Floating microspheres of valacyclovir HCl: Formulation, optimization, characterization, in vitro and in vivo floatability studies.

Floating microspheres are multiple unit Gastroretentive drug delivery systems. Valacyclovir hydrochloride (VCH) is L-valyl ester prodrug of acyclovir. VCH degrades in intestinal fluid. The objective was to develop floating microspheres of VCH to localise the drug at upper part of GIT, for improved absorption. Floating microspheres were prepared by W/O emulsification solvent evaporation method using Ethylcellulose (EC) as polymer. Particle size and % EE were 550.021±0.241 μm, 79.88±2.236% respectively. in vitro and in vivo floatability studies confirmed floating behaviour of microspheres. VCH loaded floating microspheres can be a suitable alternative to the conventional formulation, by localizing the drug at upper GIT.

The oral route is considered as the most promising and most frequently used route of administration. Oral sustained release delivery systems are widely used to treat diseases. However, the problem frequently encountered with sustained release dosage forms is rapid gastrointestinal transit leading to incomplete absorption of drugs which are absorbed from the upper part of the intestine. Gastro Retentive Drug Delivery Systems (GRDDS) are formulations having gastric retentive behaviour. Floating microspheres are multiple unit GRDDS, enabling delivery of drug at absorption site for a prolonged period of time. Valacyclovir hydrochloride (VCH) is the L-valyl ester prodrug of acyclovir. VCH is chemically stable along the acidic pH side, while it degrades in alkaline medium through a base-catalyzed pseudo-first-order kinetics. The degradation of the VCH progress faster in intestinal fluid. VCH is nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is absorbed slowly and incompletely from the human gastrointestinal tract. The objective of the present work was to develop Gastroretentive floating microspheres of VCH to localise the drug at upper part of GIT, for improved absorption and oral bioavailability.

Materials and Methods

Preparation

Floating microspheres loaded with VCH were prepared by using water-in-oil (W/O) emulsification solvent evaporation method.[1] Polymer (EC) was dissolved in mixture of dichloromethane and ethanol (1:1). Drug was dispersed in polymer solution by stirring with high speed stirrer for 15 min. The dispersion was slowly poured into the dispersion medium (250 ml) consisting of light liquid paraffin containing 0.1% Span 80. The system was stirred using an overhead propeller agitator (Remi equipments, India) for a period of 3–4 h, to ensure complete evaporation of organic phase. Microspheres were collected by filtration and washed thrice with n-hexane and air dried. The prepared microspheres were optimized on the basis of particle size.[12]

Characterization

The particle size was determined using Mastersizer (2000, Malvern, UK). Estimation of entrapment efficiency was carried out by dissolving the microspheres in a dichloromethane and ethanol (1:1) and extracting the drug by adding same amount of dissolution medium (0.1N HCl) aqueous layer was separated and analysed by UV spectrophotometer (1700, Shimadzu, Japan) at 255 nm. Surface morphology of microspheres was studied under scanning electron microscope (JEOL, JSM 5760 LY). DSC and FTIR studies were performed to check the compatibility of drug (VCH) with ethyl cellulose using Differential Scanning Calorimeter (Shimadzu AS, Japan) and FTIR (Bruker optics, Germany). The XRD pattern of pure drug, physical mixture and prepared microspheres were obtained using a powder diffractometer (Bruker AXS D8 Advance, Germany). in vitro floatability and drug release studies were carried out in USP type II dissolution testing apparatus, using dissolution medium (0.1N HCl) containing tween-80 (0.02%) at 100 rpm. in vivo floatability study was carried out in healthy beagle dogs. X ray photograph of stomach was taken after administration of Barium sulphate loaded floating microspheres.

Results and Discussion

Particle size of optimized floating microspheres was found to be 550.021±0.241 μm. The percentage entrapment efficiency of prepared floating microspheres was 79.88± 2.236%. SEM photograph [Figure 1] revealed that, microspheres were spherical, had narrow distribution and porous. FT-IR, DSC and XRD studies [Figure 2] confirmed no interaction between VCH and ethyl cellulose. In vitro floatability studies revealed that 90% of the microspheres were floated for more than 12 hours because of their low densities and internal voids. The densities of floating microspheres were found less than the density of gastric fluid, therefore tended to float over gastric fluid. Optimized floating microspheres exhibited 94.03% drug release at 12h. X ray photographs confirmed the in vivo floatability of microspheresindogs.

Figure 1

SEM Images of VCH loaded floating microspheres showing porous surface

Figure 2

X ray photograph of barium sulphate loaded floating microspheres in dog

Conclusion

VCH loaded floating microspheres can be a suitable alternative to the conventional formulation, by localizing the drug at upper GIT. Thereby, improving the bioavailability and reducing the dosing frequency.