Passive targeting and lung tolerability of enoxaparin microspheres for a sustained antithrombotic activity in rats

Abstract

Pulmonary bed can retain microparticles (MP) larger than their capillaries' diameter, hence we offer a promising way for lung passive targeting following intravenous (IV) administration. In this study, enoxaparin (Enox)-albumin microspheres (Enox-Alb MS) were, optimally, developed as lung targeted sustained release MP for IV use. Lung tolerability and targeting efficiency of Enox-Alb MS were tested, and the pharmacokinetic profile following IV administration to albino rats was constructed. In vivo studies confirmed high lung targeting efficiency of Enox-Alb MS with lack of potential tissue toxicity. The anticoagulant activity of the selected Alb MS was significantly sustained for up to 38 h compared to 5 h for the market product. Alb MS are promising delivery carriers for controlled and targeted delivery of Enox to the lungs for prophylaxis and treatment of pulmonary embolism.

Keywords: Albumin; anticoagulant; controlled delivery; enoxaparin; microspheres; passive lung targeting.

Figure 1.

Effect of (a) span 80 concentration (% w/v), (b) EL concentration (% w/v), (c) theoretical loading (% w/w) and (d) glutaraldehyde concentration (% w/v) on the particle size and entrapment efficiency % w/w of Enox-Alb MS. D90 is the diameter where 90% of the population lies below this value.

Figure 2.

Release profiles from Enox-Alb MS in PBS pH 7.4 at 37 °C.

Figure 3.

SEM micrographs of freeze dried (a) plain and (b) Enox-Alb MS of formula F8. Magnification ×2700.

Figure 4.

FT-IR spectra of albumin, enoxaparin, plain Alb MS and Enox-Alb MS.

Figure 5.

Fluorescent microscopic images of microtome sections of rat lung (a) 10 min, (b) 6 h, (c) 24 h, (d) 48 h post-IV administration of FITC-dextran loaded Alb MS and (e) confocal microscopic images of rat lung at various depths, 30 min post-IV administration of FITC-dextran loaded Alb MS. Magnification ×200.

Figure 6.

Light photomicrograph of rat lung 24 h post-IV administration of (a) D5W and (b) formula F8 at a magnification of ×160 (a: air alveoli, b: bronchiol and v: blood vessel).

Figure 7.

AntifactorXa activity versus time curve for Enox following IV administration of Clexane® and Enox-Alb MS (F8).