Inclusion complex and nanoclusters of cyclodextrin to increase the solubility and efficacy of albendazole

Authors: PACHECO, P. - Instituto De Zootecnia; RODRIGUES, L - Universidad De Sao Paulo; Ferreira, Jorge; GOMES, A. - Instituto De Zootecnia; VERISSIMO, C. - Instituto De Zootecnia; LOUVANDINI, H. - The Center Of Nuclear Energy In Agriculture; COASTA, R. - Instituto De Zootecnia; KATIKI, L. - Instituto De Zootecnia

Submitted to: Parasitology Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/28/2017
Publication Date: 1/11/2018
Citation: Pacheco, P.A., Rodrigues, L.N., Ferreira, J.F., Gomes, A.C., Verissimo, C.J., Louvandini, H., Coasta, R.L., Katiki, L.M. 2018. Inclusion complex and nanoclusters of cyclodextrin to increase the solubility and efficacy of albendazole. Parasitology Research. 117(3):705-712. https://doi.org/10.1007/s00436-017-5740-3.
DOI: https://doi.org/10.1007/s00436-017-5740-3

Interpretive Summary: Albendazole (ABZ), a worm killer widely used to control internal nematodal worms in ruminants is poorly soluble in water. This results in variable and incomplete efficacy of the medicine and has favored the appearance of parasite resistance worldwide. Among the pharmaceutical techniques developed to increase the efficacy of medicines similar to ABZ, cyclodextrins (CD – sugar molecules bound together in a ring form) and other polymers are often used to increase solubility and efficacy. The objective of this work was to prepare ABZ formulations including '-cyclodextrin (ßCD) or hydroxypropyl-'-cyclodextrin (HPßCD), associated or not to the water-soluble polymer polyvinylpyrrolidone (PVP). These formulations had both their solubility and anthelmintic effect evaluated in vitro. In addition, their anthelmintic efficacy was evaluated in lambs naturally infected with gastrointestinal worms and evaluated through the reduction of fecal eggs (FEC) in their stool. In vitro, the complex ABZ-HPßCD had higher solubility than ABZ:ßCD. The addition of the water-soluble PVP to the complexes increased solubility and dissolution rate of ABZ more effectively for ABZ:HPßCD than for ABZ:ßCD. In vivo, 48 lambs naturally infected with gastrointestinal worms were divided into six experimental groups: Control, ABZ, ABZ:ßCD, ABZ:ßCD-PVP, ABZ:HPßCD and ABZ:HPßCD-PVP. Each treated animal received 10mg/kg of body weight of each formulation (based on the ABZ dose) for three consecutive days. After 10 days of the last administered dose, treatment efficacy was calculated through FEC. The efficacy values were: ABZ (70.33%), ABZ:ßCD (85.33%), ABZ:ßCD-PVP (82.86%), ABZ:HPßCD (78.37%) and ABZ:HPßCD-PVP (43.79%). In vitro, we concluded that ABZ:HPßCD and ABZ:HPßCD-PVP had high solubility and dissolution rates. In vivo, although the efficacies of ABZ:ßCD, ABZ:ßCD-PVP, and ABZ:HPßCD surpassed that of pure ABZ, the differences were not significant (P > 0.05). These results indicate that the dissolution and efficacy of water-insoluble medicines like ABZ can be increased by their association with cyclodextrins. Increased solubility allow farmers to treat their worm-infected livestock through the most practical oral route. However, polymers other than cyclodextrins and PVP need to be tested to increase ABZ efficacy significantly when compared to ABZ alone.

Technical Abstract: Albendazole (ABZ), a benzimidazole widely used to control gastrointestinal parasites is poorly soluble in water, resulting in variable and incomplete bioavailability, which has favored the appearance of parasite resistance and, consequently, clinical ineffectiveness. Among the pharmaceutical techniques developed and applied to increase drug efficacy, cyclodextrins (CD) and other polymers have been extensively used with pharmaceutical drugs to increase their solubility and availability. Our objective was to prepare ABZ formulations including '-cyclodextrin (ßCD) or hydroxypropyl-'-cyclodextrin (HPßCD), associated or not to the water-soluble polymer polyvinylpyrrolidone (PVP). These formulations had both their solubility and their anthelmintic effect evaluated in vitro. Also, their anthelmintic efficacy was evaluated in lambs naturally infected with gastrointestinal nematodes (GIN) using the fecal egg count (FEC) reduction test, In vitro, the complex ABZ-HPßCD had higher solubility than ABZ:ßCD. The addition of PVP to the complexes increased solubility and dissolution rate more effectively for ABZ:HPßCD than for ABZ:ßCD. In vivo, 48 lambs naturally infected with GIN were divided into six experimental groups: Control, ABZ, ABZ:ßCD, ABZ:ßCD-PVP, ABZ:HPßCD and ABZ:HPßCD-PVP. Each treated animal received 10mg/kg body weight (based on ABZ dose) for three consecutive days. After 10 days of the last administered dose, treatment efficacy was calculated through FEC. The efficacy values were: ABZ (70.33%), ABZ:ßCD (85.33%), ABZ:ßCD-PVP (82.86%), ABZ:HPßCD (78.37%) and ABZ:HPßCD-PVP (43.79%). We conclude that ABZ:HPßCD and ABZ:HPßCD-PVP had high solubilities and dissolution rates in vitro. In vivo, the efficacies of ABZ added to ßCD, ßCD-PVP and HPßCD also increased slightly when compared to pure ABZ, but not significantly (P > 0.05).