CN110354102B - Biphase transdermal drug delivery system and preparation method thereof - Google Patents
Biphase transdermal drug delivery system and preparation method thereof Download PDFInfo
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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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- 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
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- 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
- A61K9/7007—Drug-containing films, membranes or sheets
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D1/00—Processes for applying liquids or other fluent materials
- B05D1/02—Processes for applying liquids or other fluent materials performed by spraying
- B05D1/04—Processes for applying liquids or other fluent materials performed by spraying involving the use of an electrostatic field
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- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01D5/00—Formation of filaments, threads, or the like
- D01D5/0007—Electro-spinning
- D01D5/0015—Electro-spinning characterised by the initial state of the material
- D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
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- D—TEXTILES; PAPER
- D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
- D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
- D01D5/00—Formation of filaments, threads, or the like
- D01D5/0007—Electro-spinning
- D01D5/0061—Electro-spinning characterised by the electro-spinning apparatus
- D01D5/0092—Electro-spinning characterised by the electro-spinning apparatus characterised by the electrical field, e.g. combined with a magnetic fields, using biased or alternating fields
Abstract
The invention relates to a biphase transdermal drug delivery system and a preparation method thereof, which are obtained by taking a drug-loaded ethosome/natural material nanofiber membrane as a receiver to receive an electronic injection drug-loaded ethosome composite microsphere. The invention has good skin compatibility, air permeability and water permeability, is softer when wet, is more tightly attached to the skin, and is an ideal material of the transdermal drug delivery patch.
Description
Technical Field
The invention belongs to the field of drug carriers, and particularly relates to a biphasic transdermal drug delivery system and a preparation method thereof.
Background
The transdermal drug delivery system is a drug controlled release system for treating or preventing diseases by the way that drugs enter blood circulation through skin absorption, and has the advantages of avoiding the first pass effect of liver and the damage of gastrointestinal tract to drugs, prolonging the action time of drugs, reducing toxic and side effects, improving the tolerance of patients and the like. The ideal transdermal drug delivery patch is required to be well attached to the skin, and has good flexibility and air permeability, high transdermal efficiency and convenient use. Meanwhile, the characteristics of wide raw material sources, low cost, easy mass production and the like in wide application are considered.
Ethosome is a special liposome containing low molecular weight alcohol, and the structure of the ethosome has a hydrophilic head part and a hydrophobic tail part which show that the ethosome can effectively wrap hydrophilic drugs and also can wrap lipophilic drugs. Many evidences indicate that the ethosome has a remarkable permeation-promoting effect as a transdermal delivery carrier, and has the advantages of higher drug loading rate, improved drug stability, capability of causing the drug to be released suddenly or slowly, low toxicity, low immunogenicity, excellent biocompatibility and the like, so that the ethosome is widely concerned in the field of transdermal delivery.
Polyvinylpyrrolidone (PVP) is a water-soluble high-molecular polymer and has excellent biocompatibility. To compensate for the shortfall in battlefield plasma supply during the second war, PVP has been used as a plasma substitute. In recent years, PVP is more and more widely applied in the biomedical field, and can be used for preparing products such as biological valves, blood permeable membranes, microfiltration membranes, eye implants, wound dressing hydrogels, microneedle transdermal vaccines and the like. The good water solubility of PVP can ensure that the drug-loaded microspheres can be quickly released after meeting water, thereby being beneficial to the transdermal delivery of drugs.
Electrostatic spinning is a technology for forming micro-nano fibers by stretching and splitting a polymer solution in a jetting process, volatilizing a solvent and solidifying the polymer solution through high-voltage static electricity. The electrostatic spinning nanofiber has wide application in the biomedical fields of drug release, wound dressing, tissue engineering and the like. The electrostatic spinning nanofiber has the advantages of simplicity and convenience in preparation, low cost, excellent mechanical property and processability and the like, has higher specific surface area and porosity, is good in air permeability and water retention performance, and can enable the medicine to be released more easily to achieve a treatment effect. In recent years, as no toxic or harmful substance is involved in the preparation process of the green electrospinning technology, the obtained product is non-toxic and harmless, so that the product is concerned about and is more beneficial to industrial production.
