Chitosan-pectin multiparticulate systems associated with enteric polymers for colonic drug delivery

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Multiparticulate systems of pectin-chitosan: Study of swelling and drug release

The aim of this study was to prepare multiparticulate systems of pectin:chitosan (PC:CS) and to evaluate their swelling ratio and the drug release in different environments. PC:CS particles containing triamcinolone were prepared by a complex coacervation/ionotropic gelation method in aqueous environment. The polymer ratio, the calcium concentration and the contact time of the capsules with chitosan dispersion for particles formation and the structures obtained were analyzed. The systems were characterized in relation to morphology, size, swelling, and drug release behavior. The methodology used allowed the production of spherical particles with narrow range of size distribution. The entrapment efficiency for triamcinolone was 84.31 ± 439. It was observed that the particles present a relatively low swelling ratio in acidic medium and a larger swelling ratio in enteric medium. The release profile was dependent on pH and can be related with the swelling ratio.

Formulation of multiparticulate systems as lyophilised orally disintegrating tablets

The current study aimed to exploit the electrostatic associative interaction between carrageenan and gelatin to optimise a formulation of lyophilised orally disintegrating tablets (ODTs) suitable for multiparticulate delivery. A central composite face centred (CCF) design was applied to study the influence of formulation variables (gelatin, carrageenan and alanine concentrations) on the crucial responses of the formulation (disintegration time, hardness, viscosity and pH). The disintegration time and viscosity were controlled by the associative interaction between gelatin and carrageenan upon hydration which forms a strong complex that increases the viscosity of the stock solution and forms tablet with higher resistant to disintegration in aqueous medium. Therefore, the levels of carrageenan, gelatin and their interaction in the formulation were the significant factors. In terms of hardness, increasing gelatin and alanine concentration was the most effective way to improve tablet hardness. Accordingly, optimum concentrations of these excipients were needed to find the best balance that fulfilled all formulation requirements. The revised model showed high degree of predictability and optimisation reliability and therefore was successful in developing an ODT formulation with optimised properties that were able deliver enteric coated multiparticulates of omeprazole without compromising their functionality.

Alginate-chitosan systems: In vitro controlled release of triamcinolone and in vivo gastrointestinal transit

The aim of this study was to develop multiparticulate therapeutic systems of alginate (AL) and chitosan (CS) containing triamcinolone (TC) to colonic drug delivery. Multiparticulate systems of AL-CS, prepared by a complex coacervation/ionotropic gelation method, were characterized for morphological and size aspects, swelling degree, encapsulation content and efficiency, in vitro release profile in different environments simulating the gastrointestinal tract (GIT) and in vivo gastrointestinal transit. The systems showed suitable morphological characteristics with particle diameters of approximately 1.6 mm. In simulated gastric environment, at pH 1.2, the capsules presented low degree of swelling and in vitro release of drug. A higher swelling degree was observed in simulated enteric environment, pH 7.5, followed by erosion. Practically all the drug was released after 6 h of in vitro assay. The in vivo analysis of gastrointestinal transit, carried out in rats, showed that the systems passed practically intact through the stomach and did not show the same profile of swelling observed in the in vitro tests. It was possible to verify the presence of capsules in the colonic region of GIT. The results indicate that AL-CS multiparticulate systems can be used as an adjuvant for the preparation of therapeutic systems to colonic delivery of drugs. (C) 2010 Elsevier Ltd. All rights reserved.

Novos sistemas de liberação de fármacos à base de xilana

The aim of this work was to perform the extraction and characterization of xylan from corn cobs and prepare xylan-based microcapsules. For that purpose, an alkaline extraction of xylan was carried out followed by the polymer characterization regarding its technological properties, such as angle of repose, Hausner factor, density, compressibility and compactability. Also, a low-cost and rapid analytical procedure to identify xylan by means of infrared spectroscopy was studied. Xylan was characterized as a yellowish fine powder with low density and poor flow properties. After the extraction and characterization of the polymer, xylan-based microcapsules were prepared by means of interfacial crosslinking polymerization and their characterization was performed in order to obtain gastroresistant multiparticulate systems. This work involved the most suitable parameters of the preparation of microcapsules as well as the study of the process, scale-up methodology and biological analysis. Magnetic nanoparticles were used as a model system to be encapsulated by the xylan microcapsules. According to the results, xylan-based microcapsules were shown to be resistant to several conditions found along the gastrointestinal tract and they were able to avoid the early degradation of the magnetic nanoparticles

