Topical Liposomal Gel of Idoxuridine for the Treatment of Herpes Simplex: Pharmaceutical and Clinical Implications

The optimization of the method of preparation of idoxuridine (IDU) liposomes by the reverse phase evaporation (REV) method was carried out by three variables at three levels (33) factorial design. The three independent variables selected were volume of organic phase (x1), volume of aqueous phase (x2), and drug/phosphatidylcholine/cholesterol in molar ratio (x3). Twenty‐seven batches of IDU liposomes were prepared by the REV method and subjected to evaluation for percentage drug entrapment (PDE), size, and size distribution. A reduced polynomial equation was derived by multiple regression of the data of PDE and the transformed values of the three independent variables. Three contour plots at fixed level of–1 (low), 0 (medium), and 1 (high) of major contributing variable (x3) were plotted between x1 and x2 at predetermined PDE to understand the physical meaning of independent variables. Liposomal gels were prepared by dispersing optimized IDU liposomes in 2%w/w and 5%w/w (HPMC) K4M gel bases so as to contain 1%w/w IDU (LIG‐1 and LIG‐2, respectively). The percentage of drug retention (PDR) studies of optimized batch 14 (Lipo‐14) and LIG‐1 and LIG‐2 were carried out at three different storage conditions (2–8°C, 25 ± 2°C, and 37°C). A comparative diffusion study of LIG‐1 and LIG‐2 with PIG‐1 and PIG‐2 (1%w/w IDU with components of liposome dispersed in 2%w/w and 5%w/w HPMC K4M gel bases, respectively), respectively, through human cadaver skin was conducted. A comparative double blind clinical pilot study of optimized LIG‐2 gel was carried out for eight weeks and compared with PIG‐2 on 20 Herpes simplex patients (10 patients each for HSV‐1 and HSV‐2, divided into two groups each of 5 patients). Batch 14 (Lipo‐14) was found to have maximum PDE of 74.4%. The PDR study showed maximum drug retention at 2–8°C. A significant increase in PDR (p < 0.05) was observed in LIG‐1 and LIG‐2 when compared with Lipo‐14 at all the three temperatures. In the diffusion studies, a significant (p < 0.05) flux reduction; 3.5 times in LIG‐1 when compared with PIG‐1 and 2.3 times in LIG‐2 when compared with PIG‐2 was observed. Approximately 2.2‐ and 2.5‐fold increase in skin drug retention in LIG‐1 and LIG‐2, respectively, was determined. A double blind clinical study demonstrated an approximately 2.0‐ and 1.6‐fold increase in average percentage improvement in healing of the lesions in patients suffering from HSV‐1 and HSV‐2 diseases, respectively, when treated with LIG‐2 compared with PIG‐2. However, complete removal of lesions was not observed. Local side effects such as itching, burning, inflammation in HSV‐1 and HSV‐2, and burning micturation in HSV‐2 associated with the use of PIG‐2 were reduced considerably with the use of LIG‐2. The findings of this investigation establish the role of the derived equation and plotted contour plots in predicting the values of independent variables for preparation of IDU liposomes by the REV method. The study also demonstrated that IDU liposomal gels retain more drug when compared with plain liposomes at all temperatures for the period of three months, while maximum PDR was found at refrigeration temperature. The skin retention of IDU was enhanced due to its entrapment in the liposomal vesicles. The clinical study suggested the improvement of therapeutic efficacy of IDU entrapped in liposomes in treatment of HSV‐1 and HSV‐2 patients.