In the field of drug delivery, the traditional preparation methods of drug-loaded microspheres include a multiple emulsion method, a spray drying method, a coacervation method and the like, but the methods have the defects of drug burst release, uncontrollable release rate, easy inactivation of active drugs in the entrapment process, inapplicability to temperature-sensitive drugs due to heating in the preparation process and the like. In recent years, electrostatic spraying technology is attracting attention for preparing drug-loaded microspheres. The electrostatic spraying charges polymer solution droplets through high-voltage static electricity, and micro-nano microspheres can be prepared through solvent volatilization in the spraying process. The electrospray microsphere has uniform particle size and high thermal stability, can effectively wrap hydrophilic and hydrophobic drugs, and improves the stability and bioavailability of the drugs. The electrospray microsphere has high encapsulation efficiency, can effectively inhibit the burst release of the drug and has excellent biocompatibility. Therefore, the electrospray microsphere has wide development prospect in transdermal, oral, injection, nasal cavity, rectum, vagina, eye and other administration routes.
Disclosure of Invention
The invention aims to provide a biphasic transdermal drug delivery system and a preparation method thereof. The transdermal drug delivery membrane is prepared by utilizing electrostatic spinning and electrostatic spraying technologies, and is not limited by the electrostatic spinning technology, so that the drug loading of the transdermal drug delivery membrane can be greatly improved, the requirement of clinical treatment can be met, and a more ideal application effect can be obtained.
The invention provides a biphasic transdermal drug delivery system, which is obtained by taking a drug loaded ethosome/natural material nanofiber membrane as a receiver to receive an electronic injection drug loaded ethosome composite microsphere.
The ethosome is prepared from egg yolk lecithin, cholesterol or octadecylamine by a thin film dispersion method.
The drug in the drug-loaded ethosome is one or more of doxorubicin hydrochloride, lidocaine, sinomenine hydrochloride, ketoprofen, naproxen, indomethacin, tripterine, cnidium lactone, propranolol, progesterone, felodipine, melatonin, rheum officinale, insulin, epinephrine, ropivacaine, hydrobromic acid, flurbiprofen, fluconazole, pramipexole, tofacidine, curcumin, oxaprozin, donepezil, danshenin and aconitine.
The natural material is one or more of chitosan, silk fibroin and collagen.
The invention also provides a preparation method of the biphasic transdermal drug delivery system, which comprises the following steps:
(1) mixing a natural material, an ethosome, a medicine and a solvent according to a mass ratio of 500-1000: 50-100: 5-10: 10000-20000 to obtain a blending solution A; transferring the blending solution A into an injector for electrostatic spinning to obtain a drug-loaded ethosome/natural material nanofiber membrane, and finally performing crosslinking;
(2) mixing polyvinylpyrrolidone, ethosome, a drug and a solvent according to a mass ratio of 100-200: 25-50: 5-10: 1000-2000 to obtain a blending solution B; and transferring the blending solution B into an injector, and performing electrostatic spraying by using the cross-linked drug-loaded ethosome/natural material nanofiber membrane as a receiver to obtain the biphasic transdermal drug delivery system.
The solvent in the step (1) is ultrapure water.
The electrostatic spinning in the step (1) comprises the following technological parameters: the voltage is 10-15 kV, the propelling speed is 0.5-1 ml/h, the receiving distance is 10-15 cm, the temperature is 20-40 ℃, and the humidity is 5-10%.
The crosslinking in the step (1) is carried out in ethanol steam (with the concentration of 75 percent), and the crosslinking time is 24-48 h.
The solvent in the step (2) is prepared from the following raw materials in a mass ratio of 6-60: 10 to 100% of an ethanol aqueous solution.
The molecular weight of the polyvinylpyrrolidone in the step (2) is 4000.
The technological parameters of electrostatic spraying in the step (2) are as follows: the voltage is 15-20 kV, the propelling speed is 0.1-0.8 ml/h, the receiving distance is 10-15 cm, the temperature is 20-40 ℃, and the humidity is 5-8%.
Advantageous effects
(1) The biphase transdermal drug delivery system has good skin compatibility, air permeability and water permeability, can be softer after being wetted, is more tightly attached to the skin, and is an ideal material of a transdermal drug delivery patch.
(2) The invention has simple preparation process, wide raw material source and low cost, and is produced in large batch.
(3) The biphasic transdermal drug delivery system not only improves the solubility of water-insoluble drugs, but also enables the drugs to have the characteristics of quick-slow release, and can meet the release requirements of special drugs; has high stability, easy preservation, good skin affinity and transdermal performance, and can be widely applied to the field of transdermal drug delivery.
