Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: Physico‐chemistry and molecular modeling

Abstract

The busulfan is an alkylating agent widely used for the treatment of haematological malignancies and nonmalignant disorders. For a long time, it has been available only in an oral form. This treatment leads to a wide variability in bioavailability and side effects such as the veino-occlusive disease. Thus, an intravenous formulation of busulfan-loaded nanoparticles may be considered as a major progress. This study deals with busulfan entrapment by nanoprecipitation into five different types of poly(alkyl cyanoacrylate) polymers. The polymers leading to the highest busulfan loading efficiencies were poly(isobutyl cyanoacrylate) (PIBCA) and poly(ethyl cyanoacrylate). Molecular modeling along with energy minimization process was employed to identify the nature of the interactions occurring between busulfan and PIBCA. Further, optimization studies enabled to obtain PIBCA nanoparticles displaying busulfan loading ratios equal to 5.9% (w/w) together with nanoparticle yields of 71% (w/w). Since busulfan is a highly reactive molecule, we performed (1)H-NMR spectroscopy experiments showing that chemical integrity of the drug was preserved after loading into nanoparticles. The in vitro release studies under sink conditions, in water, or in rat plasma showed a fast release in the first 10 min followed by a slower one over 6 h. This phenomenon could be explained by the semi-polar characteristics of busulfan.

Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles

“…35 , when encapsulating busulfan in biodegradable poly(alkyl cyanoacrylate) NPs. The busulfan free crystals in the NPs suspensions were extremely difficult to be removed.…”

Porous Metal Organic Framework Nanoparticles to Address The Challenges Related to Busulfan Encapsulation

“…Indeed, busulfan readily degrades in water, [12,41], into tetrahydrofuran and methanesulphonic acid as shown by 1 H-NMR [12]. Noteworthy, the tetrahydrofuran resonance peaks ((CH 2 -O, multiplet) and (CH 2 , multiplet)) and the methanesulphonic acid resonance peak (CH 3 , singlet) were not superimposed with the busulfan peaks [20]. These differences have been advantageously used previously to prove that busulfan conserved its integrity when encapsulated into biodegradable polymeric NPs [20].…”

“…For example, busulfan loading in poly(lactic acid) NPs was only 1% (w/w) [19] due to a massive drug leakage from the NPs during their preparation. In more recent studies, some of us have established the ability of biodegradable poly(isobutyl cyanoacrylate) (PIBCA) NPs to encapsulate larger amounts of busulfan than other polymers [20]. Moreover, these busulfan-loaded PIBCA NPs with 6 wt% loading were successfully coated with a PEG shell [21], could be stored after freeze drying [22], but showed a fast release.Therefore, the entrapment of busulfan in nanocarriers with loadings higher than 6 wt% is a clearly identified challenge [23].…”

Development and lyophilization of itraconazole loaded poly(butylcyanoacrylate) nanospheres as a drug delivery system

“…Poly(butyl cyanoacrylate) and poly(ethyl cyanoacrylate) were synthesized by modified anionic polymerization of BCA and/or ECA monomers in water as already described in the literature (Layre et al, 2006). Briefly, 1 ml of either ECA or BCA monomer was added to 15 ml of 0.2 lm membrane filtered deionized water (dH 2 O).…”