CN114099438A - Kaempferol liposome gel and preparation method thereof - Google Patents
Kaempferol liposome gel and preparation method thereof Download PDFInfo
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- IYRMWMYZSQPJKC-UHFFFAOYSA-N kaempferol Chemical compound C1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 IYRMWMYZSQPJKC-UHFFFAOYSA-N 0.000 title claims abstract description 172
- UBSCDKPKWHYZNX-UHFFFAOYSA-N Demethoxycapillarisin Natural products C1=CC(O)=CC=C1OC1=CC(=O)C2=C(O)C=C(O)C=C2O1 UBSCDKPKWHYZNX-UHFFFAOYSA-N 0.000 title claims abstract description 86
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 235000008777 kaempferol Nutrition 0.000 title claims abstract description 86
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- 239000002502 liposome Substances 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 238000001879 gelation Methods 0.000 title description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 24
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 24
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 8
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- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 6
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
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- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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Abstract
The invention discloses kaempferol liposome gel and a preparation method thereof. The kaempferol liposome gel comprises the following components in parts by weight: 1-5% of kaempferol, 10-50% of soybean lecithin, 1-10% of cholesterol, 0.5-5% of carbomer, 5-30% of glycerol, 5-20% of propylene glycol and 1-5% of triethanolamine. The preparation method of the kaempferol liposome gel comprises the following steps: the kaempferol is wrapped in the liposome, and the liposome is dispersed in the gel, so that the stability and viscosity of the liposome are improved, and the liposome has better biocompatibility. The kaempferol liposome has the advantages of stable production process, ideal particle size and encapsulation rate and good stability; the prepared kaempferol liposome gel has moderate viscosity and is easy to coat.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to kaempferol liposome, kaempferol gel and preparation methods thereof.
Background
Kaempferol is also called kaempferol and 5, 7-trihydroxyflavonol, and is mainly derived from rhizome of Kaempferia galanga of Zingiberaceae, and has chemical formula C15H10O6The flavone compound is yellow crystal powder, slightly soluble in water and soluble in hot ethanol, ether, DMSO and other organic solvents. It is widely found in various fruits, vegetables and beverages, and people have extracted pure products from tea leaves, broccoli, witch hazel, propolis, grapefruit and other green plants. It has been widely noticed by people because of its various effects of cancer prevention, anticancer, anti-inflammatory, antioxidant, antibacterial, antiviral, etc.
Kaempferol can inhibit various tumor cells such as gastric cancer cells, lung cancer cells, liver cancer cells and the like or induce apoptosis through different action mechanisms, such as regulating the transcription of cyclooxygenase-2, inhibiting the function and expression of P-glycoprotein, inhibiting the anti-cell proliferation of interleukin-4 and the like; the kaempferol has the functions of inhibiting AGE formation and eliminating free radicals, and has strong antioxidation. In addition, research shows that kaempferol also has anti-inflammatory and antibacterial effects and can be used for treating facial acne, inflammation and the like, but at present, the research on kaempferol in percutaneous mode is less.
The liposome is a lipid vesicle formed by taking a phospholipid bilayer as a membrane material, and can wrap both lipophilic medicaments and hydrophilic medicaments. The biomembrane-like structure of the lipoid vesicles enables the liposome to have better biocompatibility with human skin, improves the transdermal permeability of the medicine, and reduces toxic and side effects.
The liposome is used as a suspension solution, and the stability problems of aggregation, sedimentation and the like are easy to occur in the storage process, the liposome is prepared into a gel, the defect that the liposome solution is not easy to store is overcome, the retention time of the drug on the surface of the skin can be prolonged to achieve a slow release effect, the permeation quantity of the drug in the skin is improved, and the drug can be uniformly dispersed in the gel.
The invention content is as follows:
one of the purposes of the invention is to provide a kaempferol liposome gel and a preparation method thereof, so as to meet the purpose of kaempferol transdermal drug delivery.
