No abstract

5-Fluorouracil (5-FU) is an anticancer drug and is considered a gold standard for the treatment of skin cancer. At present, topical chemotherapy with 5-FU is associated with the limitations of poor skin permeation, retention at target site, and skin irritation potential. In the present study, an attempt has been made to develop an ethosome-based topical gel formulation (ethogel) for skin targeting of 5-FU. The ethosomal formulation was prepared using the classical dispersion method, and loading of 5% w/w of the drug was optimized to the commercial strength of marketed 5-FU cream. Carbopol 934P was used as a gel former in 0.5, 0.75, 1.0, and 1.5% w/w concentration for preparation of ethosome-based ethogel formulation. The ethogel formulation was characterized for viscosity, spreadability, extrudability, and pH. Viscosity of the developed ethogel and that of the marketed formulation was found to be 3070±14.7 and 2870±14.4 cP, respectively. An in-vitro skin permeation and deposition study was carried out across rat skin using the marketed cream and 5-FU drug solution as controls. The amount of drug deposition was found to increase 5.9- and 9.4-fold on treatment with ethogel in comparison with the marketed cream and drug solution, respectively. The result of antitumor activity evaluated using a Cytoselect 96-well cell transformation assay revealed a large reduction in tumor density with treatment with the 5-FU ethogel formulation in comparison with the marketed formulation. A significant reduction in the skin irritation potential of 5-FU ethogel formulation was also found in comparison with that of the marketed formulation as measured by the Draize test. The results of the present study demonstrated ethogel as a better alternative for increasing the local bioavailability of 5-FU in comparison to the marketed formulation.

Abstract. In the present study attempt was made for preparation of isotretinoin-hydroxypropyl β cyclodextrin (HP-β-CD) inclusion complex and encapsulate this complex in elastic liposomes to study the effect of dual carrier approach on skin targeting of isotretinoin. The isotretinoin HP-β-CD complex was prepared by freeze-drying method and characterized by IR spectroscopy. The drug and drug-CD complex loaded elastic liposomal formulation were prepared and characterized in vitro, ex-vivo and in vivo for shape, size, entrapment efficiency, no. of vesicles per cubic mm, in vitro skin permeation and deposition study, photodegradation and skin toxicity assay. The transdermal flux for different vesicular formulations was observed between 10.5±0.5 to 13.9±1.6 μg/cm 2 /h. This is about 15-21 folds higher than that obtained from drug solution (0.7 ±0.1 μg/cm 2 /h) and 4-5 folds higher than obtained with drug-CD complex solution (2.7±0.1 μg/cm 2 /h). The amount of drug deposit was found to increase significantly (p<0.05) by cyclodextrin complexation (30.1±0.1 μg). The encapsulation of this complex in elastic liposomal formulation further increases its skin deposition (262.2 ±21 μg). The results of skin irritation study using Draize test also showed the significant reduction in skin irritation potential of isotretinoin elastic liposomal formulation in comparison to free drug. The results of the present study demonstrated that isotretinoin elastic liposomal formulation possesses great potential for skin targeting, prolonging drug release, reduction of photodegradation, reducing skin irritation and improving topical delivery of isotretinoin.

Recently, the anticancer activity of telmisartan (TEL) has been discovered against prostate cancer. Nevertheless, despite favorable therapeutic profile, poor aqueous solubility and suboptimal oral bioavailability hamper the anticancer efficacy of TEL. Therefore, in this investigation, sigma-2 receptor ligand, 3-(4-cyclohexylpiperazine-1-yl) propyl amine (CPPA) anchored nanostructured lipid particles of telmisartan (CPPA-TEL-NLPs) were engineered using stearic acid for targeting prostate cancer, PC-3 cells. The mean particle size of TEL-NLPs was measured to be 25.4 ± 3.2 nm, significantly (p < 0.05) lower than 32.6 ± 5.3 nm of CPPA-TEL-NLPs. Correspondingly, the zeta-potential of TEL-NLPs was measured to be -15.4 ± 2.3 mV significantly (p < 0.05) higher than -9.6 ± 2.7 mV of CPPA-TEL-NLPs. The encapsulation efficiency of CPPA-TEL-NLPs was estimated to be 72.7 ± 4.3%, significantly (p < 0.05) lower than 77.5 ± 5.4%, displayed by TEL-NLPs. In addition, FT-IR and PXRD confirmed the molecular encapsulation of the drug in amorphous state. In vitro drug release study was conducted to determine the drug delivery potential of tailored nanoparticles. TEL-NLPs released 93.36% of drug significantly (p < 0.05) higher than 85.81%, released by CPPA-TEL-NLPs in 24 h. The IC of CPPA-TEL-NLPs was measured to be 20.3 µM significantly (p < 0.05) lower than 36.3 µM presented by TEL-NLPs in PC-3 cells. In contrast, CPPA-TEL-NLPs displayed the IC of 41.3 µM, significantly (p > 0.05) not different from 43.4 µM, exhibited by TEL-NLPs in PNT-2 cells. We elucidated that CPPA-TEL-NLPs entered the PC-3 cells via receptor mediated endocytosis pathway and thus exhibited superior cytotoxicity, apoptosis and greater extent of cellular uptake in PC-3 cells. In conclusion, CPPA-TEL-NLPs may be a promising nanomedicine and warrant further in vivo investigations for gaining clinical success.

5-Fluorouracil (5-FU) is one of the most effective antineoplastic agents used for the treatment of skin cancers and actinic keratosis (AK). Currently commercial formulation for topical 5-FU administration is available in the form of solution or cream. Commercial topical formulations are associated with the limitation of very short retention time at the administration site resulting in very poor skin permeation and deposition of drug. In the present study attempt was made for the preparation, optimization and characterization of bioadhesive gel formulations for localized delivery of 5-FU. Four bioadhesive gel formers, Carbopol 934, Carbopol 980, Methylcellulose (MC) and Poloxamer 188 were selected for the preparation of 5-FU bioadhesive gel formulations. The formulations were characterized for characteristic parameters including bioadhesive strength, skin deposition and interaction study. Carbopol 934 based bioadhesive gel formulation at the concentration of 1.5% w/w showed the best physicochemical properties such as viscosity (2670±12.2 cP), which was similar to the value obtained with the marketed cream (2870±14.4 cP), highest skin deposition (1290±56.4μg) and bioadhesive strength (18.62 gf). Cutaneous irritation of optimized bioadhesive gel formulations was also tested using the Draize test and only very slight erythema and no oedema was observed. In comparison, marketed formulation showed well defined erythema along with oedema formation. The result of the present study demonstrated that formulation of Carbopol 934 based 5-FU bioadhesive gel is a better alternative to the traditional cream base for enhanced topical delivery of 5-FU. The developed formulation will have the ease of application, better skin deposition and sustained release characteristic with reduced skin toxicity.