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CN-121987485-A - Moxa-based carbon quantum dot compound photo-thermal drug synergistic system and preparation method and application thereof

CN121987485ACN 121987485 ACN121987485 ACN 121987485ACN-121987485-A

Abstract

The application provides a mugwort-based carbon quantum dot compound photo-thermal drug synergistic system and a preparation method and application thereof. The photo-thermal conversion unit is formed by constructing a 0D/2D heterojunction by nitrogen-sulfur co-doped carbon quantum dots derived from mugwort biomass and two-dimensional graphene through a dielectric isolation layer, near infrared conversion and accurate thermal therapy of wide spectrum light are realized, and the drug-loaded transdermal unit is formed by thermosensitive liposome gel containing 'mugwort-blumea balsamifera-ginger' compound micro-nano active ingredients. The application innovatively designs a space-time cooperative mechanism of light-to-light-to-heat permeation, namely, a specific thermal field generated by a light-to-heat conversion unit triggers liposome phase change, so that the on-demand release and deep transdermal of the medicine are realized. The system perfectly re-inscribes the 'photo-thermal-medicine' composite effect of the traditional barrier moxibustion, the medicine transdermal synergistic effect index is more than 2.5, and the photo-thermal conversion efficiency is not lower than 35%. Has the effects of no smoke, accurate temperature control and high transdermal efficiency.

Inventors

  • CHEN FUKUN
  • WU YOU
  • WU ZHOUQIANG
  • CHEN BAIHAN
  • XU WEN

Assignees

  • 南阳神农艾草生物制品有限公司

Dates

Publication Date
20260508
Application Date
20260212

Claims (18)

