WO2024027219A1 - 大蒜素-环糊精包合物共晶的晶型及其制备方法和应用 - Google Patents

大蒜素-环糊精包合物共晶的晶型及其制备方法和应用 Download PDF

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WO2024027219A1
WO2024027219A1 PCT/CN2023/090363 CN2023090363W WO2024027219A1 WO 2024027219 A1 WO2024027219 A1 WO 2024027219A1 CN 2023090363 W CN2023090363 W CN 2023090363W WO 2024027219 A1 WO2024027219 A1 WO 2024027219A1
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allicin
cyclodextrin
crystal form
solution
inclusion complex
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French (fr)
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黄永焯
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刘二刚
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中科中山药物创新研究院
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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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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
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    • A23K—FODDER
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    • A23K20/10—Organic substances
    • A23K20/163—Sugars; Polysaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
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    • 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
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    • 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
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
    • A23L29/35—Degradation products of starch, e.g. hydrolysates, dextrins; Enzymatically modified starches
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    • 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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    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the field of fine chemicals and applications, and in particular to a crystal form of an allicin-cyclodextrin inclusion complex eutectic and its preparation method and application.
  • Allicin is diallyl thiosulfinate, an active ingredient extracted from garlic (Allicin Sativum L.) of the genus Allium of the Liliaceae family. Allicin has broad-spectrum antibacterial activity. It can inhibit a variety of Gram-positive cocci and Gram-negative bacilli at very low concentrations. It has a significant inhibitory effect on Escherichia coli and Shigella dysenteriae, and has a significant inhibitory effect on molds, viruses, protozoa, and pinworms. etc. also have inhibitory effects. At the same time, allicin also has good anti-inflammatory activity. Therefore, allicin is an active substance that is widely used. It can be used as an insecticide and fungicide in agriculture, as well as in feed, food, medicine, etc.
  • allicin has problems such as poor water solubility, easy degradation, strong odor, and strong irritation. Microemulsions, cyclodextrin inclusion compounds, or solid excipients (such as silica, PEG, etc.) are often used for application. ) to prepare allicin products by adsorption and solidification.
  • microemulsions, cyclodextrin inclusion compounds, or solid excipients such as silica, PEG, etc.
  • the present invention provides a crystal form of an allicin-cyclodextrin inclusion complex cocrystal with good water solubility, stable properties and not easily degraded, and its preparation method and application.
  • a first aspect of the present invention provides a crystal form of an allicin-cyclodextrin inclusion complex cocrystal, where the cyclodextrin is ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrin.
  • the crystal form of the allicin-cyclodextrin inclusion complex cocrystal is selected from any of the following groups:
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 1;
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 2;
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 3.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin has an endothermic peak at 277.9 ⁇ 3°C;
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin has an endothermic peak at 258.3 ⁇ 3°C;
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin has an endothermic peak at 248.6 ⁇ 3°C.
  • a second aspect of the present invention provides a method for preparing the crystal form of the allicin-cyclodextrin inclusion complex cocrystal, which includes the following steps:
  • the first solvent is an organic solvent miscible with water
  • the cyclodextrin is ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrin.
  • the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropyl alcohol and ethylene glycol.
  • the molar ratio of allicin to cyclodextrin is 1: (1-20); and/or
  • the volume ratio of the allicin solution and the cyclodextrin aqueous solution is (1-3): (20-7).
  • the adding time is controlled to be 0.5 min to 30 min based on 1 mL to 3 mL of the allicin solution;
  • a third aspect of the present invention provides a composition comprising:
  • the fourth aspect of the present invention provides the crystal form of the allicin-cyclodextrin inclusion complex eutectic described in the first aspect, or the antibacterial composition described in the third aspect in the preparation of chemical preparations, drugs, and foods with antibacterial efficacy. or feed applications.
  • the fifth aspect of the present invention provides the crystal form of the allicin-cyclodextrin inclusion complex cocrystal described in the first aspect, or the anti-inflammatory composition described in the third aspect in the preparation of chemical preparations and drugs with anti-inflammatory effects. , food or feed applications.
  • the present invention obtains inclusion complex co-crystals formed by allicin and ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrin through research and preparation. Compared with traditional inclusion compounds, this inclusion compound cocrystal has a clear crystal structure and better stability, is not easily degraded, and has good water solubility. At the same time, unlike traditional co-crystal preparations that utilize hydrogen bonds and electrostatic interactions between drugs and co-crystal ligands to form crystals, inclusion compound co-crystals take advantage of the characteristics of cyclodextrin and allicin to form inclusion compounds. , both participate in crystal formation in the form of inclusion compounds.
  • different inclusion crystals can be prepared by using cyclodextrins with different pore sizes, thereby controlling the drug release rate and effectively solidifying allicin. It can be used as an intermediate raw material for allicin in the preparation of solid and semi-allicin. Solid and other preparation forms.
  • the present invention combines the solvent injection method to prepare nanoparticles and the anti-solvent method for crystallization, combined with appropriate heating temperature, to realize the inclusion complex co-crystal formed by allicin and ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrin.
  • the preparation method is simple and easy to promote and apply.
  • Figure 1 is the XPRD pattern of allicin- ⁇ -cyclodextrin (the abscissa is the angle 2 ⁇ (°), the ordinate is the intensity);
  • Figure 2 is the XPRD pattern of allicin- ⁇ -cyclodextrin (the abscissa is the angle 2 ⁇ (°), the ordinate is the intensity);
  • Figure 3 is the XPRD pattern of allicin- ⁇ -cyclodextrin (the abscissa is the angle 2 ⁇ (°), the ordinate is the intensity);
  • Figure 4 is the DSC spectrum of allicin- ⁇ -cyclodextrin (the abscissa is temperature (°C), the ordinate is heat flow rate (W/g));
  • Figure 5 is the DSC spectrum of allicin- ⁇ -cyclodextrin (the abscissa is temperature (°C), the ordinate is heat flow rate (W/g));
  • Figure 6 is the DSC spectrum of allicin- ⁇ -cyclodextrin (the abscissa is temperature (°C), the ordinate is heat flow rate (W/g));
  • Figure 7 is an overlay of DSC spectra of allicin- ⁇ -cyclodextrin, allicin- ⁇ -cyclodextrin and allicin- ⁇ -cyclodextrin;
  • Figure 8 is a micrograph of allicin, inclusion complex eutectic formed by allicin and ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin (scale bar: 50 ⁇ m);
  • Figure 9 is a 1 H-NMR spectrum of allicin, inclusion complex cocrystals formed by allicin and ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin;
  • Figure 10 is an infrared spectrum of allicin, inclusion complex cocrystals formed by allicin and ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin;
  • Figure 11 shows the co-crystals of the traditional allicin-cyclodextrin inclusion complex and the inclusion complex formed by allicin and ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin at 25°C and 60°C. Content changes and degradation trends.
