Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson’s disease

Abstract

A microsphere–gel in situ forming implant (MS–Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson’s disease. This injectable complex depot system combined an in situ phase transition gel with high drug-loading and encapsulation efficiency RM–MS prepared by a modified emulsion-phase separation method and optimized by Box–Behnken design. It was evaluated for in vitro drug release, in vivo pharmacokinetics, and in vivo pharmacodynamics. We found that the RM-MS-Gel ISFI system showed no initial burst release and had a long period of in vitro drug release (60 days). An in vivo pharmacokinetic study indicated a significant reduction (p < .01) in the initial high plasma drug concentration of the RM–MS–Gel ISFI system compared to that of the single RM–MS and RM–in situ gel systems after intramuscular injection to rats. A pharmacodynamic study demonstrated a significant reduction (p < .05) in 6-hydroxydopamine-induced contralateral rotation behavior and an effective improvement (p < .05) in dopamine levels in the striatum of the lesioned side after 28 days in animals treated with the RM–MS–Gel ISFI compared with that of animals treated with saline. MS-embedded in situ phase transition gel is superior for use as a biodegradable and injectable sustained drug delivery system with a low initial burst and long period of drug release for highly hydrophilic small molecule drugs.

Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson’s Disease: Past, Present, and Future

“…Pharmacokinetic studies in healthy Chinese populations showed that the transdermal rasagiline patch was able to prolong the duration of administration with good safety and tolerability, providing a continuous treatment modality for patients who were not able to routinely take oral medications [ 133 ]. Furthermore, animal studies showed that injectable rasagiline based on an injectable long-acting formulation system significantly increases dopamine levels in PD model rats ( p < 0.05) and effectively improves motor symptoms [ 134 ]. Encapsulation rasagiline in polycaprolactone microspheres prolonged drug release for 1 month by a single subcutaneous dose, and no significant difference was found with daily rasagiline administration in animal studies [ 135 ].…”

Effects of Drug Physicochemical Properties on In-Situ Forming Implant Polymer Degradation and Drug Release Kinetics

“…In-situ forming implants (ISFIs) are sustained drug delivery systems consisting of a biocompatible, water-miscible solvent such as N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO) and a biodegradable polymer, most commonly a polyester such as PLGA [1][2][3][4]. The water-miscible solvent is used to dissolve both the polymer and drug to form a liquid formulation that can be injected into the intramuscular or subcutaneous space [5][6][7]. The implant is formed via phase inversion, during which the water-miscible solvent diffuses from the ISFI into the aqueous injection site, leaving the precipitated polymer to trap the drug in a solid matrix [8,9].…”

Micro- and Nano-Systems Developed for Tolcapone in Parkinson’s Disease

“…The potential applications of MPs and NPs for PD therapy have been explored in the last few years for different drugs, such as levodopa [ 12 , 13 ], rasagiline [ 14 , 15 ], puerarin [ 16 ], schisantherin A [ 17 ], glial cell line-derived neurotrophic factor (GDNF) [ 18 ], ropinirole [ 19 ], and apomorphine [ 20 ].…”