Preparation and in vitro characterization of valsartan-loaded ethyl cellulose and poly(methyl methacrylate) nanoparticles

Abstract

Valsartan is an antihypertensive drug used primarily orally, however, due to its hydrophobic nature it has got low bio-availability thus requiring higher dosage/frequency and causing more side effects. The aim of our work was to prepare valsartan-loaded nanoparticles by using ethyl cellulose and poly(methyl methacrylate) polymers which can be administered orally and to investigate the preparation conditions and their significance as potential drug carriers for valsartan delivery by in vitro release studies. Ethyl cellulose and poly(methyl methacrylate) polymers were used for the preparation of nanoparticles by single emulsion-solvent evaporation technique. The formation of drug-loaded nanoparticles was designed by experimental design for size and encapsulation efficiency, in addition the prepared nanosuspensions were nano spray dried in order to gain a powder form that is easy to handle and store. Both of the nano spray dried formulations had an amorphous structure in contrast to the pure drug according to differential scanning calorimetry and X-ray diffraction analysis, which can be advantageous in drug absorption. The originally processed ethyl cellulose-valsartan nanoparticles increased the solubility of the drug in the model intestinal medium, while poly(methyl methacrylate)-valsartan nanoparticles enabled substantially prolonged drug release. The release kinetics of both types of nanoparticles could be described by the Weibull model.

Fig. 1. Particle size distribution of poly(methyl methacrylate)-valsartan (PMV4) and ethyl cellulose-valsartan (ECV54) nanoparticles.

Fig. 2. TEM images of ethyl cellulose- (A) and poly(methyl methacrylate)-valsartan (B) nanoparticles.

Fig. 3. Particle size distribution of nano spray dried suspension of poly(methyl methacrylate-valsartan) (PMV4-P) and ethyl cellulose-valsartan (ECV54-P) nanoparticles.

Fig. 4. SEM images of nano spray dried ethyl cellulose- (A) and poly(methyl methacrylate)-valsartan (B) nanoparticles.

Fig. 5. Size distribution of ethyl cellulose-valsartan nanosuspension (ECV54), its spray dried and resuspended suspension (ECV54-P redisp) and the spray dried subsequently redispersed suspension using sonication (ECV54-P redisp-US).

Fig. 6. Size distribution of poly(methyl methacrylate)-valsartan nanosuspension (PMV4) and of the spray-dried and resuspended suspension (PMV4-P redisp).

Fig. 7. DSC diagrams of PVA emulsifier, valsartan, and the polymers as well as that of nano spray dried suspension of poly(methyl methacrylate) (PMMA)-valsartan (PMV4-P, (A)) and ethyl cellulose (EC-4)-valsartan (ECV54-P, (B)) nanoparticles.

Fig. 8. TG diagrams of PVA emulsifier, valsartan, and the polymers as well as that of nano spray dried suspension of poly(methyl methacrylate) (PMMA)-valsartan (PMV4-P, (A)) and ethyl cellulose (EC-4)-valsartan (ECV54-P, (B)) nanoparticles.

Fig. 9. XRD results of nano spray dried samples from ethyl cellulose (EC-4)-valsartan (ECV28, red line) and poly(methyl methacrylate) (PMMA)-valsartan (PMV4, green line) nanoparticle suspensions and that of the raw materials: EC-4 (blue line), PMMA (yellow line), valsartan (black line), PVA (grey line).

Fig. 10. In vitro release profile of valsartan from ethyl cellulose-valsartan nanoparticles in 0.1 N HCl for 2 h and in phosphate buffer solution at pH 6.8 for further 4 h.

Fig. 11. Zero order kinetics of valsartan, ethyl cellulose-valsartan- (EC-valsartan) and poly(methyl methacrylate)-valsartan (PMMA-valsartan) nanoparticles in the acidic medium.

Fig. 12. Weibull model at T_i = 135 min for valsartan, ethyl cellulose-valsartan- (EC-valsartan) and poly(methyl methacrylate)-valsartan (PMMA-valsartan) nanoparticles.

Fig. 13. Linear and non-linear regression of Weibull model and the biphasic model for valsartan dissolution at pH = 6.8.

Fig. 14. Biphasic model of valsartan, ethyl cellulose-valsartan- (EC-valsartan) and poly(methyl methacrylate)-valsartan (PMMA-valsartan at pH = 6.8.).