  • first aspect”, “second aspect”, “third aspect”, “fourth aspect”, etc. are only used for description purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as An implicit indication of the importance or quantity of the technical feature indicated. Furthermore, “first”, “second”, “third”, “fourth”, etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation of quantity.
  • the technical features described in open terms include closed technical solutions composed of the listed features, and also include open technical solutions including the listed features.
  • the above numerical interval is regarded as continuous and includes the minimum value and maximum value of the range, as well as every value between the minimum value and the maximum value. Further, when a range refers to an integer, every integer between the minimum value and the maximum value of the range is included. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
  • the percentage content involved in the present invention refers to mass percentage for solid-liquid mixing and solid-solid phase mixing, and refers to volume percentage for liquid-liquid phase mixing.
  • the percentage concentration involved in the present invention refers to the final concentration unless otherwise specified.
  • the final concentration refers to the proportion of the added component in the system after adding the component.
  • the temperature parameters in the present invention allow for constant temperature treatment or treatment within a certain temperature range.
  • the thermostatic treatment described allows the temperature to fluctuate within the accuracy of the instrument control.
  • the invention provides a crystal form of an allicin-cyclodextrin inclusion complex cocrystal, and the cyclodextrin is ⁇ -cyclodextrin or ⁇ -cyclodextrin. Or gamma-cyclodextrin.
  • the crystal form of the allicin-cyclodextrin inclusion compound cocrystal is allicin- ⁇ -cyclodextrin, and its X-ray powder diffraction pattern has characteristic diffraction at the following 2 ⁇ (°) angle peak:
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 1.
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is shown in Figure 1.
  • the differential scanning calorimetry curve of allicin- ⁇ -cyclodextrin has an endothermic peak at 277.9 ⁇ 3°C. Furthermore, there is an endothermic peak at 277.9 ⁇ 2°C. Furthermore, there is an endothermic peak at 277.9 ⁇ 0.5°C.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 4.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin is shown in Figure 4.
  • the crystal form of the allicin-cyclodextrin inclusion complex cocrystal is allicin- ⁇ -cyclodextrin, and its X-ray powder diffraction pattern has characteristic diffraction at the following 2 ⁇ (°) angle peak:
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 2.
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is shown in Figure 2.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin has an endothermic peak at 258.3 ⁇ 3°C. Furthermore, there is an endothermic peak at 258.3 ⁇ 2°C. Furthermore, there is an endothermic peak at 258.3 ⁇ 0.5°C.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 5.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin is shown in Figure 5.
  • the crystal form of the allicin-cyclodextrin inclusion compound cocrystal is allicin- ⁇ -cyclodextrin, and its X-ray powder diffraction pattern has characteristic diffraction at the following 2 ⁇ (°) angle peak:
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 3.
  • the X-ray powder diffraction pattern of the allicin- ⁇ -cyclodextrin is shown in Figure 3.
  • the differential scanning calorimetry curve of allicin- ⁇ -cyclodextrin at 248.6 ⁇ 3°C has Endothermic peak. Furthermore, there is an endothermic peak at 248.6 ⁇ 2°C. Furthermore, there is an endothermic peak at 248.6 ⁇ 0.5°C.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin is basically as shown in Figure 6.
  • the differential scanning calorimetry curve of the allicin- ⁇ -cyclodextrin is shown in Figure 6.
  • the present invention also provides a method for preparing the crystal form of the allicin-cyclodextrin inclusion complex cocrystal, which includes the following steps:
  • the first solvent is an organic solvent miscible with water
  • the cyclodextrin is ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrin.
  • the above-mentioned preparation method combines the process principles of preparing nanoparticles by solvent injection method and crystallization by anti-solvent method.
  • the key lies in: 1) selecting an organic solvent that is miscible with water as the solvent (first solvent) of allicin; 2) preparing the inclusion complex of allicin and cyclodextrin by solvent injection method under appropriate temperature conditions. crystal.
  • the first solvent serves as a solvent for allicin and can be used as a diluent and delivery medium for the drug.
  • the allicin solution is injected into the aqueous solution of cyclodextrin, the solvent can quickly combine with water molecules, thus promoting the release of allicin.
  • Dispersion in water and formation of inclusion complexes on the other hand, the first solvent can serve as a poor solvent for cyclodextrin, promoting the precipitation of inclusion complexes from the solution.
  • the concentration of allicin in the allicin solution is 0.5-5 mg/mL.
  • the concentration of allicin in the allicin solution includes but is not limited to: 0.5mg/mL, 1mg/mL, 1.5mg/mL, 2mg/mL, 2.5mg/mL, 3mg/mL, 4mg/mL, 5mg /mL.
  • the concentration of cyclodextrin in the aqueous cyclodextrin solution is 3 to 50 mg/mL. Furthermore, depending on the type of cyclodextrin, it can be controlled as follows:
  • the concentration of ⁇ -cyclodextrin in the ⁇ -cyclodextrin aqueous solution is 3 to 30 mg/mL.
  • the concentration of ⁇ -cyclodextrin in the ⁇ -cyclodextrin aqueous solution includes but is not limited to: 3 mg/mL, 6 mg/mL, 8 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 23 mg/mL, 25mg/mL, 27mg/mL, 30mg/mL.
  • the concentration of ⁇ -cyclodextrin in the ⁇ -cyclodextrin aqueous solution is 3 to 15 mg/mL.
  • the concentration of ⁇ -cyclodextrin in the ⁇ -cyclodextrin aqueous solution includes but is not limited to: 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, 12mg/mL, 15mg/mL.
  • the concentration of ⁇ -cyclodextrin in the ⁇ -cyclodextrin aqueous solution is 3 to 30 mg/mL.
  • the concentration of ⁇ -cyclodextrin in the ⁇ -cyclodextrin aqueous solution includes but is not limited to: 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10mg/mL, 12mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, 30mg/mL.
  • the cyclodextrin aqueous solution is heated to 30°C to 60°C.
  • the temperature to which the cyclodextrin aqueous solution is heated includes, but is not limited to: 30°C, 35°C, 38°C, 40°C, 42°C, 45°C, 48°C, 50°C, 52°C, 55°C, 58°C, 60°C.
  • the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropyl alcohol and ethylene glycol.
  • the molar ratio of allicin and cyclodextrin in the mixed liquid is 1: (1-20).
  • the molar ratio of allicin to cyclodextrin includes but is not limited to: 1:1, 1:3, 1:5, 1:7, 1:9, 1:11 , 1:13, 1:15, 1:17, 1:19, 1:20.
  • the volume ratio of the allicin solution and the cyclodextrin aqueous solution is (1-3): (20-7).
  • the volume ratio of the allicin solution and the cyclodextrin aqueous solution includes but is not limited to: 1:20, 1:15, 1:10, 3:20, 3:10, 3:7 . It can be understood that when the amounts of the allicin solution and the cyclodextrin aqueous solution are insufficient after the addition is completed, the corresponding blank solvent (first solvent or water) can be used to make up to the above-mentioned allicin solution and the cyclodextrin aqueous solution. within the volume ratio range.
