Efavirenz oral delivery via lipid nanocapsules: formulation, optimisation, and ex‐vivo gut permeation study

et al. 2020

Preprint

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.

Section: Discussionsupporting

confidence: 80%

A single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

et al. 2020

Preprint

Section: Discussionsupporting

confidence: 76%

“…LNCs are nanostructures with great potentials in drug delivery [25][26][27]. Owing to their relatively small and controllable size (20-100 nm), structural integrity in simulated gastrointestinal (GI) uids and possible active transport across the intestinal epithelium, LNCs are highly promising as oral nanovectors [28,29]. In schistosomiasis treatment, oral LNCs also showed potential S. mansoni tegumental targeting [24].…”

Section: Introductionmentioning

confidence: 99%

Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

et al. 2020

Preprint

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 a non-treated 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, and on days 21 and 42 post-infection. Scanning electron microscopic, parasitological, and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukeyʼs 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 nanocombination dose 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 microscopy 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.

“…Noteworthy, no such nanostructures were observed for free unencapsulated MFS [13,15] nor PZQ treatments [24]. Findings regarding these nanoobjects corroborate published data documenting possible intestinal translocation of LNCs across the intestinal wall [29,63]. Combined data emphasize the role of oral nanocarriers in mediating cellular drug delivery, providing new avenues for modi ed therapies [64].…”

Section: Selection Of Lncs As Nanocarrier For the Oral Administrationsupporting

confidence: 77%

“…LNCs are nanostructures with great potentials in drug delivery [25][26][27]. Owing to the their relatively small and controllable size (20-100 nm), structural integrity in simulated gastrointestinal (GI) uids and possible active transport across the intestinal epithelium, LNCs are highly promising as oral nanovectors [28,29]. In schistosomiasis treatment, LNCs also showed potential S. mansoni tegumental targeting [24].…”

Section: Introductionmentioning

confidence: 99%

A single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

et al. 2020

Preprint

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.