Marco Fabrizio Saettone

Evaluation of muco-adhesive properties and in vivo activity of ophthalmic vehicles based on hyaluronic acid

Abstract A series of prospective ophthalmic vehicles based on hyaluronic acid (HA) and on polyacrylic acid (PAA) (solutions, gels, matrices prepared by compression and by casting) containing pilocarpine (Pi) or tropicamide (Tr) was evaluated for muco-adhesion, for ocular retention and for biological activity (miosis, mydriasis) in rabbits. The muco-adhesive properties were investigated in vitro using a tensile apparatus with mucin-coated surfaces, while the ocular behaviour was estimated visually, using vehicles containing a fluorescent marker. Good to excellent muco-adhesive properties were detected in the HA preparations. The bioavailability-enhancing effect, however, was not very satisfactory with Pi, probably on account of the high solubility and diffusivity of the drug. The effect was more evident with the less soluble drug Tr. The validity of the method used for evaluating bioadhesion, and the relevance of the physicochemical characteristics of the drug to a muco-adhesive ocular delivery system are discussed.

Ocular inserts for topical delivery

Abstract In spite of extensive pharmacological and clinical data pointing to the usefulness and advantages of solid devices for topical drug delivery to the eye, liquid, and to a smaller extent, gel-type preparations appear to enjoy the continued interest of manufacturers and ophthalmologists. In the present update, the authors discuss the advantages, disadvantages and requirement for sucess of ocular inserts, and examine the few inserts which are available on the market or are being developed by pharmaceutical companies for drug delivery. The article discusses S.O.D.I., Ocusert ® , Collagen Shields, Ocufit ® , Minidisc and Nods ® with special attention to biological/ clinical performances, and potential for future applications and developments.

Polymer effects on ocular bioavailability: the influence of different liquid vehicles on the mydriatic response of tropicamide in humans and in rabbits

Five viscous polymeric vehicles containing 0.2% tropicamide were tested for mydriatic activity in humans and in rabbits. The polymers were carboxymethylcellulose (CMC), low molecular weight hydroxypropylcellulose (HPCL). medium molecular weight hydroxypropylcellulose (HPCM). poly(vinylpvrrolidone) (PVP) and poly(vinyl alcohol) (PVA), Their concentrations were adjusted in order to give iso-viscous (70 ± 2 cps) Newtonian solutions (HPCL, PVP, PVA) or pseudoplastic solutions with an apparent viscosity of 70 cps at a rate of shear of 700 s−1 (CMC. HPCM). All vehicles increased the ocular bioavailability of the drug in both species, when compared with a non-viscous solution. However, in humans PVP and PVA were significantly more active with respect to the other polymers. The different activity of the polymeric vehicles in humans could neither be correlated with drug binding, nor with surface or interfacial tension, nor with the rheological behaviour of the solutions (Newtonian vs pseudoplastic). On the basis of experimental evidence, the hypothesis is advanced that some polymers may increase the ocular bioavailability of tropicamide not by viscous effects aione, but also by influencing the spreading characteristics and the thickness of the medication layer over the precorneal area. The reasons for the interspecies differences in activity, presumably residing in different precorneal dynamics of the applied solution, are also discussed.

Evaluation of pilocarpine-loaded albumin particles as controlled drug delivery systems for the eye. II. Co-administration with bioadhesive and viscous polymers

Abstract The aim of the present investigation was to investigate the influence of various polymers at different concentrations on the in vivo activity of pilocarpine-loaded albumin nanoparticles. It was speculated that co-administration with viscous or bioadhesive polymers would increase the time of residence in the eye of the drug-loaded particle systems, and hence the drug bioavailability. For this purpose, different formulations containing bioadhesive (hyaluronic acid, mucin, sodium car☐ymethylcellulose, and polyacrylic acid) or viscosity-enhancing polymers (methylcellulose, polyvinyl alcohol, and hydroxypropylmethylcellulose) were tested in rabbits for miotic effect and reduction of intraocular pressure (IOP, betamethasone model). In the presence of some polymers, the nanoparticles induced a significantly improved pharmacological response when compared with particle dispersions in buffer or with particle-free polymeric vehicles. Bioadhesive polymers exhibited superior effects with respect to viscous polymers: the best results for miotic response and IOP reduction were observed with mucin. It can be assumed that coadministration of particles with these polymers leads to an improved adhesion to the precomeal/conjunctival mucin layer and hence to a prolongation of the residence time of the medication in the eye.

