Mechanistic studies on transcorneal permeation of fluorometholone.

The mechanism of corneal fluorometholone penetration was studied using albino rabbits, and the apparent rate and extent of steroid accumulation in the various cell layers of the cornea and aqueous humor were determined for normal and abraded eyes. The results are compared and contrasted to the mechanism previously reported for pilocarpine. Fluorometholone readily penetrates the intact corneal epithelium and accumulates in the hydrophilic stromal layers of the cornea. The kinetic profile is similar to that of pilocarpine and is largely a result of the pre-corneal dynamic processes. Pharmacokinetic parameters for each tissue were determined to establish an overall mechanism for corneal permeation of the steroid.

Vehicle effects on ocular drug bioavailability III: Shear-facilitated pilocarpine release from ointments.

Pilocarpine release from water-in-oil emulsion ointments was studied in vitro and in vivo, using albino rabbits. Pilocarpine release from the vehicle to the ocular fluids was dependent on shear, i.e.,blinking, and the dosing system emulsifying efficiency. A mechanical shearing component was vital for correlating corneal drug penetration and the in vitro pilocarpine release pattern. Simple diffusion studies with the vehicles did not predict drug in vivo release, but the ointment systems were all superior to an aqueous pilocarpine solution. Incorporation of a mechanical shearing component to mimic blinking gave good correlation of in vitro and in vivo results. Also, increasing the vehicle emulsifying efficiency by surfactant addition decreased shear-facilitated drug release and in vivo performance. Finally, increasing the internal aqueous phase volume fraction decreased in vivo performance and was linked to the influence of effective drug concentration in the vehicle.

Vehicle effects on ocular drug bioavailability II: Evaluation of pilocarpine.

The influence of vehicle composition on ocular penetration of pilocarpine was studied in the albino rabbit. Increasing the pH of a vehicle promoted increased corneal penetration for pilocarpine, in accordance with the pH-partition hypothesis, but a similar series of experiments with a nonionizable drug, glycerin, gave similar results. The extent of pH-induced lacrimation by the vehicle and its effect on precorneal drug concentration also was determined. Increased pilocarpine absorption at neutral to slightly alkaline pH was due primarily to its peculiar solubility characteristics coupled with less irritation and lacrimation rather than a direct pH effect on the molecule. Incorporation of pilocarpine into a petrolatum-based ointment vehicle resulted in increased aqueous humor pilocarpine levels above those provided by an equivalent dose of aqueous solution. The mechanism of this increase was determined to be a higher effective concentration of pilocarpine in the ointment vehicle coupled with an increase in contact time of the dose. The ointment system also exerted an unusual form of vehicle control in that it promoted the corneal penetration of pilocarpine while impeding uniform mixing of the dose with tears and thereby imposed a restriction on the amount of pilocarpine available to the ocular tissues.

Mechanistic studies on transcorneal permeation of pilocarpine.

The mechanism of corneal pilocarpine penetration was studied in the albino rabbit using radiochemical techniques. The apparent rate and extent of pilocarpine accumulation in the aqueous humor and the various cell layers of the cornea were determined for both intact and abraded eyes. For the first time, drug levels were monitored in the epithelium and stroma-endothelium of the intact cornea using a tissue-scraping technique. In addition, a new postinstillation rinsing method was devised to evaluate the rate of corneal uptake. The results demonstrate a dual role for the corneal epithelium, both as a barrier to drug penetration and as a reservoir for drug in the intact cornea. The transcorneal pilocarpine flux is slower than the data appear to indicate, and previous overestimates of the apparent absorption rate constant are due to parallel elimination processes occurring at the absorption site. Pharmacokinetic parameters were determined for each tissue to generate an overall mechanism for corneal permeation.

Vehicle effects on ocular drug bioavailability i: evaluation of fluorometholone.

The influences of drug concentration and vehicle composition on the corneal penetration of the steroid fluorometholone were studied in the albino rabbit. Aqueous dosing systems included a saturated solution and 0.1, 0.05, and 0.1% suspensions of micronized fluorometholone. Two different doses of a 0.1% oleaginous ointment were also studied. The results from the 0.1 and 0.5% suspensions show a peak aqueous humor steroid concentration at 30 min and a substantial sustaining effect with these two concentrations. The results also support the belief that moderate dilution of a suspension of a slowly soluble drug may not substantially lower the aqueous humor drug levels or, conversely, that use of a higher concentration suspension may not improve the aqueous humor drug concentration-time profile. The 0.1% suspension and the saturated solution did not produce a sustaining effect. The results demonstrate for the first time that the particles present in a dose of suspension are retained within the cul-de-sac of the eye and contribute significantly to the amount of steroid penetrating the cornea. This finding was confirmed by a study in which the eye was rinsed with saline solution 30 min after instillation of a dose of a 0.05% suspension. The rinsing procedure prematurely terminated the sustaining effect of the suspension. The results of the ointment studies show that partitioning of the lipophilic steroid from the oleaginous vehicle has a greater rate-limiting influence on corneal penetration than the dissolution rate parameter associated with the aqueous suspensions. Peak aqueous humor concentration was not achieved until 3 hr after dosing and was comparable to the 0.1 and 0.05% suspensions. Predosing of the eye with a saturated solution or the 0.1% suspension prior to dosing with ointment overcomes the inability of the ointment to provide adequate drug at short times following dosing. In this case, peak levels were achieved within 60 min and then maintained. The duration of aqueous humor levels and the amount penetrating from the ointment were greater than the suspensions, and these effects are discussed relative to the mechanism. Differences in aqueous humor levels produced by 25- and 50-mg doses of ointment were minimal. A discussion of the results from all studies is presented in the context of present theories regarding the role of the lipophilic epithelial layer of the cornea as a barrier to drug penetration.