  1. 1. The photo-thermal drug synergistic system is characterized by comprising a photo-thermal conversion unit (100) and a drug-carrying transdermal unit (200) which are integrated; The photothermal conversion unit (100) includes: A light-transmitting substrate (110); a photo-thermal functional layer (120) attached to the light-transmissive substrate; The photo-thermal functional layer (120) comprises a two-dimensional graphene material (121), a dielectric isolation layer (122) and nitrogen-sulfur co-doped carbon quantum dots (123) derived from mugwort biomass, so that a 0D/2D heterojunction structure is formed; The carbon quantum dots (123) are anchored to the surface of the dielectric isolation layer (122) through covalent bonding; The photo-thermal conversion unit (100) outputs near infrared light with the wavelength within the range of 650-950nm under the irradiation of broad spectrum light, and forms a thermal field at 40-50 ℃ on the surface of the unit; The drug-loaded transdermal unit (200) comprises: a transparent gel layer attached to the light-emitting side of the photothermal conversion unit (100); thermosensitive liposomes (210) dispersed in the gel layer; the phase transition temperature of the thermosensitive liposome (210) is 40-45 ℃; the thermosensitive liposome (210) is encapsulated with a compound traditional Chinese medicine micro-nano active ingredient; the compound traditional Chinese medicine micro-nano active ingredient is prepared from blumea balsamifera, blumea balsamifera and ginger by a molecular state conservation extraction process.
  2. 2. The system according to claim 1, wherein the conservation extraction process comprises the steps of mixing (2-4): (1-2): (1-3) of wormwood, blumea balsamifera and ginger according to the mass ratio (2-2): (1-2), homogenizing and crushing under ultrahigh pressure to retain molecular configuration, separating by a gradient ceramic membrane to retain active components, purifying by macroporous resin to remove impurities and retaining active components at the same time, so as to obtain the compound traditional Chinese medicine micro-nano active components; the mass ratio of gingerol, eucalyptol and borneol in the active ingredients is (3-5) (1-2) (0.5-1.5).
  3. 3. The system of claim 1, wherein the dielectric isolation layer (122) has a thickness of 2-5nm and is made of Or (b) The nitrogen content of the carbon quantum dots (123) is 3-8at%, the sulfur content is 1-3at%, and the fluorescence quantum yield under 450nm excitation is not lower than 15%.
  4. 4. The system of claim 1, wherein the thermosensitive liposome (210) has an average particle size of 50-200nm and a polydispersity index of less than 0.2, and the membrane material of the thermosensitive liposome (210) comprises thermosensitive phospholipid and cholesterol with a phase transition temperature of 40-42 ℃, and the molar ratio of the thermosensitive phospholipid to the cholesterol is (7-9): 1-3.
  5. 5. The system of claim 1, wherein the gel matrix of the drug-loaded transdermal unit (200) is at least one of hyaluronic acid, carbomer, or poloxamer having a light transmittance of not less than 85% at wavelengths of 650-950 nm.
  6. 6. The system according to claim 1, wherein the photothermal conversion efficiency of the photothermal conversion unit (100) is not lower than 35%, and the drug transdermal synergistic effect index of the system is not lower than 2.5; the method for calculating the Synergistic Effect Index (SEI) comprises the following steps: ; Where Q_system is the cumulative transdermal flux of the complete system, Q_drug is the cumulative transdermal flux of the drug alone but without heat, Q_heat is the cumulative transdermal flux of the thermal field alone but without drug carrier, Q_light is the cumulative transdermal flux of the light alone but without thermal field without drug, SEI >0 indicates that there is a positive synergistic effect, the greater the SEI the stronger the synergistic effect.
  7. 7. The system of claim 1, wherein the photothermal conversion unit (100) and the drug-loaded transdermal unit (200) are detachably coupled by a reversible mechanical connection, and in the coupled state, the thermal resistance of the contact interface between the two is less than 0.01m 2-K/W.
  8. 8. A photothermal conversion unit, characterized by comprising: A light-transmitting substrate (110); a photo-thermal functional layer (120) attached to the light-transmissive substrate; The photo-thermal functional layer (120) comprises a two-dimensional graphene material (121), a dielectric isolation layer (122) and nitrogen-sulfur co-doped carbon quantum dots (123) derived from mugwort biomass; The dielectric isolation layer (122) is coated on the surface of the two-dimensional graphene material (121); The carbon quantum dots (123) are covalently bonded to the surface of the dielectric isolation layer (122) through EDC/NHS coupling reaction to form a 0D/2D heterojunction structure; the nitrogen content of the carbon quantum dots (123) is 3-8at% and the sulfur content is 1-3at%.
  9. 9. The photothermal conversion unit according to claim 8, wherein the dielectric isolation layer (122) is The thickness of the layer is 2-5nm, and the two-dimensional graphene material (121) is graphene oxide or reduced graphene oxide.
  10. 10. The light-to-heat conversion unit according to claim 8, wherein the light-to-heat conversion unit has a relative intensity enhancement of the output spectrum at a wavelength band of 700 to 900nm of not less than 2 times and a light-to-heat conversion efficiency of not less than 35% under broad spectrum light irradiation.
  11. 11. A method of preparing the photothermal drug synergistic system of any one of claims 1 to 7 comprising the steps of: A. Preparing Ai Caoyuan nitrogen-sulfur co-doped carbon quantum dots, namely drying and crushing a moxa processing byproduct, mixing the moxa processing byproduct with water, adding cellulase for enzymolysis pretreatment, wherein the enzymolysis temperature is 45-55 ℃ and the enzymolysis time is 2-6 hours, transferring enzymolysis slurry into a microwave hydrothermal reactor, reacting for 20-40 minutes under the conditions of 400-600W of microwave power and 160-180 ℃ of reaction temperature, centrifuging, dialyzing, purifying and drying the reaction product to obtain the nitrogen-sulfur co-doped carbon quantum dots; B. Preparation Dispersing graphene oxide in ethanol water solution, adding tetraethoxysilane and ammonia water, stirring at 40-60deg.C for 2-6 hr to obtain modified graphene The dielectric layer grows on the surface of the graphene oxide in situ to obtain Modified graphene; C. constructing a 0D/2D heterojunction compound, namely, the step B is carried out Dispersing modified graphene in MES buffer solution, adding EDC and NHS for activation, then adding the carbon quantum dot dispersion liquid obtained in the step A, and reacting for 2-6 hours at room temperature to enable the carbon quantum dots to be covalently bonded to the MES buffer solution through amide bonds The surface is provided with a heterojunction compound; D. c, preparing a photo-thermal conversion unit, namely dispersing the heterojunction compound obtained in the step C in a solvent, coating the solvent on a light-transmitting substrate, and drying and curing to obtain the photo-thermal conversion unit; E. The preparation of the compound traditional Chinese medicine micro-nano active ingredient comprises the steps of mixing the wormwood, blumea balsamifera and ginger according to the mass ratio of (2-4) to (1-2) to (1-3), adding water, homogenizing and crushing under ultra-high pressure, sequentially carrying out gradient separation through a 500nm ceramic membrane and a 100nm ultrafiltration membrane, adsorbing filtrate through macroporous resin, eluting with ethanol, concentrating and drying eluent to obtain the compound traditional Chinese medicine micro-nano active ingredient; F. Preparing a drug-loaded thermosensitive liposome, namely dissolving thermosensitive phospholipid and cholesterol in an organic solvent, performing rotary evaporation to form a lipid film, adding a buffer solution containing the active ingredients obtained in the step E, hydrating at a temperature higher than the phase transition temperature of the phospholipid, and extruding the membrane to obtain the drug-loaded thermosensitive liposome; G. F, preparing a drug-loaded transdermal unit, namely dispersing the drug-loaded thermosensitive liposome obtained in the step F in a gel matrix solution, and casting into a film to obtain the drug-loaded transdermal unit; H. And D, attaching the drug-carrying transdermal unit obtained in the step G to the surface of the photo-thermal functional layer of the photo-thermal conversion unit obtained in the step D to obtain the photo-thermal drug synergistic system.
  12. 12. The method according to claim 11, wherein in the step A, the addition amount of the cellulase is 1-3% of the dry weight of the by-product of mugwort processing, and the enzyme activity is not less than 10000U/g.
  13. 13. The method according to claim 11, wherein in the step B, the mass ratio of the graphene oxide, the tetraethoxysilane and the ammonia water is 1 (0.5-2): 0.1-0.5.
  14. 14. The method according to claim 11, wherein in step F, the heat sensitive phospholipid is dipalmitoyl phosphatidylcholine having a phase transition temperature of 41 ℃, a hydration temperature of 50-60 ℃ and a hydration time of 0.5-2 hours, and the film extrusion is 100-200nm polycarbonate film.
  15. 15. Use of the photo-thermal drug co-system of any one of claims 1-7 or the photo-thermal conversion unit of any one of claims 8-10 for the manufacture of a smokeless intelligent moxibustion device.
  16. 16. Use of the photothermal drug synergistic system of any one of claims 1 to 7 for the preparation of a transdermal drug delivery formulation for warming and activating meridians, dispelling cold and dehumidifying.
  17. 17. A kit comprising a photothermal conversion unit according to any one of claims 8 to 10, and at least one replaceable drug-loaded transdermal unit comprising drug-loaded thermosensitive liposomes dispersed in a gel matrix.
  18. 18. The kit of claim 17, wherein the drug-loaded transdermal units are individually packaged disposable units and the photothermal conversion units are reusable units.

