Combining Mechanochemistry and Spray Congealing for New Praziquantel Pediatric Formulations in Schistosomiasis Treatment

Abstract

Praziquantel (PZQ) is the first line drug for the treatment of schistosome infections and is included in the WHO Model List of Essential Medicines for Children. In this study, the association of mechanochemical activation (MA) and the spray congealing (SC) technology was evaluated for developing a child-friendly PZQ dosage form, with better product handling and biopharmaceutical properties, compared to MA materials. A 1:1 by wt PZQ—Povidone coground—was prepared in a vibrational mill under cryogenic conditions, for favoring amorphization. PZQ was neat ground to obtain its polymorphic form (Form B), which has an improved solubility and bioactivity. Then, activated PZQ powders were loaded into microparticles (MPs) by the SC technology, using the self-emulsifying agent Gelucire® 50/13 as a carrier. Both, the activated powders and the corresponding loaded MPs were characterized for morphology, wettability, solubility, dissolution behavior, drug content, and drug solid state (Hot Stage Microscopy (HSM), Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction Studies (PXRD), and FT-IR). Samples were also in vitro tested for a comparison with PZQ against Schistosoma mansoni newly transformed schistosomula (NTS) and adults. MPs containing both MA systems showed a further increase of biopharmaceutical properties, compared to the milled powders, while maintaining PZQ bioactivity. MPs containing PZQ Form B represented the most promising product for designing a new PZQ formulation.

Therapeutic Applications of Solid Dispersions for Drugs and New Molecules: In Vitro and In Vivo Activities

“…Praziquantel (PZQ) is a drug widely used in the treatment of parasitic diseases, especially schistosomiasis, popularly known as “water belly” in Brazil, which is caused by contact of the parasite Schistosoma mansoni with the skin of the individual. Despite being the only drug in the treatment of flattened worms, PZQ has several limitations due to its low water solubility, which implies the need to administer it in high doses to patients [ 30 , 31 ].…”

“…In another study performed by Albertini et al [ 31 ] with the aim to improve the antiparasitic activity of PZQ, a SD with PVP K30 was prepared by the mechanochemical activation process and spray congealing technique. For in vitro testing of SDs, newly transformed schistosomula, obtained by mechanical transformation from S. mansoni and adult forms of the parasite were used.…”

Paediatric Formulation: Design and Development

“…Here, Albertini and co-workers [ 12 ] evaluated the association of mechanochemical activation and spray congealing technology for developing a child-friendly praziquantel (PZQ) dosage form, with better product handling and biopharmaceutical properties, compared to mechanochemical activation materials. PZQ is the first line drug for the treatment of schistosome infections and is included in the WHO Model List of Essential Medicines for Children.…”

Spray Congealing: An Emerging Technology to Prepare Solid Dispersions with Enhanced Oral Bioavailability of Poorly Water Soluble Drugs

“…For example, the melting endotherm of carbamazepine, loaded from 5 to 20% w/w into Gelucire 50/13 MPs, was not detected in DSC analysis [37]. The melting peak of PZQ contained in spray congealed MPs of Gelucire 50/13 was observed in the DSC profile when the drug content was as high as 30% w/w [36] while in another study, the same API loaded at 15% w/w , completely solubilized in the molten Gelucire 50/13 during the scan [70]. Specifically, in case of high drug amounts, the amount of molten carrier is not sufficient to dissolve the drug crystals during DSC scan.…”

“…In addition, a preliminary in vivo study in five rats demonstrated that the system substantially improved the oral bioavailability of the extract main components. Recently, a similar approach was used to develop a child-friendly dosage form of PZQ, the first line drug used in endemic countries for the treatment and prevention of schistosome infections [70]. The high dose required for PZQ to be effective per os administration, because of its low aqueous solubility and high first pass effect, make this drug available in large tablets difficult to be swallowed by children [11].…”