Influence of layer position on in vitro and in vivo release of levodopa methyl ester and carbidopa from three-layer matrix tablets.

A versatile oral controlled release system for the simultaneous delivery of levodopa methyl ester and carbidopa, consisting of a three-layer matrix tablet, has been studied and developed. Each individual layer of the matrix exhibited a different release mechanism, i.e. the first layer was swellable (S), the second one was erodible (E) and the third one was disintegrating (D). The three layers have been assembled in the monolithic matrix in different relative positions. It was found that in the monolith the three layers could interact, producing in vitro release profiles depending on their relative position. The monoliths having the configurations DSE and SDE were administered to human volunteers in order to determine the plasma profiles. The pharmacokinetic data showed a significant difference between the early time plasma curves: the monolith DSE, having the fast release profile, gave rise to a rapid appearance of a high levodopa plasma level, whereas the slower releasing monolith SDE produced a smoothed plasma concentration profile.

Translocation of drug particles in HPMC matrix gel layer: effect of drug solubility and influence on release rate.

The aim of this work was to study the release mechanisms of drugs having different solubility (buflomedil pyridoxalphosphate 65%, sodium diclofenac 3.1%, nitrofutantoin 0.02% w/v,) from hydroxypropyl methylcellulose (HPMC) matrices by concomitantly studying swelling, diffusion and erosion fronts movement and drug delivery. The main goal was to clarify the role played by polymer swelling in drug transport. The results showed that the rate and amount of drug released from swellable matrices was dependent not only from drug dissolution and diffusion but also from solid drug translocation in the gel due to polymer swelling. In fact, as drug solubility decreased, the slower drug dissolution rate in the gel layer allowed drug particles to be transported close to the matrix erosion front. The presence of solid particles in the gel reduced the swelling and the entanglement of polymer chains and affected the resistance of gel towards erosion. As a consequence, the matrix became more erodible. The erosive delivery accelerated after the matrix had been completely transformed into the rubbery state, particularly when a considerable amount of solid drug particles remained in the gel phase.

Disintegration propensity of tablets evaluated by means of disintegrating force kinetics.

The aim of this work was to measure the disintegrating force concomitantly with tablet disintegration, in order to evaluate the disintegration propensity of tablets. Disintegration and dissolution were measured on tablets containing two poorly soluble drugs (diclofenac sodium or ketoprofen), including different percentages of two disintegrants (Explotab or Ac-Di-Sol). Because of the experimental setup, the disintegrating force measured was the result of the force generated by disintegrant swelling and dissipated by tablet disintegration. The disintegrating force versus time curves had shapes ranging from a skewed distribution curve to a bell-shaped curve, depending on slow or rapid disintegration of tablets, respectively. Interestingly, the shape of the resulting curves was very sensitive to the composition of the tablet. When the disintegrant in the formula was increased, the force-time curve approached the bell-like shape. The disintegration propensity of the tablet can be evaluated by the disintegrating force development during disintegration. The disintegration improvement of the formula can be predicted. The disintegrating force curve allows for the clear identification of the optimal percentage of disintegrant to be used.

Effect of drying methods on retention of moist sucralfate gel properties.

The aim of this work was to find a drying procedure for moist sucralfate gel capable of producing dried sucralfate gel that retains the original gel properties of bioadhesion, rheology, and micromeritics. Spray-drying and microwave-drying procedures were employed. Mannitol was used as a gel-protective substance during the drying processes. The spray drying of moist sucralfate gel gave rise to a powder whose water suspensions showed significantly reduced viscosity. The bioadhesion of spray-dried sucralfate gel was strongly reduced by drying. When mannitol was used as a gel protector, the spray-dried sucralfate in part maintained the original bioadhesion of moist sucralfate gel. The preparation of a dried sucralfate gel retaining the bioadhesion characteristics, avoiding the use of mannitol, was made possible using the microwave-drying procedure. The microwave-dried product possesses a granular morphology suitable for direct compression because it is a free flowing and strongly coherent granular powder.

Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropylmethyl cellulose matrices containing a soluble drug.

