Development and in vitro evaluation of a liposomal vaginal delivery system for acyclovir.

Design of a liposome delivery system for vaginal administration of acyclovir, able to provide sustained release and improved bioavailability of the encapsulated drug for the local treatment of genital herpes was investigated. Acyclovir was encapsulated in liposomes prepared by the polyol dilution method, whereby various phospholipid compositions were used: egg phosphatidylcholin (PC)/egg phosphatidylglycerol (PG) 9:1, egg phosphatidylcholine (PC) and egg phosphatidycholine (PC)/stearylamine (SA) 9:3. All liposome preparations were characterized and compared for particle size, polydispersity, encapsulation efficiency and tested for in vitro stability in different media chosen to simulate human vaginal conditions: buffer, pH 4.5 (corresponding to normal human vaginal pH), vaginal fluid simulant (medium developed so as to mimic the fluid produced in the vagina) with or without mucin. To be closer to in vivo application of liposomes and to achieve further improvement of their stability, liposomes were incorporated in a vehicle suitable for vaginal self-administration. Bioadhesive hydrogel made from Carbopol 974P NF resin with adequate pH value and desirable viscosity was chosen as a vehicle for liposomes containing acyclovir. In vitro release studies of liposomes incorporated in the hydrogel proved their applicability as a novel vaginal delivery system with localized and sustained release of encapsulated acyclovir. Even after 24 h of incubation in vaginal fluid simulant more than 35% of the originally encapsulated drug was retained in the hydrogel.

Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption.

A method of producing self-emulsifying pellets by wet granulation of powder mixture composed of microcrystalline cellulose, lactose and nimesulide as model drug with a mixture containing mono- and di-glycerides, polisorbate 80 and water, in a 10-l high shear mixer has been investigated. The effects of the formulation variables on pellets characteristics were evaluated by mixtures experimental design and by a polynomial model, in order to describe the phenomenon, to verify eventual interactions among components of the mixture and to investigate the feasibility of scaling-up. After determination of size distribution, the pellets were characterised by scanning electron microscopy, dissolution and disintegration tests, and by in vitro absorption test Such an approach, applied to the development of a self-emulsifying system for nimesulide as poorly water-soluble model drug, resulted in different formulations with improved drug solubility and permeability characteristics. The data demonstrate that pellets composed of oil to surfactant ratio of 1:4 (w/w) presented improvement in performance in permeation experiments.

Spray-dried carbamazepine-loaded chitosan and HPMC microspheres: preparation and characterisation.

In this study, the potential of the spray-drying technique for preparing microspheres able to modify the release profile of carbamazepine was investigated. Low-, medium- and high-molecular-weight chitosan and hydroxypropyl methylcellulose (HPMC) in different drug-polymer ratios were used for the preparation of microspheres. The microspheres, characterized by X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC), were also studied with respect to particle size distribution, drug content and drug release. The results indicated that the entrapment efficiency (EE), as well as carbamazepine release profile, depended on polymeric composition and drug-polymer ratios of the microspheres prepared. The best entrapment efficiencies were obtained when chitosan of low-molecular-weight (CL) or HPMC were used for the microencapsulation. For all types of polymer used, the microspheres with low carbamazepine loading (6.3% w/w) showed better control of drug release than the microspheres with higher drug loadings. The HPMC microspheres showed the slowest carbamazepine release profile with no initial burst effect. Carbamazepine release profiles from ternary systems, carbamazepine-CL-HPMC microspheres, depended mostly on HPMC content and showed similar carbamazepine release profile as CL microspheres when HPMC content was low (9:1 CL-HPMC ratio, w/w). Otherwise, the carbamazepine release from CL-HPMC microspheres was remarkably faster than from either chitosan or HPMC microspheres. The release profile of carbamazepine from the microspheres was highly correlated with the crystalline changes occurring in the matrix.

Gemfibrozil encapsulation and release from microspheres and macromolecular conjugates.

The purpose of this study was to evaluate and compare the ability of the macromolecular conjugates and microspheres to modify the release rate of gemfibrozil (Gem). Gem was covalently linked to two similar polymers: poly[alpha,beta-(N-2-hydroxyethyl-DL-aspartamide)] (PHEA) and poly[alpha,beta-(N-3-hydroxypropyl-DL-aspartamide)] (PHPA) by an ester linkage. The polymer-drug conjugates obtained (PHEA-G(1-3) and PHPA-G) differ in weight-average molecular weight, length of spacer and Gem content. Microspheres, composed of chitosans of different molecular weight alone or as a mixture with (2-hydroxypropyl)methylcellulose (HPMC), PHEA or PHPA and with different theoretical polymer/drug ratio (2:1 and 3:1, w/w) were prepared by spray drying. The microparticulate systems were morphologically characterised by scanning electron microscopy, particle size analysis and Gem content was determined. In vitro dissolution tests were performed to evaluate the feasibility of conjugates and microspheres in modulating Gem release. The results obtained show that microspheres are always suitable to modulate Gem release and that the best conditions are achieved by microspheres composed of the low molecular weight chitosan (CL) combined with PHPA or HPMC with either 2:1 or 3:1 (w/w) polymer/drug ratio. The PHEA-G conjugates exhibited rapid Gem release within less than 2 h, while the PHPA-G conjugate showed sustained Gem release profiles over a 10-h period.