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 At different times after administration, samples of aqueous humor were withdrawn and analyzed by high-pressure liquid chromatography.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.

Penetration enhancement of ibuprofen from supersaturated solutions through human skin.

Systematic investigations on the diffusion of ibuprofen (IBU) from supersaturated solutions through human epidermis are reported. Significant flux enhancement was obtained from supersaturated solutions compared to the saturated solution. Hydroxypropyl methylcellulose (HPMC), when used as an additive was found to be effective in maintaining the high activity state at high degrees of saturation (DS). The increase in the flux was proportional to the DS. In the presence of 2-hydroxypropyl-beta-cyclodextrin (CD) at DS 2 and 3 a lower flux was observed compared to HPMC. At DS 5 a higher flux enhancement was found suggesting that CD might act as a penetration enhancer at certain CD/drug ratios. Studies on the mechanism of stabilisation of HPMC and CD on IBU crystallisation from supersaturated systems showed that HPMC acts as a growth inhibitor and habit modifier whereas CD does not influence the crystallisation process.

Solubilization of tropicamide by hydroxypropyl-beta-cyclodextrin and water-soluble polymers: in vitro/in vivo studies.

1% (w/v) aqueous solutions of tropicamide (TR), a poorly water-soluble mydriatic-cycloplegic drug, are usually obtained by adjusting the pH to approximately 5.0, at the expense, however, of ocular tolerance and bioavailability. The capacity of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) to solubilize TR in pH 7.4 0.02 M phosphate buffer was investigated in the absence and presence of hydrophilic polymers (PVP, CMC and HPMC). Approximately 3.5% (w/v) HP-beta-CD was required to solubilize 1% (w/v) TR in pH 7.4 buffer at room temperature. The required amount was reduced to 0.9% (w/v) by heating at 120 degrees C in the presence of 0.1% (w/v) HPMC. Mydriatic activity tests in rabbits showed an improved bioavailability and maximal mydriatic response for two CD formulations, with and without HPMC, when compared to standard 1% (w/v) TR eyedrops, buffered at pH 5.0. The improved in vivo behaviour of the CD formulations are likely due to their physiological pH, resulting in a reduced irritant effect, although an effect of HP-beta-CD on corneal permeability cannot be dismissed a priori.

Chromatographic indexes on immobilized artificial membranes for the prediction of transdermal transport of drugs.

A set of 12 drugs, consisting of structurally unrelated neutral, basic, acidic and amphoteric compounds, was examined by high performance liquid chromatrography (HPLC) on a model of fluid membrane bilayers, the immobilized artificial membrane (IAM) column. The logarithms of chromatographic capacity factors extrapolated to 100% aqueous phase at pH 5.5 (log kw) were measured and compared to the n-octanol/water partition coefficients (log P). The scale derived from the IAM system was different from the lipophilicity scale expressed by the log P, due to the peculiar capability of phospholipids to well accommodate the ionized form of some molecules and show additive or repulsive extra-interactions when particular structural motifs on the molecule are present. The relationship between log P and log kw previously obtained for compounds interacting on IAM phase by a uniquely lipophilicity-based mechanism, allowed us to calculate, from log P, the values of log kw expected for the drugs considered. These values were subtracted from the log kw experimentally determined and the differences were assumed to quantify the amount of extra-interactions (hydrogen bond and electrostatic interactions) with phospholipids (delta log kw). The coefficients of permeability through the human skin (Kp) for the compounds considered did not correlate with either log kw or log P values. However, the Kp values correlated well with the delta log kw values indicating that the higher the ability of a molecule to cross the skin barrier, the lower its component of interaction with phospholipids not accounted for by lipophilicity-based interactions.

Water soluble drug delivery systems based on a non-biological bioadhesive polymeric system.

