Brunella Cappello

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 drugs 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.

Solubilization of tropicamide by hydroxypropyl-β-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.

Diclofenac β-Cyclodextrin Binary Systems: A Study in Solution and in the Solid State

This study was carried out with the aim to optimize the dissolution propertiesof diclofenac (DIC) – a non-steroidal anti-inflammatory drug sparingly solublein water – through association -with β-cyclodextrin (βCD). Theeffect of βCD on the aqueous solubility of DIC was evaluated by thephase solubility method. The amount of DIC dissolved increased linearly withthe addition of βCD according to an AL type plot and without precipitationof the complex. The apparent stability constant of the complex, calculated supposinga 1:1 stoichiometry, was 295 M-1; this value was confirmed by circulardichroism analysis. DIC/βCD interactions were also studied in water by1H and 13C NMR spectroscopy. Equimolar DIC/βCD solid systems were prepared by physical-mixing, kneading, co-evaporation andfreeze-drying, and their properties in the solid state studied by DifferentialScanning Calorimetry, X-ray powder diffractometry and Fourier-TransformInfrared analysis. For sake of comparison, the mixture of DIC and βCDseparately lyophilized was investigated too. The results demonstrated that thefreeze-dried product had the highest degree of amorphization and they were inagreement with the existence of an inclusion complex in the solid state. Thedissolution profiles of the drug from each solid system were affected by its physico-chemical properties, the freeze-dried being the most rapidly dissolvingforms.

Drug/cyclodextrin solid systems in the design of hydrophilic matrices: a strategy to modulate drug delivery rate.

The aim of this study was to investigate how the delivery rate of erodible sustained-release hydrophilic matrices intended for the delivery of poorly soluble drugs can be optimized through the incorporation of drug/cyclodextrin binary systems. Carvedilol (CAR), a sparingly water-soluble antihypertensive drug, was selected as a model for the study. As first, we attempted to improve CAR apparent solubility by association with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and then incorporated CAR/HPbetaCD binary systems in sustained-release tablets made of poly(ethyleneoxide) (PEO). Solid CAR/HPbetaCD binary systems were prepared by physical mixing, kneading, co-melting and freeze-drying methods and characterized by DSC and X-ray powder diffractometry. The amount of CAR dissolved from all the HPbetaCD-containing systems was higher than pure CAR, the co-molten and freeze-dried products showing the best dissolution performance. The incorporation of the binary systems in PEO tablets resulted in a CAR release rate much higher than tablets containing only CAR. It was found that the time necessary to achieve complete release from the tablet was linearly related to the dissolution parameters of CAR/HPbetaCD powders. In the case of co-molten and freeze-dried products, all CAR content could be released in about 12 and 10 h, respectively. Our results demonstrate that the incorporation of drug/cyclodextrin solid systems in erodable PEO matrices intended for the delivery of poorly water-soluble drugs is useful to modulate the release rate by controlling the dissolution properties of the drug inside the tablet.

Etodolac/cyclodextrin formulations: physicochemical characterization and in vivo pharmacological studies

Background: The formulation of nonsteroidal anti-inflammatory drugs with cyclodextrins (CDs) has demonstrated to be a suitable strategy to increase drug aqueous solubility, dissolution rate, and gastric tolerance. Aim: We investigated the effects of the CDs on the physicochemical and pharmacological properties of Etodolac (ET), a practically water-insoluble nonsteroidal anti-inflammatory drug, to individuate a drug formulation with optimized pharmacokinetics and pharmacodynamics. Methods: The interactions in solution of ET with β-CD, hydroxypropyl-β-CD (HP-β-CD), and γ-CD were studied by 13C-NMR spectroscopy and phase solubility method. Solid binary systems, prepared by physical mixing and freeze-drying, were characterized by differential scanning calorimetry, X-ray analysis and Fourier transform infrared spectroscopy, and dissolution studies. An in vivo pharmacological investigation (analgesic activity and gastric tolerance studies) was performed on freeze-dried ET/CD formulations. Results: 13C-NMR and phase solubility studies demonstrated the ability of CDs to complex with ET and increase drug solubility. ET/CD interactions at the solid state occurred at the molecular level only for freezed-dried samples. All binary systems, mainly those containing HP-β-CD and γ -CD, showed a significantly improved dissolution profile of ET. In vivo pharmacological studies evidenced an improvement of analgesic activity and a reduction of gastrolesivity of ET/CD-tested formulations with respect to ET alone. Conclusions: The formulation of ET with CDs demonstrates relevant pharmaceutical potential in view of decreasing dose and side effects of ET. For industrial applications, HP-β-CD appears to be the best partner for ET, as it is less expensive than γ-CD and gives rise to higher drug solubilization than β-CD.

