CN113842377A - PDMS microneedle patch for transdermal delivery of elemene and preparation method thereof - Google Patents
PDMS microneedle patch for transdermal delivery of elemene and preparation method thereof Download PDFInfo
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- CN113842377A CN113842377A CN202110920953.XA CN202110920953A CN113842377A CN 113842377 A CN113842377 A CN 113842377A CN 202110920953 A CN202110920953 A CN 202110920953A CN 113842377 A CN113842377 A CN 113842377A
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- 239000004205 dimethyl polysiloxane Substances 0.000 title claims abstract description 67
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 title claims abstract description 67
- OPFTUNCRGUEPRZ-UHFFFAOYSA-N (+)-beta-Elemen Natural products CC(=C)C1CCC(C)(C=C)C(C(C)=C)C1 OPFTUNCRGUEPRZ-UHFFFAOYSA-N 0.000 title claims abstract description 51
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-beta-elemene Chemical compound CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 title claims abstract description 50
- 230000037317 transdermal delivery Effects 0.000 title claims abstract description 13
- 235000013870 dimethyl polysiloxane Nutrition 0.000 title claims abstract 24
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 title claims abstract 24
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 title claims abstract 24
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- BQSLMQNYHVFRDT-CABCVRRESA-N (-)-gamma-Elemene Natural products CC(C)=C1CC[C@](C)(C=C)[C@@H](C(C)=C)C1 BQSLMQNYHVFRDT-CABCVRRESA-N 0.000 description 1
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- QDUJKDRUFBJYSQ-OAHLLOKOSA-N elemene Chemical compound CC(C)C1=CC(=C(C)C)CC[C@@]1(C)C=C QDUJKDRUFBJYSQ-OAHLLOKOSA-N 0.000 description 1
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- 201000004101 esophageal cancer Diseases 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- BQSLMQNYHVFRDT-LSDHHAIUSA-N gamma-elemene Chemical compound CC(C)=C1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 BQSLMQNYHVFRDT-LSDHHAIUSA-N 0.000 description 1
- RVOXATXFYDNXRE-UHFFFAOYSA-N gamma-elemene Natural products CC(=C1CCC(C)(C(C1)C(=C)C)C(=C)C)C RVOXATXFYDNXRE-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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- 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
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses a PDMS microneedle patch for transdermal delivery of elemene, which comprises a needle body, a drug carrying substrate and a patch layer, wherein the needle body is arranged on the drug carrying substrate, the patch layer is bonded and arranged on the other side of the drug carrying substrate, which is far away from the needle body, a drug carrying groove is arranged in the drug carrying substrate, a mixed solution of PDMS and elemene is stored in the drug carrying groove, and an opening of the drug carrying groove faces the patch layer and is wrapped and isolated by gummed paper. The invention provides a novel dosage form of elemene transdermal drug delivery, a PDMS micro-needle patch for transdermal drug delivery of elemene can be free from the limitation of a manufacturing area, and the drug loading capacity can be enlarged by enlarging the area. By combining elemene and the micro-needle made of PDMS, the defects of the traditional elemene dosage form at present are overcome to a limited extent, the advantages of the micro-needle and the effect of the elemene are brought into play, so that the medicine is more effectively utilized, and painless and accurate administration is realized.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a PDMS microneedle patch for transdermal delivery of elemene and a preparation method thereof.
Background
Elemene is effective anticancer active substance extracted from Curcuma aromatica of Zingiberaceae, and has chemical name of 1-methyl-1-vinyl-2, 4-diisopropenyl cyclohexane and molecular formula of C15H24, and has anticancer and antitumor effects. Elemene contains various isomers, mainly including alpha-elemene, beta-elemene, gamma-elemene, etc.
Transdermal Drug Delivery Systems (TDDS) are one of the important areas of drug delivery research, where transdermal drug delivery has many advantages, including improved patient compliance, sustained release, avoidance of gastric irritation, and elimination of pre-systemic first pass effects. However, only a very small number of drugs can be delivered by the transdermal route at therapeutic doses. In recent years, microneedle-based drug delivery methods have attracted much attention, and they can be used as TDDS to allow drugs to penetrate the skin more effectively and to achieve painless precise administration.
The organic silicon polymer Polydimethylsiloxane (PDMS) material is a high-elasticity and completely transparent biocompatible material formed by monomer coupling crosslinking, and the PDMS can form larger molecular holes in the molecular bonding crosslinking process, so that the PDMS has better air permeability and vapor permeability. In addition, the PDMS is easy to form, has good biological reaction inertia and hardness, and can be applied to the manufacture of microneedles.