A Submicron Emulsion as Ocular Vehicle for Delta-8-Tetrahydrocannabinol: Effect on Intraocular Pressure in Rabbits

delta 8-Tetrahydrocannabinol (delta 8-THC), a known antiglaucoma lipophilic drug, was incorporated in a submicron emulsion for ocular administration. The mean droplet size of the emulsion was 130 +/- 41 nm, and no droplet was larger than 400 nm. No change in pH, particle size distribution or zeta potential was noted after sterilization by steam autoclaving or long-term storage over 9 months. An intense and long-lasting intraocular pressure (IOP)-depressant effect was observed after ocular application (50 microliters) of the THC emulsion, 0.4% (w/w), to rabbits with ocular hypertension (chymotrypsin model). Lesser effects were observed in normotensive rabbits. No irritation effect of either the emulsion vehicle or THC emulsion on the rabbit eyes was detected. These results underline the promising properties of submicron emulsions as vehicles for lipophilic ophthalmic drugs. The mechanism by which the emulsion induced the marked delta 8-THC antiglaucoma effect remains unclear. However, the possible involvement of delta 8-THC systemic absorption in the hypotensive effect induced by the emulsion cannot be excluded and will be the subject of further investigation.

Solubilization of tropicamide by poloxamers: physicochemical data and activity data in rabbits and humans☆

Abstract A series of polyoxyethylene-polyoxypropylene (POE/POP) block copolymers (Poloxamers, or Pluronics) were evaluated as solubilizers for tropicamide, a poorly water-soluble mydriatic/cycloplegic drug. The selected Pluronics were L64, P65 and F68 (POP weight 1750, POE weight 1150, 1650 and 6650, respectively), P75 and F77 (POP weight 2050, POE weight 2100 and 4550, respectively), P84, P85, F87 and F88 (POP weight 2250, POE weight 1950, 2350, 5450 and 9150, respectively) and F127 (POP weight 4000, POE weight 8600). The following studies were carried out: solubility of tropicamide in polymer solutions, partition coefficient of the drug between isopropyl myristate and polymer solutions, critical micelle concentration (CMC) of the polymers, viscosity of the polymeric solutions containing tropicamide, mydriatic activity tests on rabbits and humans, cycloplegic activity tests on humans. The solubility isotherms (25 °C) showed that the saturation solubility of the drug increased linearly with increasing surfactants concentration in the 4.0–20.0 w/v concentration range. In the presence of 20% w/v Pluronics the drug solubility increased substantially, ranging from 1.9 times (F88) to ca. 3.0 times (P85) the solubility in water at the same temperature (0.57 g/100 ml). Analysis of the solubility data indicated that the solubility of tropicamide increased as the oxyethylene content of the surfactants increased, and that the amount of drug solubilized per EO unit decreased with increasing hydrophilicity (increasing OE chain length) of surfactants. Calculation of the relative amount of drug bound to the POE and to the POP portions of the surfactant molecules indicated that binding occurs in part to the hydrophilic (POE) outer mantle, and in part to the hydrophobic, (POP) inner core of the micellar aggregates, with POE/POP binding ratios varying from 1.17 to 3.13, depending on the polymer type. Biological activity tests were carried out with some 15% w/v polymeric solutions (L64, P75, P84, P85 and F87) containing 1.0% w/v tropicamide, and with some 20.0% w/v solutions (P85, F87) containing 1 5 % w/v drug. The results indicate that tropicamide bioavailability, both in rabbits and in humans, was not decreased by micellar Solubilization, and that some Poloxamers can perform satisfactorily as solubilizing vehicles for tropicamide, producing neutral 1.0% and 1.5% drug solutions which are better tolerated and more effective than the standard aqueous eyedrops.

