4-Methylbenzylidene camphor microspheres: reconstituted epidermis (Skinethic®) permeation and distribution.

OBJECTIVE: The UV filter 3(4-methylbenzylidene) camphor (4-MBC) is a common ingredient in sunscreen cosmetic products. However, different 'in vitro' and 'in vivo' studies suggest that 4-MBC can cause endocrine disrupting effects. Therefore, there is a need for new systems able to minimize the skin penetration of this UV filter. The aim of this study was to evaluate cutaneous permeation and distribution, through and into EPISKIN reconstituted epidermis (RE) from an O/W emulsion containing 4-MBC free or encapsulated in polymeric substantive microspheres. METHODS: Microspheres containing 4-MBC were prepared using the emulsification-solvent evaporation method and characterized for shape and surface morphology and encapsulation efficiency. O/A emulsions containing sunscreen free or encapsulated in microspheres were undergone to permeation tests through RE using vertical diffusion cells. At the end of the in vitro permeation experiments, the skin was subjected to tape stripping procedure to separate stratum corneum from viable epidermis. Each part was properly treated to extract the sunscreen retained and subject to quantitative analysis. RESULTS: The encapsulation of the sunscreen in the microspheres remarkably reduced the permeation of 4-MBC and increased its retention on the skin surface where its action is more desirable. CONCLUSIONS: The results of this study confirm the validity of substantive microspheres as an ideal formulation candidate to use in sunscreen preparation as they appear minimizing its systemic uptake and the potential associate toxicological risks. Therefore, more of the active sunscreen remains on the surface of the skin where it is intended to act and a higher activity it will explicate.

Validation of bovine hoof slices as a model for infected human toenails: in vitro ciclopirox transungual permeation.

BACKGROUND: Topical therapy has recently been proposed for treating onychomycosis and other nail disturbances. However, the clinical outcome may be limited by the difficulty of active ingredients effectively penetrating the nail plate. Bovine hoof membranes have been widely used to predict in vitro efficacy of drug products in nail diseases. Many studies have compared bovine hooves with human healthy nails, considering the difference between healthy and unhealthy nails to be negligible. OBJECTIVES: To validate bovine hoof slices as a model for human unhealthy nails by investigating the transungual permeation/retention of ciclopirox (CPX) through bovine hoof slices and excised infected human toenails after application of a new film-forming formulation (P-3051). To investigate the ability of CPX to achieve fungicidal concentrations in and through infected toenails. METHODS: A new experimental technique based on a permeation unit allowed analysis by high-performance liquid chromatography of the amounts of CPX permeating through and retained in the membranes. The efficacy index was evaluated as follows: amount of permeated CPX/Trichophyton rubrum minimum inhibiting concentration. RESULTS: Extrapolated CPX flux through bovine hoof slices was about 14-fold higher than through infected human toenails, the difference being mainly due to the fourfold higher thickness of the toenails. In toenails, the CPX efficacy index for T. rubrum was positive (>1·0) soon after P-3051 application. CONCLUSIONS: This study confirms the validity of bovine hoof slices as a model for infected human nails, and suggests a substantial equivalence between the two models. Following P-3051 application, CPX reaches fungicidal concentrations in and through human infected toenails.

Hydrosoluble medicated nail lacquers: in vitro drug permeation and corresponding antimycotic activity.

BACKGROUND: Two nail lacquers, containing ciclopirox (CPX) or amorolfine (MRF), based on water-insoluble polymers are currently considered mainstays of topical treatment of onychomycosis. The present study aimed at evaluating the antimycotic activity of a new water-soluble nail lacquer containing CPX (CPX/sol), easily removable by washing with water and applicable to periungual skin. OBJECTIVES: To compare transungual permeation of CPX with that of MRF in the same hydroxypropyl chitosan-based nail lacquer (MRF/sol) and with a nonwater-soluble reference (Loceryl); Galderma International, La Défense, France), and to evaluate the antimycotic activity of CPX/sol and Loceryl against the most common fungal strains that cause onychomycosis. Methods In vitro drug permeation experiments with CPX/sol, MRF/sol and Loceryl were carried out through bovine hoof slices. Experimental permeates from CPX/sol and Loceryl underwent in vitro susceptibility testing against clinical isolates of dermatophytes, moulds and yeast. Results MRF transungual flux from MRF/sol lacquer was significantly higher when compared with Loceryl. CPX was able to permeate hoof membranes more easily compared with MRF. CPX and MRF concentrations in the subungual fluids collected after application of CPX/sol or Loceryl were sufficient to inhibit fungal growth, with the exception of Candida parapsilosis. Smaller amounts of fluid containing CPX were required for complete inhibition of fungal growth. Efficacy index values were significantly higher for CPX/sol. Conclusions Application of the CPX/sol nail lacquer allows rapid nail penetration of CPX, providing CPX levels sufficient to inhibit fungal growth for a prolonged period of time (30 h) after application of lacquer dose. CPX/sol nail lacquer appeared superior to the market reference Loceryl in terms of both vehicle (hydroxypropyl chitosan) and active ingredient (CPX) as witnessed by its higher efficacy on all nail pathogens.