  • the adding time is controlled to be 0.5 min to 30 min based on 1 mL to 3 mL of the allicin solution.
  • the controlled adding time includes but is not limited to: 0.5 min, 1 min, 2 min, 3 min, 4 min, 5 min, 7 min, 10 min, 15min, 20min, 25min, 30min.
  • the mixture is stirred at a speed of 50 rpm to 1000 rpm.
  • the stirring speed includes but is not limited to: 50rpm, 60rpm, 70rpm, 80rpm, 90rpm, 100rpm, 110rpm, 120rpm, 130rpm, 140rpm, 150rpm, 200rpm, 500rpm, 800rpm, 900rpm, 950rpm, 1000rpm.
  • cooling refers to stopping heating, and the temperature reached by cooling may be 20°C to 30°C.
  • the standing time can be 2 to 48 hours, and the temperature can be maintained at the temperature reached by the aforementioned cooling.
  • suction filtration can be used to collect the precipitated solids.
  • the solid obtained by suction filtration can be washed 1 to 3 times with ice water or pre-cooled (0-25°C) first solvent.
  • a step of drying the collected solids is also included. Further, drying conditions include: temperature is 30°C to 60°C, and time is 1h to 24h.
  • the present invention also provides an antibacterial composition, which includes:
  • the present invention also provides the crystal form of the above-mentioned allicin-cyclodextrin inclusion complex cocrystal, or the application of the above-mentioned antibacterial composition in the preparation of chemical preparations, drugs, foods or feeds with antibacterial efficacy.
  • the present invention also provides an anti-inflammatory composition, which includes:
  • the present invention also provides the crystal form of the above-mentioned allicin-cyclodextrin inclusion complex cocrystal, or the application of the above-mentioned anti-inflammatory composition in the preparation of chemical preparations, drugs, foods or feeds with anti-inflammatory effects.
  • the cocrystals prepared in Examples 1 to 3 were placed on a glass slide and examined under an optical microscope (10 ⁇ 20 ) Observe and record the morphology of each sample; disperse 1 mL of allicin methanol solution (3 mg/mL) in 10 mL of water, stir evenly, and place a drop of the liquid on a glass slide as a control (recorded as allicin aqueous solution).
  • the co-crystals formed by allicin and cyclodextrin have clear crystal habits: the three inclusion complex co-crystals are respectively short rod-shaped (allicin/ ⁇ CD), block-shaped (allicin/ ⁇ CD), and long rod-shaped (allicin/ ⁇ CD).
  • the three inclusion complex co-crystals are respectively short rod-shaped (allicin/ ⁇ CD), block-shaped (allicin/ ⁇ CD), and long rod-shaped (allicin/ ⁇ CD).
  • the infrared spectra of allicin and the cocrystals prepared in Examples 1 to 3 are shown in Figure 10.
  • the characteristic peaks of allicin are at 575cm -1 , 708cm -1 , 915cm -1 , 990cm -1 , 1208cm -1 , 1395-1425cm -1 , 1625cm -1 ; cyclodextrin
  • the characteristic peaks of allicin are between 400-2000cm -1 ; compared with the two, most of the characteristic peaks of allicin in the infrared spectrum of the inclusion complex eutectic formed by allicin and several cyclodextrins disappear, and its infrared
  • the spectrum is generally consistent with cyclodextrin, indicating that the drug forms an inclusion complex with cyclodextrin, so the characteristic peaks of allicin in the structure are masked by cyclodextrin.
  • the XRD diffraction peaks of ⁇ -CD/allicin cocrystal are at 5.745°, 7.374°, 11.502°, 11.927°, 12.198°, 12.808°, 19.040°, 19.683°, 21.692°, 22.311°;
  • the XRD diffraction peaks of ⁇ -CD/allicin cocrystal are at 5.778°, 6.583°, 6.865°, 10.998°, 11.561°, 11.867°, 14.212°, 14.507°, 14.975°, 15.549°, 16.737°, 17.035°, 17.363 °, 17.621°, 17.98°, 18.332°, 19.886°, 20.728°, 20.988°, 23.692°, 23.912°, 24.475°;
  • the XRD diffraction peaks of ⁇ -CD/allicin cocrystal are at 5.787°, 6.006°, 7.393°, 10.175°, 10.521°, 11.763°, 12.043°, 14.171°, 14.905°, 15.792°, 16.193°, 16.654°, 19.167 °, 20.251°, 21.128°, 21.787°, 22.411°, 23.636°, 26.669°, 27.571°.
  • Allicin is an oily compound at room temperature. After forming a eutectic with cyclodextrin, the melting points of its inclusion complex eutectic are 277.9°C ( ⁇ -CD/allicin eutectic) and 258.3°C ( ⁇ -CD) respectively. /allicin eutectic) and 248.6°C ( ⁇ -CD/allicin eutectic). The results show that the thermal stability of allicin after forming an inclusion compound eutectic is significantly improved.
  • the cyclodextrin inclusion complex cocrystal improves the solubility of drugs in water.
  • Literature shows that the solubility of allicin free drug in water is 8 ⁇ g/mL, the solubility of ⁇ -CD/allicin eutectic is 480 ⁇ g/mL, the solubility of ⁇ -CD/allicin eutectic is 30 ⁇ g/mL, and the solubility of ⁇ -CD/allicin eutectic is 30 ⁇ g/mL.
  • the solubility of the eutectic is 10 ⁇ g/mL, which increases by 60 times, 3.75 times and 1.25 times respectively.
  • test method place the same mass of allicin/ ⁇ -CD eutectic, allicin/ ⁇ -CD eutectic and allicin/ ⁇ -CD eutectic at 25°C and 60°C respectively, and take samples at corresponding intervals. Allicin content was determined by HPLC.
  • preparation methods of CD-allicin samples with different molar ratios in Table 1 refer to the preparation steps of Examples 1-3.
  • test results are shown in Figure 11 and Table 1: Compared with allicin inclusion complexes, allicin eutectic has higher stability. At the same time, ⁇ -CD/allicin eutectic almost does not degrade within 30 days at 25°C, and degrades approximately 6.5% at 60°C; ⁇ -CD/allicin eutectic degrades to a similar degree at 25°C and 60°C, degrading approximately 9.8%. ; ⁇ -CD/allicin eutectic hardly degrades within 14 days at 25°C, approximately 25% degrades in 30 days, and 50.7% degrades in 3 days at 60°C.

