[Formulation and stability of suspensions for preclinical study]. / Formulazione e stabilità di sospensioni per studi preclinici.

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).

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.

Semisolid ophthalmic vehicles.

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.

Preparation and evaluation in rabbits of topical solutions containing forskolin.

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.

Activity of lavandino essential oil against non-tubercular opportunistic rapid grown mycobacteria.

Four samples of lavandino essential oil were investigated for their antimycobacterial activity, and were found to be very effective against some strains of non-tubercolar Mycobacteria (NTM). The mechanism of this effect is discussed.

Substantivity of sunscreens-preparation and evaluation of some quaternary ammonium benzophenone derivatives.

Synopsis In continuation of previous studies on keratin-substantive sunscreens, two series of quaternary ammonium compounds, derived from 2,4-dihydroxy and from 4-hydroxybenzophenone and containing O-alkyl and N-alkyl chains of different length were prepared and submitted to substantivity tests on wool, to microbiological tests on two bacterial and two fungal species, and to tests for allergenicity/irritation on human skin. All compounds were rapidly adsorbed by wool in aqueous solution: as expected, the maximum amounts adsorbed at equilibrium (S(max)), indicative of the skin substantivity, were greatest for the C12 N-alkyl derivatives, and showed a progressive decrease with increasing length of the N-alkyl substituent. No substantial substantivity differences were detected in four C12 quaternary derivatives, differing by the presence (or absence) of a 2-OH group in the benzophenone moiety and by the length of the O-alkyl (n= 2 or 3) side chain. When tested for antimicrobial activity, however, only the 4-hydroxybenzophenone C12 quaternary derivatives showed an order of activity comparable with that of two reference compounds. The conditions leading to a maximal antibacterial activity in the present compounds appeared to be the absence of the 2-OH group, and a shorter O-alkyl side chain. None of the new quaternary derivatives showed skin-irritant properties. The results of this investigation, while confirming the peak substantivity of C12 quaternary derivatives, indicate the possibility of dissociating, in a quaternary ammonium sunscreen, the skin substantivity from other unwanted side-effects, and offer some guidelines for the development of safer agents of this type.

Substantivity of sunscreens: an appraisal of some quaternary ammonium sunscreens.

Synopsis Two series of quaternary ammonium UV-B sunscreens, derived from salicylic acid (S) and from p-methoxycinnamic acid (C), and containing N-alkyl chains of different length (C(2) to C(16)) were prepared and submitted to substantivity tests on animal (wool) keratin, and to microbiological tests. A direct correlation between substantivity and antimicrobial/antifungal activity was observed in all cases, the compounds bearing C(12) alkyl chains displaying peak values. The C-derivatives, when compared with the S-derivatives, showed relatively higher substantivity and sunscreen index (SI) values, coupled with lower antibacterial activity. The substantivity-microbiological activity correlations and the particular behaviour of the C(12) derivatives are briefly discussed in the light of the existing literature data. On the basis of the experimental results, possible guidelines for the development of substantive and non-antibacterial (and possibly, non-irritant) quaternary ammonium sunscreens are indicated.

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.

Inhibition of bergaptene toxicity by UV-A filters.

Synopsis It is well known that 5-methoxypsoralen (5-MOP, bergaptene) exerts several biological actions on irradiation with long wavelength (UV-A, lambda > 320 nm) UV light. The present study had the purpose of evaluating if the phototoxic activity elicited in guinea-pigs by topical application of 5-MOP followed by irradiation, could be reduced or inhibited by the simultaneous application of substances which absorb in the UV-A region. The photo-sensitizing solutions were: an alcoholic solution of 5-MOP, diluted bergamot oil, and an experimental perfume. Of the filters tested, two dibenzoylmethane derivatives proved particularly effective. Interestingly, the inhibitory activity of the filters was significantly greater when these were co-administered with bergamot oil or with the perfume, with respect to the activity shown in the 5-MOP alcoholic solution. A distyrylbiphenyl derivative showing an absorption maximum at 350 nm, was also found particularly effective.

Vehicle effects in percutaneous absorption: in vitro study of influence of solvent power and microscopic viscosity of vehicle on benzocaine release from suspension hydrogels.

The release through silicone rubber membranes of benzocaine suspended in carbomer hydrogels containing different concentrations of low molecular weight polysols (ethylene glycol, propylene glycol, glycerol, and sorbitol) was studied to establish general principles and procedures for control of the effects on percutaneous absorption caused by changes in drug solubility and/or diffusivity in the vehicle. The effect of the additives on the release is expressed in terms of the relative released amount, i.e., the ratio, Q/Qw, of the amount of drug released from each additive-containing gel to the amount released at the same time from the additive-free gel. The experimental Q/Qw values are correlated with values calculated by a simple equation involving known or readily measurable parameters such as the drug concentration in the gel, the drug solubility in the pure liquid phase, and the viscosity of this phase. Derivation of such a relationship from a known equation describing the vehicle-controlled relase of suspended drugs was possible because an inverse proportionality was observed between drug diffusivity in the gels and the viscosity of the respective solvents. This relationship is interpreted with respect to current theories on drug diffusion in diluted gels.