Skin permeation and distribution of two sunscreens: a comparison between reconstituted human skin and hairless rat skin.

The aims of this work were (a) to develop a simple and reproducible procedure for percutaneous absorption and distribution tests of sunscreens using one human skin culture model (Epiderm 606; reconstructed epidermis, RE), (b) to compare the said model with rat skin (RS) in vitro and (c) to evaluate the effect of different formulations. The cutaneous permeation and distribution of two UV filters, ethylhexylmethoxycinnamate (MC80) and ethylhexyltriazone (T150), using 3 different vehicles were investigated. The permeation studies demonstrated that neither MC80 nor T150 permeated through both RS and RE in spite of different thicknesses of the 2 substrates. Distribution studies demonstrated that sectioning by cryomicrotome to obtain horizontal skin layers was suitable for both RS and RE (apart from its small thickness) with a good reproducibility of data. The amounts of sunscreens retained in the 2 substrates were in the same order of magnitude for all formulations with a greater depot in RS. Different distribution profiles of the tested formulations could be ascribed to the different lipid compositions of RE and RS. Since the physicochemical characteristics of RE are closer to those of human skin, the results obtained with reconstructed human skin models could be suitable to replace human skin in 'in vitro testing'.

Rufloxacin eyedrops: effect of different formulations on ocular pharmacokinetics in rabbits.

PURPOSE: To evaluate the aqueous humor pharmacokinetics of rufloxacin in rabbits after topical administration of different formulations, and to individuate the ones showing the best pharmacokinetic profile. METHODS: Six formulations were instilled in rabbit eyes: two pH 7.2 suspensions of non-salified rufloxacin base, or zwitterion (RUF), one of which was viscosized with tamarind seed polysaccharide (TSP); two pH 7.2 solutions of RUF obtained using hydroxypropyl-beta-cyclodextrin (CD), one of which was viscosized with TSP; and two pH 5.0 solutions of rufloxacin hydrochloride (RUF-HCl ), one of which was viscosized with TSP. At different times after administration, samples of aqueous humor were withdrawn and analyzed by high-pressure liquid chromatography. The main pharmacokinetic parameters of RUF in the aqueous humor produced by the different formulations were calculated and statistical differences were assessed. RESULTS: The best results, in terms of aqueous humor bioavailability, were observed with two TSP-viscosized formulations: a solution of the hydrochloride (TSP/RUF-HCl) and a suspension of the base (TSP/RUF), followed by the non-viscosized solution of RUF-HCl. The formulations containing CD-solubilized RUF were much less effective. CONCLUSIONS: The present data confirm the significant availability-enhancing properties of tamarind seed polysaccharide, and indicate that solubilization of RUF with hydroxypropyl-beta-cyclodextrin (CD/RUF) results in decreased drug availability with respect to standard formulations. Two of the TSP-viscosized formulations (RUF suspension and RUF-HCl solution) produced aqueous humor RUF concentrations in the range of activity against Enterobacteriaceae and Pseudomonas aeruginosa, thus warranting further studies on applications of rufloxacin in ocular therapy.

Silicone rubber/hydrogel composite ophthalmic inserts: preparation and preliminary in vitro/in vivo evaluation.