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Abstract

本发明涉及一种大蒜素-环糊精包合物共晶的晶型及其制备方法和应用。所述大蒜素-环糊精包合物共晶的晶型中所述环糊精为α-环糊精、β-环糊精或γ-环糊精。所述大蒜素-环糊精包合物共晶的晶型的水溶性好，性质稳定，不易降解。

Description

大蒜素-环糊精包合物共晶的晶型及其制备方法和应用 技术领域
本发明涉及精细化工与应用领域，特别是涉及一种大蒜素-环糊精包合物共晶的晶型及其制备方法和应用。
背景技术
大蒜素为二烯丙基硫代亚磺酸酯，是从百合科葱属植物大蒜(Allicin Sativum L.)中提取得到的活性成分。大蒜素具有广谱的抗菌活性，在极低浓度时即可抑制多种革兰氏阳性球菌和革兰氏阴性杆菌，对大肠杆菌、痢疾杆菌抑制效果明显，对霉菌、病毒、原虫、蛲虫等也有抑制作用。同时，大蒜素还具有良好的抗炎活性。因此，大蒜素是应用十分广泛的活性物质，如可用作农业上的杀虫、杀菌剂，也用作饲料、食品、医药等。
然而，大蒜素在实际应用过程中存在水溶性差、易降解，以及异味重、刺激性强等问题，应用时多采用微乳、环糊精包合物或固体辅料(如二氧化硅、PEG等)吸附固化等方式制备大蒜素产品。但是大蒜素的水溶性差和易降解的问题依然有待进一步的研究和改善。
发明内容
基于此，本发明提供一种水溶性好，性质稳定，不易降解的大蒜素-环糊精包合物共晶的晶型及其制备方法和应用。
具体技术方案如下：
本发明的第一方面，提供一种大蒜素-环糊精包合物共晶的晶型，所述环糊精为α-环糊精、β-环糊精或γ-环糊精。
在其中一个实施例中，所述大蒜素-环糊精包合物共晶的晶型选自以下任一组：
(i)大蒜素-α环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
5.745±0.2、7.374±0.2、11.502±0.2、11.927±0.2、12.198±0.2、12.808±0.2、19.040±0.2、19.683±0.2、21.692±0.2和22.311±0.2；
(ii)大蒜素-β环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
5.778±0.2、6.583±0.2、6.865±0.2、10.998±0.2、11.561±0.2、11.867±0.2、14.212±0.2、14.507±0.2、14.975±0.2、15.549±0.2、16.737±0.2、17.035±0.2、17.363±0.2、17.621±0.2、17.98±0.2、18.332±0.2、19.886±0.2、20.728±0.2、20.988±0.2、23.692±0.2、23.912±0.2和24.475±0.2；
(iii)大蒜素-γ环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
5.787±0.2、6.006±0.2、7.393±0.2、10.175±0.2、10.521±0.2、11.763±0.2、12.043±0.2、14.171±0.2、14.905±0.2、15.792±0.2、16.193±0.2、16.654±0.2、19.167±0.2、20.251±0.2、21.128±0.2、21.787±0.2、22.411±0.2、23.636±0.2、26.669±0.2和27.571±0.2。
在其中一个实施例中，
所述大蒜素-α环糊精的X射线粉末衍射图谱基本如图1所示；
所述大蒜素-β环糊精的X射线粉末衍射图谱基本如图2所示；
所述大蒜素-γ环糊精的X射线粉末衍射图谱基本如图3所示。
在其中一个实施例中，
所述大蒜素-α环糊精的差示扫描量热曲线在277.9±3℃处具有吸热峰；
所述大蒜素-β环糊精的差示扫描量热曲线在258.3±3℃处具有吸热峰；
所述大蒜素-γ环糊精的差示扫描量热曲线在248.6±3℃处具有吸热峰。
本发明的第二方面，提供所述的大蒜素-环糊精包合物共晶的晶型的制备方法，包括如下步骤：
将大蒜素与第一溶剂混合，制备大蒜素溶液；
将环糊精与水混合，制备环糊精水溶液；
将所述环糊精水溶液加热至30℃～60℃，然后加入所述大蒜素溶液，制备混合液；
将所述混合物冷却，静置，收集析出的固体；
其中，所述第一溶剂为可与水混溶的有机溶剂；
所述环糊精为α-环糊精、β-环糊精或γ-环糊精。
在其中一个实施例中，所述第一溶剂选自甲醇、乙醇、乙腈、丙酮、四氢呋喃、异丙醇和乙二醇中的一种或多种。
在其中一个实施例中，所述混合液中，所述大蒜素与所述环糊精的摩尔比为1:(1～20)；和/或
所述混合液中，所述大蒜素溶液与环糊精水溶液的体积比为(1～3):(20～7)。
在其中一个实施例中，加入所述大蒜素溶液的过程中，以1mL～3mL所述大蒜素溶液计，控制加入的时间为0.5min～30min；和/或
加入所述大蒜素溶液的过程中，以50rpm～1000rpm的速率搅拌。
本发明的第三方面，提供一种组合物，所述组合物包括：
(a)第一方面所述的大蒜素-环糊精包合物共晶的晶型；以及
(b)辅料或载体。
本发明的第四方面，提供第一方面所述的大蒜素-环糊精包合物共晶的晶型，或第三方面所述抗菌组合物在制备具有抗菌功效的化学制剂、药物、食品或饲料中的应用。
本发明的第五方面，提供第一方面所述的大蒜素-环糊精包合物共晶的晶型，或第三方面所述抗炎组合物在制备具有抗炎功效的化学制剂、药物、食品或饲料中的应用。
本发明通过研究并制备得到大蒜素与α-环糊精、β-环糊精或γ-环糊精形成的包合物共晶。与传统的包合物相比，该包合物共晶具有明确的晶体结构和更好的稳定性，不易降解，且具有良好的水溶性。同时，与传统的共晶制备中利用药物与共晶配体之间的氢键、静电作用等形成晶体的方式不同，包合物共晶利用了环糊精与大蒜素可形成包合物的特点，二者以包合物的形式参与晶体形成。另外，可通过采用孔径大小不同的环糊精制备不同的包合物晶体，由此调控释药速率，且能够对大蒜素进行有效的固化，可作为大蒜素的中间原料用于制备固体、半固体等各种制剂形式。
本发明融合溶剂注入法制备纳米粒和反溶剂法结晶，结合合适的加热温度，能够实现大蒜素与α-环糊精、β-环糊精或γ-环糊精形成的包合物共晶的制备，且制备方法简单易行，便于推广应用。
附图说明
图1为大蒜素-α环糊精的XPRD图谱(横坐标为角度2θ(°)，纵坐标为强度)；
图2为大蒜素-β环糊精的XPRD图谱(横坐标为角度2θ(°)，纵坐标为强度)；
图3为大蒜素-γ环糊精的XPRD图谱(横坐标为角度2θ(°)，纵坐标为强度)；
图4为大蒜素-α环糊精的DSC图谱(横坐标为温度(℃)，纵坐标为热流率(W/g))；
图5为大蒜素-β环糊精的DSC图谱(横坐标为温度(℃)，纵坐标为热流率(W/g))；
