Besifloxacin Nanocrystal: Towards an Innovative Ophthalmic Preparation

Abstract

Bacterial conjunctivitis significantly impacts public health, including more than one-third of eye diseases reported worldwide. It is an infection caused by various aerobic and anaerobic bacteria and is highly contagious. Therefore, it has a high incidence of bacterial resistance to the antibiotics commonly used for treatment. Among the most recent antibiotics, besifloxacin is a fourth-generation fluoroquinolone antibiotic indicated exclusively for topical ophthalmic use. Due to its importance in treating bacterial conjunctivitis and its low solubility in water, limiting its efficacy, a nanotechnology-based drug delivery preparation was developed to overcome this hurdle. Besifloxacin nanocrystals were prepared by small-scale wet milling and response surface methodology, using Povacoat® as a stabilizer. The particle’s average hydrodynamic diameter (Z-ave) was approximately 550 nm (17 times smaller than raw material), with a polydispersity index (PdI) of less than 0.2. The saturation solubility increased about two times compared to the raw material, making it possible to increase the dissolution rate of this drug substance, potentially improving its bioavailability and safety. The optimized preparation was stable under an accelerated stability study (90 days). The Z-ave, PZ, PdI, and content did not alter significantly during this period. Furthermore, the 0.6% m/m besifloxacin nanocrystals at the maximum dose and the Povacoat® stabilizer did not show toxicity in Galleria mellonella larvae. The innovative ophthalmic preparation minimum inhibitory concentration (MIC) was 0.0960 µg/mL and 1.60 µg/mL against Staphylococcus aureus and Pseudomonas aeruginosa, respectively, confirming in vitro efficacy. Therefore, besifloxacin nanocrystals revealed the potential for reduced dosing of the drug substance, with a minor occurrence of adverse effects and greater patient adherence to treatment.

Mechanochemically Induced Solid-State Transformations of Levofloxacin

“…Another investigation was carried out on gatifloxacin (GAT) whereby the amorphous form was achieved by milling and melt quenching to better understand the characteristics of various amorphous forms of GAT with multiple hydrate and anhydrous polymorphs being reported in their crystalline form. 29 Also, CIP hydrochloride monohydrate was BMed to reduce its particle size before spray drying (SDing) to produce antibiotic inhalation powders. 33 Spray drying (SDing) is another method that can be employed to alter the physicochemical properties of drugs.…”

“…Nanocrystals were produced via wet bead milling to enhance dissolution, with the promising potential of improving bioavailability. Another investigation was carried out on gatifloxacin (GAT) whereby the amorphous form was achieved by milling and melt quenching to better understand the characteristics of various amorphous forms of GAT with multiple hydrate and anhydrous polymorphs being reported in their crystalline form . Also, CIP hydrochloride monohydrate was BMed to reduce its particle size before spray drying (SDing) to produce antibiotic inhalation powders …”

“…Research shows that multiple fluoroquinolones have been ball milled (BMed) to improve the properties of the drugs, such as solubility and dissolution rates, reduce particle size, enhance crystal engineering, 28 and detect new polymorphic forms. 29 Examples include CIP 30 , 31 and enrofloxacin (ENRO), 32 which were BMed with amino acids 9 and acidic polymers 31 , 32 to produce amorphous binary and ternary systems for solubility 30 − 32 and dissolution enhancement. 32 Norfloxacin (NOR), CIP, and ENRO were investigated via ball milling (BMing) to enhance the crystal engineering understanding of fluoroquinolone drugs.…”