Spray freeze-dried carriers for lymphatic drug targeting as novel therapeutic approach in Chagas disease

• Applicant: Professor Dr. Alf Lamprecht
• Subject Area: Pharmacy ; Biomaterials ; Chemical and Thermal Process Engineering ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 543949948

Chagas disease is an infectious illness caused by Trypanosoma cruzi. About 6 – 7 million people are infected worldwide, with 12000 deaths (WHO), mostly in Latin America where the T.cruzi is endemic. Antimicrobial drugs benznidazole and nifurtimox are the first line therapy. Widely used in the last four decades, for they are effective drugs in the treatment of chagas disease, but the dosage and duration of the drug therapy must be kept as short as possible, due to serious side effects and the subsequent loss of compliance of the patient. However, these drugs are poorly water-soluble, which strongly limits their bioavailability upon oral administration in doses relevant for their antimicrobial effect. Rapid dissolution and corresponding fast absorption is necessary to achieve high Cmax, as high plasma concentration of the antimicrobial drug is crucial for its antimicrobial therapeutic effectiveness. The T.cruzi upon infection mostly resides in blood and the lymphatic system, infecting macrophages where it multiplies. Spray freeze-drying enables the production of free-flowing lyophilizates, which means completely new possibilities for the design of the dosage form due to the unique formulation technology. For example, lyophilizates can be formulated relatively easily as lyophilizates for nasal or pulmonary administration. However, spray freeze-drying was limited to aqueous solvent systems up to now, which precluded the use of SFD for poorly water-soluble drugs. Recently, we were able to extend the field of application to the application of poorly water-soluble drugs by investigating the suitability of dimethyl sulphoxide (DMSO) for the formulation of SFD particles. The main objective of this project is to translate this solvent-based technology into the design of SFD particles allowing for pulmonary delivery of nifurtimox, one of the before-mentioned actives. SFD process parameters as well as excipient choice for producing inhalable particles of nifurtimox with a DMSO-based SFD technique will be characterized in view of an optimized pulmonary drug deposition in-vitro (next generator impactor test according to PharmEur). A subsequent intention is to reach sufficiently high drug levels in the lymphatic system to treat Chagas disease and to obtain a deeper insight into the dosage-form related mechanisms responsible for the drug partitioning between blood stream and lymphatic system. Accordingly, pharmacokinetics in rats after pulmonary drug administration will elucidate the pulmonary drug availability per se (versus an oral control group), and allow to determine the ratio of drug that is detectable in the lymphatic system after pulmonary administration. Finally, the study will be completed by a first evaluation of the therapeutic efficacy of pulmonary SFD particle administration in a Chagas disease model in rats.

• DFG Programme: Research Grants
• International Connection: Argentina
• Partner Organisation: Consejo Nacional de Investigaciones Científicas y Técnicas
• Cooperation Partner: Professor Claudio J. Salomon, Ph.D.