Marilena Vlachou

Development and Evaluation of oral multiple-unit and single-unit hydrophilic controlled-release systems

This study compared the release behavior of single-unit (tablets, capsules) and multiple-unit (minitablets in capsules) controlled-release systems of furosemide. The swelling and erosion behaviors of these systems, which contained the swellable hydrophilic polymers sodium alginate (high viscosity) and Carbopol 974P, were compared. Swelling and erosion experiments showed a high degree of swelling and limited erosion for the Carbopol preparations, whereas less swelling but greater erosion was observed for the sodium alginate preparations. The sodium alginate preparations were eroded in 6 hours, while Carbopol preparations exhibited limited erosion within this period of time. These results appear to be attributed to the physicochemical characteristics of the polymers used in this study. Polymer characteristics greatly influenced the release of furosemide (model drug) from the formulations prepared and tested. Sodium alginate had a less pronounced sustained release effect compared with Carbopol (ie, in 8 hours all 3 sodium alginate dosage forms displayed complete release of furosemide, while only 30% of the drug was released from Carbopol dosage forms). Finally, all 3 Carbopol dosage forms (single- and multiple-unit) displayed similar release behavior while sodium alginate dosage forms displayed a different and more distinctive behavior. Minitablets and tablets showed a greater sustained release effect compared with capsules. Evaluation of the release data indicates that the release mechanism for sodium alginate formulations may be attributed to erosion/dissolution, while for Carbopol it may be attributed mainly to polymer relaxation and diffusion of the drug from the polymer surface.

Effects of Excipients on Swelling and Drug Release from Compressed Matrices

AbstractPolymers, and particularly hydrogels, are becoming very popular in formulating controlled-release tablets because they are excellent drug carriers. The effects of hydrophilic and hydrophobic polymers, incorporated in matrices containing soluble (propranolol HCl) or less soluble (flurbiprofen) drugs, on swelling and release kinetics were investigated. The results indicate that swelling and release profiles were affected by the amount of ingredients, the characteristics of the polymer, and the drug substances incorporated in the matrices. Swelling may influence the release rate of the drugs from the matrices. The data obtained from the in vitro dissolution study were evaluated on the basis of a theoretical dissolution equation, by linear transformation of the dissolution curve, and by the Peppas equation. The release mechanisms appeared complex and are affected by the composition of the matrix

Polymers for use in controlled release systems: the effect of surfactants on their swelling properties.

The effect of an ampholytic surfactant on the swelling properties of polymeric materials was studied, using various swelling liquids. Tablets were prepared consisting of hydroxypropyl methylcellulose, poly(oxyethylene) and sodium alginate. Tego betain was the non-ionic surfactant used as an additive in a series of samples made of the above polymers. Those tablets were immersed in distilled water, phosphate buffer and 0.1 N HCl, and their weight uptake was recorded as a function of time, in order to assess the swelling process. Measurements of the contact angle of the above systems were also carried out for estimating their wetting properties. The results of this study showed a selectivity among polymers, surfactant and surrounding liquid. Clearly, an enhancement of the swelling capacity of hydroxypropyl methylcellulose tablets due to the surfactant was recorded. An unclear effect was observed in the case of poly(oxyethylene), whereas for sodium alginate, the dominant factor is its water solubility that controls swelling behaviour.

Swelling properties of various polymers used in controlled release systems.

The effect of powder packing and porosity of specimens on the swelling properties of polymeric materials was studied, in various swelling liquids, such as distilled water and 0.1 N hydrochloric acid solution. Capsules, tablets and films of hydroxypropyl methylcellulose, poly(ethylene oxide) and sodium alginate were prepared and their weight uptake after immersion into the above solutions was recorded as a function of time, in order to assess the swelling process. Measurements of some characteristics of the as received powders were also performed as an attempt to classify the specimens prepared according to their porosity. Within the experimental conditions of this work, it was shown that the porosity of polymeric specimens is a dominant factor that controls their swelling behaviour. Increased porosity leads to fast initial rates of weight uptake and high extent of equilibrium swelling. On the other hand, dissolution and possible degradation of polymers susceptible to acid hydrolysis, results in some variations from the above-mentioned behaviour. With respect to the application in controlled release systems, the overall delivery rate from a polymeric specimen is expected to be a function of both swelling and disintegration characteristics of a specimen and, therefore, the weight uptake can be considered a measure of the release only in the case of polymers with low water solubility and increased stability to hydrolysis.

Development and in vitro evaluation of griseofulvin gels using Franz diffusion cells

Abstract The strong antidermatophytic action of griseofulvin, following oral administration, results from its concentration in the stratum corneum. However, this route of administration is often associated with various side effects. The purpose of this work was the preparation and in vitro evaluation of several gel formulations of griseofulvin, in which the drug was dissolved, for further clinical studies as an alternative topical dosage form. The in vitro release profiles of these formulations through artificial membranes and excised human skin, determined using Franz diffusion cells, showed that griseofulvin is released from the topical gel formulations employed and diffuses through skin. Additionally, stability studies conducted under room conditions for 16 months indicated that these formulations were adequately stable. Finally, preliminary clinical studies in humans showed that griseofulvin gels were effective and also well tolerated.

