CN117547509A - Folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, preparation method and application thereof - Google Patents
Folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, preparation method and application thereof Download PDFInfo
- Publication number
- CN117547509A CN117547509A CN202311511850.3A CN202311511850A CN117547509A CN 117547509 A CN117547509 A CN 117547509A CN 202311511850 A CN202311511850 A CN 202311511850A CN 117547509 A CN117547509 A CN 117547509A
- Authority
- CN
- China
- Prior art keywords
- peppermint oil
- quercetin
- folic acid
- acid modified
- oil microemulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims abstract description 220
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- 229960000304 folic acid Drugs 0.000 title claims abstract description 110
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- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims abstract description 122
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims abstract description 61
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- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims abstract description 61
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Abstract
The invention discloses a folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, a preparation method and application thereof. According to the invention, quercetin and peppermint oil are loaded into microemulsion to prepare folic acid modified quercetin-peppermint oil microemulsion, and folic acid modified quercetin-peppermint oil microemulsion is distributed in temperature-sensitive gel composed of poloxamer 407 and poly-N-isopropyl acrylamide. The prepared folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel retains the advantage of gel drug loading and has in-situ periodontal injection performance. The solubility of the quercetin is obviously improved by the peppermint oil, and the folic acid modified quercetin-peppermint oil microemulsion can play a role in continuous free radical removal, anti-inflammation and bone tissue regeneration promotion through targeting macrophages, so that a new preparation is provided for periodontitis treatment.
Description
Technical Field
The invention belongs to the field of liquid medicine carrying gel, and in particular relates to folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, a preparation method and application thereof.
Background
Periodontitis is a chronic inflammatory disease, and is clinically characterized by gingival bleeding, repeated swelling and pain, alveolar bone resorption, and the like; if the treatment is not in time, the teeth are loosened and fall off, the chewing function is lost, and even the digestive system is affected. The potential connection between periodontitis and diabetes, alzheimer disease and the like can also increase the risk of patients suffering from rheumatoid arthritis, inhalation pneumonia and even cancers, harm the health of human beings and cause great burden to public health and the whole social health care system.
Studies have shown that periodontal tissue damage and destruction is not directly caused by pathogenic microorganisms, but is mainly caused by host immune overreactions. Therefore, finding a rational means to control the host inflammatory response and regulate the immune response is critical in the treatment of periodontitis. At present, traditional periodontal treatments, including ultrasonic tooth cleaning, scraping and root planing, and antibiotic assistance, play a positive role in controlling bacterial biofilm and reducing periodontal pocket depth and achieving clinical levels of attachment. However, the antibiotics have the problems of drug resistance, dysbacteriosis of organisms and the like after long-term use.
In order to overcome these limitations and provide more effective treatment, a periodontal local drug delivery system capable of having a therapeutic effect and avoiding side effects of drugs has been developed, and has become a research hotspot in the field of periodontitis treatment.
Quercetin (Quercetin, qu) is a traditional Chinese medicine active ingredient with potential antioxidant and anti-inflammatory properties, and the therapeutic effect is expressed by various mechanisms: (1) The catechol reducing structure of Qu can be combined with active oxygen radicals; (2) Qu can reduce intracellular reactive oxygen species (Reactive oxygen species, ROS) levels by increasing intracellular superoxide dismutase (Superoxide dismutase, SOD) and glutathione peroxidase (Glutathione peroxidase, GSH-Px) activities; (3) Qu exerts antioxidant activity by increasing Nrf2 activity; (4) Qu has the effect of inhibiting macrophage M1 type polarization and regulating macrophage M1/M2 phenotype ratio. From this, qu has the potential to clear excess ROS from periodontal tissue, reverse oxidative stress-inflammatory response, and regulate immune balance. However, due to the poor dissolution and low bioavailability of quercetin Pi Sushui, there is an urgent need for an administration vehicle that improves the biopharmaceutical properties of quercetin.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, a preparation method and application thereof.