Elemene is a volatile oil, is insoluble in water, is generally used as an antitumor drug for drug delivery by injection or oral administration, and at present, reports on the use of micro-needle transdermal drug delivery for treating lung cancer, liver cancer, esophageal cancer, nasopharyngeal cancer, brain cancer, leukemia, bone metastasis cancer and other diseases are not found.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a PDMS microneedle patch for transdermal delivery of elemene and a preparation method thereof.
The invention is realized by the following technical scheme:
a PDMS micro-needle paster of elemene is carried to percutaneous, its characterized in that includes needle body, medicine carrying base and paster layer, the needle body is arranged in on the medicine carrying base, the opposite side of needle body is kept away from at the medicine carrying base to paster layer bonding setting, the medicine carrying recess has been put to the inside of medicine carrying base, store PDMS and elemene in the medicine carrying recess and mix the liquid, the opening orientation paster layer of medicine carrying recess is and is kept apart with the adhesive tape package.
Preferably, the needle body is a needle cluster consisting of 1-200 drug-permeable PDMS micro-needles, and the distance between the tips of the adjacent micro-needles is 500-.
Preferably, the needle body is in the shape of a cone, a cone-like body or a cylinder with a sharp top.
Preferably, the diameter of the needle body connected with the drug-carrying substrate is 800-800 μm, and the height is 500-5000 μm.
Preferably, the needle body raw material consists of a monomer A and a monomer B of PDMS, and the mass ratio of the monomer A to the monomer B is 0.5:1-1000: 1.
The preparation method of the PDMS microneedle patch for transdermal delivery of elemene is characterized by comprising the following steps:
1) manufacturing a female die plate: placing a plastic spacer on a male die as the male die, heating at 100-200 ℃ for 5-20min, placing a weight with the mass of 10-500g on the male die, slightly melting the spacer into the male die, cooling to 60-160 ℃, cooling for 1-15 min, cooling to room temperature, and separating the spacer from the male die; mixing a monomer A and a monomer B of PDMS to obtain a solution I; placing the spacer into a culture dish, pouring and filling the solution I, standing and solidifying, and digging out the part of the solution I above the spacer to form a microneedle female mould plate;
2) preparing a needle body: mixing a PDMS monomer A with a monomer B to obtain a solution II; pouring the solution II on a microneedle female die plate, standing, vacuumizing to-3-1 MPa, placing a drug-loaded spacer after all bubbles are discharged, heating at 50-150 ℃ for 10-30 min to solidify, cooling after solidification, taking down the drug-loaded spacer to form a drug-loaded groove, and obtaining a microneedle body;
3) preparing a drug-loaded substrate: mixing a PDMS monomer A with a monomer B to obtain a solution III; uniformly mixing the solution III and elemene, adding the mixture into a medicine carrying groove, wrapping and isolating the medicine carrying groove by using adhesive paper, and discharging air bubbles; mixing a PDMS monomer A and a monomer B to obtain a solution IV; coating the casting solution IV;
4) cutting: cutting the microneedle out after standing and solidifying, and trimming to a proper size;
5) and pasting a medical adhesive tape on the back surface of the solidified and dried substrate to be used as a patch layer.
Preferably, the mixing mass ratio of the PDMS monomer A to the monomer B in the solution I, the solution II, the solution III and the solution IV is 0.5:1-1000: 1.
Preferably, the mixing mass ratio of the PDMS monomer A to the monomer B in the solution I is 1: 2; the mixing mass ratio of the PDMS monomer A to the monomer B in the solution II is 100: 1; the mixing mass ratio of the PDMS monomer A to the monomer B in the solution III is 200: 1; the mixing mass ratio of the PDMS monomer A to the monomer B in the solution IV is 75: 1.
Preferably, the mass ratio of the solution III to the elemene in the step 3) is 1: 2.
The invention provides a novel dosage form of elemene transdermal drug delivery, a PDMS micro-needle patch for transdermal drug delivery of elemene can be free from the limitation of a manufacturing area, and the drug loading capacity can be enlarged by enlarging the area. By combining elemene and the micro-needle made of PDMS, the defects of the traditional elemene dosage form at present are overcome to a limited extent, the advantages of the micro-needle and the effect of the elemene are brought into play, so that the medicine is more effectively utilized, and painless and accurate administration is realized.
Drawings
Fig. 1 is a schematic view of the overall structure of a microneedle patch of the present invention;
FIG. 2 is a flow chart of the preparation of the present invention;
fig. 3 is an appearance view of an elemene PDMS microneedle patch;
FIG. 4 is a diagram showing the shape of a needle hole left by a needle on a connective tissue pigskin;
fig. 5 is a graph of the drug release amount of the PDMS drug-loaded microneedle patch over 24 h;
fig. 6 is a graph of the transdermal drug release amount of the PDMS drug-loaded microneedle patch over 24 h;
in the figure, 1-needle body, 2-drug-carrying substrate, 3-patch layer, 4-drug-carrying groove and 5-gummed paper.
