A novel concept in enteric coating: a double-coating system providing rapid drug release in the proximal small intestine.

A novel double-coating enteric system was developed to accelerate drug release in conditions resembling the upper small intestine. The system comprises an inner coat (partially neutralised EUDRAGIT L 30 D-55 and organic acid) and an outer coat (standard EUDRAGIT L 30 D-55). Prednisolone tablets were coated with double layer formulations with inner coats neutralised to pH 5.6 in the presence of 10% citric acid or adipic acid. A conventional single coating was also applied for comparison purposes. There was no drug release from the single coated or double-coated tablets in 0.1M HCl for 2 h using USP II apparatus. The lag times of drug release in subsequent pH 5.6 phosphate buffer (to resemble the pH condition of the proximal small intestine) were 102, 42 and 28 min for the single coated, adipic acid and citric acid double-coated tablets respectively. The lag time for release from the double-coated tablets was further reduced to 5 min when the inner coat was neutralised to pH 6.0 in the presence of 10% citric acid. The rapid drug release from the double-coating system was associated with faster polymer dissolution rates compared to the single coating. The novel double-coated system has the potential to provide rapid drug release in the proximal small intestine, overcoming the limitations of conventional enteric coatings.

SEM/EDX and confocal microscopy analysis of novel and conventional enteric-coated systems.

A novel double coating enteric system (comprising an inner layer of neutralised EUDRAGIT) L 30 D-55 and organic acid, and an outer layer of standard EUDRAGIT) L 30 D-55) was developed to provide fast dissolution in proximal small intestinal conditions. The mechanisms involved in the dissolution of the double coating were investigated and compared with a conventional single layer enteric coating and an hypromellose (HPMC) sub-coated enteric system. Rates of drug release from coated prednisolone pellets were established using USP II dissolution methods (0.1M HCl for 2h and subsequently pH 5.5 phosphate buffer) and the coating dissolution process was illustrated using confocal laser scanning microscopy (CLSM). The distribution of sodium, as a representative ion, in the double-coating system during dissolution was determined using scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX). The double-coating system showed faster dissolution compared to the single coating and the HPMC sub-coated system in pH 5.5 buffer. The dissolution process of the double-coating was unusual; the inner coat dissolved before the outer coat and this accelerated the dissolution of the outer coat. During dissolution, sodium ions diffused from the inner coat to the outer coat. This migration of ions and the increased ionic strength and buffer capacity of the inner coat contribute to the rapid dissolution of the double-coating system.

Use of the BioDis to generate a physiologically relevant IVIVC.

In the last decades there has been continual interest in site-specific delivery to the colon. Recently, new types of site-specific delivery formulations have been developed for the treatment of ulcerative colitis and other colon related diseases. The aim of the present study was to establish a physiologically relevant IVIVC for two prototypes using a prospective in vitro study. Caffeine, a drug being absorbed along the entire gastrointestinal tract, was selected as a model drug. USP apparatus 3, the BioDis, was used for all experiments and the passage through the gastrointestinal tract was simulated with a physiologically based pH-gradient. Subsequently, the fraction of drug released in vitro was compared with the fraction of drug released in vivo, which was determined in humans in a separate study. Results indicated that the BioDis method is very useful in terms of predicting the site/timing and extent of drug release from the prototypes, since an a priori IVIVC could be established. Moreover, from the results generated in the present study, it is obvious that novel pH- and time-based multi-unit formulations would improve selectivity of drug delivery to the distal ileum and the colon and therefore might be very helpful in the treatment of colonic diseases.

Proton-actuated membrane-destabilizing polyion complex micelles.

The efficiency of nucleic acid-based drugs is usually hampered by the fact that, following their uptake by the cell, these drugs end up in acidic organelles (i.e., endosomes/lysosomes) from which they barely escape. This work relates to the preparation and characterization of polyion complex micelles (PICM) formed by the self-assembly of three polyelectrolytes: a diblock cationic copolymer; a membranolytic, methacrylic acid copolymer; and an oligonucleotide. It is demonstrated that a synthetic membrane-active polyanion can be successfully integrated within the structure of PICM to yield well-defined, narrowly distributed micelles (30 nm) with a core/shell architecture. Besides their ability to protect the oligonucleotide against nuclease degradation, PICM partly dissociate under mildly acidic conditions, releasing chain clusters that destabilize bilayer membranes. This association/dissociation behavior illustrates the potential of these pH-sensitive PICM for the transport and efficient delivery of polyionic drugs.

Modulated release metoprolol succinate formulation based on ionic interactions: in vivo proof of concept.

