Application of hydroxyapatite nanoparticles in development of an enhanced formulation for delivering sustained release of triamcinolone acetonide

Abstract

We report an analysis of in vitro and in vivo drug release from an in situ formulation consisting of triamcinolone acetonide (TR) and poly(D,L-lactide-co-glycolide) (PLGA) and the additives glycofurol (GL) and hydroxyapatite nanoparticles (HA). We found that these additives enhanced drug release rate. We used the Taguchi method to predict optimum formulation variables to minimize the initial burst. This method decreased the burst rate from 8% to 1.3%. PLGA-HA acted as a strong buffer, thereby preventing tissue inflammation at the injection site caused by the acidic degradation products of PLGA. Characterization of the optimized formulation by a variety of techniques, including scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transform near infrared spectroscopy, revealed that the crystalline structure of TR was converted to an amorphous form. Therefore, this hydrophobic agent can serve as an additive to modify drug release rates. Data generated by in vitro and in vivo experiments were in good agreement.

Keywords: PLGA; glycofurol; hydroxyapatite nanoparticle; triamcinolone acetonide.

Figure 1

Poly(d,l-lactide-co-glycolide) hydrolysis.

Figure 2

Structures of A) triamcinolone acetonide and B) polyethylene glycol ether.

Figure 3

Triamcinolone acetonide release kinetics in poly(d,l-lactide-co-glycolide) in phosphate buffer.

Figure 4

Hydroxyapatite nanoparticles.

Figure 5

Cumulative triamcinolone acetonide release kinetics in poly(d,l-lactide-co-glycolide)-hydroxyapatite in phosphate buffer.

Figure 6

Cumulative TR release kinetics in poly(d,l-lactide-co-glycolide)-hydroxyapatite in phosphate buffer (after 1.5 days).

Figure 7

Effects of variables vs parameter levels.

Figure 8

Effects on pH of triamcinolone acetonide (5%) with PLGA or PLGA-HA. Abbreviations: PGLA, poly(d,l-lactide-co-glycolide); PGLA-HA, poly(d,l-lactide-co-glycolide) with hydroxyapatite.

Figure 9

SEM image of membranes after immersion in phosphate buffer for 20 days: A) poly(d,l-lactide-co-glycolide) and B) PGLA-HA: poly(d,l-lactide-co-glycolide) with hydroxyapatite.

Figure 10

Diffractograms of A) triamcinolone acetonide B) PLGA and triamcinolone acetonide (15%), C) PLGA and triamcinolone acetonide (15%) and polyethylene glycol ether (3%). Abbreviation: PLGA, poly(D,L-lactide-co-glycolide).

Figure 11

Scanning electron microgram of poly(d,l-lactide-co-glycolide) membranes: A) 3% and B) 0% polyethylene glycol ether.

Figure 12

Fourier transform near infrared spectra of poly(d,l-lactide-co-glycolide) membranes in the presence of A) 0%, B) 1%, and C) 3% polyethylene glycol ether.

Figure 13

Hot-plate response of mice (n = 5) administered triamcinolone acetonide.

Figure 14

Hot-plate response of mice (n = 5) administered triamcinolone acetonide with poly(d,l-lactide-co-glycolide).