Controlled-release nanoencapsulating microcapsules to combat inflammatory diseases

Abstract

The World Health Organization (WHO) has reported that globally 235 million people suffer from chronic and other inflammatory diseases. The short half-lives of nonsteroidal anti-inflammatory drugs (NSAIDs) and their notoriety in causing gastrointestinal discomforts, warrants these drugs to be released in a controlled and sustained manner. Although polymeric particles have been widely used for drug delivery, there are few reports that showcase their ability in encapsulating and sustaining the release of NSAIDs. In this paper, polymeric nanoencapsulating microcapsules loaded with NSAIDs were fabricated using solid/water/oil/water emulsion solvent evaporation method. Two NSAIDs, ibuprofen and naproxen, were first pre-loaded into nanoparticles and then encapsulated into a larger hollow microcapsule that contained the third NSAID, celecoxib. A high encapsulation efficiency (%) of these NSAIDs was achieved and a sustained release (up to 30 days) of these drugs in phosphate-buffered saline was observed. Then, a gastrointestinal drug - cimetidine (CIM) - was co-loaded with the NSAIDs. This floating delivery system exhibited excellent buoyancy (~88% up to 24 h) in simulated gastric fluid. It also allowed a sequential release of the drugs, whereby an immediate release of CIM followed by NSAIDs was observed. Drug release of the NSAIDs observed Fickian diffusion mechanism, whereas CIM observed non-Fickian diffusion. Therefore, this delivery system is a promising platform to control the delivery of NSAIDs to combat inflammatory diseases, thereby protecting against possible gastrointestinal side effects that may arise from the overuse of NSAIDs.

Keywords: NSAIDs; diffusion; emulsion; floating oral drug delivery; injectable system; multi-drug encapsulation; oral delivery systems; sequential release; sustained release.

Figure 1

(A) CLSM images of PLGA microcapsule. Z-stack comprises four confocal sections that represent Nile Red (red) encapsulated in PLGA nanoparticles, FITC (green) encapsulated in PLLA NPs, COU343 (yellow) loaded in PLGA MC shell, and merged fluorescence measured from center to top of the multiple-dye-loaded PLGA microcapsule (scale bars represent 50 µm). SEM images of (B) cross-sectional view and (C) merged fluorescence of Z-stacks (scale bar represents 50 µm). Abbreviations: CLSM, confocal laser microscope; COU343, coumarin 343; FITC, fluorescein isothiocyanate; MC, microcapsule; NP, nanoparticle; PLGA, poly(d,l-lactide-co-glycolide); PLLA, poly(l-lactide); SEM, scanning electron microscopy.

Figure 2

FESEM images of (A) IBU-loaded PLGA nanoparticles, (B) NAP-loaded PLLA nanoparticles, (C) cross-sectioned CEL-loaded PLGA microcapsules containing PLGA and PLLA nanoparticles, and (D) CEL-loaded PLGA/PCL microcapsule containing PLGA and PLLA nanoparticles. Subsequent magnifications show PLGA and PLLA nanoparticles within the hollow cavity of the microcapsule. Abbreviations: CEL, celecoxib; FESEM, field emission scanning electronic microscopy; IBU, ibuprofen; NAP, naproxen; PCL, polycaprolactone; PLGA, poly(d,l-lactide-co-glycolide); PLLA, poly(l-lactide).

Figure 3

Release profiles of three NSAIDs from (A) control solid PLGA microparticles (without nanoparticles), (B) PLGA hollow microcapsules (with nanoparticles), and (C) PLGA/PCL hollow microcapsules (with nanoparticles) in PBS (pH 7.4) at 37°C for 30 days (n=3). Abbreviations: CEL, celecoxib; IBU, ibuprofen; NAP, naproxen; NSAIDs, nonsteroidal anti-inflammatory drugs; PBS, phosphate buffered saline; PCL, polycaprolactone; PLGA, poly(d,l-lactide-co-glycolide).

Figure 4

(A) Average molecular weight of PLGA, (B) water uptake, and (C) SEM images of the degrading PLGA microcapsules and PLGA/PCL microcapsules over time. Abbreviations: PCL, polycaprolactone; PLGA, poly(d,l-lactide-co-glycolide); SEM, scanning electron microscopy.

Figure 5

Buoyancy (%) vs time profile of the PLGA and PLGA/PCL microcapsules containing drugs in SGF at 37°C for 24 h (n=3). Abbreviations: PCL, polycaprolactone; PLGA, poly(d,l-lactide-co-glycolide); SGF, simulated gastric fluid.

Figure 6

Release profiles of CIM, IBU, and NAP from PLGA microcapsules in SGF and SIF for 24 h at 37°C (n=3). Abbreviations: CIM, cimetidine; IBU, ibuprofen; NAP, naproxen; PLGA, poly(d,l-lactide-co-glycolide); SGF, simulated gastric fluid; SIF, simulated intestinal fluid.

Scheme 1

Schematic illustration of the encapsulation of NSAIDs into controlled-release microcapsules and the corresponding release of these drugs from the two drug delivery systems (PLGA shell vs PLGA/PCL shell). Abbreviations: CEL, celecoxib; CIM, cimetidine; IBU, ibuprofen; NAP, naproxen; NP, nanoparticle; PCL, polycaprolactone; PLGA, poly(d,l-lactide-co-glycolide); PLLA, poly(l-lactide); S/W₁, solid/water; S/W₁/O, solid/water/oil; S/W₁/O/W₂, solid/water/oil/water.