Semisolid ophthalmic vehicles. III: An evaluation of four organic hydrogels containing pilocarpine

Abstract The validity of four hydrogels, based on synthetic polymers as vehicles for topical ophthalmic drugs was evaluated by determining, in rabbits and in humans, the miotic response induced by pilocarpine. The hydrogels were prepared with two different types of poly(acrylic acid), PAA-1 and PAA-2; with poly(acrylamide) PAAm and with ethylene maleic anhydride, EMA. Their biological effect was compared with that induced by an aqueous solution of the drug (AS). The rheological characteristics of the vehicles were investigated: PAA-1, PAA-2 and EMA displayed a plastic type of flow, while PAAm was pseudo-plastic. In rabbits administration of pilocarpine in the hydrogel vehicles doubled the drug bioavailability (as expressed by the area under the miotic response vs time curve, AUC) with respect to AS; however, no statistical differences were apparent among the AUC values of the hydrogels. In humans, the same vehicles showed more pronounced activity differences. While PAA-2 and PAAm produced an approximately 3-fold bioavailability increase with respect to AS, PAA-1 only doubled the bioavailability and EMA showed activity parameters not different from those of the aqueous solution. Possible correlations between the viscosity parameters of the vehicles and ophthalmic bioavailability in the two species are discussed. The present results appear to confirm previous observations on the poor validity of rabbits for studies on the influence of vehicle viscosity on bioavailability of topical ophthalmic drugs.

Polymer effects on ocular bioavailability. II. The influence of benzalkonium chloride on the mydriatic response of tropicamide in different polymeric vehicles

The effect of 0.01% benzalkonium chloride (BZ) on the mydriatic response of tropicamide in different vehicles was tested on rabbits and on humans. The vehicles were an isotonic buffered solution (AS) and four iso-viscous polymeric solutions: low molecular weight hydroxypropylcellulose (HPCL), medium molecular weight hydroxypropylcellulose (HPCM), poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP). In rabbits, the BZ-containing vehicles did not show any statistically significant activity difference respect to identical, BZ-free preparations. In humans, BZ did not produce any significant bioavailability increase in AS, even at the 0.05% concentration, while it appeared to depress the bioavailability enhancement produced by the polymeric solutions. This effect was statistically significant (P < 0.05) for PVA and PVP. On the basis of some physicochemical evidence, the hypothesis is advanced that the reduced efficacy in humans of the polymeric vehicles in the presence of BZ may be due to a reduced adhesion tension (AT) of the solutions to the corneal surface. This would interfere with the blinking-assisted spreading process of the vehicles over the precorneal area. The present experiments confirmed the poor performance of rabbits as models for investigations on polymeric ophthalmic vehicles, that may modulate the drug availability not by viscous effects alone, but also by dynamic surface spreading phenomena.

Albumin microspheres for ocular delivery of Piroxicam

This investigation deals with the preparation, in-vitro characterization and preliminary in-vivo evaluation of albumin microspheres containing piroxicam. The albumin-piroxicam microspheres, designed for ocular administration, were prepared by a spray-drying technique. The morphological and dimensional characteristics of the particles were studied by scanning-electron microscopy and particle-size analysis. Their in-vitro release behaviour was investigated in pH 7-0 USP23 buffer by use of a flow-through apparatus. Piroxicam in the albumin microspheres dissolved more quickly in-vitro than did piroxicam powder. The pharmacokinetic profile of piroxicam in aqueous humour was investigated in albino rabbits. The albumin-piroxicam microspheres resulted in greater bioavailability of piroxicam than commercial piroxicam eyedrops.

Polymer Drug Delivery Systems in Ophthalmic Applications

ilocarpine is a cholinergic agent which is often used in glaucoma treatme t to reduce the elevated intraocular pressure (IOP). Such a disease if not properly treated tends to narrow the visual field leading to myopia and eventually to blindness. Poor penetration of topically applied drugs into the anterior chamber of the eye is a well-known disadvantage in ophthalmic therapy. Liquid (eye drops) and, to a lesser extent, semisolid dosage forms (ointments) are rapidly diluted and removed from the absorption surface by different concurring mechanisms such as reflex tearing, blinking, and tear turnover. Therefore, frequent administration of the eye drop concentrated solutions is required to maintain the drug therapeutic level in the aqueous humour. The addition of suitable water soluble polymers to liquid collyria may be a possible way to increase the drug bioavailability by prolonging the corneal contact time. However, so far no marked sustaining effect has been attained by this method [1,2]. On the other hand, the commonly available ophthalmic ointments, although better retained than collyria, do not efficiently release the drug and are ill-tolerated by many patients due to blurried vision. These factors have stimulated the