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Background: The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy.Methods: Two nanocombinations were prepared to provide 250 mg praziquantel-20 mg miltefosine/kg (higher fixed dose) or 125 mg praziquantel-10 mg miltefosine/kg (lower fixed dose) respectively. Their antischistosomal efficacy in comparison with nontreated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral dose of either formulation was administered on the initial day of infection, the 21st and 42nd days post infection. Scanning electron microscopic, parasitological and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukey post hoc test for pairwise comparisons.Results: Lipid nanocapsules (~58 nm) showed high entrapment efficiency of both drugs (>97%). Compared to singly loaded praziquantel-lipid nanocapsules, the higher dose nanocombination showed a significant increase in antischistosomal efficacy in terms of statistically significant decrease in mean worm burden, particularly against invasive and juvenile worms, and amelioration of hepatic granulomas (p ≤0.05). In addition, scanning electron microscopic examination showed extensive dorsal tegumental damage with noticeable deposition of nanostructures. Conclusions: The therapeutic profile of praziquantel could be improved by a novel multiple approach integrating drug repurposing, combination therapy and nanotechnology. Multistage activity and amelioration of liver pathology could be achieved by a new praziquantel-miltefosine fixed dose nanocombination providing 250 mg praziquantel-20 mg miltefosine/kg. To the best of our knowledge, this is the first report of a fixed dose nano-based combinatorial therapy for schistosomiasis mansoni. Further studies are needed to document the nanocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.

Background: Schistosomiasis control has been centered to date on praziquantel, with shortcomings involving ineffectiveness against immature worms, reinfection and emergence of drug resistance. Strategies based on drug repurposing and/or praziquantel combination therapy proved effective, though with some limitations. Combining such strategies with nanotechnology would further augment therapeutic benefits. Nanocarrier-mediated delivery of multiple drugs in schistosomiasis control has not been documented to date. Our objective was to combine drug repurposing, combinational therapy and nanotechnology for the development of a single oral fixed dose nanocombination to improve praziquantel therapeutic profile. This was based on praziquantel and an antischistosomal repurposing candidate miltefosine, co-loaded into lipid nanocapsules in reduced doses. Methods: Two fixed dose lipid nanocapsule formulations were prepared at two concentration levels of praziquantel and miltefosine. Their antischistosomal activity in comparison with control singly loaded lipoid nanocapsules was assessed in Schistosoma mansoni- infected mice. Single oral dos of 250mg praziquantel-20mg miltefosine/kg and 125mg praziquantel-10mg miltefosine/kg were administered on the initial day of infection, 21st and 42nd days post infection. Scanning electron microscopy, parasitological and histopathological studies were used for assessment. In vivo data were subjected to analysis of variance and post hoc test (Tukey) was used for pairwise comparisons. Results: Lipid nanocapsules showed a mean diameter of 58 nm and high entrapment efficiency of both drugs (>95%). Compared to singly loaded lipid nanocapsules, the larger dose praziquantel-miltefosine nanocombination exerted high antischistosomal efficacy in terms of % reduction of worm burden, particularly when given against invasive and juvenile worms, and amelioration of hepatic granulomas. Scanning electron microscopy revealed extensive tegumental damage with noticeable deposition of nanostructures. Conclusions: A fixed dose praziquantel-miltefosine nanocombination offers great potential as a novel single dose oral antischistosomal therapy offering multistage activity and protection against hepatic pathology. The novel drug repurposing/combination therapy/nanotechnology multiple approach has the potentials of improving the therapeutic profile of praziquantel, achieving radical cure, hindering resistance to the component drugs, and simplifying praziquantel chemotherapy. Key words: Praziquantel, miltefosine, lipid nanocapsules, Schistosoma mansoni, nanocombination, multistage activity, tegumental targeting, scanning electron microscopy. ​ [LE1] [LE1]

Formulation of local anesthetics in liposomal topical drug delivery system could provide a sustained and localized anesthesia. The aim of this study was to develop a liposomal dibucaine base (DB) local anesthetic delivery system. DB-loaded multilamellar vesicles (MLVs) were prepared through varying lipid composition, induced charge and pH of the hydration medium. Liposomes were characterized for morphology, size, entrapment efficiency (EE), in vitro drug release and stability including leakage stability. The percentage of drug entrapped in liposomes was found to be hydration medium pH dependent and charge dependent and more pronounced for negatively charged liposomes prepared using hydration medium of pH 9. In vitro release studies of liposomes have shown a sustained release of entrapped dibucaine compared to control solution. Results revealed that adjusting the various formulation variables of dibucaine base MLVs could yield stable and effective topical liposomal local anesthetic formulations.

Possible leakage of 5-fluorouracil from stable plurilamellar vesicles was monitored during storage of the liposomal concentrates, gels and lyophilized powders. Changes in release profile of dibucaine were taken as indicator of instability. Release profiles were obtained using the dialysis technique for a freshly prepared liposomal concentrate, gel or reconstituted lyophilized powder (zero time) and storage for one, two and four weeks in well closed tubes at 4 degrees C for the liposomal concentrate or gel and at 25 degrees C for liposomal lyophilized powder. Aiming at increasing stability of 5-fluorouracil liposomal dispersion, freshly prepared liposomal concentrates were directly incorporated in hydroxypropyl methylcellulose gel. Stability release profiles of liposomal gels and concentrates indicated a significant increase in stability of liposomal formulations. Also, lyophilization increases the shelf life of liposomes by preserving it in a dry form as a lyophilized cake to be reconstituted immediately prior to administration or direct incorporation into a final dosage form. Release and physico-chemical stability studies showed superior potentials of the lyophilized product after reconstitution in comparison to concentrate and gel forms. It could be concluded that lyophilization of liposomes loaded with a water-soluble drug such as 5-fluorouracil could significantly increase the stability of the liposomal vesicles and decrease leakage from it.