Obtenção de sistemas multiparticulados de isoniazida revestidos com polímero de liberação entérica

Known for thousands of years, tuberculosis (TB) is the leading cause of mortality by a single infectious disease due to lack of patient adherence to available treatment regimens, the rising of multidrug resistant strains of TB (MDR-TB) and co-infection with HIV virus. Isoniazid and rifampicin are the most powerful bactericidal agents against M. tuberculosis. Because of that, this couple of drugs becomes unanimity in anti-TB treatment around the world. However, the rifampicin in acidic conditions in the stomach can be degraded rapidly, especially in the presence of isoniazid, which reduces the amount of available drug for absorption, as well as its bioavailability, contributing to the growing resistance to tuberculostatic drugs. Rifampicin is well absorbed in the stomach because of its high solubility between pH 1 and 2 and the gastric absorption of isoniazid is considered poor, therefore it is mostly intestinal. This work has as objective the development of gastro-resistant multiple-systems (granules and pellets) of isoniazid aiming to prevent the contact with rifampicin, with consequent degradation in acid stomach and modulate the release of isoniazid in the intestine. Granules of isoniazid were obtained by wet method using both alcoholic and aqueous solutions of PVP K-30 as aggregating and binder agent, at proportions of 5, 8 and 10%. The influence of the excipients (starch, cellulose or filler default) on the physical and technological properties of the granules was investigated. The pellets were produced by extrusionesferonization technique using isoniazid and microcrystalline cellulose MC 101 (at the proportion of 85:15) and aqueous solution of 1% Methocel as platelet. The pellets presented advantages over granular, such as: higher apparent density, smaller difference between apparent and compaction densities, smoother surface and, especially, smaller friability, and then were coated with an organic solution of Acrycoat L 100 ® in a fluidized bed. Different percentages of coating (15, 25 and 50%) were applied to the pellets which had their behavior evaluated in vitro by dissolution in acidic and basic medium. Rifampicin dissolution in the presence of uncoated and coated isoniazid pellets was evaluated too. The results indicate that the gastro resistance was only achieved with the greatest amount of coating and isoniazid is released successfully in basic step. The amount of rifampicin in the dissolution medium when the isoniazid pellets were not coated was lower than in the presence of enteric release pellets. Therefore, the polymer Acrycoat L 100 ® was efficient for coating with gastro-resistant function and can solve the problem of low bioavailability of rifampicin and help to reduce its dosage

Desenvolvimento de dispersões sólidas para liberação colônica de metronidazol

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Novel formulation strategies for the fabrication of lyophilised orally disintegrating tablets

