Fluoroquinolone Amorphous Polymeric Salts and Dispersions for Veterinary Uses

Abstract

Enrofloxacin (ENRO) is a poorly soluble drug used in veterinary medicine. It differs from the more widely used fluoroquinolone ciprofloxacin (CIP) by the presence of an ethyl substituent on its piperazine amino group. While a number of recent studies have examined amorphous composite formulations of CIP, little research has been conducted with ENRO in this area. Therefore, the main purpose of this work was to produce amorphous solid dispersions (ASDs) of ENRO. The solid-state properties of these samples were investigated and compared to those of the equivalent CIP ASDs, and their water uptake behavior, solubility, dissolution, and antibacterial activity were assessed. Like CIP, X-ray amorphous solid dispersions were obtained when ENRO was ball milled with acidic polymers, whereas the use of neutral polymers resulted in semi-crystalline products. Proton transfer from the carboxylic acids of the polymers to the tertiary amine of ENRO’s piperazine group appears to occur in the ASDs, resulting in an ionic bond between the two components. Therefore, these ASDs can be referred to as amorphous polymeric salts (APSs). The glass transition temperatures of the APSs were significantly higher than that of ENRO, and they were also resistant to crystallization when exposed to high humidity levels. Greater concentrations were achieved with the APSs than the pure drug during solubility and dissolution studies, and this enhancement was sustained for the duration of the experiments. In addition, the antimicrobial activity of ENRO was not affected by APS formation, while the minimum inhibitory concentrations and minimum bactericidal concentrations obtained with the APS containing hydroxypropyl methylcellulose acetate succinate grade MG (HPMCAS-MG) were significantly lower than those of the pure drug. Therefore, APS formation is one method of improving the pharmaceutical properties of this drug.

Application of a Physiologically Based Pharmacokinetic Model to Develop a Veterinary Amorphous Enrofloxacin Solid Dispersion

“…In addition, no ENR peak in the stearic acid mixture was observed, which might be due to the formation of amorphous ENR in the presence of stearic acid at high DCS temperatures. The XRD results indicated that the most intense peaks in the XRD of the ENR powder were visible at 9.7 2-theta degrees, which agreed with previous studies [ 44 ]. Although the ENR peak was reduced in the binary physical mixture, the ENR peak did not disappear, suggesting that ENR was present as crystals during the compatibility tests ( Figure 3 B–D).…”

Antimicrobial Activities of Highly Bioavailable Organic Salts and Ionic Liquids from Fluoroquinolones

“…The combination of this antibiotic with the selected cations has rendered very interesting results against these bacteria strains, mostly K. pneumoniae , as similarly observed in previous works by Tajber and co-workers [ 42 , 43 ]. More specifically, all Cip–OSILs showed increased activity against this Gram-negative bacteria strain, with IC 50 values comprehended between 9.88 ([C 16 Py][Cip]) and 64.8 nM ([EMIM][Cip]), which correspond to a remarkable relative decrease of inhibitory concentrations (RDIC 50 ) of 19.9 and 3.0, respectively.…”

“…The combination of this antibiotic with the selected cations has rendered very interesting results against these bacteria strains, mostly K. pneumoniae, as similarly observed in previous works by Tajber and co-workers [42,43] In its turn, free norfloxacin shows that, similarly to ciprofloxacin, it is also more active against Gram-positive bacteria (S. aureus and B. subtilis) than Gram-negative (K. pneumoniae) strains, but to a smaller extent than its fluoroquinolone sibling. Table 4 shows this data, as well as the one observed for the Nor-based OSILs.…”

“…More precisely, these fluoroquinolones have been combined with dicarboxylic acids (malonic and tartaric [31], adipic, fumaric [32] and maleic [33,34], succinic [35]), citric acid [32], saccharine [36,37] and acesulfame [36], as well as with other drugs (diflunisal and ibuprofen [38], salicylic [39] and barbituric acids [40]). Some works involve the combination of ciprofloxacin or enrofloxacin as cations and/or as anions with amino acids [41] and ionic polymers [42,43]. While most works focus on the study of the chemical and physicochemical properties of the prepared salts, including bioavailability, crystallinity/amorphous profiles and thermodynamic stability, the amorphous-solid dispersions of ciprofloxacin and enrofloxacin showed, in addition, that the antimicrobial activity of the salts is enhanced in comparison with the parent drugs, in particular against Gram-negative bacteria strains.…”

Fluoroquinolone-Based Organic Salts and Ionic Liquids as Highly Bioavailable Broad-Spectrum Antimicrobials

“…More precisely, these fluoroquinolones have been combined with several dicarboxylic acids [17][18][19][20][21], citric acid [17], as well as with other drugs [22][23][24] in order to assess bioavailability, crystallinity/amorphous profiles and thermodynamic stability. Some works involve the combination of ciprofloxacin or enrofloxacin as cations and/or as anions, by combination with amino acids [25] and ionic polymers [26,27] have indeed presented for the first time enhanced antimicrobial activity of the salts in comparison with the parent drugs, in particular against Gramnegative bacteria strains.…”