Drawings
FIG. 1 is a scanning electron micrograph of the product obtained in example 1;
FIG. 2 is a graph of the in vitro transdermal drug cumulative release of the product obtained in example 1;
FIG. 3 is a schematic view of the preparation process of the present invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
(1) Preparing silk fibroin spinning solution (solvent is water) containing 20% of silk fibroin (mass-volume ratio) and 2% of PEO (mass-volume ratio), and adding drug-loaded ethosome according to the volume ratio of 40%, wherein the drug is doxorubicin hydrochloride, and the concentration is 1mg/mL (mass-volume ratio);
(2) transferring the spinning solution obtained in the step (1) into a syringe, and setting electrospinning parameters: the voltage is 12kV, the propelling speed is 1mL/h, the receiving distance is 15cm, the temperature is 25 ℃, the humidity is 10%, and a receiver is used for receiving to prepare the drug-loaded ethosome-fibroin nanofiber membrane;
(3) placing the nanofiber membrane prepared in the step (2) in a fumigator containing 75% ethanol for crosslinking for 24 hours;
(4) preparing an electronic injection solution (the solvent is an ethanol water solution with the mass ratio of 1-10: 10-100) of 10% of polyvinylpyrrolidone K30 (mass-to-volume ratio), and adding a drug-loaded ethosome according to the volume ratio of 40%, wherein the drug is doxorubicin hydrochloride and the concentration is 1mg/mL (mass-to-volume ratio);
(5) transferring the blended solution in the step (4) into an injector, carrying out electric spraying by using a high-voltage generating device, and setting electric spraying parameters: the voltage is 15kV, the propelling speed is 0.5mL/h, the receiving distance is 10cm, the temperature is 25 ℃, the humidity is 5%, the nanofiber membrane obtained in the step (3) is used as a receiver to receive the electronic injection composite microspheres, and the two-phase drug delivery system can be obtained.
(6) Taking an ICR mouse with the mass of 18-25g, cutting off the neck, killing, fixing the back on a workbench, removing the hair on the abdomen, immediately shearing the skin on the hairless part of the abdomen, carefully removing the subcutaneous adipose tissues by using scissors, repeatedly washing the skin of the mouse by using normal saline, selecting undamaged skin, soaking the skin in the normal saline, and storing at-20 ℃.
(7) Adding appropriate amount of water into a constant temperature water bath layer of the intelligent transdermal diffusion instrument, setting the temperature of the transdermal instrument to be 37 +/-1 ℃, and setting the rotating speed to be 150 r/min. And (3) when the water temperature is stabilized at 37 ℃, adding 15ml of LPBS (sodium benzoate) serving as a receiving liquid and a magnetic stirrer into the three-dimensional diffusion cell, placing the horny layer of the in-vitro skin of the mouse in the step (6) upwards between the supply chamber and the receiving chamber, fixing the in-vitro skin of the mouse by using a clamp, attaching the biphasic transdermal drug delivery film prepared in the step (5) onto the skin of the mouse (one side of the electrosprayed composite microspheres of the biphasic transdermal drug delivery film is close to the skin of the mouse), and sealing the supply chamber by using a preservative film to avoid the influence caused by evaporation. And (3) placing the three-dimensional diffusion cell in the right center of a magnetic stirrer of the transdermal instrument, and starting timing. Samples were taken at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 and 60 hours for 2mL and then supplemented with 2mL of fresh phosphate buffer (pH 7.4) (care was taken to evacuate air bubbles to ensure complete contact of the receiving solution with the skin). Detecting the content of Dox in the sample by using an ultraviolet-visible spectrophotometer, and calculating the cumulative release amount of the drug according to the following formula;
note: q is the cumulative drug release amount, V is the volume of the receiving solution in the diffusion cell, Q' is the amount of drug actually contained in Eth, Ci is the concentration of drug at the time of the ith sampling, and Vi is the volume at the time of sampling.
As shown in figure 2, the drug adhered to the surface of the fibrous membrane appears in burst release before 4h, the drug is released quickly, and then the drug is released slowly, and the cumulative release amount of the drug reaches the maximum at 24h, and the percentage is 67%.
Example 2
(1) Preparing a collagen spinning solution (water is used as a solvent) containing 20% of collagen (mass-volume ratio) and 2% of PEO (mass-volume ratio), and adding a drug-loaded ethosome according to the proportion of 40% of the volume ratio, wherein the drug is ketoprofen, and the concentration is 1mg/mL (mass-volume ratio);
(2) transferring the spinning solution obtained in the step (1) into a syringe, and setting electrospinning parameters: the voltage is 15kV, the propelling speed is 0.5mL/h, the receiving distance is 10cm, the temperature is 30 ℃, the humidity is 5%, and the drug-loaded ethosome-fibroin nanofiber membrane is prepared by receiving with a receiver;
(3) placing the nanofiber membrane prepared in the step (2) in a fumigator containing 75% ethanol for crosslinking for 24 hours;
(4) preparing an electric injection solution (the solvent is an ethanol water solution with the mass ratio of 1-10: 10-100) of 10% polyvinylpyrrolidone k30 (mass to volume), and adding a medicament-loaded ethosome according to the volume ratio of 40%, wherein the medicament is ketoprofen, and the concentration is 1mg/mL (mass to volume);
(5) transferring the blended solution in the step (4) into an injector, carrying out electric spraying by using a high-voltage generating device, and setting electric spraying parameters: the voltage is 20kV, the propelling speed is 0.2mL/h, the receiving distance is 15cm, the temperature is 30 ℃, the humidity is 8%, the nanofiber membrane obtained in the step (3) is used as a receiver to receive the electronic injection composite microspheres, and the two-phase drug delivery system can be obtained.
