Monia Zignani

Topical semi-solid drug delivery: kinetics and tolerance of ophthalmic hydrogels

The efficacy of ophthalmic semi-solid hydrogels is mostly based on an increase of ocular residence time, via enhanced viscosity and mucoadhesive properties. Preformed and in particular in situ gelling systems improve bioavailability and decrease the side effects induced by the systemic absorption of topically applied ophthalmic drugs. Since increased viscosity often causes the discomfort of blurred vision and foreign body sensation, it is important to assess the optimal range of viscosity as well as the most suitable rheological behavior which will ensure good efficacy and tolerance.

Concomitant and controlled release of dexamethasone and 5-fluorouracil from poly(ortho ester)

A viscous bioerodible and hydrophobic poly(ortho ester) has been developed as a biocompatible, sustained drug release system for an ophthalmic application in intraocular proliferative disorders. The combination of wound healing modulators such as 5-fluorouracil and dexamethasone is a major advantage since these drugs act at different stages of these diseases. Since 5-fluorouracil is an acidic, water-soluble compound and dexamethasone exists in three chemical forms, i.e. the water-insoluble base, the highly hydrophobic acetate ester or the basic phosphate salt, it was of interest to investigate whether the physicochemical properties of the drugs have an influence on their release rates, and whether a concomitant and sustained release of both 5-fluorouracil and dexamethasone could be achieved. It has been found that lipophilicity and acidobasicity play a major role in controlling drug release rates and polymer degradation. The combination of 5-fluorouracil and dexamethasone phosphate allows a sustained and concomitant release of both drugs, due to the basic characteristics of the corticosteroid which stabilize the polymer. This system appears to be promising for concomitant and controlled drug delivery aimed at the pharmacological treatment of intraocular proliferative disorders.

A poly(ortho ester) designed for combined ocular delivery of dexamethasone sodium phosphate and 5-fluorouracil: subconjunctival tolerance and in vitro release

A viscous hydrophobic poly(ortho ester) (POE) has been developed as a biocompatible, biodegradable sustained release system for selected cases of glaucoma filtering surgery. Dexamethasone and 5-fluorouracil (5-FU) are frequently administered together post-operatively, for their anti-fibroblastic and anti-inflammatory properties, respectively. A combined sustained release of both drugs could be advantageously used. Drug release kinetics were studied using specially designed thermostated cells. Subconjunctival tolerance was evaluated on New Zealand albino rabbits by clinical evaluation. Due to its basicity, the addition of dexamethasone sodium phosphate (DEX-P) stabilized the polymer and prolonged 5-FU in vitro release from 2 to 4 days. Both therapeutic agents were released concomitantly, according to a linear profile. The presence of 5-FU only slightly affected the overall subconjunctival tolerance of POE in rabbits, whereas the addition of DEX-P markedly improved POE tolerance by reducing the hyperemia of the conjunctiva to a minimal grade.

Ocular drug delivery in veterinary medicine

This paper provides a comprehensive overview of the various approaches currently used in the development of ocular drug delivery systems for the treatment of ocular diseases in animals. It is obvious from the literature that most of the products that are currently available are derived from human medicine without consideration given to the differences which exist between the anatomy and physiology of the eye of various animal species which ultimately affect product design and performance. As a result, many of the products for animal use seem in many circumstances inappropriate for animal care. The article deals with some aspects of eye anatomy and physiology of different animals, and then provides an overview of the most commonly encountered pathologies. The paper then discusses the currently available drug products and finally reviews new delivery concepts. Several hundred references are included in the paper and provide access to further information on the subject.

New generation of poly(ortho esters): synthesis, characterization, kinetics, sterilization and biocompatibility

Abstract After a brief historical overview of the development of three families of poly(ortho esters) (POEs), the physico-chemical characteristics, drug release properties and biocompatibility of the third generation is discussed. Its synthesis is based on a transesterification reaction between 1,2,6-hexanetriol and trimethylorthoacetate. This viscous hydrophobic polymer has been used for the sustained release of 5-fluorouracil (5-FU) or mitomycin C (MMC) in glaucoma filtering surgery. It shows a good correlation between drug release and polymer erosion and can be injected using a hydraulic syringe. Drug release can be modulated by using different molecular weights of the polymer, or by adding basic or acidic excipients. Because conventional sterilization methods using gamma or electron beam-irradiation can not be used due to changes in molecular weight and dynamic viscosity resulting from backbone cleavage, an aseptic fabrication procedure has been developed and validated. POE biocompatibility has been established after subconjunctival injections of POE, monomers and degradation products in rabbits. Better control of the microenvironmental pH during polymer degradation has been achieved by using an in situ formed buffer system.

Improved biocompatibility of a viscous bioerodible poly(ortho ester) by controlling the environmental pH during degradation

The poly(ortho ester), POE, used in this investigation, is a viscous bioerodible polymer (8 kDa), which rapidly degrades into a triol and an acidic by-product, acetic acid. In order to improve biocompatibility, we have evaluated the addition of various basic excipients, such as sodium acetate, hydroxyapatite, calcium carbonate and magnesium hydroxide, which buffered and neutralized the acidic degradation product and prolonged the polymer lifetime and drug release. This decrease of POE degradation rate results in a decreased rate of formation of the acidic by-product. Similarly, a POE of higher molecular weight (14 kDa) has been tested. Sodium acetate was too hydrophilic to affect the drug release and the biocompatibility of the polymer, whereas the presence of magnesium hydroxide markedly prolonged the drug release and improved the acceptability of the polymer. The increased molecular weight POE did not improve biocompatibility and a similar but delayed, inflammatory reaction was observed.