Mf Saettone

Development and in vitro/in vivo testing of mucoadhesive buccal patches releasing benzydamine and lidocaine

Mucoadhesive patches releasing topical drugs in the oral cavity at a slow, predetermined rate may present distinct advantages over traditional dosage forms such as mouthwashes, oral gels and lozenges. The present study was concerned with the preparation and evaluation of mucoadhesive buccal patches for controlled release of benzydamine (BNZ) and lidocaine (LDC). The drugs were used as hydrochlorides, or, to reduce their solubility and improve their release characteristics, as salts with pectin or polyacrylic acid. A LDC-tannic acid complex was also prepared and tested. After an initial screening of mucoadhesive polymers, tamarind gum (TG), a polysaccharide obtained from the seeds of Tamarindus indica, was selected as the adhesive component. In vitro tests, carried out on a cell line of human buccal epithelial origin, indicated a very low sensitivity for TG. The patches, prepared by compressing appropriate mixtures containing the drug salts/complexes, lactose and TG, were tested in vitro for mucoadhesion and drug release, and in vivo on human volunteers for retention and release of BNZ. The devices containing the salts of BNZ with pectin and polyacrylic acid, and the complex of LDC with tannic acid showed zero-order release kinetics in vitro. The patches adhered for over 8 h to the upper gums of the volunteers, and were perfectly tolerated. BNZ hydrochloride was released in vivo and in vitro with practically identical profiles.

Gel-forming erodible inserts for ocular controlled delivery of ofloxacin

A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo. Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression. The in vitro drug release from inserts was mainly controlled by insert erosion. The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71). The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds. Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17. Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type. On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs. 1.39 +/- 0.05 microg ml(-1); 693.6 vs. 62.7 microg ml(-1) min; and 290 vs. 148 min, respectively). Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.

Development of a Simple Dry Eye Model in the Albino Rabbit and Evaluation of Some Tear Substitutes

The present paper is concerned with the development of a simple dry eye model in the rabbit, induced by daily repeated instillations of 1.0% atropine sulphate. The evolution of the dry eye syndrome in the animals was assessed by the Schirmer I test and by examination of the cornea after fluorescein staining. The model produced rapidly some typical dry eye symptoms and could be satisfactorily used for a preliminary assessment of the protective activity of some polymeric tear substitutes. These were based on hydroxypropylmethylcellulose, sodium hyaluronate, sodium polyacrylate or tamarind gum. The latter polymer showed the best overall results. Ferning tests on the formulations were also performed: their validity as predictors of the efficacy of tear substitutes is discussed.

In vitro transungual permeation of ciclopirox from a hydroxypropyl chitosan-based, water-soluble nail lacquer.

Commercial antimycotic nail lacquers are commonly based on water-insoluble resins. The present study was aimed at evaluating a novel, experimental nail lacquer (P-3051, Polichem SA, Lugano, Switzerland) based on the water-soluble film-forming agent hydroxypropyl chitosan (HPCH). The in vitro permeation of ciclopirox (CPX) from P-3051 and from a commercial, water-insoluble lacquer based on a vinyl resin (Penlac™, Aventis Pharma), was investigated using thin membranes obtained from bovine hooves, an accepted model for human nails. Similar CPX permeation fluxes at steady state through the membranes, but significantly different lag times were observed for P-3051 and Penlac™, when these were tested as dry films. The formulations thus appeared to influence only the time required by CPX to saturate the membrane, and not the final drug concentration gradient in the membrane. Permeation experiments performed on the same membranes and on hairless mouse skin with P-3051 and with a similar, HPCH-free vehicle (ERV), both tested in liquid form, disproved the possibility that HPCH might act as a permeation enhancer for CPX in either substrate. The possible reasons for the greater efficiency of the HPCH vehicle in terms of CPX transfer from the vehicle itself to the keratin membrane are discussed. This effect might be tentatively attributed to a particular affinity of HPCH for the membrane, resulting in intimate contact and strong adhesion of the HPCH lacquer to the keratin substrate.

Evaluation of high- and low-molecular weight fractions of sodium hyaluronate and an ionic complex as adjuvants for topical ophthalmic vehicles containing pilocarpine

Ophthalmic vehicle; Hyaluronic acid; Pilocarpine; Miotic test; Ocular permanence test; Rabbit; Bioadhesion Summary Two low-molecular-weight fractions of sodium hyaluronate (Na-HA), denominated Hyalastin® and Hyalectin®, were investigated as potential adjuvants for ophthalmic vehicles containing pilocarpine nitrate (PiN). Tests were also performed on an ionic complex (HA/PiB) prepared from hyaluronic acid (derived from Hyalastin®) and pilocarpine base. The performance of the vehicles under study was verified by miosis and ocular retention tests carried out on albino rabbits, against a series of reference vehicles, three of which contained a high-molecular-weight fraction of Na-HA (Healon®). The group of 14 reference and test preparations exhibited Newtonian or pseudoplastic flow characteristics and encompassed a wide range of apparent viscosities (1 to 1054 mPa s). The results indicate that the HA/PiB salt and the high-MW Na-HA can significantly increase the bioavailability of pilocarpine with respect to reference vehicles of comparable viscosity: an effect that can be reasonably attributed to muco-adhesive effects. Conversely, in the present rabbit tests, the low-MW fractions of Na-HA performed poorly as adjuvants for the PiN solutions.