The present report describes the development and in vitro/in vivo testing of rod-shaped mucoadhesive ophthalmic inserts fitting the upper or lower conjunctival fornix. Cylindrical devices (diameter 0.9 mm, length 6-12 mm, weight 3-8 mg) all containing 0.8 mg oxytetracycline HCl (OXT) were prepared from appropriate mixtures of silicone elastomer, OXT and sodium chloride as release modifier. A stable polyacrylic acid (PAA) or polymethacrylic acid (PMA) interpenetrating polymer network (IPN; 30 or 46% w/w) was grafted onto the inserts' surface by treatment with a mixture of acrylic (or methacrylic) acid and ethylene glycol dimethacrylate in xylene at 100 degrees C. Mucoadhesion studies in vitro showed that the mucoadhesive properties increased significantly with increasing thickness of the IPN layer. The inserts were tested for drug release in vitro, and for drug release and retention in rabbit eyes. The presence of IPN, as well as of NaCl, in general increased the drug release rate. The PMA-grafted devices released OXT at lower rates when compared with the PAA-grafted ones. A nearly zero-order release rate for about 1 week was observed in vitro for some types of inserts. When tested in rabbits, some IPN-grafted inserts maintained in the lacrimal fluid a OXT concentration of 20-30 microg/ml for several days: the in vitro minimum inhibitory concentration values (MIC 90%) of OXT against micro-organisms responsible of common ocular infections range from 0.8 to 2.0 microg/ml, while MIC 90% values in the range 14-50 microg/ml have been indicated for Pseudomonas aeruginosa. The ocular retention of IPN-grafted samples was significantly higher with respect to ungrafted ones. The presently described mucoadhesive silicone inserts might prove efficient therapeutic systems for chemotherapy of ocular bacterial infections, such as trachoma.

Cytotoxicity of potential ocular permeation enhancers evaluated on rabbit and human corneal epithelial cell lines.

A series of prospective ocular permeation enhancers, benzalkonium chloride (BAC), cetylpyridinium chloride (CPC), ethylenediaminetetraacetic acid (EDTA), polyoxyethylene (20) stearyl ether (PSE) and polyethoxylated castor oil (PCO) were tested for cytotoxicity on cultures of rabbit (RCE) and human (HCE) corneal epithelial cells. The cells were treated for 5,15 and 60 min with different concentrations of the test substances, in serum-free medium and in medium containing 15% foetal bovine serum (FBS). The cytotoxicity was evaluated by WST-1 test. The EC(50) values for HCE, after 15 min exposure and in the presence of FBS, indicate the following order of cytotoxicity: PSE> or =BAC>CPC>EDTA>PCO. After 1 h exposure the order of decreasing cytotoxicity was PSE> or =BAC>CPC>PCO>EDTA. In all cases the presence of FBS appeared to exert a protective effect against the cytotoxic effect.

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.

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.

Comparison of the effect of ultrasound and of chemical enhancers on transdermal permeation of caffeine and morphine through hairless mouse skin in vitro.

The effect of ultrasound (US) on permeation of two model drugs, caffeine (CAF) and morphine (MOR), through hairless mouse skin in vitro was compared with that of three chemical enhancers. Low-frequency (40 KHz), low-power (<0.5 W/cm(2)) US was used; the effect of high-frequency US (1.5-3.0 MHz) was also evaluated in the case of CAF. The chemical enhancers, tested in combination with propylene glycol (PG), were benzalkonium chloride (BAC) oleyl alcohol (OA) and alpha-terpineol (TER). The high-frequency US enhancement of CAF transdermal flux was not statistically significant, while low frequency produced a small but significant increase of the enhancement factor. The effect of US on CAF permeation, however, was lower than that produced by chemical enhancers, in particular OA. The effect of low-frequency US on permeation of MOR was significantly greater (about 10-fold) when compared, on the same frequency and intensity basis, with the effect on CAF. The most active chemical enhancer for MOR, OA, had practically the same effect as low-frequency US. Sonicated skin, although showing slight histological changes, recovered its original low permeability characteristics after turning off sonication. Within the tested system, chemical enhancement appears to offer some advantages over low-frequency US.

Increased corneal hydration induced by potential ocular penetration enhancers: assessment by differential scanning calorimetry (DSC) and by desiccation.

The corneal toxicity of some surfactants of possible use as ocular penetration enhancers was investigated by measuring their effect on hydration of rabbit corneas 'in vitro'. The tested substances were benzalkonium chloride (BAC), cetylpyridinium chloride (CPC), ethylenediaminetetraacetic acid disodium salt (EDTA), polyoxyethylene-20-stearyl ether (Brij 78, PSE), polyethoxylated castor oil (Cremophor EL, PCO) and sodium deoxycholate (DC). Freshly excised corneas, mounted in perfusion cells, were kept in contact for 1 h with solutions of these agents; corneal hydration was then evaluated by measuring: (a) their total (free+bound) water content by desiccation (gravimetric analysis); and (b) their free water content by differential scanning calorimetry (DSC). The DSC measurements also provided a rough quantitative estimate of corneal solutes. All tested agents significantly influenced corneal hydration, evidently as a consequence of alteration of the corneal epithelium. Although a brief contact with the precorneal tissues 'in vivo' may not prove harmful, the use of these compounds as potential ocular permeation enhancers or otherwise as ingredients of topical ocular formulations for long-term use should be considered with caution.