图6为大蒜素-γ环糊精的DSC图谱(横坐标为温度(℃)，纵坐标为热流率(W/g))；
图7为大蒜素-α环糊精、大蒜素-β环糊精与大蒜素-γ环糊精的DSC图谱叠加图；
图8为大蒜素、大蒜素与α-环糊精、β-环糊精和γ-环糊精形成的包合物共晶的显微镜照片(标尺：50μm)；
图9为大蒜素、大蒜素与α-环糊精、β-环糊精和γ-环糊精形成的包合物共晶的1H-NMR谱图；
图10为大蒜素、大蒜素与α-环糊精、β-环糊精和γ-环糊精形成的包合物共晶的红外光谱图；
图11为传统大蒜素-环糊精包合物、大蒜素与α-环糊精、β-环糊精和γ-环糊精形成的包合物共晶在25℃与60℃条件下的含量变化与降解趋势。
具体实施方式
以下结合具体实施例对本发明的大蒜素-环糊精包合物共晶的晶型及其制备方法和应用作进一步详细的说明。本发明可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使对本发明公开内容理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
本文所使用的术语“和/或”、“或/和”、“及/或”的可选范围包括两个或两个以上相关所列项目中任一个项目，也包括相关所列项目的任意的和所有的组合，所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。
本文中，“一种或多种”指所列项目的任一种、任两种或任两种以上。
本发明中，“第一方面”、“第二方面”、“第三方面”、“第四方面”等仅用于描述目的，不能理解为指示或暗示相对重要性或数量，也不能理解为隐含指明所指示的技术特征的重要性或数量。而且“第一”、“第二”、“第三”、“第四”等仅起到非穷举式的列举描述目的，应当理解并不构成对数量的封闭式限定。
本发明中，以开放式描述的技术特征中，包括所列举特征组成的封闭式技术方案，也包括包含所列举特征的开放式技术方案。
本发明中，涉及到数值区间，如无特别说明，上述数值区间内视为连续，且包括该范围的最小值及最大值，以及这种最小值与最大值之间的每一个值。进一步地，当范围是指整数时，包括该范围的最小值与最大值之间的每一个整数。此外，当提供多个范围描述特征或特性时，可以合并该范围。换言之，除非另有指明，否则本文中所公开之所有范围应理解为包括其中所归入的任何及所有的子范围。
本发明中涉及的百分比含量，如无特别说明，对于固液混合和固相-固相混合均指质量百分比，对于液相-液相混合指体积百分比。
本发明中涉及的百分比浓度，如无特别说明，均指终浓度。所述终浓度，指添加成分在添加该成分后的体系中的占比。
本发明中的温度参数，如无特别限定，既允许为恒温处理，也允许在一定温度区间内进行处理。所述的恒温处理允许温度在仪器控制的精度范围内进行波动。
本发明的提供一种大蒜素-环糊精包合物共晶的晶型，所述环糊精为α-环糊精、β-环糊精 或γ-环糊精。
在其中一个具体的示例中，所述大蒜素-环糊精包合物共晶的晶型为大蒜素-α环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
5.745±0.2、7.374±0.2、11.502±0.2、11.927±0.2、12.198±0.2、12.808±0.2、19.040±0.2、19.683±0.2、21.692±0.2和22.311±0.2。
在其中一个具体的示例中，所述大蒜素-α环糊精的X射线粉末衍射图谱基本如图1所示。
在其中一个具体的示例中，所述大蒜素-α环糊精的X射线粉末衍射图谱如图1所示。
在其中一个具体的示例中，所述大蒜素-α环糊精的差示扫描量热曲线在277.9±3℃处具有吸热峰。进一步地，在277.9±2℃处具有吸热峰。更进一步地，在277.9±0.5℃处具有吸热峰。
在其中一个具体的示例中，所述大蒜素-α环糊精的差示扫描量热曲线基本如图4所示。
在其中一个具体的示例中，所述大蒜素-α环糊精的差示扫描量热曲线如图4所示。
在其中一个具体的示例中，所述大蒜素-环糊精包合物共晶的晶型为大蒜素-β环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
5.778±0.2、6.583±0.2、6.865±0.2、10.998±0.2、11.561±0.2、11.867±0.2、14.212±0.2、14.507±0.2、14.975±0.2、15.549±0.2、16.737±0.2、17.035±0.2、17.363±0.2、17.621±0.2、17.98±0.2、18.332±0.2、19.886±0.2、20.728±0.2、20.988±0.2、23.692±0.2、23.912±0.2和24.475±0.2。
在其中一个具体的示例中，所述大蒜素-β环糊精的X射线粉末衍射图谱基本如图2所示。
在其中一个具体的示例中，所述大蒜素-β环糊精的X射线粉末衍射图谱如图2所示。
在其中一个具体的示例中，所述大蒜素-β环糊精的差示扫描量热曲线在258.3±3℃处具有吸热峰。进一步地，在258.3±2℃处具有吸热峰。更进一步地，在258.3±0.5℃处具有吸热峰。
在其中一个具体的示例中，所述大蒜素-β环糊精的差示扫描量热曲线基本如图5所示。
在其中一个具体的示例中，所述大蒜素-β环糊精的差示扫描量热曲线如图5所示。
在其中一个具体的示例中，所述大蒜素-环糊精包合物共晶的晶型为大蒜素-γ环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
5.787±0.2、6.006±0.2、7.393±0.2、10.175±0.2、10.521±0.2、11.763±0.2、12.043±0.2、14.171±0.2、14.905±0.2、15.792±0.2、16.193±0.2、16.654±0.2、19.167±0.2、20.251±0.2、21.128±0.2、21.787±0.2、22.411±0.2、23.636±0.2、26.669±0.2和27.571±0.2。
在其中一个具体的示例中，所述大蒜素-γ环糊精的X射线粉末衍射图谱基本如图3所示。
在其中一个具体的示例中，所述大蒜素-γ环糊精的X射线粉末衍射图谱如图3所示。
在其中一个具体的示例中，所述大蒜素-γ环糊精的差示扫描量热曲线在248.6±3℃处具有 吸热峰。进一步地，在248.6±2℃处具有吸热峰。更进一步地，在248.6±0.5℃处具有吸热峰。
在其中一个具体的示例中，所述大蒜素-γ环糊精的差示扫描量热曲线基本如图6所示。
在其中一个具体的示例中，所述大蒜素-γ环糊精的差示扫描量热曲线如图6所示。
本发明还提供所述的大蒜素-环糊精包合物共晶的晶型的制备方法，包括如下步骤：
将大蒜素与第一溶剂混合，制备大蒜素溶液；
