodextrin form the eutectic, and the melting point is increased compared with that of the baicalein, which indicates that the thermal stability of the baicalein/gamma-cyclodextrin inclusion compound eutectic is increased.
The solubility measurement experiment is carried out on baicalein, gamma-cyclodextrin and the baicalein-gamma-cyclodextrin inclusion compound eutectic prepared in the embodiment 1, and the result is as follows:
the baicalein/gamma cyclodextrin inclusion compound eutectic prepared in example 1 improves the solubility of the medicament in water. Baicalein is almost insoluble in water, the solubility is about 8 mug/mL, and the solubility of baicalein/gamma cyclodextrin inclusion compound eutectic in water is about 30 mug/mL, so that the water solubility is obviously improved.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.
Claims (11)
1. A baicalein clathrate co-crystal comprising a co-crystal ligand and a pharmaceutically active ingredient clathrated by the co-crystal ligand; the active component of the medicine is baicalein, and the eutectic ligand is cyclodextrin;
the baicalein and the cyclodextrin are assembled by a host and a guest to form inclusion compound eutectic;
the cyclodextrin is gamma-cyclodextrin; the X-ray powder diffraction pattern of the baicalein/gamma cyclodextrin inclusion compound co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
3.74 ° ± 0.5 °, 6.41 ° ± 0.5 °, 7.37 ° ± 0.5 °, 9.18 ° ± 0.5 °, 10.48 ° ± 0.5 °, 11.42 ° ± 0.5 °, 12.00 ° ± 0.5 °, 14.15 ° ± 0.5 °, 14.89 ° ± 0.5 °, 15.79 ° ± 0.5 °, 16.65 ° ± 0.5 °, 19.19 ° ± 0.5 °, 20.29 ° ± 0.5 °, 21.13 ° ± 0.5 °, 21.81 ° ± 0.5 °, 22.48 ° ± 0.5 °, 24.49 ° ± 0.5 °, 26.78 ° ± 0.5 ° and 34.96 ° ± 0.5 °.
2. The baicalein clathrate co-crystal of claim 1, wherein the baicalein/gamma cyclodextrin clathrate co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 5.
3. The baicalein clathrate co-crystal according to claim 1, wherein the baicalein/gamma cyclodextrin clathrate co-crystal has a melting point of 280 ℃ ± 5 ℃.
4. The baicalein clathrate co-crystal according to any one of claims 1 to 3, wherein the baicalein mass percentage of the baicalein clathrate co-crystal is 12% -13%.
5. A method for preparing the baicalein clathrate compound eutectic according to any one of claims 1 to 4, comprising the following steps:
mixing baicalein with a first solvent to prepare a baicalein solution;
mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;
heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the baicalein solution to prepare a mixed solution;
cooling the mixed solution, standing and collecting precipitated solid;
wherein the first solvent is a water-miscible organic solvent.
6. The method for preparing baicalein clathrate co-crystal according to claim 5, wherein the first solvent is one or more selected from methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol and ethylene glycol.
7. The method for preparing baicalein clathrate compound eutectic according to claim 5, wherein the volume ratio of the first solvent to water in the mixed solution is 3 (7-60).
8. The method for preparing a baicalein clathrate compound eutectic according to claim 5, wherein the molar ratio of baicalein to cyclodextrin in the mixed solution is 1 (1-20).
9. The method for preparing baicalein clathrate co-crystal according to any one of claims 5 to 8, wherein the adding process of the baicalein solution satisfies one or more of the following conditions:
(1) Controlling the adding time to be 0.5 min-30 min according to 1 mL-3 mL of baicalein solution;
(2) And stirring the cyclodextrin aqueous solution at a rotating speed of 100-1000 rpm.
10. A traditional Chinese medicine composition, which is characterized by comprising the baicalein clathrate eutectic of any one of claims 1-4 and a carrier or an auxiliary material.
11. The baicalein clathrate co-crystal of any one of claims 1-4 or the application of the traditional Chinese medicine composition of claim 10 in preparing chemical preparations, medicines or foods.
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| CN114555124A (en) * | 2019-08-19 | 2022-05-27 | 瑟拉诺沃控股有限公司 | Pharmaceutical co-crystal salt formulation |
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| CN102698283A (en) * | 2012-06-07 | 2012-10-03 | 上海中医药大学 | Baicalein clathrate and preparation method thereof |
| CN103351342A (en) * | 2013-07-03 | 2013-10-16 | 浙江中医药大学 | Edaravone pharmaceutical co-crystal and preparation method thereof |
| CN105218500A (en) * | 2015-11-02 | 2016-01-06 | 诸城市浩天药业有限公司 | Scutellarin caffeine eutectic, its preparation method, pharmaceutical composition and application thereof |
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