In preclinical studies, poorly soluble drugs are usually administered orally to experimental animals as suspensions. The present study was aimed at providing data allowing predictive estimations of the stability of such suspensions. To this purpose aqueous suspensions of three drugs (griseofulvin, ibuprofen and indomethacin) were prepared at different concentrations using four different suspending agents: sodium carboxymethylcellulose (CMC), microcrystalline cellulose/carboxymethylcellulose (MC/CMC), hydroxypropylmethylcellulose (HPMC) and jota carragenaan (CJ). The physical and physico-chemical characteristics of the drugs, the rheological properties of the suspending media and of the corresponding drug suspensions, and the physical and chemical stability of the suspensions was then evaluated. The type of suspending agent, rather than the physical characteristics of the drug, appeared to exert the main influence on the physical stability of suspensions. The most stable formulations were produced by suspending agents with low-temperature gelation characteristics (CJ) or with thixotropic flux (MC/CMC).

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.

The in vitro permeation rate of dapiprazole base (DAP-B) through hairless mouse skin was investigated, as a preliminary step towards the development of a transdermal therapeutic system. The study involved the evaluation of the permeability coefficient of the drug applied to the skin in a series of liquid and semisolid vehicles, both in the absence and in the presence of different penetration enhancers. In liquid vehicles the permeability coefficient of DAP-B was significantly promoted (up to 73 times) by some terpenes (1-limonene, α-bisabolol, terpinolene) and by a mixture of unsaturated fatty acids. Similar effects were noted in semisolid vehicles, although the permeability coefficients were lower. Iontophoretic experiments on DAP-B in physiological saline solution, at constant current densities in the range of 0.05-0.5 mA/cm2, produced up to 115-fold permeability increases relative to passive diffusion. The present results, even if needing further corroboration by tests on human skin, evidenced the activity of some molecules as skin permeation enhancers for DAP-B, and confirmed the synergy between propylene glycol and the enhancers, already reported in the literature. The possibility of promoting DAP-B transport through the skin by iontophoresis was also established.

Ophthalmic inserts (denominated mini-tablets, MT) for sustained release of timolol were prepared by a standard compression and coating technique. An adequate control of the in vitro drug release from the devices could be obtained by adjusting the type and amount of acrylic polymer coating.

A series of cylindrical ophthalmic inserts based on mixtures of PVA, glyceryl behenate and different polymers (xanthan gum, jota-carrageenan, hydroxypropyl methylcellulose, hyaluronic acid), and containing pilocarpine nitrate (PiN) were prepared by extrusion, and were subsequently coated with a mixture of Eudragit RL and RS. The inserts had the following characteristics: diameter, 1.5 mm; length, 3 mm; weight, 7 mg; PiN content, 1.16 mg. The applied coating was 4% of the inserts' weight. The inserts were submitted to release tests in vitro, and to miotic activity tests in rabbits. The uncoated inserts released 50% of the drug within 20–30 min, with predominantly diffusive kinetics. The release profiles of the four types of uncoated inserts were essentially similar. The coated units released 50% PiN in 3–5 h, depending on the core composition. Zero-order release kinetics were observed in the case of three of the four types of coated inserts. Release was incomplete in all cases: this was due, as shown by equilibrium dialysis tests, to PiN binding by the polymers. The uncoated inserts, when tested for miotic activity in albino rabbits, showed little or no sustained activity, and moderate AUC increases with respect to an aqueous solution of the drug. Conversely, the coated inserts showed miotic activity profiles indicating a prolonged-pulse or sustained release (9–10 h duration, shift of the peak time to 120–240 minutes, over 3-fold increases in AUC over the aqueous solution). The in vitro/in vivo relationships, the effects of different core compositions and coating thicknesses, and the possible mechanism governing release from the coated inserts are discussed. This preliminary study indicates the possibility of realizing, using relatively simple techniques and common pharmaceutical materials, ocular delivery devices showing substantially improved properties when compared with traditional ophthalmic vehicles.

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.