The invention is realized by the following technical scheme:
a folic acid modified quercetin-peppermint oil microemulsion temperature sensitive gel comprises folic acid modified quercetin-peppermint oil microemulsion and gel matrix;
the folic acid modified quercetin-peppermint oil microemulsion is prepared by taking quercetin and peppermint oil as raw material medicines, taking peppermint oil and lipid compounds as mixed oil phases, taking a surfactant and a cosurfactant as mixed surfactants and modifying folic acid, wherein the components in parts by weight are as follows:
1-10 parts of quercetin, 30-250 parts of peppermint oil, 20-80 parts of lipid compound, 180-280 parts of surfactant, 50-100 parts of cosurfactant and DSPE-PEG (polyethylene-polyethylene glycol) 2000 FA0.1-5 parts;
the gel matrix comprises: 120-250 parts of poloxamer 407 and 10-50 parts of poly-N-isopropyl acrylamide.
According to the invention, both water-insoluble medicines of quercetin and peppermint oil are compatible and encapsulated into the microemulsion, and the nano microemulsion constructed by taking the peppermint oil and lipid compounds as mixed oil phases can remarkably improve the solubility of the quercetin and the performance of the peppermint oil in scavenging active oxygen, improve the overall drug loading rate and reduce the dosage of auxiliary materials. And simultaneously, the folic acid ligand is combined for modification, and the inflammation and the immune microenvironment are improved by targeting macrophages.
Poloxamers are capable of forming hydrogels above their critical solution temperature through the hydrophilic-hydrophobic interactions between the polymer of ethylene oxide and propylene oxide. Thus, poloxamer solutions exhibit a sol-gel reversible transition as the temperature changes. Based on the sol-gel transition property of poloxamer, poloxamer can be used as a drug carrier for local administration for treating periodontitis. However, poloxamers have low mechanical strength and wide gel response temperature due to low relative molecular mass, resulting in too fast release rate of the loaded drug. The sol-gel transition temperature of the composite hydrogel is controlled between 28 ℃ and 33 ℃ by adding the poly N-isopropyl acrylamide, which is beneficial to delaying the drug release speed. Therefore, poloxamer 407 and poly-N-isopropyl acrylamide are used as temperature-sensitive gel matrixes, so that the medicine can be stably attached in periodontal pockets, the medicine is slowly released, and the periodontitis treatment effect is improved.
Preferably, the lipid compound is selected from one or more of triacetin, tributyrin, tripropionate, trioctanoate and tricapranate.
Preferably, the surfactant is selected from one or more of polyethylene glycol 15 hydroxystearate (HS-15), polyoxyethylene 40 hydrogenated castor oil (RH-40), tween 80, castor oil polyoxyethylene ether, tween 20, poloxamer 188, carbitol and lecithin.
Preferably, the cosurfactant is selected from one or more of polyethylene glycol 400, glycerol, 1, 2-propylene glycol, n-butanol, isopropanol and absolute ethanol.
Preferably, the mass ratio of the peppermint oil to the lipid compound is 1:1-5:1.
Preferably, the mass ratio of the surfactant to the cosurfactant is 1:1-5:1.
Preferably, the mass ratio of the mixed oil phase to the mixed surfactant is 1:9-5:5.
Preferably, the mass ratio of the quercetin to the poloxamer 407 is 1:120-1:250, and the mass ratio of the quercetin to the poly-N-isopropyl acrylamide is 1:10-1:50, so that phase transition can occur after about 45s, and the periodontal medicament delivery requirement is met.
The invention also provides a preparation method of the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, which comprises the following steps:
(1) Taking quercetin, peppermint oil, surfactant, cosurfactant and DSPE-PEG 2000 FA is fully and uniformly stirred, deionized water is added, and folic acid modified quercetin-peppermint oil microemulsion is obtained by an emulsification method;
(2) Adding poloxamer and poly-N-isopropyl acrylamide into folic acid modified quercetin-peppermint oil microemulsion solution to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel.
