Rifapentine is a semisynthetic rifamycin antibiotic highly active against a broad spectrum of microorganisms including Mycobacterium tuberculosis. Rifapentine solubility in water is very low (0.1 mg/ml); therefore, its dosage forms are currently limited to tablets or capsules (e.g. Priftin®). At the same time, development of water-compatible injectable formulations would extend its clinical potential. Therefore, the objective of the present study was to investigate the applicability of proteins: human serum albumin, succinylated gelatin, and sodium caseinate − for solubilization of rifapentine and evaluate the efficacy and safety of the novel injectable formulations.
The formulations were obtained by precipitation or homogenization yielding freeze-dryable suspensions. Upon reconstitution and proper dilution the lyophilizates formed stable colloidal solutions with the particle size of 10-15 nm suitable for i.v. administration. The best results were obtained with albumin (RFP-HSA) and casein that enabled total concentrations of rifapentine in the aqueous phase of up to 10 mg/ml, which was ~100-fold higher than the solubility of the pure substance.
The antituberculosis effect of RFP-HSA evaluated in Balb/C mice infected with M. tuberculosis (H37Rv, ~106 CFU per animal) was similar to that of the oral substance in the lower treatment doses (5 and 10 mg/kg) and appeared to be superior in the highest dose (20 mg/kg).
Based on the moderate LD50 value (340 mg/kg) in BDF mice, the RFP-HSA formulation could be classified as low toxic. In the chronic toxicity study (outbred rats) RFP-HSA administered i.v. and RFP substance given per os exhibited similar adverse effects. However, in contrast to conventional oral formulations, the intravenous formulation of rifapentine did not induce any signs of gastrointestinal toxicity and cardiotoxicity, thus suggesting its usefulness for clinical application. In conclusion, solubilization with proteins appeared to be a promising approach for development of the effective and safe injectable formulations of rifapentine.
•The possibility to obtain a new form of antibiotic which proved to be safe and effective, is a reason for further research in this field and manufacture of a novel pharmaceutical.
•Water-compatible form of rifapentine is an example how to make poorly soluble substances more soluble and stable in the aqueous media, without use of toxic and synthetic excipients. This technology is practically universal and can find broad application in other fields.