Formulation and Preliminary in vivo Testing of Rufloxacin-Cyclodextrin Ophthalmic Solutions

Aim of the present work was to investigate the effect of somecyclodextrins (CDs) on the solubility and ocular bioavailability of rufloxacin base (RUF), with theultimate goal of developing an ophthalmic formulation. Phase solubility studies of RUF inpH 7.4 buffer were carried out in the presence of β-cyclodextrin (β-CD),hydroxypropyl-β-cyclodextrin (HP-β-CD) and γ-cyclodextrin(γ-CD). The effect of hydroxypropyl methylcellulose (HPMC) on RUF solubility was evaluated after heating the solutionscontaining HP-β-CD at 120 °C.A significant enhancement of RUF solubility was achieved by associatingthe drug with CDs, particularly HP-β-CD. This CD formed with RUF a less stablecomplex than that formed by β-CD, but did not suffer the solubility limitations ofthe parent CD, and showed a higher solubilizing capacity than γ-CD. Addition of 0.25%(w/v) HPMC to solutions containing HP-β-CD increased the solubilizing effect of this CD,thus allowing reduction of the amount necessary for solubilization of 0.3% (w/v) RUF.Preliminary pharmacokinetic data in rabbits indicated that theocular bioavailability of 0.3% (w/v) RUF solubilized by HP-β-CD was higher when compared witha 0.3% (w/v) RUF suspension used as reference.

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-β-cyclodextrin (CD), one of which was viscosized with TSP; and two pH 5.0 solutions of rufloxacin hydrochloride (RUF-HCI), 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-HCI) and a suspension of the base (TSP/RUF), followed by the non-viscosized solution of RUF-HCI. 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-β-cyclodextrin (CD/RUF) results in decreased drug availability with respect to standard formulations. Two of the TSP-viscosized formulations (RUF suspension and RUF-HCI 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.

Investigation on the Interaction of Bendazac with β-, Hydroxypropyl-β-, and γ-, yclodextrins

The interactions of Bendazac, a topical non-steroidal anti-inflammatory drug, withβ-cyclodextrin, hydroxypropyl-β-cyclodextrin and γ-cyclodextrinwere investigated to evaluate possibilities to improve the drugs poor water solubilityand eventually to enhance the topical delivery of Bendazac. Phase solubility studiesdemonstrated the ability of the selected cyclodextrins to complex with Bendazac andincrease drug solubility. The amount of solubilized Bendazac increased linearly withthe addition of each cyclodextrin according toAL type plots. 13C-NMR studiesshowed that the Bendazac A-ring was included in the cavity of the three cyclodextrins.The γ-cyclodextrin was also able to include the B-ring of Bendazac, forminga complex where one drug molecule fitted into two cyclodextrin molecules. Equimolarsolid systems of the drug with each cyclodextrin carrier were prepared using varioustechniques (physical mixing, spray-drying and freeze-drying). The results of differential scanning calorimetry and Fourier transform infrared analysis, performed on the solid systems, demonstrated that freeze-dried and spray-dried products had a high degree of amorphization and agreed with the hypothesis of the existence of drug–cyclodextrin interaction in the solid state. The cyclodextrins tested were able to improve the dissolution of Bendazac. The dissolution profile of the drug was also affected by the physico-chemical properties of each solid system, the freeze-dried products being the most rapidly dissolving forms.

Influence of Different Cyclodextrins on Physico-Chemical and Pharmacological Properties of Etodolac

Etodolac (Et), an indolacetic acid derivative, is an useful non steroidal antiinflammatory drug (NSAID) marketed for the treatment of pain and inflammation associated with various forms of arthritis; like other NSAIDS, it is scarcely water soluble and highly lipophilic. The dissolution rate is often the limiting step for oral absorption of poorly soluble drugs and can also strongly affect the bioavailability. Therefore, the optimization of the pharmaceutical formulation of Et should be considered to improve drug dissolution rate in order to achieve an improvement of both oral availability and onset rate of analgesic effect.