Preferably, in the step (2), the mass concentration of the quercetin is 1-10 mg/mL, the mass concentration of the peppermint oil is 30-250 mg/mL, the mass concentration of the poloxamer 407 is 120-250 mg/mL, and the mass concentration of the poly-N-isopropyl acrylamide is 10-50 mg/mL.
The invention also provides application of the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel in preparation of medicines for treating periodontitis.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, quercetin and peppermint oil are loaded into the microemulsion, and folic acid is modified on the surface of the microemulsion to prepare the folic acid modified quercetin-peppermint oil microemulsion. And then poloxamer 407 and poly-N-isopropyl acrylamide are distributed on the folic acid modified quercetin-peppermint oil microemulsion to form the temperature-sensitive gel. The prepared folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel keeps the advantage of gel drug loading and has in-situ periodontal injection performance. The gel is gelled into semisolid at the temperature of the oral cavity, and is adhered to the periodontal pocket to form a local drug reservoir, so that the drug loss can be effectively prevented, the acting time of the drug is prolonged, the bioavailability of the drug is improved, the compliance of the drug administration of a patient is enhanced, a plurality of adverse reactions caused by systemic administration are avoided, and the preparation method has the advantages of safety, simplicity and convenience and effectiveness in treating periodontitis.
The folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel prepared by the invention can play an anti-inflammatory and antioxidant role, and provides a new preparation type for periodontal local administration. The evaluation result shows that the preparation can realize continuous antioxidation, anti-inflammatory and tooth bone tissue regeneration promotion effects, and provides a new means for treating periodontitis.
Drawings
FIG. 1 is a graph showing the solubility of quercetin in an oil phase and a mixed oil phase according to the present invention;
FIG. 2 is a graph showing the results of screening a folic acid modified quercetin-peppermint oil microemulsion prescription according to the present invention (A is a surfactant, B is a cosurfactant, and C is Km);
FIG. 3 is a graph of particle size and potential of folic acid modified quercetin-peppermint oil microemulsion of the present invention;
FIG. 4 is an appearance of a folic acid modified quercetin-peppermint oil microemulsion of the present invention;
FIG. 5 is a view of the appearance and scanning electron microscope of a folic acid modified quercetin-peppermint oil microemulsion temperature sensitive gel of the present invention;
FIG. 6 is a rheological diagram of a temperature-sensitive gel of a folic acid modified quercetin-peppermint oil microemulsion of the present invention;
FIG. 7 is a graph showing the radical scavenging properties of folic acid modified quercetin-peppermint oil microemulsion of the present invention;
FIG. 8 is a graph showing the kinetics of folic acid modified quercetin-peppermint oil microemulsion uptake by macrophages according to the present invention;
FIG. 9 shows the therapeutic effect of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel on periodontitis rats.
Detailed Description
The present invention will be further described by the following specific embodiments, which are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the following examples.
The raw materials used in the examples of the present invention were all from commercial sources.
Example 1: solubility of quercetin in oil and Mixed oil phases
Weighing excessive quercetin, respectively dissolving in equal volumes of Peppermint oil (Peppermint oil) and tricaprylin (1, 2, 3-Tri-n-octanylglycol) and mixed oil PTO1, PTO2, PTO3 (Peppermint oil+1,2, 3-Tri-n-octanylglycol, ratio of 1:1,2:1, 3:1), placing in a glass test tube with plug, ultrasonic treating for 30min, placing in a constant temperature oscillator at 37deg.C for 24 hr to reach dissolution balance, 13000rmin -1 Centrifuging for 10min, collecting supernatant 20 μl, adding methanol for dilution, and detecting its solubility by HPLC method. The best solubility of quercetin in the oil phase was screened.
As shown in FIG. 1, quercetin has the highest solubility in peppermint oil-glycerol trioctanoate (2:1) up to 55.96 + -0.33 μg mL -1 The nanometer microemulsion constructed by using peppermint oil and lipid compounds as mixed oil phases is shown to be capable of remarkably improving the solubility of quercetin.