In the present work, the drug volume fraction profiles of a colored and very soluble drug, buflomedil pyridoxal phosphate, in the gel layer of initially glassy hydroxypropylmethyl cellulose matrices were studied, using image analysis of pictures of the matrices during swelling and release. The goal was to correlate the drug release kinetics with the dynamic behavior of the drug gradient in the gel layer. An inert (nonswellable) matrix, manufactured by substituting hydroxypropylmethyl cellulose with an inert polymer and containing the same amount of buflomedil pyridoxal phosphate, was prepared as well. The drug color gradient in the partially extracted region and the flux of this matrix were compared to the swellable matrix. The drug gradient in the dissolved drug gel layer of swellable matrices was observed. It was demonstrated that drug release kinetics does not only depend on drug diffusion and matrix erosion, but also on drug dissolution in the gel and on polymer relaxation.

Partial permselective coating adds an osmotic contribution to drug release from swellable matrixes.

A swellable matrix tablet is described which is partially coated with cellulose acetate (CA) to obtain a film having the shape of a cup, whose permeability to water and solutes was altered by mixing increasing amounts of poly(ethylene glycol) 400 (PEG). The drug-release mechanism from such systems was assessed by carrying out drug-release experiments both in water and saline solutions. Drug permeability through the polymeric cup and SEM analysis on the films were also performed. It was found that the systems exhibited drug-release kinetics very close to linearity. The mechanisms governing drug release were (i) drug diffusion through the uncoated gel layer, (ii) drug transport through the gel layer due to the osmotic pressure difference, and (iii) drug diffusion through the cup pores. The relative importance of each contribution depended on the amount of PEG in the film. The systems with a cup containing 1%, 13%, and 33% PEG w/w behaved in part as osmotic systems, whereas the system having a permeable cup behaved as a hybrid reservoir system. These modifications of the coating permeability introduce a further possibility of modulating drug-release kinetics and lead to a reduced dependence of swellable matrix tablet release on environmental conditions.

Transdermal iontophoresis of salmon calcitonin can reproduce the hypocalcemic effect of intravenous administration.

Salmon calcitonin (sCt) was administered by transdermal iontophoresis in rabbits, using a new drug reservoir assembled directly on the skin, based on a dry disc containing sCt to be dissolved at the application site. The hypocalcemic effect was taken as a measure of the pharmacodynamic response. In rabbits, the results obtained show that salmon calcitonin skin penetration by iontophoresis, using pulsatile current of 0.8 mA/cm2 on a reservoir containing 100 IU/Kg of sCt, was governed by the quantity of electric charge applied, mimicking the hypocalcemic response of 10 IU/Kg intravenous administration.

Drug reservoir composition and transport of salmon calcitonin in transdermal iontophoresis.

PURPOSE: The aim of the work was to study iontophoretic transdermal administration of salmon calcitonin (sCt) in rabbits, with particular attention to drug reservoir composition. A dry sCt disc, to be dissolved on the application site, was used for preparing the reservoir for transdermal iontophoresis. As a reference drug reservoir, a pad wetted with drug solution was used. METHODS: Experiments were done in rabbits depositing 100 IU of salmon calcitonin on skin and applying anodal iontophoresis. Serum calcium concentration was measured during iontophoresis, passive diffusion and after i.v. administration. Parameters such as pH value and reservoir type were examined. RESULTS: Transdermal iontophoresis of sCt elicited a decrease in the serum calcium level, whereas, in the absence of electric current, no significant fall was measured. Using the reservoir prepared from drug solution, anodal iontophoresis at pH 4.2 was more effective than at pH 7.4, probably due to higher sCt net positive charge. Using the reservoir prepared from dry disc, similar kinetics and extent of drug effect were observed at both pH values. The reservoir prepared from solid drug deposit concentrated sCt next to the skin. CONCLUSIONS: Anodal iontophoresis for transdermal calcitonin administration shows therapeutical applicability. The type of reservoir is an important parameter affecting sCt transdermal iontophoresis.

Delivery of nasal powders of beta-cyclodextrin by insufflation.