将环糊精与水混合，制备环糊精水溶液；
将所述环糊精水溶液加热至30℃～60℃，然后加入所述大蒜素溶液，制备混合液；
将所述混合物冷却，静置，收集析出的固体；
其中，所述第一溶剂为可与水混溶的有机溶剂；
所述环糊精为α-环糊精、β-环糊精或γ-环糊精。
上述制备方法融合了溶剂注入法制备纳米粒和反溶剂法结晶的工艺原理。其关键在于：1)选用可与水混溶的有机溶剂作为大蒜素的溶剂(第一溶剂)；2)在合适的温度条件下通过溶剂注入法制备大蒜素与环糊精的包合物共晶。其中，第一溶剂一方面作为大蒜素的溶剂，可以作为药物的稀释剂和传递介质，当大蒜素溶液注入环糊精的水溶液后，溶剂可迅速与水分子发生结合，从而促进了大蒜素在水中的分散和包合物的形成；另一方面，第一溶剂可作为环糊精的不良溶剂，促进包合物从溶液中析出。
在其中一个具体的示例中，所述大蒜素溶液中大蒜素的浓度为0.5～5mg/mL。具体地，所述大蒜素溶液中大蒜素的浓度包括但不限于：0.5mg/mL、1mg/mL、1.5mg/mL、2mg/mL、2.5mg/mL、3mg/mL、4mg/mL、5mg/mL。
在其中一个具体的示例中，所述环糊精水溶液中环糊精的浓度为3～50mg/mL。进一步地，根据环糊精种类的不同，可以分别控制为：
α-环糊精水溶液中α-环糊精的浓度为3～30mg/mL。具体地，α-环糊精水溶液中α-环糊精的浓度包括但不限于：3mg/mL、6mg/mL、8mg/mL、10mg/mL、15mg/mL、20mg/mL、23mg/mL、25mg/mL、27mg/mL、30mg/mL。
β-环糊精水溶液中β-环糊精的浓度为3～15mg/mL。具体地，β-环糊精水溶液中β-环糊精的浓度包括但不限于：3mg/mL、4mg/mL、5mg/mL、6mg/mL、7mg/mL、8mg/mL、9mg/mL、10mg/mL、12mg/mL、15mg/mL。
γ-环糊精水溶液中γ-环糊精的浓度为3～30mg/mL。具体地，γ-环糊精水溶液中γ-环糊精的浓度包括但不限于：3mg/mL、4mg/mL、5mg/mL、6mg/mL、7mg/mL、8mg/mL、9mg/mL、10mg/mL、12mg/mL、15mg/mL、20mg/mL、25mg/mL、30mg/mL。
在其中一个具体的示例中，将所述环糊精水溶液加热至30℃～60℃。具体地，将所述环糊精水溶液加热所至的温度包括但不限于：30℃、35℃、38℃、40℃、42℃、45℃、48℃、50℃、52℃、55℃、58℃、60℃。
在其中一个具体的示例中，所述第一溶剂选自甲醇、乙醇、乙腈、丙酮、四氢呋喃、异丙醇和乙二醇中的一种或多种。
在其中一个具体的示例中，所述混合液中，所述大蒜素与所述环糊精的摩尔比为1:(1～20)。具体地，所述混合液中，所述大蒜素与所述环糊精的摩尔比包括但不限于：1:1、1:3、1:5、1:7、1:9、1:11、1:13、1:15、1:17、1:19、1:20。
在其中一个具体的示例中，所述混合液中，所述大蒜素溶液与环糊精水溶液的体积比为(1～3):(20～7)。具体地，所述混合液中，所述大蒜素溶液与环糊精水溶液的体积比包括但不限于：1:20、1:15、1:10、3:20、3:10、3:7。可以理解地，当加入完成后，所述大蒜素溶液与环糊精水溶液的量不足时，可用相应的空白溶剂(第一溶剂或水)补足至上述所述大蒜素溶液与环糊精水溶液的体积比范围内。
在其中一个具体的示例中，加入所述大蒜素溶液的过程中，以1mL～3mL所述大蒜素溶液计，控制加入的时间为0.5min～30min。具体地，加入所述大蒜素溶液的过程中，以1mL～3mL所述大蒜素溶液计，控制加入的时间包括但不限于：0.5min、1min、2min、3min、4min、5min、7min、10min、15min、20min、25min、30min。
在其中一个具体的示例中，加入所述大蒜素溶液的过程中，以50rpm～1000rpm的速率搅拌。具体地，加入所述大蒜素溶液的过程中，搅拌速率包括但不限于：50rpm、60rpm、70rpm、80rpm、90rpm、100rpm、110rpm、120rpm、130rpm、140rpm、150rpm、200rpm、500rpm、800rpm、900rpm、950rpm、1000rpm。
可以理解地，冷却是指停止加热，冷却所至的温度可为20℃～30℃。
可以理解地，静置的目的在于使溶液中的晶体析出完全，静置的时间为可为2h～48h，温度保持为前述冷却所至的温度即可。
可以理解地，收集析出的固体可以采用抽滤的方式。抽滤所得固体可以用冰水或预冷(0-25℃)的第一溶剂洗涤1～3次。
在其中一个具体的示例中，还包括对收集的固体进行干燥的步骤。进一步地，干燥的条件包括：温度为30℃～60℃，时间为1h～24h。
本发明还提供一种抗菌组合物，所述抗菌组合物包括：
(a)第一方面所述的大蒜素-环糊精包合物共晶的晶型；以及
(b)辅料或载体。
本发明还提供上述的大蒜素-环糊精包合物共晶的晶型，或上述的抗菌组合物在制备具有抗菌功效的化学制剂、药物、食品或饲料中的应用。
本发明还提供一种抗炎组合物，所述抗炎组合物包括：
(a)第一方面所述的大蒜素-环糊精包合物共晶的晶型；以及
(b)辅料或载体。
本发明还提供上述的大蒜素-环糊精包合物共晶的晶型，或上述抗炎组合物在制备具有抗炎功效的化学制剂、药物、食品或饲料中的应用。
以下为具体的实施例。
实施例1α-环糊精-大蒜素包合物共晶的制备
1)分别配制α-环糊精的水溶液与大蒜素溶液，其中，大蒜素的溶剂为甲醇，大蒜素浓度为2.5mg/mL，α-环糊精的浓度为25mg/mL；
2)将α-环糊精水溶液加热至40℃，然后在100rpm搅拌条件下，于7mLα-环糊精水溶液中注入3mL的大蒜素溶液，注入时间控制为3min；继续搅拌1min。
3)停止加热和搅拌，将大蒜素与α-环糊精的混合溶液冷却至20℃，放置2小时，待溶液中晶体析出完全。
4)抽滤得到白色固体，用4℃的冰水洗涤2次；然后产品置于55℃条件下干燥1小时，即可得到白色固体，其为大蒜素与α-环糊精形成的包合物共晶，包合物共晶产品中α-环糊精与大蒜素的摩尔比＝2:1。产品以大蒜素计，收率为50％。
实施例2β-环糊精-大蒜素包合物共晶的制备
1)分别配制β-环糊精的水溶液与大蒜素溶液，其中，大蒜素的溶剂为乙醇，大蒜素浓度为2mg/mL，β-环糊精的浓度为6mg/mL。
2)把β-环糊精水溶液加热至60℃，然后在1000rpm搅拌条件下，于20mLβ-环糊精水溶液中注入1mL的大蒜素溶液，注入时间控制为3min；继续搅拌30分钟。
3)停止加热和搅拌，将大蒜素与β-环糊精的混合溶液冷却至20℃，放置48小时，待溶液中晶体析出完全。