Example 2:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
8 parts of quercetin, 150 parts of peppermint oil, 50 parts of tricaprylin, HS-15 parts of PEG400, 75 parts of DSPE-PEG2000-FA 1 parts;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:150, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:30.
Example 3:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
6 parts of quercetin, 120 parts of peppermint oil, 80 parts of tricaprylin, RH-40 parts, 400 parts of PEG (polyethylene glycol) 400 and 2000-FA 2 parts of DSPE-PEG;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:120, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:20.
Example 4:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
10 parts of quercetin, 133 parts of peppermint oil, 67 parts of tributyrin, 250 parts of tween-80, 400 parts of PEG (polyethylene glycol) and 2000-FA 1 parts of DSPE (polyethylene glycol) -PEG;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:170, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:40.
Example 5:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
10 parts of quercetin, 150 parts of peppermint oil, 50 parts of tricaprin, HS-15 parts of glycerin, 50 parts of glycerin and 2000-FA 1 parts of DSPE-PEG;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:170, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:40.
Example 6:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
10 parts of quercetin, 133 parts of peppermint oil, 67 parts of tricaprylin, RH-40 parts of n-butanol 50 parts and DSPE-PEG2000-FA 1 parts;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:170, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:40.
Example 7:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
8 parts of quercetin, 150 parts of peppermint oil, 50 parts of trioctanoate, 188 200 parts of poloxamer, 50 parts of absolute ethyl alcohol and 2000-FA 1 parts of DSPE-PEG;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:150, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:30.
Example 8:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
8 parts of quercetin, 150 parts of peppermint oil, 50 parts of tricaprylin, 200 parts of lecithin, 50 parts of n-butanol and 2000-FA 1 parts of DSPE-PEG;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:120, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:50.
Example 9:
(1) Preparation of folic acid modified quercetin-peppermint oil microemulsion
8 parts of quercetin, 150 parts of peppermint oil, 50 parts of trioctanoate, 188 200 parts of poloxamer, 50 parts of 1, 2-propylene glycol and 1 part of DSPE-PEG 2000-FA;
the above components were placed in a vessel and stirred at 37℃for 10min, vortexed for 5min (1500 rpm) and then stirred at 37℃until homogeneous. Dropwise adding deionized water into the prepared mixed system at a constant speed slowly and quantitatively, and continuously stirring the system at a constant speed until a transparent and clear system appears, so as to obtain folic acid modified quercetin-peppermint oil microemulsion;
(2) Preparation of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
Taking the prepared folic acid modified quercetin-peppermint oil microemulsion as a water phase, and adding poloxamer 407 and PNIPAM into the water phase to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, wherein the mass ratio of quercetin to poloxamer 407 is 1:150, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:30.
Example 10: microemulsion surfactant, cosurfactant and Km value prescription screening
Screening surfactant of the microemulsion: the fixed peppermint oil-glycerol trioctanoate is a mixed oil phase (3:1, w:w), and the polyethylene glycol 400 (PEG 400) is a cosurfactant, preferably a microemulsion surfactant. The method comprises the steps of respectively mixing different types of surfactants (HS-15, tween 80 and castor oil polyoxyethylene ether) with cosurfactants according to a mass ratio of 1:1 are mixed to form the mixed surfactant. The mixed oil phase and the mixed surfactant are mixed according to the mass ratio of 1: 9. 2: 8. 3: 7. 4: 6. 5:5, titrating with ultrapure water, and recording the critical change value of the water phase of the microemulsion system. The O/W type microemulsion region was determined by drawing a pseudo ternary phase diagram with the aid of Origin 2021 software, and the optimum surfactant was determined based on the area of the microemulsion region, and the result is shown in FIG. 2A.