Preparation and Characterization of the Inclusion Complex of Furosemide with Hydroxypropyl-β-Cyclodextrin:

A highly hydrophobic drug, furosemide, was treated with 2-Hydroxypropyl-β-Cyclodextrin in an attempt to produce modified compounds with increased water solubility. Following a freeze-drying process, the interactions of furosemide and cyclodextrin led to the formation of an inclusion complex, whose dissolution rate in water was studied by the solubility method. Furthermore, mechanical mixtures of furosemide and cyclodextrin were also prepared and tested for their solubility. The reaction products were characterized in the solid state by differential scanning calorimetry (DSC), which provided some evidence about complexation. Additional evidence was obtained by recording the 1HNMR spectra of aqueous solutions of these same products. The study of phase solubility was based on the Higuchi & Connors method and showed an impressive enhancement of the miscibility of furosemide with water. In fact, a 11 fold increase of the drug solubility was recorded for the inclusion complex, in the first stages of dissolution. The experimental results of this work show that 2-Hydroxypropyl-β-Cyclodextrin isan efficient complexation agent for furosemide. Combination of those two substances can be carried out by simple techniques, providing easy control and the obtained inclusion complex is characterized by acceptable water solubility and increased dissolution rate.

Two- and three-layer tablet drug delivery systems for oral sustained release of soluble and poorly soluble drugs

Background: Multilayer tablets are gaining importance in oral sustained drug delivery. They consist of an active matrix core and one or more layers applied during tableting which may act as barriers and regulate drug release. Objective: To examine the release performance of two model drugs, diclofenac sodium and furosemide, from two- and three-layer drug delivery systems using as carriers hydrophilic swellable polymers, namely, Metolose, Polyox, Xantham gum, and an erodible material Gantrez. Results and discussion: All prepared formulations demonstrated sustained release profiles. They also indicated that the carrier characteristics (particularly swelling-expansion, erosion-dissolution) and drug solubility in combination with tablet structure considerably influenced the performance of examined formulations as well as their mode and mechanisms of release. In general our findings show that the differences in drug release between the two- and three-layer tablets are small as it appears that two-layer tablets exhibit a slightly higher release. Because of its greater erosion Gantrez formulations displayed faster release relative to Xantham gum, as did Metolose formulations compared to Polyox formulations. A faster release rate was also noted with diclofenac formulations compared to those of furosemide because of diclofenacs higher solubility mainly seen at early time period. Conclusions: All three-layer Gantrez tablets containing either diclofenac or furosemide and the two-layer furosemide formulation demonstrated a biphasic release. The above indicate that both structures may be used successfully for sustained release drug delivery. In addition the use of multilayer tablets, consisting of materials with suitable properties, may result in modulation of drug release.

Itraconazole in the treatment of tinea corporis and tinea cruris

Forty‐five patients with tinea corporis or tinea cruris were treated with oral itraconazole 100 mg daily for 15 days. At the end of the 15‐day treatment, 80% of the patients were healed or had markedly improved. At the first follow‐up visit, 2 weeks after stopping therapy, 80% of patients were considered responders. An additional follow‐up visit another month later (i. e. 6 weeks post‐treatment) showed that 32 of 41 patients had responded (78%). Overall, the mycological cure rate (culture and microscopy negative) was somewhat lower than the clinical response rate. Only three patients reported minor side effects (7%). Nausea was reported by two patients and an urticarial reaction was seen in one patient after 8 days treatment. This latter patient discontinued therapy because of the adverse experience. It is concluded that itraconazole, given at a daily dose of 100 mg for 15 days, is effective in the treatment of tinea corporis and tinea cruris. Response rates at the last visit (6 weeks post‐therapy) remained at the same satisfactory levels as at the first follow‐up visit (2 weeks post‐therapy), even though treatment was stopped after 2 weeks. Itraconazole appears to be well tolerated by patients. These results, both in terms of efficacy and side effects, are in line with results reported by other investigators. The fact that the mycological cure rates were somewhat lower than the clinical response rates had apparently no influence on the relapse rate at 6 weeks follow‐up post‐therapy.

The effect of modification of acrylic resins on controlled release and bioadhesion.

The effect of various treatments on the properties of an acrylic matrix was studied, in terms of its swelling properties in buffer solution. The release of two types of drugs from those matrices and their bioadhesive character were also considered. Calcium stearate and sodium lauryl sulfate were used as additives for the matrix treatment. 2-Hydroxyethyl methacrylate was also used as a reactive agent for the acrylic resin treatment. The main function of the above chemicals is the modification of the hydrophilic/hydrophobic character of the matrix. This investigation showed that controlled release systems can be designed by adjusting the matrix properties via additives or chemical reaction.

Comparative In Vitro Controlled Release Studies on the Chronobiotic Hormone Melatonin from Cyclodextrins-Containing Matrices and Cyclodextrin: Melatonin Complexes

A series of hydrophilic matrix tablets was prepared and tested with respect to their ability to release the hormone melatonin in a controlled manner, in order to alleviate sleep onset and sleep maintenance dysfunctions. Besides the active ingredient, the tablets were comprised of combinations of the following: HPMC K 15M, low viscosity sodium alginate, microcrystalline cellulose (Avicel PH 102), magnesium stearate, and the cyclodextrins, α-CD, β-CD, γ-CD, HP-β-CD, sulfated β-CD, HP-α-CD and HP-γ-CD, and MLT (guest):CD (host) complexes of the above cyclodextrins, in 1:1 ratio. The controlled release studies were conducted in two aqueous dissolution media at pH 1.2 and 7.4. The stoichiometry of the formed complexes was examined by applying the continuous variation method (Job plot), while the stability constants were calculated by monitoring the spectrophotometric properties of free and CD-encapsulated melatonin (UV-Vis). Host-guest interactions were studied by Nuclear Magnetic Resonance (NMR) spectroscopy. The dissolution data suggest that melatonin is released faster from the MLT:CD complexes than from the rest matrix systems. This enhancement in the dissolution rate and the % release of melatonin from the complexes is due to the increased solubility of the MLT:CD complexes.