Effect of iontophoresis on transcorneal permeation 'in vitro' of two beta-blocking agents, and on corneal hydration.

Purpose of the present investigation was to examine the effect of iontophoresis on permeation of two beta-blocking agents, timolol maleate (TM) and betaxolol hydrochloride (BX) across rabbit corneas in vitro. Continuous or pulsed current of variable intensity and duration was applied, and possible corneal damage due to the electric treatment was assessed by measuring the corneal hydration level. The effect of iontophoresis on corneal permeation of the relatively more hydrophilic TM was much greater than the effect on the more lipophilic BX. It was found that for both drugs the iontophoretically driven transcorneal penetration is governed only by current density and overall time of treatment, irrespective of the type of treatment (single or repeated) and of current (constant or pulsed). For both drugs all significant permeation increases due to iontophoresis were invariably accompanied by a significant increased corneal hydration, indicative of damage to the corneal epithelium. Even if the present in vitro data cannot be extrapolated to an in vivo treatment, they confirm the potential risk associated with ocular iontophoresis.

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.

Relevance of polymer molecular weight to the in vitro/in vivo performances of ocular inserts based on poly(ethylene oxide).

A previous study of the present authors on gel-forming erodible inserts, based on high molecular weight (MW, 400 kDa) poly(ethylene oxide) (PEO), for ocular controlled delivery of ofloxacin (OFX) has been extended to investigate the effects of PEO MW, in the 200-2000 kDa range, on insert properties relevant to therapeutic efficacy. Mucoadhesion has shown a dependence on MW, with a maximum for PEO 400. The in vitro drug release from inserts based on PEO 200, PEO 400 and PEO 900 was mainly controlled by insert erosion, whereas with PEO 2000 it was mainly diffusion-controlled in a first phase, followed by an erosion-controlled phase. The erosion time scale depended directly on MW. Immediately after application in the lower conjunctival sac of the rabbit eye, the inserts based on PEO of whichever MW formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. PEO 2000 was unsuitable as an insert material, since the resulting gel spilled from the eye, due to excessive swelling. The gel residence time in the precorneal area, the drug permanence time in the aqueous humor at concentrations > MIC and the time to reach the maximal drug concentration in the aqueous humor (C(max)) depended directly on MW, indicating that transcorneal absorption was governed by gel erosion. All inserts increased Cmax and AUCeff (AUC for concentrations > MIC) with respect to the commercial eyedrops. The increases caused by PEO 400 and PEO 900 were similar (3.78- and 3.16-fold, respectively, for Cmax; 11.06- and 12.37-fold, respectively, for AUCeff), whereas smaller increases were produced by PEO 200. The PEO 400 and PEO 900 inserts have shown a potential for a topical treatment of endophthalmitis.

Effect of different terpene-containing essential oils on permeation of estradiol through hairless mouse skin.

Purpose of the present investigation was to evaluate six terpene-containing essential oils for their capacity to promote permeation of estradiol (ES) through hairless mouse skin in vitro. Tests on cajuput, cardamom, melissa, myrtle, niaouli and orange oil, all used at the 10% w/w concentration in propylene glycol (PG), evidenced niaouli oil (NIA) as the best permeation promoter for ES. Tests on the main terpene components of NIA (1,8 cineole, alpha-pinene, alpha-terpineol and D-limonene), evaluated neat (10% w/w in PG) or in admixture, confirmed the better promoting activity of whole NIA. The present data point to the validity of complex terpene mixtures, such as that composing NIA, as transdermal penetration enhancers for moderately lipophilic drugs like ES.

Vehicle effects in ophthalmic bioavailability: an evaluation of polymeric inserts containing pilocarpine.

A series of polymeric ophthalmic inserts containing pilocarpine were formulated with four different types of polyvinyl alcohol, PVA, and two types of hydroxypropylcellulose. Pilocarpine was present as the nitrate, or as the salt with polyacrylic acid, PAA. In-vivo miosis vs time experiments on albino rabbits, showed that all inserts increased significantly the bioavailability of pilocarpine, with respect to a standard solution of pilocarpine nitrate. Two PVA inserts, containing the PAA-salt of pilocarpine, were particularly effective. The preparations were also submitted to in-vitro release tests and to differential scanning calorimetry, to ascertain the release mechanism, and to verify, via the thermal behaviour, possible interactions between drug and polymers. The chemical and physiochemical factors, most likely to influence the ophthalmic bioavailability of pilocarpine from the present preparations, are briefly reviewed.

Xyloglucan as a novel vehicle for timolol: pharmacokinetics and pressure lowering activity in rabbits.