Screening cosurfactant of microemulsion: fixed peppermint oil-tricaprylin is a mixed oil phase (3:1, w: w), and HS-15 is a surfactant, preferably a cosurfactant of microemulsion. HS-15 was combined with different types of cosurfactants (polyethylene glycol 400, glycerol, 1, 2-propanediol) in a mass ratio of 1:1 are mixed to form the mixed surfactant. The mixed oil phase and the mixed surfactant are mixed according to the mass ratio of 1: 9. 2: 8. 3: 7. 4: 6. 5:5, titrating with ultrapure water, and recording the critical change value of the water phase of the microemulsion system. The O/W type microemulsion region was determined by drawing a pseudo ternary phase diagram with the aid of Origin 2021 software, and the optimum cosurfactant was determined based on the area of the microemulsion region, the results of which are shown in FIG. 2B.
Surfactant to cosurfactant (w: w) ratio (Km value) screening of microemulsion: fixed peppermint oil-glycerol trioctanoate is a mixed oil phase (3:1, w: w), HS-15 is a surfactant, PEG400 is a cosurfactant, and the mixed surfactant is formed by Km values of 1:1, 1:1 and 1:1 respectively. The mixed oil phase and the mixed surfactant are mixed according to the mass ratio of 1: 9. 2: 8. 3: 7. 4: 6. 5:5, titrating with ultrapure water, and recording the critical change value of the water phase of the microemulsion system. The O/W type micro emulsion area is determined by drawing a pseudo ternary phase diagram by using Origin 2021 software, and the optimal Km value is determined according to the area of the micro emulsion area, and the result is shown as C in figure 2.
The preferable formula of the obtained microemulsion is as follows: HS-15 is used as a surfactant, PEG400 is used as a cosurfactant, and Km value is 3:1.
The folic acid modified quercetin-peppermint oil microemulsion and folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel prepared in the embodiment 2 are tested by the following examples:
example 11: characterization of Folic acid modified quercetin-peppermint oil microemulsion
FIG. 3 shows the particle size and potential map of folic acid modified quercetin-peppermint oil microemulsion obtained in example 2, with a particle size of 39.80 + -2.55 nm and a potential of-36.73+ -2.00 mV.
As shown in FIG. 4, the folic acid modified quercetin-peppermint oil microemulsion obtained in example 2 is clear and transparent in appearance and is light yellow.
Example 12: preparation and characterization of folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel
And determining the gel time of the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel at 30 ℃ by adopting a test tube inversion method. The prepared microemulsion is taken as a water phase, poloxamer 407 and PNIPAM with different masses are added into the microemulsion, and the gel time of different proportions of preparations at 30 ℃ is evaluated. Weighing 30 parts of 1mL of temperature-sensitive gel, respectively placing in 5mL test tubes, fixing with a floating plate, placing in a water bath kettle at 30 ℃, taking up one test tube every 1s from 21 st s, observing whether the gel turns into gel, and recording the gelation time. Experiments were repeated 3 times. As shown in Table 1, when the mass ratio of quercetin to poloxamer 407 is 1:150 and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:30, phase transition can occur within 45 seconds, and the periodontal medicament delivery requirement is met.
As shown in fig. 5, the transition from solution to gel can be observed from the macroscopic state. And (3) freeze-drying the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel, adhering a sample on a conductive adhesive tape on a sample seat, placing the sample seat in a vacuum coating machine, closing a cover, opening a ventilation valve to vacuumize a gold steaming chamber, spraying gold on the surface of the sample, taking out the sample, and observing the form of the gel in a scanning electron microscope and taking a picture of the form of the gel. As a result, as shown in FIG. 5, gel scaffolds generally have a porous network structure that is advantageous for loading drug delivery systems.
TABLE 1 gel state and gel time for different prescriptions
Example 13: folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel rheology research
The temperature sensitive gel has two rheological properties, namely viscous liquid and elastic solid, wherein the viscous liquid property is expressed by rheological parameter viscous modulus G ', and the elastic solid property is expressed by rheological parameter elastic modulus G' (storage modulus). Rheological studies were performed using a DHR-2 rheometer equipped with a 20mm parallel plate clamp.