The present review is concerned with some essential formulative and therapeutic aspects of semisolid ophthalmic vehicles. The history and the most recent developments of the traditional lipophilic vehicles (ointments) are first outlined. The hydrophilic vehicles (hydrogels) based on synthetic polymers (polyacrylates, PEG, PVA, Pluronics, etc.), semisynthetic polymers (cellulose derivatives) and natural polymers (hyaluronic and polygalacturonic acid, alginates, etc.) are then examined. Some recent formulations of particular type are finally described.

Pilocarpine (Pi), a widely used anti-glaucoma drug, is characterized by a very low bioavailability, due to poor corneal penetration and extensive precorneal loss. Purpose of the present study was the preparation and “in vivo” evaluation of a series of liquid formulations containing salts (or ionic complexes) of Pi with soluble polyanionic polymers of natural, synthetic or semi-synthetic origin. It was speculated that since to some of the polymers have been attributed muco-adhesive properties, they might favour the preocular retention of the ionically bound drug, and enhance its bioavailability. The polymers submitted to investigation were a) hyaluronic acid (HA); b) poly-(galacturonic acid) (PGA); c) Mesoglycan (MG, a complex mixture of mucopolysaccharides); d) Carboxymethylchitin (CMCh) and d) two poly(acrylic acids) of different molecular weight (PAA1 and PAA2). Aqueous solutions of the Pi polymer salts, each containing 1.53% w/w Pi base (equivalent to 2.0% Pi nitrate) were tested for miotic activity in albino rabbits, using as reference an aqueous, 2% solution of Pi nitrate, either as such or viscosized with 1.5 and 5.0% poly(vinyl alcohol), (PVA). All polymeric solutions enhanced, in some cases to a statistically significant extent, the bioavailability of the drug with respect to the reference solutions. The relevance of viscosity effects, and of possible muco-adhesive phenomena to the bioavailability of Pi from the salt-vehicles are discussed

Forskolin, a diterpene which displays a potent IOP-lowering activity in several animal species, is very poorly water soluble. This characteristic imposes the ocular administration of the drug as a suspension, a type of formulation which may present several preparative and biological disadvantages, such as e.g. difficulty of sterilization and poor bioavailability. The present report is concerned with an investigation on the solubilization of forskolin by some eye-compatible polymeric agents. While beta- and gamma-cyclodextrin were not particularly effective solubilizers, one polyoxyethylene-polyoxypropylene block copolymer (PluronicR F-127) increased 40 times the drug solubility in water (c. 120 mg/100 ml vs. c. 3 mg/100 ml). When tested on rabbits with artificially increased IOP, the Pluronic vehicle prolonged significantly the duration of the hypotensive activity of forskolin with respect to a standard 1.0% suspension of the drug. The potential of these alternative formulations for increasing the ocular bioavailability of forskolin is discussed.

The present investigation is concerned with the development and “in vivo” evaluation of a long-acting ocular vehicle for the α-adrenergic blocking drug dapiprazole (DAP). The approaches tested for prolonging the activity were a) salification of the drug base with polygalacturonic acid (PGA), and b) formulation as a highly viscous hydrogel. The vehicles prepared by applying (singly or in combination) these techniques, and two reference aqueous vehicles containing DAP-HCl were submitted to a series of biological tests on rabbits (miosis and reversion of mydriasis). When compared with an aqueous solution an aqueous solution, reconstituted prior to use from a freeze-dried formulation (marketed in Italy as GlamidoloR, Angelini)The topical administration of ophthalmic drugs from aqueous solutions (collyria) is characterized by a poor bioavailability and a short duration of action, as a result of a series of concomitant physiological factors (induced lacrimation, tear turnover, solution drainage etc.) which concur in removing the solution from the eye. These factors have been widely investigated and detailed in the relevant literature, and several approaches to extend the ocular residence time of topically applied medications have been reported (4). In the present study two such approaches, namely, a) salification of the basic drug with a polyanionic polymer and b) increased vehicle viscosity, were applied to the development of a long-acting ocular formulation for DAP. The effect of the said manipulations on the biological activity of a series of DAP vehicles was submitted to a preliminary verification “in vivo”, by performing miosis and reversion of tropicamide-induced mydriasis tests in rabbits

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.