Freeze-dried matrices for ocular administration of bevacizumab: a comparison between subconjunctival and intravitreal administration in rabbits.

This work was aimed to tune solid matrices for bevacizumab (BVZ) subconjunctival or intravitreal administration in order to prolong drug release, to reduce the number of applications and consequently the side effects. Matrices, with sizes suitable for intravitreal or subconjunctival administration, based on hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and polyacrylic acid (PAA) were obtained by freeze-drying of polymeric dispersions either in phosphate buffer solution or water and were sterilized by gamma rays. The matrices were characterized from the technological point of view and evaluated for in vitro release of dextran and BVZ. In vivo evaluation of BVZ release in ocular humours was finally carried out on rabbits. The obtained matrices showed solvent sorption time ranging from a few seconds for PAA to 46 min for HPMC, with shorter times when prepared in buffer solution. The hydration times were up to 5.5-fold higher after sterilization. HPMC and PVA matrices showed a slowdown of the release rate of both dextran and BVZ, but HPMC was selected for following in vivo studies also in consideration of its higher viscosity after rehydration of the matrix. HPMC matrix was well tolerated by the rabbit eye when intravitreally and subconjunctivally administered. The different treatment produced the same effect in terms of drug concentration in aqueous and vitreous humour up to 12 weeks after administration. The results of this study support the possible use of lyophilized matrices as a BVZ delivery system to the posterior segment of the eye.

Nonpolymeric nanoassemblies for ocular administration of acyclovir: pharmacokinetic evaluation in rabbits.

The aim of this study was to increase bioavailability of the antiviral drug acyclovir (ACV) when administered by the ocular route. For this purpose, a new lipophilic derivative of acyclovir was synthesized, both possessing greater lipophilicity and providing the formation of a homogeneous water dispersion with higher amount of ACV than the aqueous solution of the parent drug. This was done by chemically linking acyclovir to the isoprenoid chain of squalene, obtaining 4'-trisnorsqualenoylacyclovir (SQACV), in which squalene is covalently coupled to the 4'-hydroxy group of acyclovir. This new prodrug was then formulated as nonpolymeric nanoassemblies through nanoprecipitation; the resulting particles were characterized in terms of mean diameter, zeta potential, and stability. The pharmacokinetic profile of the prodrug in the tear fluid and in the aqueous humor of rabbits was evaluated and compared to that of the parent drug. Data showed that SQACV nanoassemblies increased the amount of ACV in the aqueous humor of rabbits compared to free ACV solution. This new amphiphilic prodrug of acyclovir is a very promising tool to increase the ocular bioavailability of the parent drug.

Arabinogalactan as active compound in the management of corneal wounds: in vitro toxicity and in vivo investigations on rabbits.

PURPOSE: Aims of the present investigation were to prove that natural polysaccharide arabinogalactan (AG) is well tolerated after ocular administration and exerts a high restoring effect on corneal epithelium abrasions. MATERIALS AND METHODS: AG interactions with corneal cells, as well as its effect on their proliferation, were evaluated employing rabbit corneal epithelial cell cultures. The effects due to the presence of benzalkonium chloride (BAK) were also studied on cell cultures, ex vivo on rabbit isolated corneas, evaluating the hydration level, and on the healing rate of experimental corneal wounds in rabbits. Furthermore, the healing process of corneal lesions treated with an experimental 5.0% AG solution was studied and compared with those obtained applying solutions of hyaluronic acid and tamarind seed polysaccharide, both chosen as a reference by virtue of their well-known adjuvant properties on corneal trophism; the study was carried out by light and transmission electron microscopy. RESULTS: BAK showed toxic effects on corneal epithelium in all experiments. AG proved to stimulate the growth of the corneal epithelial cells by interacting at the level of the cell plasma membrane. The microscopy observations of the epithelial surface of AG-treated damaged corneas revealed a well-restored and histologically organized ultrastructure characterized by fully formed microvilli and glycocalyx; the healing process resulted faster with respect to spontaneously recovered untreated corneas. CONCLUSION: Our results suggest that AG can interact with corneal epithelial cells without any toxic side effect; moreover, it proved to stimulate cell proliferation, thus promoting tissue re-epithelialization and reorganization just 48 hr post-wounding.

Larch arabinogalactan for dry eye protection and treatment of corneal lesions: investigations in rabbits.

PURPOSE: The aim of the present study was to investigate the corneal protective and healing properties of arabinogalactan (AG), a natural polysaccharide present in conifers of the genus Larix (Larch). AG was tested in comparison with other two polysaccharides possessing well-established properties in the treatment of dry eye: tamarind seed polysaccharide and hyaluronic acid. METHODS: The AG formulation was subjected to the following investigations: rheologic measurements; evaluation of mucoadhesive properties by rheologic interaction with mucin; ferning test; and in vivo evaluation on rabbits, including treatment of an experimental dry eye; evaluation of the preocular retention; and evaluation of healing rate of experimental corneal wound. RESULTS: AG dispersions showed a newtonian nonviscous behavior, eta = 1.6 mPa . s for 10% w/w solution; it possessed good mucoadhesive properties useful for retention on the eye surface. In fact, a prolonged time of residence in rabbit eyes was ascertained using fluorescein-labeled AG. Five percent (5.0%) w/w AG exerted a good protective effect against the appearance of corneal dry spots. It also reduced significantly the healing time of an experimental corneal lesion since 27 h after the first treatment. CONCLUSIONS: These findings suggest that AG may be a potential therapeutic product for dry eye protection and for the treatment of corneal wounds.