The sol-gel transition temperature of folic acid modified quercetin-peppermint oil microemulsion temperature sensitive gel was measured in oscillation mode. The frequency was fixed at 1Hz and 0.1% strain was applied. The sample was heated at a rate of 2 ℃/min and a temperature in the range of 20 ℃ to 45 ℃. The test results are shown in fig. 6, where as T increases, G 'and G "gradually increase, indicating that the formulation is in the sol state when the rheological modulus of the gel G' < G". The temperature continued to rise and G ' increased rapidly, with a crossover point between G ' and G ', indicating that a sol-gel phase transition occurred at 29.8 ℃. This temperature is less than 37 ℃ of the tooth Zhou Huanjing temperature, so that rapid gelation can occur after injection into the periodontal pocket.
Example 14: folic acid modified quercetin-peppermint oil microemulsion free radical scavenging performance
The free radical scavenging properties of folic acid modified quercetin-peppermint oil microemulsion were evaluated using a 2, 2-diphenyl-1-picric hydrazine (DPPH) reagent. Ethanol solutions (quercetin: 1.6. Mu.g/mL, peppermint Oil: 168. Mu.g/mL) containing quercetin (Qu), peppermint Oil (Peppermint Oil), and folic acid-modified quercetin-Peppermint Oil microemulsion (FA-Qu-MEs) were prepared, respectively. 2mL of the sample was taken in a test tube, 2mL of DPPH solution (0.1 mmol/L) was added, the mixture was uniformly mixed, the mixture was left in the dark for 30min, and the absorbance Ac of each sample was measured at 517nm and 3 times per sample were performed in parallel. DPPH clearance was calculated using the following equation:
DPPH clearance (%) = (Ac-As)/ac×100%;
where Ac refers to the absorbance value of the control group and As refers to the absorbance value of the sample.
DPPH scavenging ability of Qu, peppermint Oil, FA-Qu-MEs is shown in FIG. 7. DPPH removing capacities of Peppermint Oil, qu and FA-Qu-MEs are respectively 15.39%, 24.19% and 31.62%. The result shows that the folic acid modified quercetin-peppermint oil microemulsion has better free radical scavenging performance, and the free radical scavenging performance is superior to that of the quercetin or the peppermint oil singly.
Example 15: targeted evaluation of folic acid modified quercetin-peppermint oil microemulsion on macrophages
Coumarin 6 (C6) is adopted to replace quercetin, fluorescence-labeled folic acid modified microemulsion (FA-C6-MEs) is prepared, and targeting of macrophages is examined. Taking RAW264.7 cells in logarithmic growth phase at 1×10 5 The density of each well was inoculated into a 6-well plate, and after culturing for 24 hours, FA-C6-MEs was added to the 6-well plate so that the final concentration of C6 was 2. Mu.M. After 2h incubation in incubator, the medium was discarded, washed repeatedly 3 times with PBS, fixed with 4% paraformaldehyde fixing solution for 10min, washed off with PBS, stained with DAPI for 5min, and washed three times with PBS. The intracellular uptake of C6 was observed qualitatively using fluorescence microscopy. After 2h incubation in incubator, the medium was discarded, repeatedly washed 3 times with PBS, digested 2min with trypsin, resuspended with PBS, centrifuged at 1000rpm for 5min and then resuspended with PBS continuously, and the intracellular fluorescence intensity was quantitatively detected with a flow cytometer.
The results are shown in FIG. 8, where the intracellular fluorescence of the C6-MEs microemulsion group is more enhanced than that of the C6 group, indicating that the cellular uptake rate of the microemulsion is higher. In addition, the average fluorescence intensity in the FA-C6-MEs group macrophages is highest, which indicates that folic acid modification can further improve the performance of the microemulsion-targeted macrophages.
