Skin Delivery Of Hyaluronic Acid And Cyclosporine A By The Combined Use Of Sponge Spicules And Liposomes

A new skin drug delivery technology was introduced in this study to increase the skin absorption of hydrophilic and hydrophobic drugs with the the combined use of sponge spicules and liposomes.We demonstrated that the topically combined use of sponge Haliclona sp.spicules(SHS)and flexible liposomes(FL),referred to as SFLS(SHS-Flexible Liposomes combined System),can result in synergy to improve the skin absorption and deposition of Hyaluronic acid(HA),especially in skin deep layers,both in vitro and in vivo.SHS treatment can result in skin micro-channels which are continuous,deep enough(48.6±13.5?m)and available in large quantities(850±125 micro-channels per mm2).These micro-channels gradually closed up in 120 hrs and also allowed the intact vesicles of flexible liposomes as well as vesicle-bound or vesicle-encapsulated HA to penetrate into the skin-deep layers under the driving force of transdermal osmotic gradients.Specifically,SFLS topical application enhanced the penetration of FITC-HA(MW:250 kDa)into porcine skin in vitro up to 23.2±3.7%,which is 19.4:1±3.1-fold higher(p<0.001)than Phosphate Buffered Saline(PBS)group,3.4±0.5-fold higher(p<0.01)than SHS group and 3.6±0.6-fold higher(p<0.01)than that from the combined use of Dermaroller and flexible liposomes.Moreover,SFLS can lead to significant enhanced skin deposition of HA in all skin layers,especially in skin deep layers:up to 86.8 ± 4.1%of HA skin absorbed was accumulated in deep skin layers.The effectiveness of SFLS topical application was also confirmed in vivo by using BALB/c mice.The HA percutaneous penetration induced by SFLS after 6h non-occlusive topical application in vivo(8.1 ± 1.6%)was dramatically increased,which is 7.0±1.4-fold higher(p<0.01)than PBS control,2.3±0.4-fold higher(p<0.05)than FL group,and 2.1 ±0.4-fold higher(p<0.05)than SHS group.In addition,the skin irritation and toxicity study showed that the SFLS treatment may cause very minimal redness and the skin can get recovery in short time.In sum,the combined use of SHS and FL(SFLS)offers a promising strategy to safely and effectively improve skin delivery of hydrophilic biomacromolecules such as HA.Meanwhile,we also demonstrated that the topically combined use of SHS and ethosomes can result in synergy to improve the skin absorption and deposition of Cyclosporine A(CSA).The combined use of SHS and ethosomes enhanced the penetration of CSA into porcine skin in vitro up to 32.98±0.71%,14.36± 1.44%of CSA was accumulated in viable epidermis layers,which accounts for 43.55±4.14%of total skin absorption of CSA.It is 1.53±0.15-fo]d higher than SHS group,and 2.99±0.28-fold higher than ethosomes group.Above all,SHS can be used in conjunction with both flexible liposomes and ethosomes to enhance the absorption of HA and CSA.Compared with traditional micro needles and microneedle patch,It provides a more convenient,effective and safe way for skin drug delivery.