Matrix properties and release behaviour of monolithic devices based on a water soluble polymer has been investigated. Polyethyleneoxides of different molecular weights have been used and different molecular weight fractions have been blended in order to tune the release mechanism. Drug release kinetics have been closely related to swelling and dissolution properties of the adopted matrices. In particular the development of the external swollen layer of the tablet as well as the kinetic of dissolution have been monitored. The different drug delivery behaviours observed were related to the different matrix properties. Viscoelastic properties of the matrices have been also investigated. In fact, in order to obtain effective bioadhesive drug release devices, apart from the intrinsic mucoadhesive capabilities of the used polymers, also the viscoelastic properties of the water-polymer gel must also be taken into account. A good interpenetration between the adjacent layers of the mucus and the polymer gel is ineffective in holding the mucoadhesive tablet at a specific site if the polymer gel does not have a proper viscoelastic behaviour. The best compromise between good release, viscoelatic and mucoadhesive properties was obtained in the case of 50% by weight blend of the two adopted polymer fractions (600,000 and 4,000,000 molecular weight).

Synthesis and muscarinic receptor binding profiles of antagonist benzotriazole derivatives.

A series of benzotriazole derivatives were synthesized and tested in order to determine their activities for muscarinic receptor subtypes (M1, M2 and M3). Binding affinities were measured as KI values by competition against [3H]-N-methylscopolamine in rat cortex, atria and ileum. Pharmacological in vitro tests were performed on isolated tissue preparations (rabbit vas deferens, guinea pig atria and ileum); the compounds showed antimuscarinic activity. The synthesized ligands were characterized by moderate activity; however, some of them displayed interesting selectivity profiles (M2/M1 and M2/M3); particularly, the selectivity exhibited by the benzotriazole derivative 14b was quite similar to that observed for AF-DX 116, a typical M2 specific antagonist.

Poly(ethylene oxide) (PEO) and different molecular weight PEO blends monolithic devices for drug release.

An interpretation of the drug release from monolithic water-swellable and soluble polymer tablets is presented. A convenient parameter, alpha, which compares the drug-diffusive conductance in the gel layer with the swelling and dissolving characteristics of the unpenetrated polymer was used to describe the release behaviour of beta-hydroxyethyl-theophylline (etofylline) from compression-moulded tablets of hydrophilic pure semicrystalline poly(ethylene oxides) of mol wt 600,000 and 4,000,000 and of two blends of the two molecular weights of poly(ethylene oxides). The water swelling and dissolution characteristics of two polymers and two blends were analysed, monitoring the thickness increase of the surface-dissolving layer and the rates of water swelling and penetration in the tablets. The drug diffusivities in the water-penetrated polymer gels were measured by carrying out permeation tests. Finally, drug release tests were performed to investigate the release kinetics of the different systems in an aqueous environment at 37 degrees C. The drug release from the high molecular weight poly(ethylene oxide) is principally related to the material swelling rather than polymer dissolution, leading to a progressive decrease of the drug's diffusive conductance in the growing swollen layer, and hence to a non-constant release induced by the prevailing diffusive control. Conversely, drug release from the low molecular weight poly(ethylene oxide) is strictly related to the polymer dissolution mechanism. The achievement of stationary conditions, in which the rate of swelling equals the rate of dissolution, ensures a constant release rate, even in the case of very low drug-diffusive conductance in the external gel layer. Intermediate behaviours were detected in the case of the two blends.

[Cyclosporin in a bioadhesive formulation in the therapy of oral erosive lichen planus. A clinico-experimental evaluation]. / La ciclosporina in formulazione bioadesiva nella terapia del Lichen planus orale erosivo. Valutazione clinico-sperimentale.

This study illustrates the possible topical therapy of OLP with cyclosporine A under bioadhesive gel formula. The treatment was carried out on 6 patients for 8 weeks in much lower (48 mg/day) than those used by other authors. The novelty of this study lies in the use of a bioadhesive formula with carbosymethylcellulose which allows CsA to remain on oral mucosa for about two hours. The remarkable results have shown a reduction ranging from 50 to 80% of oral lesions, thus proposing its specific use in all the forms resisting usual therapy.

[Preparation and pharmacologic activity of N-oxides of 4'-(benzotriazol-2-yl-phenylalkanoic and -phenoxyalkanoic acids]. / Preparazione e attività farmacologica di n-ossidi di acidi 4'-(benzotriazol-2-il)-fenilalcanoici e-fenossialcanoici.