Example 10: folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel effect post-periodontitis rat treatment effect
After 100 male healthy SPF-class rats are adaptively fed for 2 weeks, except for the normal group, the abdominal anesthesia of the rats is carried out by adopting 3% pentobarbital sodium (30 mg/kg), the rats are supine on an experiment table, the heads and limbs of the rats are fixed, the upper and lower jaws are pulled to fully expose the first molar of the left upper jaw, a ligature wire of 0.2mm is used for penetrating through the gap between the first molar and the second molar of the rats, ligature wire is ligated on the neck of the first molar and knotted on the palate side, the ligature wire with redundant length is cut off, and meanwhile, the ligature knot is buried under the gingiva. After 4 weeks, the periodontal condition of the rats was observed, and the rats successfully modeled were randomly grouped: normal (Normal), model (Model), positive (period), quercetin bare gel (qu@gel), quercetin-peppermint oil microemulsion gel (Qu-mes@gel), folic acid modified quercetin-peppermint oil microemulsion gel (FA-Qu-mes@gel) prepared in example 2. Every 3 days, 20 mu L of corresponding preparation is injected under the parietal mucoperiosteum of the central alveolar ridge on the cheek and palate side of the first molar of the upper jaw, and the normal group and the model group are injected with the physiological saline with the same volume.
The preparation method of the quercetin bare medicine gel group (Qu@gel) comprises the following steps: (1) Adding poloxamer 407 and poly-N-isopropyl acrylamide into pure water to obtain a temperature-sensitive gel matrix; (2) Adding quercetin into the temperature-sensitive gel matrix, and stirring uniformly to obtain Qu@gel.
The preparation method of the quercetin-peppermint oil microemulsion gel group (Qu-MEs@gel) comprises the following steps: (1) Taking quercetin, peppermint oil, surfactant HS-15 and cosurfactant PEG400, uniformly stirring, and then adding deionized water for fully and uniformly mixing to obtain quercetin-peppermint oil microemulsion; (2) Adding poloxamer 407 and poly-N-isopropyl acrylamide into quercetin-peppermint oil microemulsion to obtain quercetin-peppermint oil microemulsion gel.
A preparation method of a folic acid modified quercetin-peppermint oil microemulsion gel group (FA-Qu-MEs@gel) comprises the following steps: as described in example 2.
Four weeks after dosing, SD rats were euthanized, left maxilla was isolated, blood stain was washed with normal saline, tissue near the first molar was collected, washed and stored at-80 ℃. And removing redundant soft tissues by using fine scissors, and placing the specimen into 4% paraformaldehyde for fixation for 48 hours. Standard procedures of decalcification, dehydration, embedding, slicing and the like are carried out. Histological changes of periodontal tissue after 4 weeks were observed by hematoxylin-eosin staining (H & E).
The H & E staining results showed clear structure of Normal group periodontal tissue, epithelium close to enamel surface, complete and compact arrangement of periodontal fibers, no alveolar bone resorption, almost no inflammatory cell infiltration, as shown in fig. 9 a. Model group interdental papillae disappeared and deep periodontal pockets were formed by migration of the combined epithelium to the root. Periodontal fibrous structure disorder, absorptive pits are visible in cementum, and a large number of inflammatory cell infiltrates can be found in the surrounding area. The inflammatory cell infiltration of the group of Qu-MEs@gel and FA-Qu-MEs@gel is obviously reduced, and the epithelial structure is clear. The result shows that the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel can effectively inhibit the progress of periodontitis.
To evaluate the alveolar bone injury of each dosing group, the distance between the rat maxillary first molar from the cementum kingdom (CEJ) to the alveolar ridge crest (ABC) was measured and the results are shown in fig. 9B. The Model group CEJ-ABC was higher in distance than the Normal group, indicating successful Model establishment for chronic periodontitis. The CEJ-ABC of the FA-Qu-mes@gel group was 3.175.+ -. 0.368mm, with a significantly shorter distance compared to the Model group (4.250.+ -. 0.242 mm). This shows that folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel can relieve periodontitis alveolar bone injury.