Pectin microspheres as ophthalmic carriers for piroxicam: evaluation in vitro and in vivo in albino rabbits

Microparticulate polymeric delivery systems have been suggested as a possible approach to improve the low bioavailability characteristics shown by standard ophthalmic vehicles (collyria). Purpose of this study was the evaluation of pectin microspheres as delivery system for piroxicam (Px). The microspheres were prepared by a spray-drying technique; their morphological characteristics were investigated by scanning electron microscopy (SEM), and their in vitro release behavior was evaluated in pH 7.0 USP buffer using a flow-through apparatus. Px loaded in the pectin microspheres showed a faster in vitro dissolution rate with respect to solid micronized drug. The precorneal retention of fluorescein-loaded microspheres was evaluated in vivo in albino rabbits: an aqueous dispersion of fluorescent microspheres showed a significantly increased residence time in the eye (2.5 vs. 0.5 h) when compared with a fluorescein solution. In vivo tests in rabbits of dispersions of Px-loaded microspheres also indicated a significant improvement of Px bioavailability in the aqueous humour (2.5-fold) when compared with commercial Px eyedrops. The potential advantages and limitations of this delivery system are discussed.

Preparation and evaluation in vitro of colloidal lipospheres containing pilocarpine as ion pair

Abstract Aqueous dispersions of solid lipospheres containing up to 7.5% pilocarpine as lipophilic ion pairs were submitted to a preliminary evaluation. The lipospheres (diameter 75–85 nm) consisted mainly of stearic acid and egg lecithin; pilocarpine base was incorporated as ion pair with mono-octylphosphate, monodecylphosphate and monohexade-cylphosphate. The following parameters were investigated: stability constants (β) and lipophilicity of the ion pairs, size, polydispersity and drug content of the lipospheres, pilocarpine release in vitro. The preparations might constitute a promising vehicle for sustained ocular delivery of pilocarpine.

Effect of chitosan on in vitro release and ocular delivery of ofloxacin from erodible inserts based on poly(ethylene oxide)

The effects of chitosan hydrochloride (CH-HCl) on in vitro release of ofloxacin (OFX) from mucoadhesive erodible ocular inserts and on the relevant ocular pharmacokinetics have been studied both to contribute evidence of the ability of CH-HCl to enhance transcorneal penetration of drugs and to increase the therapeutic efficacy of topically applied OFX. Circular inserts of 6 mm in diameter, 0.8-0.9 mm in thickness and 20 mg in weight, medicated with 0.3 mg drug, were prepared by powder compression. The addition of 10, 20 or 30% medicated CH-HCl microparticles, obtained by spray-drying, to formulations based on poly(ethylene oxide) of MW 900 kDa (PEO 900) or 2000 kDa (PEO 2000) produced changes in the insert microstructure which accelerated both insert erosion and OFX release from inserts. The effect was stronger with higher CH-HCl fractions. Of the CH-HCl-containing formulations based on either PEO 900 or PEO 2000, PEO 900-CH-HCl (9:1 w/w) was more suitable for a prolonged OFX release. Following insertion in the lower conjunctival sac of the rabbits eye, such an insert produced no substantial increase of AUC(eff) (AUC in the aqueous humour for concentrations >MIC(90%)) with respect to inserts based on plain PEO; however, it produced a concentration peak in the aqueous significantly higher than that produced by any of the CH-HCl-free PEO inserts, and well higher than the MIC(90%) for the more resistant ocular pathogens (7 microg/ml vs. 4 microg/ml). It has been argued that the increase was due to the ability of CH-HCl to enhance the transcorneal permeability of the drug.

Ocular toxicity of some corneal penetration enhancers evaluated by electrophysiology measurements on isolated rabbit corneas

The influence on electrical resistance and membrane potential of rabbit corneas in vitro of some chemicals used as adjuvants in ophthalmic formulations was investigated, in the attempt to correlate changes in electrophysiological properties of the corneal tissue (possibly indicative of toxic/damaging effects to the corneal epithelium), with the promoting effect of the substances on transcorneal permeation in vitro of timolol maleate (TM). The chemicals, tested at different concentrations, were benzalkonium chloride (BAC), sodium ethylenediaminetetraacetate (EDTA), polyoxyethylene-20-stearyl ether (PSE), polyethoxylated castor oil (PCO), deoxycholic acid sodium salt (DC) and cetylpyridinium chloride (CPC). For these substances, definite correlations were found between promoting activity for permeation of TM and modification of electrophysiological parameters. These parameters were in all cases significantly altered by all agents at all concentrations after a 5-h contact. However, after a 1-h contact, 0.001% PSE and CPC did not significantly modify the corneal resistance, while PCO and PSE did not significantly modify the transcorneal potential at the tested concentrations. Only 0.001% PSE, a nonionic surfactant used as solubilizer and emulsifier, active as promoter for TM, did not modify both electrophysiological parameters to a significant extent after 1 h. The results of this study indicate correlations between ocular toxicity, promoting activity for transcorneal permeation of timolol and modification of the electrophysiological parameters.

Effect of different polymer-plasticizer combinations on ‘in vitro' release of theophylline from coated pellets

Abstract Plasticizers are added to the polymer coating of sustained-release granules to improve the mechanical properties of the coating shell. The present investigation evaluated the influence of different plasticizer/polymer combinations on theophylline (TH) release from pellets coated with latex aqueous dispersions of ethylcellulose (EC) or acrylic polymers (ACR). The plasticizers, present in the coating films in amounts ranging from 8 to 30%, were acetylated monoglycerides (AMG), diethyl phthalate (DEP), dibutyl phthalate (DBP) and dibutyl sebacate (DBS). The release profiles of TH from the coated pellets were influenced by the type and amount of plasticizer and of coating material, and by the ratio polymer-plasticizer. For both types of coating, the drug release rate decreased with increasing plasticizer content. A correlation was found between the permeability coefficients (Pwv) to water vapour of free films, having the same composition as those used for coating, and drug release.