Description

Moxa-based carbon quantum dot compound photo-thermal drug synergistic system and preparation method and application thereof Technical Field The application relates to the technical field of photothermal materials and traditional Chinese medicine transdermal drug delivery, in particular to a mugwort-based carbon quantum dot compound photothermal drug synergistic system and a preparation method and application thereof. Background Moxibustion is an important component of traditional Chinese medicine, and has clinical application history of thousands of years. The traditional moxibustion achieves the therapeutic effects of warming channels, dispelling cold, strengthening yang, relieving depletion, removing blood stasis and resolving hard mass by acting on human body acupuncture points through heat radiation and light radiation generated by burning moxa. Wherein, the 'barrier moxibustion' is a moxibustion method in which a medicine (such as ginger slices, garlic slices, aconite cakes and the like) is placed between skin and moxa cone, and the transdermal penetration of the medicine is stimulated by the heat of moxa fire, so as to realize the three-in-one therapeutic effect of 'light-heat-medicine'. Modern researches have shown that the therapeutic effect of traditional barrier moxibustion is mainly derived from three aspects: (1) The light effect is that light radiation generated by burning moxa, especially near infrared light (700-1100 nm), can penetrate the skin to act on deep tissues to generate a photo-biological regulation effect; (2) The thermal effect is that the warm stimulation (usually 40-50 ℃) generated by the moxa fire can promote local blood circulation, improve tissue metabolism and enhance skin permeability; (3) The medicine effect is that the active ingredients in the partition (medicine cake) permeate through skin under the action of a thermal field to exert pharmacological action. However, the following problems are to be solved in the conventional barrier moxibustion: (1) The smoke problem is that moxa sticks burn to generate a large amount of smoke, and the PM2.5 concentration can reach hundreds of micrograms per cubic meter, so that the application of the moxa sticks in a closed space is limited; (2) The temperature is uncontrollable, the moxa temperature is difficult to control accurately, and local overheating or insufficient temperature is easy to cause; (3) The spectrum is uncontrollable, the moxa spectrum is broad-spectrum radiation, the near infrared light duty ratio is limited, and the light energy utilization efficiency is low; (4) The drug release is uncontrollable, wherein the drug in the traditional drug cake is released by passive diffusion, and the release rate and the release amount are difficult to control; (5) The light-heat-medicine time-space is asynchronous, in the traditional barrier moxibustion, the time-space relationship of the light effect, the heat effect and the medicine effect is difficult to accurately regulate and control. In view of the above problems, researchers have attempted to develop various "smokeless moxibustion" or "electronic moxibustion" devices, but the prior art has the following limitations: 1. limitations of existing photothermal materials The materials currently used for photothermal conversion mainly include: (1) Noble metal nanomaterials (e.g., gold nanorods) are photo-thermal efficient, but are expensive and biosafety is a issue; (2) Graphene and derivatives thereof have higher photo-thermal efficiency, but the spectrum is uncontrollable, so that the light output of a specific wave band is difficult to realize; (3) Ordinary carbon quantum dots have good biocompatibility, but have lower photo-thermal efficiency (usually less than 25 percent) and no specific function. 2. Limitations of existing transdermal drug delivery techniques The current transdermal drug delivery technology mainly comprises: (1) Passive diffusion, low efficiency and shallow penetration depth, and is only suitable for small-molecule lipophilic medicines; (2) Chemical permeation promoters, which may cause skin irritation, present safety concerns; (3) Physical permeation promotion (such as iontophoresis and ultrasound) requires complicated equipment, and is costly and inconvenient to operate. 3. Limitations of existing "photothermal + drug delivery" combination techniques In the prior art, reports of combining photothermal materials with drug delivery systems have mainly the following problems: (1) The photo-thermal material and the drug carrying system are only physically mixed, so that no synergistic effect exists; (2) The temperature mismatch is that the output temperature of the photo-thermal material is not matched with the phase change temperature of the thermosensitive carrier, so that the drug release can not be effectively triggered; (3) The time and space are asynchronous, and the medicine release and the thermal field are decoupled, so that the accurate time and spa