This study was aimed at verifying the performances of a mucoadhesive polysaccharide from tamarind seed (xyloglucan or TSP, tamarind seed polysaccharide) as an adjuvant for ophthalmic vehicles containing timolol. Three formulations (one experimental vehicle based on TSP and two reference commercial eye drops) containing 5 mg/ml timolol base equivalents were administered to the eyes of pigmented rabbits. Drug concentrations in tear fluid, cornea, iris-ciliary body, aqueous humor and plasma were determined, as well as intraocular pressure. The polymer under investigation, in spite of a comparatively low viscosity, produced high timolol concentrations in the ocular tissues and a low systemic absorption. The performances of the TSP vehicle were comparable to those of a reference "in situ" gelling formulation (Timoptic XE). The results point to TSP as a potentially useful adjuvant for ophthalmic delivery systems.

Pharmacokinetics and anti-inflammatory activity in rabbits of a novel indomethacin ophthalmic solution.

The formulation of aqueous ophthalmic solutions containing indomethacin (IND) presents serious problems due to poor solubility and stability of the drug. The purpose of this study was to evaluate a novel 0.1% IND formulation containing a poly(oxyethylene)-poly(oxypropylene) block copolymer (poloxamer 407) as solubilizer. This formulation was evaluated for stability, bioavailability and anti-inflammatory activity in comparison with an ophthalmic IND solution currently on the market. The experimental solution, tested for IND stability at different temperatures, compared favorably with the commercial solution. In rabbits, it produced significantly higher IND levels in the aqueous humor and, in an immunogenic uveitis model, it induced a comparatively faster resolution of the symptoms, as determined by inflammation scores and by IOP measurements. The data indicate poloxamer 407 as a potentially valuable nonirritating, solubilizing and stabilizing agent for indomethacin.

Prolonged, contemporaneous administration of pilocarpine and timolol increases the aqueous humor pilocarpine levels in rabbits.

The purpose of this study was to gather information on the mechanism by which timolol/pilocarpine (TI/PI) combination eyedrops provide additive ocular hypotensive effects. An hypothesis, according to which the combination eyedrops prolong the intraocular permanence of PI as a consequence of decreased aqueous humor secretion induced by TI, was not supported by clear-cut literature evidence. It was thus sought to verify if repeated instillations in albino rabbits of combination TI/PI eyedrops do effectively prolong the turnover of PI. Commercial eyedrops containing 0.68% w/v TI maleate and 2.0% w/v PI hydrochloride, buffered at pH 6.8, and two reference solutions containing PI hydrochloride alone (2% w/v), buffered at pH 5.5 and 6.8, were instilled b.i.d. in albino rabbits for five days. Aqueous humor samples, analyzed after the last treatment, showed that the aqueous humor PI levels observed after administration of the combination eyedrops were significantly higher than those resulting from administration of the reference formulations. When compared with the pH 6.8 reference solution, the pH 5.5 one produced slightly higher and more sustained drug levels in the aqueous humor. The present results appear to confirm the assumption that an increased retention of PI in the aqueous humor is responsible for the additive effects on intraocular pressure reported by several authors for the combination TI/PI eyedrops.

Ocular mini-tablets for controlled release of timolol: evaluation in rabbits.

Topical delivery of timolol by inserts or similar controlled-release devices may offer distinct advantages over administration by eyedrops. The purpose of this investigation was the evaluation in rabbits of ophthalmic inserts (denominated mini-tablets, MT) for sustained/controlled release of timolol maleate (TiM). The MTs (diameter 3.5 mm, thickness 1.5 mm, average TiM content 0.34 or 0.68 mg) were prepared by compressing appropriate mixtures of powders with a standard tabletting machine. A thin, rate-controlling membrane was applied over the devices by spraying aqueous dispersions of acrylic copolymers. A first series of different (uncoated and coated) MTs were tested for release of TiM to the lacrimal fluid, using commercial eyedrops (Timoptol 0.5%) as a reference standard. Two MTs (one of which was coated) and the same reference solution were then selected for an ocular absorption study. Analysis of TiM in the aqueous humor indicated that the coated MT was capable of maintaining low and steady levels of TiM for at least 19 h, while the other device, identical but uncoated, produced a prolonged-pulse effect lasting about 8 h. The apparent mean residence time (MRT) of TiM in the aqueous humor was 1.3 h for the reference solution, 3.2 h for the uncoated MT, and 5.7 h for the coated one. The present preliminary results point to the potential validity of coated mini-tablets as simple systems for controlled ocular delivery of timolol.