In order to achieve the above objects and other related objects, the present invention adopts the following technical solutions:
a kaempferol liposome solution is composed of the following components by weight:
preferably, the kaempferol liposome solution consists of the following components in percentage by weight:
more preferably, the kaempferol liposome solution consists of the following components in percentage by weight:
the second purpose of the invention is to provide a preparation method of kaempferol liposome solution, which comprises the following steps:
(1) weighing kaempferol, cholesterol and soybean lecithin according to the component amount, and dissolving in an organic solvent;
(2) placing the solution in a round-bottom flask, heating in a water bath for dissolving, placing the round-bottom flask on a rotary evaporator in the water bath for evaporating the organic solvent in a reduced pressure manner by a thin film dispersion method, and adding a phosphate buffer solution with the pH value of 7.4 for hydration;
(3) and (3) putting the liposome solution into a beaker, and carrying out ultrasonic treatment under the ice bath condition to obtain the kaempferol liposome solution. Preferably, the adding amount of the organic solvent is 1-20%, the organic solution is methanol, ethanol or chloroform, and ethanol is more preferred; the water bath heating temperature is 35-60 ℃; the ultrasonic power is 100-200 w, and the ultrasonic time is 5-20 min.
The invention finally aims to provide the kaempferol liposome gel, which consists of the following components in percentage by weight:
preferably, the kaempferol liposome gel consists of the following components in percentage by weight:
the invention also aims to provide a preparation method of the kaempferol liposome gel, which comprises the following steps:
(1) weighing carbomer, glycerol, propylene glycol and water in component amounts in a beaker, uniformly stirring to fully swell the carbomer, the glycerol, the propylene glycol and the water, and adding triethanolamine to adjust the pH value to obtain blank gel;
(2) mixing the blank gel and the kaempferol liposome solution and stirring uniformly to obtain the kaempferol liposome gel.
Preferably, the pH value is adjusted to 6-8.
The invention has the advantages that the liposome is prepared from lecithin, has a bimolecular lipid layer similar to a biological membrane structure, the central hydrophilic chain part can dissolve hydrophilic drugs, and the double-layer phospholipid part can dissolve lipophilic drugs, thereby increasing the solubility of the drugs. Liposomes can be used as an excellent carrier for transdermal administration, but in clinical use, liquid preparations as transdermal administration are inconvenient to administer, and the application of the liquid preparations in external administration is limited. The gel matrix can increase the viscosity of the liposome and the residence time of the drug on the skin surface, and the hydrophilic gel has the advantages of being suitable for smearing, easy to clean, free of polluting clothes and the like.
The in vitro release result of the kaempferol liposome gel shows that compared with the kaempferol common gel, the kaempferol liposome gel has obvious slow release effect, and the cumulative permeation amount and the skin retention amount of the in vitro skin of 24 hours are obviously improved, which shows that compared with the common gel, the kaempferol liposome gel has the advantage of being used as a percutaneous absorption carrier of the medicine.
The present invention will be described in further detail with reference to the following examples and drawings.
Drawings
FIG. 1 is a graph showing the release profile of the present invention by measuring the concentration of a sample by HPLC.
FIG. 2 is a graph of in vitro transdermal permeation of the present invention measured by HPLC method for cumulative permeation per unit.
Detailed Description
EXAMPLE 1 Kaempferol Liposol preparation
Respectively weighing 100mg of kaempferol, 3000mg of soybean lecithin and 500mg of cholesterol in a round-bottom flask, adding 20ml of ethanol, placing in a 500ml round-bottom flask, rotationally heating in a rotary evaporator in a water bath at 55 ℃, continuously rotating for 10min after the ethanol is evaporated to dryness, adding 50ml of phosphate buffer (pH7.4) for hydration at 37 ℃ for 30min, placing in a beaker, and carrying out ultrasonic treatment for 10min under the ice bath condition to obtain a kaempferol liposome solution with the concentration of 2 mg/ml.
And (3) determining the encapsulation efficiency: 0.5ml of the liposome solution was packed in a dialysis bag. Placing the dialysis bag in 20ml of 0.5% Tween-80 solution, and heating in 37 deg.C constant temperature water bath at rotation speed of 10%0rpm·min-1Under the condition, 2ml of dissolution medium is taken at 2, 4, 6, 8, 10 and 12 hours, and 2ml of dissolution medium with the same temperature is supplemented at the same time. The sample is filtered through a 0.22 μm filter and the concentration C of the sample is determinedFreeSimultaneously determining the total concentration C of the liposome solutionTotle. According to the formula EE ═ CTotle-CFree)/CTotleX 100% calculated encapsulation of kaempferol liposomes was 60.55%.
