Biodegradable Injectable In Situ Implants and Microparticles for Sustained Release of Montelukast: In Vitro Release, Pharmacokinetics, and Stability

Abstract

The objective of this study was to investigate the sustained release of a hydrophilic drug, montelukast (MK), from two biodegradable polymeric drug delivery systems, in situ implant (ISI) and in situ microparticles (ISM). N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), triacetin, and ethyl acetate were selected as solvents. The release of 10% (w/v) MK from both systems containing poly-lactic-co-glycolic acid (PLGA) as the biodegradable polymer was compared. Upon contact with the aqueous medium, the PLGA in ISI and ISM systems solidified resulting in implants and microparticles, respectively. The in vitro drug release from the ISI system showed marked difference from miscible solvents (NMP and DMSO) than the partially miscible ones (triacetin and ethyl acetate), and the drug release decreased with increased PLGA concentration. In the ISM system, the initial in vitro drug release decreased with decreased ratio of polymer phase to external oil phase. In vivo studies in rats showed that ISM had slower drug release than the drug release from ISI. Also, the ISM system when compared to ISI system had significantly reduced initial burst effect. In vitro as well as the in vivo studies for both ISI and ISM systems showed sustained release of MK. The ISM system is suitable for sustained release of MK over 4-week period with a lower initial burst compared to the ISI system. Stability studies of the ISI and ISM formulations showed that MK is stable in the formulations stored at 4°C for more than 2 years.

Preparation of Parenteral in situ Gel Formulation Based on smart PLGA polymer: Concepts to Decrease Initial Drug Burst and extend drug release

“…The initial release of the drug decreased as the polymer concentration was increased [30]. The same effect was also observed for montelukast, reported by the same research group [36].…”

“…They inferred that solvent type is among the formulation factors that have a marked effect on haloperidol initial burst and attributed this behaviour to the slow phase inversion rate, and so the aqueous solubility of the studied solvents affects the solvent exchange rate during conversion of the administered polymeric liquid into gel [30]. The same behaviour was reported for montelukast release from an ISG system prepared using PLGA in the same solvents [36]. The initial montelukast release was higher from DMSO, followed by NMP then ethyl acetate and finally triacetin.…”

“…A reduced initial bupivacaine hydrochloride release was also exhibited from the ISM compared to the ISI and they also attributed this behaviour to the presence of the external oil phase and the less porous surface of the ISM [54]. Ahmed et al also reported the same results for haloperidol and montelukast during the in vitro and in vivo release of both drugs from ISM and ISI systems [30,36].…”

“…Drug toxicity and tissue irritation are the major drawbacks associated with the phenomenon [33]. The major causes of this behaviour include: the rapid release of drug adsorbed on the polymeric surface [34], unequal distribution of the drug within the polymeric network [35] and/or rapid diffusion of the drug to the surrounding medium prior to the solidification process [36]. Several attempts have been conducted to overcome this drawback; among the factors that should be considered are: the type of solvent used, the lactide-to-glycolide ratio (L:G) of the polymer, the concentration and molecular weight (viscosity) of the polymer, incorporation of plasticizers or surfactants and formation of in situ microparticles and microglobules.…”

“…Common examples of the former include NMP, dimethyl sulfoxide (DMSO), propylene glycol, acetone, tetrahydrofuran (THF), 2-pyrrolidone, glycofurol and low molecular weight PEG [7,18,30,31,36], while the latter includes benzyl benzoate, ethyl benzoate, ethyl acetate, triacetin, triethyl citrate and benzyl alcohol [39][40][41]. Among these solvents, NMP is most frequently used due to its solvating power.…”