Detailed Description
The invention is described in further detail below with reference to the drawings and specific examples to better understand the technical solution.
As shown in figure 1, the PDMS microneedle patch for transdermal elemene delivery provides a new dosage form for transdermal elemene delivery, and specifically comprises a needle body, a drug-carrying substrate and a patch layer, wherein the needle body is arranged on the drug-carrying substrate, a needle cluster consisting of 1-200 drug-permeable PDMS microneedles is arranged, the distance between the tips of the adjacent microneedles is 500-5000 microns, the diameter of the connection between the needle body and the drug-carrying substrate is 100-800 microns, the height of the connection is 500-5000 microns, and the needle body is a cone, a cone-like body or a cylinder with a sharp top; the paster layer bonds and sets up the opposite side of keeping away from the needle body at the medicine carrying base, and the medicine carrying recess has been put to the inside of medicine carrying base, stores in the medicine carrying recess that PDMS and elemene mix the liquid, and the opening of medicine carrying recess is towards the paster layer and is kept apart with the adhesive tape package. The needle body raw material comprises a monomer A and a monomer B of PDMS, the mass ratio of the monomer A to the monomer B is 0.5:1-1000:1, wherein the monomer A is a PDMS prepolymer, and the monomer B is a PDMS curing agent.
As shown in fig. 2, the specific preparation process of the PDMS microneedle patch for transdermal delivery of elemene of the present invention is as follows:
1) manufacturing a female die plate: placing a plastic spacer on a male die as the male die, heating at 100 ℃ for 5min, placing a weight with the mass of 500g on the male die, slightly melting the spacer into the male die, cooling to 60 ℃ for 1min, cooling to room temperature, and separating the spacer from the male die; mixing a monomer A and a monomer B of PDMS according to a mass ratio of 1:2 to obtain a solution I; placing the spacer into a culture dish, pouring and filling the solution I, standing and solidifying, and digging out the part of the solution I above the spacer to form a microneedle female mould plate; see FIGS. 2 (a) - (c).
2) Preparing a needle body: mixing PDMS monomer A and monomer B according to a mass ratio of 100:1 to obtain a solution II; pouring the solution II on a microneedle female die plate, standing, vacuumizing to-3 MPa, placing a drug-loaded spacer after all bubbles are discharged, heating at 50 ℃ for 10min to solidify, cooling after solidification, taking down the drug-loaded spacer to form a drug-loaded groove, and obtaining a microneedle body; see FIGS. 2 (d) - (e).
3) Preparing a drug-loaded substrate: mixing a PDMS monomer A and a monomer B according to the mass ratio of 200:1 to obtain a solution III; uniformly mixing the solution III and elemene according to the mass ratio of 0.5:1, adding the mixture into a medicine carrying groove, wrapping and isolating the medicine carrying groove by using gummed paper, and discharging air bubbles; mixing a PDMS monomer A and a monomer B according to a mass ratio of 75:1 to obtain a solution IV; coating the casting solution IV; see FIGS. 2 (f) - (h).
4) Cutting: cutting the microneedle out after standing and solidifying, and trimming to a proper size; see FIG. 2 (i).
5) And pasting a medical adhesive tape on the back of the solidified and dried substrate to form a patch layer, and obtaining the elemene PDMS microneedle patch as shown in figure 3.
Test example 1: skin puncture ability test
The prepared drug-loaded elemene microneedle is placed on a pigskin which is treated in advance to remove redundant adipose tissues and connective tissues, the patient is removed after the patient is pressed for 1min by the thumb uniformly, and the shape of a needle hole left on the skin by the microneedle is observed, so that the drug-loaded elemene microneedle is shown in figure 4.
Test example 2: drug release experiment of PDMS drug-loaded microneedle
The temperature of the water bath is set to be 37 ℃, 10ml of prepared receiving liquid is added into a 25ml beaker, the micro-needle is completely soaked in the receiving liquid, and the receiving liquid is sealed by a sealing film and aluminum foil paper. Heating was then started. Samples were taken at 1, 2, 3, 4, 18, 20, 22, 24, respectively, and the receiving solution was replenished after each sampling and resealed. And finally, detecting the content of elemene in the sample by using a high performance liquid phase.
The results are shown in FIG. 5. It can be seen that the drug permeation amount gradually increases with time.
Test example 3: PDMS drug-loaded micro transdermal drug release experiment
Nude mice are sacrificed after taking off the spine, the complete abdominal skin is cut off, the redundant adipose tissues and connective tissues are removed, the skin integrity is checked, and the nude mice are cleaned by physiological saline for standby. The parameters of the transdermal diffusion tester were set at 37 ℃ and 100 rpm. Placing rat skin with proper size at the mouth of the receiving pool, placing the microneedle on the receiving pool, sealing and fixing the microneedle by using a sealing film and aluminum foil paper, inverting the receiving pool, injecting receiving liquid by using an injector, and sealing the sampling port by using the sealing film and the aluminum foil paper. The instrument was turned on. Samples were then taken at 1, 2, 3, 4, 18, 20, 22, 24, respectively, and the receiving solution was replenished after each sampling. And finally, detecting the content of elemene in the sample by using a high performance liquid phase.