4)抽滤得到白色固体，用10℃的30％乙醇(v/v)洗涤3次；然后将产品置于60℃条件下干燥24小时，即可得到白色粉末，其为大蒜素与β-环糊精形成的包合物共晶，包合物共晶产品中β-环糊精与大蒜素的摩尔比＝1:1。产品以大蒜素计，收率为90％。
实施例3γ-环糊精/大蒜素包合物共晶的制备
1)分别配制γ-环糊精的水溶液与大蒜素溶液，其中，大蒜素的溶剂为丙酮，大蒜素浓度为1mg/mL，γ-环糊精的浓度为7mg/mL。
2)把γ-环糊精水溶液加热至50℃，然后在50rpm搅拌条件下，于7mLγ-环糊精水溶液中注入1mL的大蒜素溶液，注入时间控制为3min，另加2mL丙酮；继续搅拌0.5min。
3)停止加热和搅拌，将大蒜素与γ-环糊精的混合溶液冷却至30℃，放置1小时，待溶液中晶体析出完全。
4)抽滤得到白色固体，用25℃的水洗涤3次；然后将产品置于30℃条件下干燥48小时，即可得到白色粉末，其为大蒜素与环糊精形成的包合物共晶，包合物共晶产品中γ-环糊精与大蒜素的摩尔比＝1:1。产品以大蒜素计，收率为70％。
实施例1～3的产品的表征数据
1)形貌观察
将实施例1～3制备得到的共晶(分别记作大蒜素/α-CD、大蒜素/β-CD、大蒜素/γ-CD)置于载玻片上，于光学显微镜下(10×20)观察和记录各样品的形态；另取1mL大蒜素的甲醇溶液(3mg/mL)分散于10mL的水中，搅拌均匀后取一滴液体置于载玻片上，作为对照(记作大蒜素水溶液)。
结果如图8所示：大蒜素经溶剂溶解后注入水中，可在水中分散形成2-3μm大小的液滴。与之相比，如将大蒜素直接加在水中则会形成难以分散的油滴。可见以与水混溶的溶剂作为介质，可以促进药物在水中以单分子状态存在，从而可以有效促进包合物的形成。与大蒜素对照相比，大蒜素与环糊精形成的共晶具有明确的晶习：三种包合物共晶分别呈短棒状(大蒜素/αCD)、块状(大蒜素/βCD)、和长棒状(大蒜素/γCD)。在该同等实验条件下，将相同体积且不包含大蒜素的第一溶剂加入环糊精水溶液中，没有晶体析出，因此可以确定大蒜素溶液加入之后析出的晶体为包合物共晶。
2)H-NMR表征
将大蒜素，以及实施例1～3制备得到的共晶用d6-DMSO溶解后测定氢谱，结果如图9所示。实施例1～3制备得到的共晶的H-NMR数据中均同时包含了大蒜素与环糊精的信号，证实晶体是由两种成分组成的。
3)红外表征
大蒜素，以及实施例1～3制备得到的共晶的红外光谱如图10所示。其中大蒜素的特征峰在575cm-1、708cm-1、915cm-1、990cm-1、1208cm-1、1395-1425cm-1、1625cm-1；环糊精 的特征峰在400-2000cm-1之间；与二者相比，大蒜素与几种环糊精形成的包合物共晶的红外光谱中有关大蒜素的大部分特征峰均消失，其红外光谱整体上与环糊精一致，表明药物与环糊精形成了包合物，因而结构中大蒜素的特征峰被环糊精所掩盖。
4)XPRD表征
大蒜素，以及实施例1～3制备得到的共晶的XPRD图谱如图1～3所示。其中：
α-CD/大蒜素共晶的XRD衍射峰在5.745°、7.374°、11.502°、11.927°、12.198°、12.808°、19.040°、19.683°、21.692°、22.311°；
β-CD/大蒜素共晶的XRD衍射峰在5.778°、6.583°、6.865°、10.998°、11.561°、11.867°、14.212°、14.507°、14.975°、15.549°、16.737°、17.035°、17.363°、17.621°、17.98°、18.332°、19.886°、20.728°、20.988°、23.692°、23.912°、24.475°；
γ-CD/大蒜素共晶的XRD衍射峰在5.787°、6.006°、7.393°、10.175°、10.521°、11.763°、12.043°、14.171°、14.905°、15.792°、16.193°、16.654°、19.167°、20.251°、21.128°、21.787°、22.411°、23.636°、26.669°、27.571°。
这三种晶体XPRD的特征衍射峰与传统的大蒜素-α环糊精包合物、大蒜素-β环糊精包合物和大蒜素-γ环糊精包合物完全不同，表明不是简单的物理混合，而是形成了新的晶型，并且HNMR结果显示该晶体同时包含环糊精和大蒜素分成，因此可确定为环糊精/大蒜素共晶。
5)DSC表征
大蒜素，以及实施例1～3制备得到的共晶的DSC图谱如图4～6所示。大蒜素在室温下是一种油状化合物，在与环糊精形成共晶之后，其包合物共晶的熔点分别为277.9℃(α-CD/大蒜素共晶)、258.3℃(β-CD/大蒜素共晶)和248.6℃(γ-CD/大蒜素共晶)，其结果显示大蒜素形成包合物共晶之后的热稳定明显提高。
实施例1～3的产品的效果数据
1)环糊精包合物共晶提高了药物在水中的溶解性。
文献中显示大蒜素游离药物在水中的溶解度为8μg/mL，α-CD/大蒜素共晶溶解度为480μg/mL、β-CD/大蒜素共晶溶解度为30μg/mL和γ-CD/大蒜素共晶溶解度为10μg/mL，分别增加了60倍、3.75倍、1.25倍。
2)大蒜素通过共晶技术固化之后，进行加速稳定性试验。
试验方法为：将同质量的大蒜素/α-CD共晶、大蒜素/β-CD共晶和大蒜素/γ-CD共晶分别置于25℃和60℃条件下，间隔相应的时间取样用HPLC测定大蒜素含量。表1中不同摩尔比的CD-大蒜素样品的制备方法参考实施例1-3的制备步骤。
试验结果如图11和表1所示：与大蒜素包合物相比，大蒜素共晶具有更高的稳定性。同时，β-CD/大蒜素共晶25℃下在30天内几乎不降解，60℃下约降解6.5％；α-CD/大蒜素共晶在25℃和60℃降解程度相近，约降解9.8％；γ-CD/大蒜素共晶25℃下在14天内几乎不降解，30天时约降解25％，而在60℃下3天即降解50.7％。综上所知，这三种共晶稳定性顺序为β-CD/大蒜素共晶>α-CD/大蒜素共晶>γ-CD/大蒜素共晶，其稳定性均明显增加。
表1
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，便于具体和详细地理解本发明的技术方案，但并不能因此而理解为对发明专利保护范围的限制。应当指出的是，对于本领域的普 通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。应当理解，本领域技术人员在本发明提供的技术方案的基础上，通过合乎逻辑的分析、推理或者有限的试验得到的技术方案，均在本发明所附权利要求的保护范围内。因此，本发明专利的保护范围应以所附权利要求的内容为准，说明书及附图可以用于解释权利要求的内容。

Claims (11)

  1. 一种大蒜素-环糊精包合物共晶的晶型，所述环糊精为α-环糊精、β-环糊精或γ-环糊精。
  2. 根据权利要求1所述的大蒜素-环糊精包合物共晶的晶型，其特征在于，所述大蒜素-环糊精包合物共晶的晶型选自以下任一组：