To further evaluate alveolar bone regeneration, the bone volume/total bone volume (BV/TV) and trabecular thickness (th.th) between the first molar and the second molar were evaluated using three-dimensional reconstruction calculation software. As shown in fig. 9C and D, BV/TV and th.th of Model groups decreased to 66.200 ±0.178% (P < 0.0001) and 0.27±0.003mm (P < 0.0001), respectively, compared to Normal group (BV/tv= 76.760 ±0.090%, tb.th=0.379±0.017 mm), meaning that alveolar bone regeneration ability of periodontitis rats was weak. After the FA-Qu-MEs@gel group is dosed, BV/TV and Tb.Th are respectively increased to 71.096 +/-0.762%, and 0.350+/-0.005 mm, which shows that the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel can promote alveolar bone regeneration.
Claims (10)
1. A folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel is characterized by comprising folic acid modified quercetin-peppermint oil microemulsion and a gel matrix;
the folic acid modified quercetin-peppermint oil microemulsion is prepared by taking quercetin and peppermint oil as raw material medicines, taking peppermint oil and lipid compounds as mixed oil phases, taking a surfactant and a cosurfactant as mixed surfactants and modifying folic acid, wherein the components in parts by weight are as follows:
1-10 parts of quercetin, 30-250 parts of peppermint oil, 20-80 parts of lipid compound, 180-280 parts of surfactant, 50-100 parts of cosurfactant and DSPE-PEG (polyethylene-polyethylene glycol) 2000 FA0.1-5 parts;
the gel matrix comprises: 120-250 parts of poloxamer 407 and 10-50 parts of poly-N-isopropyl acrylamide.
2. The folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to claim 1, wherein the lipid compound is selected from one or more of triacetin, tributyrin, tripropionate, tricaprylin and tricapranate.
3. The folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to claim 1, wherein the surfactant is selected from one or more of polyethylene glycol 15 hydroxystearate (HS-15), polyoxyethylene 40 hydrogenated castor oil (RH-40), castor oil polyoxyethylene ether, tween 80, tween 20, poloxamer 188, carbitol and lecithin.
4. The folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to claim 1, wherein the cosurfactant is selected from one or more of polyethylene glycol 400, glycerol, 1, 2-propanediol, n-butanol, isopropanol and absolute ethanol.
5. The folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to claim 1, wherein the mass ratio of the surfactant to the cosurfactant is 1:1-5:1; the mass ratio of the peppermint oil to the lipid compound is 1:1-5:1.
6. The folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to claim 5, wherein the mass ratio of the mixed oil phase to the mixed surfactant is 1:9-5:5.
7. The folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to claim 1, wherein the mass ratio of quercetin to poloxamer 407 is 1:120-1:250, and the mass ratio of quercetin to poly-N-isopropyl acrylamide is 1:10-1:50.
8. The method for preparing the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to any one of claims 1 to 7, comprising the following steps:
(1) Taking quercetin, peppermint oil, surfactant, cosurfactant and DSPE-PEG 2000 FA is fully and uniformly stirred, deionized water is added, and folic acid modified quercetin-peppermint oil microemulsion is obtained by an emulsification method;
(2) Adding poloxamer and poly-N-isopropyl acrylamide into folic acid modified quercetin-peppermint oil microemulsion solution to obtain folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel.
9. The preparation method of the folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to claim 8, wherein in the step (2), the mass concentration of quercetin is 1-10 mg/mL, the mass concentration of peppermint oil is 30-250 mg/mL, the mass concentration of poloxamer 407 is 120-250 mg/mL, and the mass concentration of poly-N-isopropyl acrylamide is 10-50 mg/mL.
10. Use of a folic acid modified quercetin-peppermint oil microemulsion temperature-sensitive gel according to any one of claims 1-7 in the preparation of a medicament for treating periodontitis.
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