Research On Transdermal Drug Delivery Systems Based On Ultrasound-responsive Transmitters

BackgroundTransdermal drug delivery has been widely studied in recent years because of its many advantages over injectable and oral drug delivery,including ease of administration,improved patient compliance,rapid termination of drug delivery,and avoidance of first-pass effect,etc.However,the development of transdermal drug delivery is limited by the presence of the stratum corneum of the skin.Therefore,the research direction on transdermal drug delivery are mainly focused on exploring the drug delivery mode through the stratum corneum and improving the drug delivery efficiency,and there is a relative lack of research on achieving drug penetration in the depth of the dermis.However,in clinical treatments,such as dermal collagen deposition diseases,due to the thickening and compactness of the skin tissue structure,the current drug delivery and treatment methods cannot fully meet the treatment needs.There is more demand for transdermal drug delivery in the deep layer of the dermis.ObjectiveA transfersome containing 5-FU,water-soluble quantum dots Cd Te,and perfluoro-n-pentane(PFP)was prepared,and combined with ultrasound to construct a transdermal drug delivery system.It first penetrated the stratum corneum based on its own high deformability.And then low-frequency and low-intensity ultrasound was applied.Based on PFP,the response of carrier to ultrasound was realized.That is,to clarify the cooperative transdermal drug delivery effect of passive drug delivery and active penetration enhancement.Finally,keloids,a skin disease characterized by massive deposition of collagen fibers in the dermis,are the target of experiment.The drug 5-FU recommended in the guideline was used as the target of administration,and the quantum dot Cd Te was used as the drug marker to explore this difficult-to-penetrate disease.The goal was to establish a transdermal drug delivery system based on an ultrasound-responsive transfersome,which meet the needs of transdermal drug delivery in the deep dermis layer in clinical treatment.Methods1.Transfersome coated with 5-FU,quantum dots Cd Te and perfluoro-n-pentane(PFP)were prepared by rotational evaporation and ultrasonic method.The structural composition,particle size,encapsulation efficiency,drug loading,deformability,and ultrasonic response of the carrier were characterized by a variety of detection methods.2.Based on the Franz in vitro diffusion cell device,an in vitro permeation platform for transdermal drug delivery was built.A static administration control experiment of free Cd Te+FU solution and transfersome-encapsulated Cd Te+FU was carried out,and the change of penetration depth within 60 min was observed at the same time.Second,transfersome of coated PFP and uncoated PFP combined with ultrasound,respectively.Finally,the influence of ultrasonic irradiation time on the penetration depth was investigated.The fluorescence distribution of quantum dots was observed by laser confocal microscope to reflect the penetration depth.3.Based on the above transdermal drug delivery experiment,a multi-channel data recorder was used to monitor and record the temperature of the diffusion cell and the temperature at 1 mm under the skin before and after the ultrasound,and the room temperature.The histopathological section was performed to observe the integrity of the tissue and whether there was damage,to explore the the safety of the transdermal drug delivery system.Results1.The carrier is spherical under the transmission electron microscope,and the inside of the sphere is black,which means that 5-FU,Cd Te and PFP have been successfully encapsulated,and the UV curve of the carrier can also support this.The average particle size is about 240.36 ± 1.38 nm,The average potential is-27.27±1.37 m V.After being stored in a refrigerator at 4°C for 7 days,there is no significant change in the particle size and potential value,indicating that the carrier structure is relatively stable.The measured carrier encapsulation efficiency is 70%,and the drug loading is 2.02 wt%.The deformability of the carrier is 15.67,compared with the deformability of the ordinary liposome without surfactant,which is 1.36,indicating that the deformability is good.After ultrasound irradiation,the carrier’s in vitro imaging is B-mode ultrasound.Both the mode and harmonic imaging show significant brightness enhancement,indicating that the transfer body obtained in this experiment is ultrasonically responsive.2.The quantum dot Cd Te solution with non-carrier structure and the quantum dot Cd Te with the transfersomes structure are allowed to stand for1 hour after administration.The fluorescence distribution can be obtained.The fluorescence of the non-carrier structure quantum dot Cd Te solution is only distributed on the top of the stratum corneum,so it did not pass through the stratum corneum,but the transfersomes wrapped quantum dots Cd Te in the experimental group,the fluorescence was distributed throughout the epidermis,indicating that it smoothly passed through the stratum corneum barrier,and the transfersomes structure helped the drug to pass through the stratum corneum barrier.Based on the above results,the advantages of the carrier are proved.After the carrier is allowed to stand for 10 min,20 min,30 min,40 min,50 min,and 60 min,the carrier is placed in a static dosing experiment.It is found that after 30 min,the fluorescence distribution can be observed in the epidermis.As time goes by,the depth of the fluorescence distribution deepens,but the depth changes less.Resume On the basis of the above experiment,the prepared transfersomes medium containing perfluoronpentane(PFP)and the transfersomes medium without containing perfluoronpentane(PFP)were put to rest for 30 mins after administration,and then applied Low-frequency and low-intensity plane ultrasound irradiation can obtain a deeper fluorescence distribution in the transfer body group with perfluoro-n-pentane(PFP),and relatively speaking,the fluorescence distribution is more uniform.Combining the above experimental results,after the transfersomes encapsulated PFP was placed for 30 minutes,ultrasonic treatment was applied,the ultrasonic frequency and ultrasonic power were fixed,the ultrasonic duration was changed,and the experimental results showed that the penetration depth gradually deepened with the prolonging of the ultrasonic action time.After 30 minutes of ultrasound,the penetration depth can reach 1400μm,and the tissue can be cut horizontally,and the fluorescence can be densely distributed at 800μm,and the distribution is uniform.After that,with the extension of the irradiation time,the depth change gradually slows down,and after 800μm depth the fluorescence distribution is reduced.3.The real-time temperature measured by the multi-channel data instrument showed that when the keloid tissue was placed on the drug delivery platform in vitro,the temperature at 1 mm subcutaneously increased from room temperature to 29±0.5°C,and the experiment remained basically constant within 60 min.After 60 min of ultrasonic irradiation with the ultrasound transdermal drug delivery device used in this experiment,the temperature at 1 mm subcutaneously rose to 31±0.5°C and remained basically stable.The results of the pathological section of the tissue showed that the epidermal dermal structure was intact and there was no obvious Damage phenomenon.It shows the safety of the transdermal drug delivery system.Conclusion1.This project has successfully prepared a transfer body encapsulating water-soluble drug 5-FU,water-soluble quantum dots Cd Te and PFP,which had good deformability and ultrasonic responsiveness.2.The transdermal delivery system was established by combining the transdermal delivery system with ultrasound,through a large number of controlled experiments on a skin disease-keloid sample characterized by a large amount of collagen deposition in the dermis,the results showed that the dermal drug delivery system could achieve deep and uniform drug release.3.The part of mechanism of the transdermal drug delivery system was clarified.4.It is expected that the transdermal drug delivery method can be used to achieve effective drug delivery and treatment of dermal lesions caused by fibroblast proliferation.