Study On Transdermal Delivery Of Cannabinol And Its Permeation-promoting Mechanism

Cannabidiol(CBD)is a non-addictive extract from Cannabis plants,which has effects of analgesic,anti-inflammatory,antioxidant,anxiolytic and anticonvulsant.However,its oral administration is dramatically limited by several unavoidable drawbacks,such as low oral bioavailability by first-pass effect,very poor solubility.It is therefore of great importance to develop and optimize other administration approaches of CBD with high drug delivery efficiency.The purpose of this paper is to investigate the transdermal permeability of high purity cannabidiol and hemp leaf extract,select suitable research objects and develop effective methods to promote penetration,and then study the mechanism and safety of the selected methods.First,the effects of different skin models on the transdermal penetration behavior of CBD were compared by in vitro transdermal permeation experiment,and the transdermal permeation behaviors of high purity CBD and hemp leaf extract were compared,and the transdermal permeation kinetics of CBD was calculated.The results showed that the skin penetration of CBD in mice skin was significantly higher than that of nude mice due to the presence of hair follicle penetration;the penetration rate of hemp leaf extract was lower than that of high purity CBD,and there was a great difference within the group,which may be due to the presence of a large amount of resin.Both stratum corneum(SC)and viable epidermis hindered the transdermal penetration of CBD to a certain extent.In order to get closer to human skin with fewer hair follicles and maintain parallelism within the group,high purity CBD and nude mouse skin were selected for follow-up experiment.Secondly,taking the enhancement ratio(ER)as the evaluation index,the effects of penetration enhancers premixing,penetration enhancers pretreatment and micelles on the transdermal penetration of CBD were compared.The results showed that in the premixing of penetration enhancers,only carbinol(TP)and Poloxamer 101(P101)showed weak penetration-promoting effect,and the ER of TP and P101 were enhanced to 1.40 and 12.97 respectively by skin pretreatment;the solubility of CBD was greatly improved by micelle formation,but the penetration-promoting effect was slightly weaker,ER was 2.76.In addition,the skin pretreatment method of P101 was further investigated.The results showed that cleaning P101 on the surface of the skin did not change the penetration effect.However,when the concentration of P101 is higher than the critical micelle concentration(CMC),the penetration effect is weakened,which is related to the weakening of the solubilization of P101 on CBD in SC.Thirdly,the skin safety of Poloxamer was investigated by in vivo skin irritation experiment.The results showed that 1%P101,4%P101,1%P407 and 1%P188 gel had no irritation to normal skin and damaged skin,and had good skin safety.Finally,the permeation mechanism of P101 was analyzed by attenuated total reflectance Fourier transform infrared spectroscopy,molecular dynamics simulation and molecular docking.The results showed that the PPO block of P101 could interact with the lipids in skin SC and disturb the ordered structure of the bilayer.The CMC of P101,P407 and P188 were6.76,16.2 and 0.41 mg/m L,respectively.At 1% concentration,P407 also had a permeation on CBD,while P188 did not.It is inferred that the percutaneous penetration of CBD by Poloxamer may exist widely in all kinds of Poloxamer when the concentration is lower than CMC.