Novel and Simple Preparation Method of Matrix-Type Composite Particles for Controlled Drug Release by Mechanical Action

Abstract

Matrix-type composite particle for controlled drug release can readily be prepared through a totally dry process by simple anaerobic mechanical vibration of mechanoradical-containing ethylcellulose (EC) with theophylline powder due to occurrence of collision-induced radical-radical coupling reaction to form interparticle matrices, as well as the formation of interparticle network when solid-state vinyl monomer was further added.Key words matrix-type composite particle; controlled release; vibratory milling; mechanoradical; radical coupling; electron spin resonance (ESR)Recently we have reported the mechanically-induced radical (mechanoradical) formation of several glucose-based polysaccharides such as anomeric cellulose and amylose, 1) and pharmaceutically important substituted-celluloses 2) under anaerobic conditions, coupled with the concomitant changes in physicochemical properties, and it was found that the mechanoradicals generated in substituted-celluloses have a greater tendency to dissipate after reaching the maximum value in spin concentration during the course of mechanical vibration. This result has been ascribed to the occurrence of intra-and inter-segmental radical-radical coupling reactions including those in an interparticle fashion. We have also demonstrated that argon plasma-irradiated polyethylene, high density (HDPE) and low density (LDPE), containing plasmainduced surface radical can undergo a radical-radical coupling reaction on its mechanical vibration, 3,4) and when the vibratory mixing was conducted in the presence of drug powder (theophylline), the composite particle for sustained drug release was obtained. 5)On the basis of a series of such studies, one may expect that the matrix-type DDS can be prepared without plasmairradiation, when the vibratory mixing is conducted using mechanoradical-containing polymers in the presence of drug powder.In fact, we were able to obtain such composite particles applicable to matrix-type DDS by simple vibratory mixing of mechanoradical-containing ethylcellulose (EC) powder, which is one of the widely used pharmaceutical excipients, in the presence of theophylline powder as a model drug, so as to immobilize it into EC matrix.A prescribed quantity of EC was ground with a vibratory ball milling apparatus (Shimadzu Corp.) equipped with a stainless-steel ball (6 mmf) in a stainless-steel twin-shell blender (7.8 mmf, 24 mm long) at 60 Hz under anaerobic conditions (nitrogen environment, oxygen concentration Ͻ0.01 ppm) in a vacuum glovebox at room temperature to generate the mechanoradicals of EC. The reaction was monitored by electron spin resonance (ESR) and showed the maximum value in spin concentration (ca. 1.6ϫ10 17 /g) on the vibratory milling for 15 min. Then, the vibratory mixing of EC powder (100 mg) thus treated for 15 min was carried out with theophylline powder (10 mg) using the same vibratory ball milling apparatus, but equipped with specially made Teflon ball (6 mmf) in Teflon twin-shell blender (7.8 mmf, 24 mm long) at 60 Hz for 4 h under which ...

Mechanochemistry: The Mechanical Activation of Covalent Bonds

“…Cross-linking was observed upon mechanical milling of polyisoprene at cryogenic conditions by Spontak and co-workers . In the recycling of polymeric waste by shear pulverization, formation of mechanoradicals is probably a desired effect, which aids the in situ compatibilization of commingled plastic waste by formation of block and graft copolymers. , Mechanochemical solid-state polymerization was also used in prodrug syntheses by Kuzuya and co-workers. − …”

“…143,144 Mechanochemical solid-state polymerization was also used in prodrug syntheses by Kuzuya and coworkers. [145][146][147][148][149][150] Mechanochemistry is also employed in the development of biodegradable resins. Biodegradable soy protein-polyester blends have been prepared in a reactive extrusion process, using glycerol as a compatibilizing agent.…”

Construction of Matrix-type Drug Delivery System using Solid Phase Polymerization initiated by Plasma-induced Radicals

“…From a plot of the square root of the microwave power vs. the signal peak height, a microwave power level of 0.01 mW was chosen. The procedure is essentially the same as that reported earlier [3][4][5][6]. Schematic representation is shown in Figure 2.…”

“…[5,6] On the basis of a series of such studies, we here report the surface modification of low-substituted hydroxypropyl cellulose (L-HPC) powder, which is one of the widely used pharmaceutical excipients, by mechanochemical reaction of N-vinylacetamide (NVA) and plasmainduced radicals of L-HPC. Furthermore, when mechanical vibration of NVA and plasmairradiated L-HPC is similarly conducted with powdered drug, it can be expected that the drug is trapped among highly cross-linked powder particles resulted from mechanically-induced radical recombination.…”

Preparation of Floating Drug Delivery System by Plasma Technique

“…[20][21][22] During the course of such studies on plasma-assisted DDS preparation, we have found that the carbon dioxide was trapped in the tablet when argon plasma was irradiated onto the DC tablet composed of plasma-crosslinkable polymers possessing carboxyl group as an outer layer. Since such tablets turned to floating system on the water, it was considered that this could be applicable to FDDS.…”