The prepared drug-loaded PDMS microneedle patch is attached to a naked rat skin and fixed on a diffusion pool by taking the naked rat skin as a research material, receiving liquid in the pool receives elemene drugs released transdermally, and the efficiency of the PDMS microneedle patch for releasing elemene transdermally is represented by measuring the content of elemene contained in the receiving liquid in the diffusion pool at different time points. The results are shown in FIG. 6. It can be seen that the dose release gradually levels off after 16 hours and is substantially complete at 24 hours.
Claims (9)
1. The utility model provides a PDMS micropin paster of elemene is delivered to percutaneous which characterized in that includes needle body (1), medicine carrying base (2) and paster layer (3), needle body (1) is arranged in on medicine carrying base (2), paster layer (3) bond and set up the opposite side of keeping away from needle body (1) in medicine carrying base (2), medicine carrying groove (4) have been put to the inside of medicine carrying base (2), store PDMS and elemene in medicine carrying groove (4) and mix the liquid, the opening of medicine carrying groove (4) is towards paster layer (3) and is wrapped the subsides with adhesive tape (5) and keep apart.
2. The PDMS microneedle patch for transdermal delivery of elemene of claim 1, wherein said needle body (1) is a cluster consisting of 1-200 drug-permeable PDMS microneedles with a distance of 500-5000 μm between adjacent microneedles.
3. A PDMS microneedle patch for transdermal delivery of elemene according to claim 1, characterized in that said needle body (1) is in the shape of a cone, a cone-like body or a cylinder with a sharp top.
4. The PDMS microneedle patch for transdermal delivery of elemene as claimed in claim 1, wherein the diameter of the needle body (1) connected to the drug-loaded substrate (2) is 800 μm and the height is 5000 μm and 100 μm.
5. The PDMS microneedle patch for transdermal delivery of elemene of claim 1, wherein the needle body (1) is made of PDMS monomer a and monomer B in a mass ratio of 0.5:1-1000: 1.
6. A preparation method of PDMS micro-needle patch for transdermal delivery of elemene is characterized by comprising the following steps:
1) manufacturing a female die plate: placing a plastic spacer on a male die as the male die, heating at 100-200 ℃ for 5-20min, placing a weight with the mass of 10-500g on the male die, slightly melting the spacer into the male die, cooling to 60-160 ℃, cooling for 1-15 min, cooling to room temperature, and separating the spacer from the male die; mixing a monomer A and a monomer B of PDMS to obtain a solution I; placing the spacer into a culture dish, pouring and filling the solution I, standing and solidifying, and digging out the part of the solution I above the spacer to form a microneedle female mould plate;
2) preparing a needle body: mixing a PDMS monomer A with a monomer B to obtain a solution II; pouring the solution II on a microneedle female die plate, standing, vacuumizing to-3-1 MPa, placing a drug-loaded spacer after all bubbles are discharged, heating at 50-150 ℃ for 10-30 min to solidify, cooling after solidification, taking down the drug-loaded spacer to form a drug-loaded groove, and obtaining a microneedle body;
3) preparing a drug-loaded substrate: mixing a PDMS monomer A with a monomer B to obtain a solution III; uniformly mixing the solution III and elemene, adding the mixture into a medicine carrying groove, wrapping and isolating the medicine carrying groove by using adhesive paper, and discharging air bubbles; mixing a PDMS monomer A and a monomer B to obtain a solution IV; coating the casting solution IV;
4) cutting: cutting the microneedle out after standing and solidifying, and trimming to a proper size;
5) and pasting a medical adhesive tape on the back surface of the solidified and dried substrate to be used as a patch layer.
7. The method of claim 6, wherein the solution I, the solution II, the solution III and the solution IV are formed by mixing PDMS monomer A and monomer B at a mass ratio of 0.5:1-1000: 1.
8. The method of claim 7, wherein the solution I comprises PDMS monomer A and monomer B at a mixing ratio of 1: 2; the mixing mass ratio of the PDMS monomer A to the monomer B in the solution II is 100: 1; the mixing mass ratio of the PDMS monomer A to the monomer B in the solution III is 200: 1; the mixing mass ratio of the PDMS monomer A to the monomer B in the solution IV is 75: 1.
9. A method of preparing a PDMS microneedle patch for transdermal delivery of elemene as claimed in claim 6, wherein the mass ratio of solution III to elemene in step 3) is 1: 2.
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