A modulated release, multiunit oral drug delivery technology using a system based on ionic interactions of anions of salts with quaternary ammonium ions of the ammoniomethacrylate polymer is described. The system consisted of a drug layered, EUDRAGIT NE-coated salt core which was further coated with EUDRAGIT RS. The relative effects of different anions on the polymer permeability have been investigated by studying their influence on the in vitro drug release. A prototype formulation of metoprolol succinate using this technology was developed and the drug release from the formulation was adjusted to have a release profile which would match the circadian rhythm i.e. a higher amount of drug would be available after an initial lower release (accelerated type of release). The formulation was tested in vivo in 12 healthy human volunteers in an open label, randomized, two-treatment, two-period, single dose crossover bio-study with reference formulation Beloc-zok. The in vivo release demonstrated that compared to the reference, a higher amount of drug was available in the plasma from the 7th hour onwards. A higher AUC of the drug was also observed compared to the reference formulation. An in vitro-in vivo correlation was attempted to identify a bio-relevant in vitro dissolution medium for the formulation.

On the role of methacrylic acid copolymers in the intracellular delivery of antisense oligonucleotides.

The delivery of active biomacromolecules to the cytoplasm is a major challenge as it is generally hindered by the endosomal/lysosomal barrier. Synthetic titratable polyanions can overcome this barrier by destabilizing membrane bilayers at pH values typically found in endosomes. This study investigates how anionic polyelectrolytes can enhance the cytoplasmic delivery of an antisense oligonucleotide (ODN). Novel methacrylic acid (MAA) copolymers were examined for their pH-sensitive properties and ability to destabilize cell membranes in a pH-dependent manner. Ternary complex formulations prepared with the ODN, a cationic lipid and a MAA copolymer were systematically characterized with respect to their size, zeta potential, antisense activity, cytotoxicity and cellular uptake using the A549 human lung carcinoma cell line. The MAA copolymer substantially increased the activity of the antisense ODN in inhibiting the expression of protein kinase C-alpha. Uptake, cytotoxicity and antisense activity were strongly dependent on copolymer concentration. Metabolic inhibitors demonstrated that endocytosis was the major internalization pathway of the complexes, and that endosomal acidification was essential for ODN activity. Confocal microscopy analysis of cells incubated with fluorescently-labeled complexes revealed selective delivery of the ODN, but not of the copolymer, to the cytoplasm/nucleus. This study provides new insight into the mechanisms of intracellular delivery of macromolecular drugs, using synthetic anionic polyelectrolytes.

Properties of enteric coated sodium valproate pellets.

The influence of subcoat application and micro-environmental pH on the dissolution properties of enteric coated sodium valproate pellets was investigated. The pellets were prepared by solution-layering or wet-mass extrusion-spheronization methods. In order to pass the USP enteric test, the solution-layered and wet-mass extruded pellets required 35 and 25% weight gain of Eudragit L 30D-55, respectively. The application of a subcoat of either Methocel-E5 (HPMC) or Opadry AMB to the pellets resulted in a delay in sodium valproate release in 0.1N HCl. Further delay in drug release was observed when citric acid was present in a HPMC subcoat or when added to the core pellet formulation. The amount of drug released from coated pellets was a function of the level of citric acid in the pellet core or subcoat and subsequent micro-environmental pH of the pellets. Citric acid exerted a plasticizing effect on the enteric polymer film and improved film formation and polymer coalescence. When greater than 10% (w/w) citric acid was present in the pellets, a decrease in drug content was observed due to the conversion of sodium valproate to the volatile compound, valproic acid. Pellets containing less than 10% (w/w) citric acid maintained potency during processing.

Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers.

The intracellular delivery of active biomacromolecules from endosomes into the cytoplasm generally requires a membrane-disrupting agent. Since endosomes have a slightly acidic pH, anionic carboxylated polymers could be potentially useful for this purpose since they can destabilize membrane bilayers by pH-triggered conformational change. In this study, five different pH-sensitive methacrylic acid (MAA) copolymers were characterized with respect to their physicochemical and membrane lytic properties as a function of pH. pH-dependent conformational changes were studied in aqueous solution by turbidimetry and spectrofluorimetry. The hydrophobic domains that formed upon a decrease in pH were found to be dependent on copolymer's composition. Hemolysis and cytotoxicity assays demonstrated that the presence of the hydrophobic ethyl acrylate monomer and/or sufficient protonation of the carboxylic acid groups were important parameters for efficient membrane destabilization. Excessive copolymer hydrophobicity was not associated with membrane destabilization, but resulted in high macrophage cytotoxicity. Overall, this study gave more insights into the structure-activity relationship of MAA copolymers with membrane bilayers. Gaining knowledge of modulation of the physicochemical properties of copolymers and the optimization of copolymer-lipid interactions may lead to the elaboration of much more efficient drug delivery systems.