Preparation Of Acyclovir Gel Plaster And Study On The Promoting Effect Of Sponge Spicules On Its Permeation

Objective:Acyclovir is an acyclic purine nucleoside analog that is highly effective in inhibiting herpes simplex virus（HSV）.However,topical acyclovir has poor efficacy,due to its low skin permeability.This study developed acyclovir gel plaster containing sponge spicules to achieve synergistic improvements in skin absorption and deposition of acyclovir,which provide new ideas and methods for further development of transdermal drug delivery promoting permeability.Methods:（1）The project established an analytical method for determination of acyclovir in vitro,and investigated its basic physicochemical properties and stability.（2）The stable formulation of acyclovir gel plaster was further optimized by Plackett-Burman design and Box-Behnken response surface design,based on the single factor study,with the indicators of sensory index and initial viscosity.Furthermore,quality evaluations（drug content,paste content,content uniformity,p H value,adhesion,formability,heat and cold resistance test,in vitro drug release,influence factor test,and skin irritation）of acyclovir gel plaster were performed.（3）In vitro transdermal test was carried out by dry heating transdermal diffusion system and rat ex vivo skin,and the cumulative permeability of acyclovir gel plaster and the retention of drug in each layer of the skin were investigated by using acyclovir gel plaster without sponge spicules and commercial acyclovir cream as the control group.（4）The method for analyzing the content of acyclovir in skin and plasma were established in rats.Rats were used as experimental animals and randomly divided into three groups:acyclovir gel plaster without sponge spicules,commercial acyclovir cream group（control group）and acyclovir gel plaster group（experimental group）.Each group was administered according to the same area（2×2 cm²,containing about 14 mg of acyclovir）.After administration,skin and plasma samples were collected and processed at a specific time point.The concentration of acyclovir in the samples was determined and the main pharmacokinetic parameters were calculated.Results:（1）The HPLC method of acyclovir met the methodological requirements.At the same time,its equilibrium solubility and oil-water partition coefficient were evaluated.Acyclovir,as a low-solubility and low-permeability drug,had a solubility that first decreased and then increased with decreasing p H and showed the weakest in neutral medium.The solubility of acyclovir in water can be increased by added a organic solvent such as ethanol.（2）The final prescription for AGP-SS was:NP-700 2 g;CMC-Na 0.6 g;glycerin 8.81 g;aluminum glycinate 0.09 g;tartaric acid 0.06 g;PVPP 0.9 g;sodium hydroxide 0.9%;acyclovir 3%;sponge spicules 1 g;water 15 g.The gel plaster was in white semi-solid state and the paste content,p H value,adhesion,formability,etc.met the requirements.Through influence factor test,the results shows that the acyclovir gel plaster should not be left in the high light for a long time,and it should be protected from light during storage.The release test of acyclovir gel plaster in vitro showed that the release of acyclovir was in accordance with the first-order kinetic process,and the sponge spicules opened skin channels only produced slight irritation to the skin,and the damaged skin barrier and internal functions would self-heal in 24 h.（3）The 24-hour cumulative penetration of the drug in the acyclovir gel plaster group was20.00±1.07μg/cm²,and the steady-state penetration rate was 5.8509μg·cm^-2·h^-1,significantly greater than the acyclovir gel plaster group without sponge spicules and the commercial acyclovir cream group.After fitting,the transdermal permeation behaviors of the three preparations were in accordance with the first-order kinetic equation,which showed that the transdermal drug transport velocity was directly proportional to the drug concentration.In addition,the retention of drug in the deep skin of the acyclovir gel plaster group was also better than that of the control groups,indicating that the addition of sponge spicules has a significant advantage in delivering drugs to the deep skin to exert the therapeutic effect.（4）The established LC-MS/MS analysis method of acyclovir in skin and plasma have strong specificity and meets the methodological requirements.Dermatopharmacokinetic analyses revealed that the C_max（78.74±11.12μg/g）of acyclovir gel plaster group was2.80 times that of the acyclovir gel plaster without sponge spicules group（28.16±3.20μg/g）,and the AUC_0-24 value of acyclovir gel plaster group（1091.81±29.05μg/g·h）was 3.80 times that of acyclovir gel plaster without sponge spicules group（287.43±35.33μg/g·h）.Similarly,C_max and AUC_0-24 of acyclovir gel plaster group were approximately1.77 or 1.97 times higher than those obtained from acyclovir cream group(C_max:44.55±1.05μg/g,AUC_0-24:553.88±65.29μg/g·h),respectively.The plasma pharmacokinetic results showed that the C_max values of three groups were 258.00±37.17,99.03±14.29,and 98.55±0.75 ng/m L,respectively.Although the drugs in three groups of formulations could be delivered transdermally into the bloodstream at the dose administered in this experiment,the plasma concentration was extremely low（<0.3μg/m L）compared to the accumulation of acyclovir in the skin,which indicated that a lower plasma concentration reduced toxicity and side effects caused by systemic administration,ensuring the safety of transdermal administration of acyclovir.Conclusion:The optimized formulation showed good adhesion,high drug loading,and the potential to deliver drugs in therapeutically relevant doses to the target site of HSV,the basal epidermis.In vitro and in vivo results revealed that acyclovir gel plaster maintained high intradermal drug concentrations and prolonged drug retention in the skin,while the plasma acyclovir concentration remained very low.Hence,the acyclovir gel plaster showed excellent therapeutic efficacy.