A number of N-oxides of 4'-(benzotriazol-2-yl)-phenylalkanoic and -phenoxyalkanoic acids bearing various substituents on position 6 of benzotriazole together with 4'-(benzotriazol-2-yl) phenylacetic acid were prepared and subjected to a wide pharmacological screening. Several compounds exhibited significant antiinflammatory and diuretic activities, while one was endowed with antihypertensive activity.

[Analysis of the correlation between hydrophilic-lipophilic balance, coefficient of diffusion and hydrogen ion concentration in a series of nonsteroidal anti-inflammatory drugs]. / Analisi correlativa fra bilancio idrofilo-lipofilo, coefficiente di diffusion e concentrazione idrogenionica in una serie di farmaci antiinfiammatori non steroidei.

A thorough investigation on the dependence of rate diffusion constants (Kd) of nonsteroidal antiinflammatory drugs on pH and pKa values was carried out. It is shown that a modified multiparametric curve-fitting technique may constitute an useful tool to describe the rate diffusion pH-profiles of ionogenic substances. A comparison between the Kd values and the corresponding distribution coefficients (log D) shows that these constants identify complementary parameters very useful in the study of structure-activity relationships of ionogenic substances.

Correlation analysis in a set of X-benzyltrimethylammonium derivatives with antimuscarinic activity.

The results of a pharmacological investigation on a series of meta-substituted benzyltrimethylammonium salts possessing an antimuscarinic activity are reported. Correlative analysis shows that the pharmacodynamic activity is a function of the hydrophobic-lipophilic parameter associated with the substituent.

Quantitative structure-activity relationships in a set of antimuscarinic agents.

Quantitative structure-activity relationships (QSAR) have been formulated for the interactions of a set of antimuscarinic agents. The antagonistic activity is found to be dependent on hydrophobic-lipophilic character and steric requirements of substituents R1 and R2 in structures of type R1R2N--CH2--CH2--+NR3R4R5. Moreover, it is shown that the incumbrance of R3, R4 and R5 groups and their polar effects on the onium ending greatly affect the antagonistic activity. A binding model which suggests new avenues for exploration is presented.

QSAR in a series of muscarinic agents. Note V. New sets of rigid and flexible ligands.

A deeper insight of muscarinic receptor attachment points is obtained on studying new sets of rigid and flexible ligands. The quantitative analysis of the correspondence between biological response and structural ligand features confirms that pD2 values are strongly dependent on hydrophobic and steric parameters. Moreover, it is shown that receptor attachment points are interrelated and their simultaneous perturbations contribute to enhance the activity with comparable effectiveness.

Inhibition of butyrylcholinesterase by organophosphorus compounds: a quantitative structure-activity analysis.

Quantitative structure-activity relationships have been formulated for the interactions of a variety of inhibitors with butyrylcholinesterase. The parameters KQ, k2 and ki are found to be strongly dependent on molar refractivity as well as on the inductive effect of the leaving group --SR' in structures of the RO (X) P (O) SR' type. A model for the interaction of organophosphorus compounds is presented which gives a consistent view of the binding step, acylation and overall inhibition.

[Hydrophobic parameters in homologous series of psychopharmaceuticals]. / Parametri idrofobici in serie omologhe di psicofarmaci.

The 1-octanol/water partition coefficients of sets of 1,4-benzodiazepine and phenothiazine derivatives are determined. The values of the hydrophobic parameters obtained by shake-flask procedure are correlated to the corresponding HPLC retention times. The existence of linear correlations between the two experimentally determined parameters clearly show that chromatographic indices model excellently the shake-flask parameters.

[Alkylation of 6-benzyl-5H-dibenzo(d,f)-(1,3)diazepine]. / Andamento dell'alchilazione della 6-benzil-5H-dibenzo(d,f)-(1,3)diazepina.

The alkylation of 6-benzyl-5H-dibenzo(d,f)-(1,3)diazepine (I) with propyl iodide and dimethylaminopropyl chloride in dimethylformamide solution and in the presence of sodium amide was investigated. In both instances the alkylation affected the methylene of benzyl group instead of the cyclic imino group, however the dimethylaminopropyl derivative does not stand the working up conditions, giving place to 2-amino-2'(alpha-phenyl-delta-dimethylamino)valerylamino-biphenyl (III).