    (i)大蒜素-α环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
    5.745±0.2、7.374±0.2、11.502±0.2、11.927±0.2、12.198±0.2、12.808±0.2、19.040±0.2、19.683±0.2、21.692±0.2和22.311±0.2；
    (ii)大蒜素-β环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：
    5.778±0.2、6.583±0.2、6.865±0.2、10.998±0.2、11.561±0.2、11.867±0.2、14.212±0.2、14.507±0.2、14.975±0.2、15.549±0.2、16.737±0.2、17.035±0.2、17.363±0.2、17.621±0.2、17.98±0.2、18.332±0.2、19.886±0.2、20.728±0.2、20.988±0.2、23.692±0.2、23.912±0.2和24.475±0.2；
    (iii)大蒜素-γ环糊精，其X射线粉末衍射图谱在下列2θ(°)角处具有特征衍射峰：和
    5.787±0.2、6.006±0.2、7.393±0.2、10.175±0.2、10.521±0.2、11.763±0.2、12.043±0.2、14.171±0.2、14.905±0.2、15.792±0.2、16.193±0.2、16.654±0.2、19.167±0.2和20.251±0.2、21.128±0.2、21.787±0.2、22.411±0.2、23.636±0.2、26.669±0.2、27.571±0.2。
  3. 根据权利要求2所述的大蒜素-环糊精包合物共晶的晶型，其特征在于，
    所述大蒜素-α环糊精的X射线粉末衍射图谱基本如图1所示；
    所述大蒜素-β环糊精的X射线粉末衍射图谱基本如图2所示；
    所述大蒜素-γ环糊精的X射线粉末衍射图谱基本如图3所示。
  4. 根据权利要求2所述的大蒜素-环糊精包合物共晶的晶型，其特征在于，
    所述大蒜素-α环糊精的差示扫描量热曲线在277.9±3℃处具有吸热峰；
    所述大蒜素-β环糊精的差示扫描量热曲线在258.3±3℃处具有吸热峰；
    所述大蒜素-γ环糊精的差示扫描量热曲线在248.6±3℃处具有吸热峰。
  5. 权利要求1～4任一项所述的大蒜素-环糊精包合物共晶的晶型的制备方法，其特征在于，包括如下步骤：
    将大蒜素与第一溶剂混合，制备大蒜素溶液；
    将环糊精与水混合，制备环糊精水溶液；
    将所述环糊精水溶液加热至30℃～60℃，然后加入所述大蒜素溶液，制备混合液；
    将所述混合物冷却，静置，收集析出的固体；
    其中，所述第一溶剂为可与水混溶的有机溶剂；
    所述环糊精为α-环糊精、β-环糊精或γ-环糊精。
  6. 根据权利要求5所述的大蒜素-环糊精包合物共晶的晶型的制备方法，其特征在于，所述第一溶剂选自甲醇、乙醇、乙腈、丙酮、四氢呋喃、异丙醇和乙二醇中的一种或多种。
  7. 根据权利要求5所述的大蒜素-环糊精包合物共晶的晶型的制备方法，其特征在于，所述混合液中，所述大蒜素与所述环糊精的摩尔比为1:(1～20)；和/或
    所述混合液中，所述大蒜素溶液与环糊精水溶液的体积比为(1～3):(20～7)。
  8. 根据权利要求5～7任一项所述的大蒜素-环糊精包合物共晶的晶型的制备方法，其特征在于，加入所述大蒜素溶液的过程中，以1mL～3mL所述大蒜素溶液计，控制加入的时间为0.5min～30min；和/或
    加入所述大蒜素溶液的过程中，以50rpm～1000rpm的速率搅拌。
  9. 一种组合物，其特征在于，所述组合物包括：
    (a)权利要求1～4任一项所述的大蒜素-环糊精包合物共晶的晶型；以及
    (b)辅料或载体。
  10. 权利要求1～4任一项所述的大蒜素-环糊精包合物共晶的晶型，或权利要求9所述组合物在制备具有抗菌功效的化学制剂、药物、食品或饲料中的应用。
  11. 权利要求1～4任一项所述的大蒜素-环糊精包合物共晶的晶型，或权利要求9所述组合物在制备具有抗炎功效的化学制剂、药物、食品或饲料中的应用。
PCT/CN2023/090363 2022-08-04 2023-04-24 大蒜素-环糊精包合物共晶的晶型及其制备方法和应用 WO2024027219A1 (zh)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1565430A (zh) * 2003-06-22 2005-01-19 毛友昌 大蒜素环糊精包合物、制剂及制备方法
CN101816744A (zh) * 2010-04-28 2010-09-01 江南大学 一种节能环保的大蒜油环糊精包合物的制备方法
US20160051594A1 (en) * 2013-04-05 2016-02-25 Manuka Health New Zealand Limited Therapeutic Compositions and Uses Thereof
CN107789345A (zh) * 2016-09-07 2018-03-13 汤臣倍健股份有限公司 矫味大蒜素‑环糊精复合物及其制备方法
CN107802842A (zh) * 2016-09-07 2018-03-16 汤臣倍健股份有限公司 大蒜素矫味制剂及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1565430A (zh) * 2003-06-22 2005-01-19 毛友昌 大蒜素环糊精包合物、制剂及制备方法
CN101816744A (zh) * 2010-04-28 2010-09-01 江南大学 一种节能环保的大蒜油环糊精包合物的制备方法
US20160051594A1 (en) * 2013-04-05 2016-02-25 Manuka Health New Zealand Limited Therapeutic Compositions and Uses Thereof
CN107789345A (zh) * 2016-09-07 2018-03-13 汤臣倍健股份有限公司 矫味大蒜素‑环糊精复合物及其制备方法
CN107802842A (zh) * 2016-09-07 2018-03-16 汤臣倍健股份有限公司 大蒜素矫味制剂及其制备方法

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