PURPOSE: Delivery of nasal powders of granulated beta-cyclodextrin by insufflation was studied in order to find the relationship between powder properties and delivery behavior. METHODS: Three nasal powder formulations, prepared by granulating beta-cyclodextrin with different binders, were delivered from a powder insufflation device, in which the dose to be emitted was loaded in a gelatin capsule. The delivery sequence of powder was recorded and characterized using an image analysis program. RESULTS: Particle size was the main parameter affecting nasal powder delivery, both as to the amount of dose sprayed and the aspect of cloud produced. Between 50-150 mu m of particle size a substantial change in delivery behavior of powders was observed. Powder of around 100 mu m in size showed useful insufflation characteristics for nasal delivery. Bioavailability of nasal formulations of progesterone/beta-cyclodextrin powders was discussed in term of delivery behavior. CONCLUSIONS: The formulation approaches for improving nasal delivery of powders require the use of size optimized carriers. Insufflation of powders over 50 mu m can favour the particle deposition by impaction, whereas for powders below 50 mu m, deposition by sedimentation is moved. beta-cyclodextrin is a suitable carrier for achieving high systemic availability following nasal administration of powder formulations.

Drug diffusion front movement is important in drug release control from swellable matrix tablets.

Swellable controlled release devices of buflomedil pyridoxalphosphate in hydroxypropyl methylcellulose were prepared, and their swelling and release behavior was investigated. The drug release as a function of time was investigated for various system parameters. Three distinct fronts were observed during the swelling and release processes, i.e., a swelling, a drug diffusion, and an erosion front. The drug diffusion front could be readily determined due to the drug's yellow color. The relative positions of the fronts and the drug release rate were studied as functions of the initial porosity and the molecular weight of the polymer carrier. It was shown that the drug diffusion front best describes the overall release behavior of the system. The fractional drug release was a strong function of the dissolved drug gel layer thickness, which separates the diffusion front from the erosion front. The effect of drug solubility was also investigated by altering the pH and the ionic strength of the dissolution medium. It was shown that as drug solubility increased, the undissolved drug gel layer thickness decreased, again showing the importance of the movement of the diffusion front in controlling the overall release.

H2-antagonists: synthesis and activity of 2-amino-5-thiazolyl derivatives.

2-Amino- and 2-guanidinothiazole derivatives having in position 5 a methylthioalkyl side-chain with urea-equivalent moieties were prepared for comparison with H2-antagonists of cimetidine and tiotidine series. Examination of the pharmacological results obtained from experiments on guinea pig atria and in cat gastric fistula, suggests some general observations about the structure-activity relationship of the compounds synthesized. The activity trend of these products is different from that of H2-imidazole antagonists while it is similar to that of the tiotidine series. Unlike the tiotidine similar compounds, the 2-guanidino-5-thiazolyl derivatives are less potent than the corresponding 2-amino-5-thiazolyl products. The activity of the latter ones is reduced in comparison to that of tiotidine or cimetidine.

[4-(3-Oxo-1,2-benzisothiazolin-2-yl)alkanoic, phenyl and phenoxyalkanoic acids: synthesis and anti-inflammatory, analgesic, and antipyretic properties]. / Acidi 4-(3-oxo-1,2-benzisotiazolin-2-il)alcanoici, fenil e fenossialcanoici: sintesi, proprietà antiflogistiche, analgesiche ed antipiretiche.

Based on previous observations, the preparation, some physicochemical (partition coefficient, pKa) and pharmacological properties of 4-(3-oxo-1,2-benzisothiazolin-2-yl)alkanoic, benzoic, phenyl, phenoxyalkanoic acids and of some of their functional derivatives are reported. All new compounds were biologically examined for their antiphlogistic, analgesic and antipiretic actions, in comparison with those of 1,2-benzisothiazolin-2-one and with those of ibuprofen as the antiphlogistic, analgesic, antipyretic arylalkanoic prototype. Structure-activity relationships showed that the 1,2-benzisothiazolin-2-one and its new alkanoic and arylalkanoic derivatives have strong actions which are however specific for some of the tested pharmacological properties. From this point of view, the synthesized substances have a narrow spectrum of activity, if compared with ibuprofen which is at the same time an antiphlogistic, analgesic and antipiretic substance. The antiphlogistic and antipyretic activities of 4-(3-oxo-1,2-benzisothiazolin-2-yl)benzoic, phenylacetic and phenylmethylacetic acids and the antipyretic and analgesic actions of 3-oxo-1,2-benzisothiazolin-2-ylacetic acid, which are comparable or higher in "potency" than those of ibuprofen, are noteworthy.