Orally disintegrating Tablets (ODTs), also known as fast-disintegrating, fast-melt or fast-dissolving tablets, are a relatively novel dosage technology that involves the rapid disintegration or dissolution of the dosage form into a solution or suspension in the mouth without the need for water. The solution containing the active ingredients is swallowed, and the active ingredients are then absorbed through the gastrointestinal epithelium to reach the target and produce the desired effect. Formulation of ODTs was originally developed to address swallowing difficulties of conventional solid oral dosage forms (tablets and capsules) experienced by wide range of patient population, especially children and elderly. The current work investigates the formulation and development of ODTs prepared by freeze drying. Initial studies focused on formulation parameters that influence the manufacturing process and performance of lyophilised tablets based on excipients used in commercial products (gelatin and saccharides). The second phase of the work was followed up by comprehensive studies to address the essential need to create saccharide free ODTs using naturally accruing amino acids individually or in combinations. Furthermore, a factorial design study was carried out to investigate the feasibility of delivering multiparticulate systems of challenging drugs using a novel formulation that exploited the electrostatic associative interaction between gelatin and carrageenan. Finally, studies aimed to replace gelatin with ethically and morally accepted components to the end users were performed and the selected binder was used in factorial design studies to investigate and optimise ODT formulations that incorporated drugs with varies physicochemical properties. Our results show that formulation of elegant lyophilised ODTs with instant disintegration and adequate mechanical strength requires carful optimisation of gelatin concentration and bloom strength in addition to saccharide type and concentration. Successful formulation of saccharides free lyophilised ODTs requires amino acids that crystallise in the frozen state or display relatively high Tg', interact and integrate completely with the binder and, also, display short wetting time with the disintegrating medium. The use of an optimised mixture of gelatin, carrageenan and alanine was able to create viscous solutions to suspend multiparticulate systems and at the same time provide tablets with short disintegration times and adequate mechanical properties. On the other hand, gum arabic showed an outstanding potential for use as a binder in the formulation of lyophilised ODTs. Compared to gelatin formulations, the use of gum arabic simplified the formulation stages, shortened the freeze drying cycles and produced tablets with superior performance in terms of the disintegration time and mechanical strength. Furthermore, formulation of lyophilised ODTs based on gum arabic showed capability to deliver diverse range of drugs with advantages over commercial products.

Magnetic multiparticulate colonic delivery systems evaluated by AC Biosusceptometry

The biomagnetic technique called Alternate Current Biosusceptometry (ACB) is a proposal to evaluate a multiparticulate drug delivery system in the human gastrointestinal tract. Results show that ACB was able to quantify the gastrointestinal transit and spreading of the magnetic material and is an attractive tool for pharmaceutical research. © 2007.

AC Biosusceptometry as a Tool for Monitoring the Gastrointestinal Transit of Multiparticulate Drug Delivery System

Drug delivery systems based on natural polysaccharides, such as chitosan (CS) and pectin (PC), rather than on synthetic polymers, have been widely studied. Some reasons for that are low toxicity and costs and high biodegradability of the formers. A multiparticulate system based on CS and PC was developed in our laboratories, including the addition of an enteric polymer, cellulose acetate phtalate (CAP). Such improvement promoted stronger gastric and enteric resistances, as assessed in vitro, making the systems more selective to enzymatic degradation in the colon. Although in vitro dissolution tests can simulate some properties concerning the gastrointestinal transit (GT), collaborating to characterize the systems behavior in the biological fluids, frequently they do not result in satisfactory in vitro/in vivo correlations. The objective of this work was to follow in vivo the GT of the particles developed by means of AC biosusceptometry (ACB), a non-invasive and of low cost methodology. The particles containing ferrite in powder form were prepared by complex coacervation using an ideal 3:1:1 mass ratio for PC:CS:CAP. The magnetic particles were administered to healthy volunteers by oral route. The GT was monitored by using multi-sensor ACB system and the signal acquisition was performed every IS min until the colonic region was reached. By means of ACB technique, it was possible to acquiring images generated by the magnetic particles within the whole gastrointestinal tract including the colonic region. Variable particles transit times were observed among the volunteers, but without interference on the mapping of the particles until the colonic region. The particles were able to produce magnetic field strong enough to generate signals adequate for mapping the particles. The results suggest that integral particles reached the colon, after they resisted against gastric and enteric media. Studies associating transit time and in vivo drug release are in development in order to confirm the efficiency of the systems.

On the zeros of the Abelian integrals for a class of Liénard systems

A planar polynomial differential system has a finite number of limit cycles. However, finding the upper bound of the number of limit cycles is an open problem for the general nonlinear dynamical systems. In this paper, we investigated a class of Liénard systems of the form x'=y, y'=f(x)+y g(x) with deg f=5 and deg g=4. We proved that the related elliptic integrals of the Liénard systems have at most three zeros including multiple zeros, which implies that the number of limit cycles bifurcated from the periodic orbits of the unperturbed system is less than or equal to 3.