Particle size and potential measurements: taking a proper amount of kaempferol liposome solution, diluting with distilled water, shaking uniformly, and measuring the particle size and zeta potential of the kaempferol liposome by adopting a laser dynamic scattering method, wherein the particle size of the kaempferol liposome is 164.3 +/-6.0 nm, and the zeta potential is-46.40 +/-2.44 mV.
And (3) observing by a transmission electron microscope: diluting the appropriate amount of kaempferol liposome suspension with distilled water, negatively dyeing with 2% phosphotungstic acid solution, dripping onto copper mesh, naturally drying, and observing under transmission electron microscope to obtain uniform spherical kaempferol liposome.
Weighing 400mg of carbomer, 6000mg of glycerol and 4000mg of propylene glycol into a beaker, adding 40ml of water, uniformly stirring, standing overnight for full swelling, and then adding 1200mg of triethanolamine to adjust the pH value to 7 to obtain the blank gel.
Mixing the blank gel and the kaempferol liposome solution and stirring uniformly to obtain the kaempferol liposome gel.
EXAMPLE 2 Kaempferol Liposol preparation
Respectively weighing 100mg of kaempferol, 2500mg of soybean lecithin and 600mg of cholesterol in a round-bottom flask, adding 30ml of ethanol, placing in a 500ml round-bottom flask, rotationally heating in a rotary evaporator at 55 ℃ in a water bath, continuously rotating for 10min after the ethanol is evaporated to dryness, adding 50ml of phosphate buffer (pH7.4) for hydration at 37 ℃ for 30min, placing in a beaker, and performing ultrasonic treatment for 10min (the ultrasonic power is 110w) under the ice bath condition to obtain the kaempferol liposome solution with the concentration of 2 mg/ml. The encapsulation efficiency of the kaempferol liposome is 59.23%, the particle size is 160.3 +/-4.3 nm, the zeta potential is-40.55 +/-3.57 mV, and the kaempferol liposome is in a uniform spherical shape when observed under a transmission electron microscope.
Weighing 400mg of carbomer, 6000mg of glycerol and 4000mg of propylene glycol into a beaker, adding 40ml of water, uniformly stirring, standing overnight for full swelling, and then adding 1200mg of triethanolamine to adjust the pH value to 7 to obtain the blank gel.
Mixing the blank gel and the kaempferol liposome solution and stirring uniformly to obtain the kaempferol liposome gel.
EXAMPLE 3 Kaempferol Liposol preparation
Respectively weighing 100mg of kaempferol, 3000mg of soybean lecithin and 500mg of cholesterol in a round-bottom flask, adding 20ml of ethanol, placing in a 500ml round-bottom flask, rotationally heating in a rotary evaporator in a water bath at 55 ℃, continuously rotating for 10min after the ethanol is evaporated to dryness, adding 50ml of phosphate buffer (pH7.4) for hydration at 37 ℃ for 30min, placing in a beaker, and carrying out ultrasonic treatment for 10min under the ice bath condition to obtain a kaempferol liposome solution with the concentration of 2 mg/ml.
Weighing 500mg of carbomer, 6000mg of glycerol and 6000mg of propylene glycol in a beaker, adding 40ml of water, uniformly stirring, standing overnight for full swelling, and then adding 1500mg of triethanolamine to adjust the pH value to 7 to obtain the blank gel.
Mixing the blank gel and the kaempferol liposome solution and stirring uniformly to obtain the kaempferol liposome gel.
Example 4 in vitro Release test of Kaempferol Liposol gel with Normal gel
Respectively putting 2g of kaempferol liposome gel and kaempferol common gel into a dialysis bag and fastening. Placing the dialysis bag in 40ml 0.5% Tween-80 solution, and placing in thermostatic water bath at 37 deg.C and rotation speed of 100rpm min-1Under the condition, 2ml of dissolution medium is taken at 2, 4, 6, 8, 10, 12h and 24h, and 2ml of dissolution medium with the same temperature is supplemented at the same time. The sample was filtered through a 0.22 μm filter and the sample concentration was determined by HPLC. The resulting release profile is shown in figure 1.
As shown in figure 1, the kaempferol ordinary gel is released quickly, and the kaempferol liposome gel is released slowly, so that the kaempferol liposome gel is finally maintained at a certain drug concentration to achieve a slow release effect, thereby prolonging the action time of the drug and reducing the administration times.