The result of the in vitro transdermal drug cumulative release curve is the same as that of example 1, and shows that the drug adhered to the surface of the fibrous membrane is released suddenly and quickly before 4 hours, then the drug is released slowly, and the cumulative release amount of the drug reaches the maximum at 24 hours, and the percentage is 65%.
Claims (9)
1. A method of making a biphasic transdermal delivery system comprising:
(1) mixing a natural material, an ethosome, a medicine and a solvent according to a mass ratio of 500-1000: 50-100: 5-10: 10000-20000 to obtain a blending solution A; transferring the blending solution A into an injector for electrostatic spinning to obtain a drug-loaded ethosome/natural material nanofiber membrane, and finally performing crosslinking;
(2) mixing polyvinylpyrrolidone, ethosome, a drug and a solvent according to a mass ratio of 100-200: 25-50: 5-10: 1000-2000 to obtain a blending solution B; and transferring the blending solution B into an injector, and performing electrostatic spraying by using the cross-linked drug-loaded ethosome/natural material nanofiber membrane as a receiver to obtain the biphasic transdermal drug delivery system.
2. The method of claim 1, wherein: the natural material in the step (1) is one or more of chitosan, silk fibroin and collagen.
3. The method of claim 1, wherein: the ethosome in the steps (1) and (2) is prepared from egg yolk lecithin, cholesterol or octadecylamine by a thin film dispersion method.
4. The method of claim 1, wherein: the medicines in the steps (1) and (2) are one or more of doxorubicin hydrochloride, lidocaine, sinomenine hydrochloride, ketoprofen, naproxen, indomethacin, celastrol, cnidium lactone, propranolol, progesterone, felodipine, melatonin, rheum officinale, insulin, epinephrine, ropivacaine, hydrobromic acid, flurbiprofen, fluconazole, pramipexole, tofacidine, curcumin, oxaprozin, donepezil, danshenin and aconitine.
5. The method of claim 1, wherein: the solvent in the step (1) is ultrapure water.
6. The method of claim 1, wherein: the electrostatic spinning in the step (1) comprises the following technological parameters: the voltage is 10-15 kV, the propelling speed is 0.5-1 ml/h, the receiving distance is 10-15 cm, the temperature is 20-40 ℃, and the humidity is 5-10%.
7. The method of claim 1, wherein: the crosslinking in the step (1) is carried out in ethanol steam for 24-48 h.
8. The method of claim 1, wherein: the solvent in the step (2) is prepared from the following raw materials in a mass ratio of 6-60: 10 to 100% of an ethanol aqueous solution.
9. The method of claim 1, wherein: the technological parameters of electrostatic spraying in the step (2) are as follows: the voltage is 15-20 kV, the propelling speed is 0.1-0.8 ml/h, the receiving distance is 10-15 cm, the temperature is 20-40 ℃, and the humidity is 5-8%.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335142A (en) * | 2011-10-25 | 2012-02-01 | 上海理工大学 | Composite microspheres of nano liposome capable of being automatically assembled into insoluble medicament in situ and preparation method for composite microspheres |
| CN103614799A (en) * | 2013-11-06 | 2014-03-05 | 东华大学 | Preparation method of natural material-ethosome composite nanofiber |
| CN106794275A (en) * | 2014-08-04 | 2017-05-31 | 圣胡安德申医院 | For the system of release bioactive agent immediately |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335142A (en) * | 2011-10-25 | 2012-02-01 | 上海理工大学 | Composite microspheres of nano liposome capable of being automatically assembled into insoluble medicament in situ and preparation method for composite microspheres |
| CN103614799A (en) * | 2013-11-06 | 2014-03-05 | 东华大学 | Preparation method of natural material-ethosome composite nanofiber |
| CN106794275A (en) * | 2014-08-04 | 2017-05-31 | 圣胡安德申医院 | For the system of release bioactive agent immediately |
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