deoxycholic-acid and Chagas-Disease

Chagas disease (CD) is a parasitic zoonosis endemic in most mainland countries of Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective if received at the early stages of the disease. Only two drugs (benznidazole and nifurtimox) have so far been marketed, and both share various limitations such as variable efficacy, many side effects, and long duration of treatment, thus reducing compliance. The in vitro and in vivo efficacy of poly-aggregated amphotericin B (AmB), encapsulated poly-aggregated AmB in albumin microspheres (AmB-AME), and dimeric AmB-sodium deoxycholate micelles (AmB-NaDC) was evaluated. Dimeric AmB-NaDC exhibited a promising selectivity index (SI = 3164) against amastigotes, which was much higher than those obtained for licensed drugs (benznidazole and nifurtimox). AmB-AME, but not AmB-NaDC, significantly reduced the parasitemia levels (3.6-fold) in comparison to the control group after parenteral administration at day 7 postinfection. However, the oral administration of AmB-NaDC (10-15 mg/kg/day for 10 days) resulted in a 75% reduction of parasitemia levels and prolonged the survival rate in 100% of the tested animals. Thus, the results presented here illustrate for the first time the oral efficacy of AmB in the treatment of trypanosomiasis. AmB-NaDC is an easily scalable, affordable formulation prepared from GRAS excipients, enabling treatment access worldwide, and therefore it can be regarded as a promising therapy for trypanosomiasis.

Topics: Albumins; Amphotericin B; Animals; Antifungal Agents; Chagas Disease; Chemistry, Pharmaceutical; Deoxycholic Acid; Drug Combinations; Excipients; Female; Mice, Inbred BALB C; Micelles; Microspheres; Particle Size; Trypanosoma cruzi

Solid dispersions (SD) of benznidazole (BNZ) in sodium deoxycholate (NaDC) or low-substituted hydroxypropylcellulose (L-HPC) were developed by freeze-drying process to improve the solubility of this low water-soluble drug and consequently, its trypanocidal activity. Although the dissolution studies showed a progressive decrease in the release rate of BNZ when formulated in the presence of NaDC, the increase in the surfactant concentration resulted in a better trypanocidal profile on epimastigotes, as well as in an enhancement of the unspecific cytotoxicity. However, such an effect was not so evident on amastigotes and in vivo (blood-trypomastigotes), where high concentrations of surfactant (BNZ:NaDC ≥ 1:6) experimented a loss of activity, correlating this fact with the minor cession of BNZ these formulations accomplished in acidic locations (i.e., dissolution test medium). According to the in vitro results, we reformulated the promising SD-1:3 (IC₅₀ epimastigotes = 33.92 ± 6.41 µM, IC₅₀ amastigotes = 0.40 ± 0.05 µM and LC₅₀ = 183.87 ± 12.30 µM) replacing NaDC by L-HPC, which achieved the fastest dissolution profile. This fact, together with the safety this carrier ensures (LC₅₀ > 256 µM), prompted us to evaluate the cellulose SD in vivo, improving the effectiveness of its NaDC equivalent (%AUPC = 96.65% and 91.93%, respectively). The results compiled in the present work suggest these solid dispersions as alternative drug delivery systems to improve the limited chemotherapy of Chagas disease.

Topics: Animals; Cells, Cultured; Cellulose; Chagas Disease; Cholagogues and Choleretics; Deoxycholic Acid; Drug Compounding; Drug Delivery Systems; Drug Liberation; Female; Fibroblasts; Freeze Drying; Humans; Inhibitory Concentration 50; Lethal Dose 50; Mice; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

This work aims to develop novel benznidazole (BZN) solid dispersions (SD) to improve its solubility and bioavailability properties. Low-substituted hydroxypropylcellulose (L-HPC) and sodium deoxycholate (NaDC) were evaluated as carriers. BZN solid dispersions containing different ratios of carrier were prepared by a freeze-drying process and characterized by SEM, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution studies. The reduced BNZ crystallinity in the new formulations was confirmed by XRD, and supported by DSC. BNZ:L-HPC solid dispersion at a 1:3 ratio (w/w) (SD-1:3 L-HPC) improved the BNZ dissolution rate (85% at 5 min) in comparison with BNZ raw material (23% at 5 min). However, NaDC formulations showed a prolonged release (24% at 30 min for SD-1:3 NaDC), due to the formation of a sustained release matrix in acidic medium. In vivo studies performed in a murine model of Chagas disease showed that the formulation achieving the highest parasitemia suppression at a low dose of 25mg/kg/day after five days of treatment was SD-1:3 L-HPC (60% of parasitemia suppression versus 33% of suppression exerted by BNZ), suggesting that BNZ:L-HPC systems enhance the bioavailability of the drug.

Topics: Animals; Calorimetry, Differential Scanning; Cellulose; Chagas Disease; Chemistry, Pharmaceutical; Crystallization; Deoxycholic Acid; Drug Carriers; Female; Mice; Microscopy, Electron, Scanning; Nitroimidazoles; Parasitemia; Powder Diffraction; Trypanocidal Agents; X-Ray Diffraction