Example 5 in vitro transdermal assay of Kaempferol Liposol gels
In vitro SD rat skin by Franz diffusion cell methodThe liquid is laid on a Franz vertical diffusion cell, the stratum corneum faces upwards, the liquid is well fixed, and the receiving liquid level is fully contacted with the lower part of the skin without air bubbles. Adding kaempferol liposome gel 1g (equivalent to kaempferol 5mg) and kaempferol common gel 1g (the preparation method is the same as that of liposome gel except that kaempferol liposome solution is replaced by kaempferol aqueous solution containing the same dosage), placing the diffusion cell in transdermal diffusion tester, constant temperature water bath at 32 + -0.5 deg.C, 400 r.min-1Stirring at rotating speed, taking 2ml of receiving solution at 1, 2, 4, 6, 8, 10 and 12h respectively, adding 2ml of receiving solution at the same temperature at once, filtering the receiving solution with a 0.22 μm filter membrane, and measuring the unit cumulative permeation amount by high performance liquid chromatography. The measurement result is shown in fig. 2, the unit accumulated permeation amount of the kaempferol liposome gel in 12h is higher than that of the kaempferol ordinary gel.
After the in vitro transdermal test is finished, the skin is taken down and cut into pieces, 2ml of methanol is added, ultrasonic extraction is carried out for 30min, and the content of the medicine is measured by high performance liquid chromatography after the supernatant is taken and filtered by a 0.22 mu m filter membrane. The result shows that the retention of the kaempferol liposome gel in the skin is obviously higher than that of the kaempferol common gel.
The above examples are only for illustrating the technical solutions of the present invention, and are not limited thereto. Those of ordinary skill in the art will understand that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (9)
1. The kaempferol liposome solution is characterized by comprising the following components in parts by weight:
2. the kaempferol liposome solution of claim 1, comprising the following components in parts by weight:
3. the kaempferol liposome solution of claim 1, comprising the following components in parts by weight:
4. a method for preparing the kaempferol liposome solution as described in claims 1-3, comprising the following steps:
(1) weighing kaempferol, cholesterol and soybean lecithin according to the component amount, and dissolving in an organic solvent;
(2) placing the solution in a round-bottom flask, heating in a water bath for dissolving, placing the round-bottom flask on a rotary evaporator in the water bath for evaporating the organic solvent in a reduced pressure manner by a thin film dispersion method, and adding a phosphate buffer solution with the pH value of 7.4 for hydration;
(3) and (3) putting the liposome solution into a beaker, and carrying out ultrasonic treatment under the ice bath condition to obtain the kaempferol liposome solution.
5. The method for preparing kaempferol liposome solution as claimed in claim 4, characterized in that:
in the step (1), the organic solvent is methanol, ethanol or chloroform, and the dosage is 1-20%;
the water bath heating temperature in the step (2) is 35-60 ℃;
in the step (3), the ultrasonic power is 100-200 w, and the ultrasonic time is 5-20 min.
6. The kaempferol liposome gel is characterized by comprising the following components in parts by weight:
7. the kaempferol liposome gel of claim 6, which is prepared from the following components in parts by weight:
8. a method for preparing the kaempferol liposome gel of claim 6 or 7, comprising the following steps:
(1) weighing carbomer, glycerol, propylene glycol and water in a formula amount in a beaker, uniformly stirring to fully swell the carbomer, the glycerol, the propylene glycol and the water, and adding triethanolamine to adjust the pH value to obtain blank gel;
(2) mixing the blank gel and the kaempferol liposome solution and stirring uniformly to obtain the kaempferol liposome gel.
9. The method for preparing kaempferol liposome gel of claim 8, wherein triethanolamine is used to adjust the pH value to 6-8.
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| CN115487205A (en) * | 2022-09-16 | 2022-12-20 | 中国计量大学 | Dark green tea polysaccharide-nuciferine microgel compound and preparation method and application thereof |
| CN116270425A (en) * | 2023-01-18 | 2023-06-23 | 哈尔滨医科大学 | Long-acting gel preparation containing arsenic trioxide nanoliposome for treating psoriasis and preparation method thereof |
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| CN104306368A (en) * | 2014-10-09 | 2015-01-28 | 中国人民解放军第二军医大学 | Application of kaempferol in preparation of anti-HCV (hepatitis c virus) infective medicaments |
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