Unidirectional Release Research Articles

Formulation of unidirectional release buccal patches of carbamazepine and study of permeation through porcine buccal mucosa

ObjectiveTo achieve transbuccal release of carbamazepine by loading in unidirectional release mucoadhesive buccal patches. MethodsBuccal patches of carbamazepine with unidirectional drug release were prepared using hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and ethyl cellulose by solvent casting method. Water impermeable backing layer (Pidilite® Biaxially-oriented polypropylene film) of patches provided unidirectional drug release. They were evaluated for thickness, mass uniformity, surface pH and folding endurance. Six formulations FA2, FA8, FA10, FB1, FB14 and FB16 (folding endurance above 250) were evaluated further for swelling studies, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, In vitro drug release, ex vivo permeation, accelerated stability studies and FTIR and XRD spectral studies. ResultsThe ex vivo mucoadhesion time of patches ranged between 109 min (FA10) to 126 min (FB14). The ex vivo mucoadhesive force was in the range of 0.278 to 0.479 kg/m/s. The In vitro drug release studies revealed that formulation FA8 released 84% and FB16 released 99.01% of drug in 140 min. ConclusionsThe prepared unidirectional buccal patches of carbamazepine provided a maximum drug release within specified mucoadhesion period and it indicates a potential alternative drug delivery system for systemic delivery of carbamazepine.

Drug Delivery from the Oral Cavity: A Focus on Mucoadhesive Buccal Drug Delivery Systems

Since the early 1980s the concept of mucoadhesion has gained considerable interest in pharmaceutical technology. The various advantages associated with these systems made buccal drug delivery as a novel route of drug administration. It prolongs the residence time of the dosage form at the site of application. These systems remain in close contact with the absorption tissue, the mucous membrane, and thus contribute to improved and/or better therapeutic performance of the drug and of both local and systemic effects. This review highlights the anatomy and structure of oral mucosa, mechanism and theories of mucoadhesion, factors affecting mucoadhesion, characteristics and properties of desired mucoadhesive polymers, various types of dosage forms, and general considerations in design of mucoadhesive buccal dosage forms, permeation enhancers, and evaluation methods. Over the past few decades the mucoadhesive buccal drug delivery system has received a great deal of attention to develop mucoadhesive dosage forms to enable the prolonged retention at the site of action, providing a controlled release of drug for improved therapeutic outcome. Mucoadhesive drug delivery gives facility to include a permeation enhancer/enzyme inhibitor or pHmodifier in the formulation and versatility in designing as multidirectional or unidirectional release systems for local and systemic action. Local delivery to tissues of the oral cavity has a number of applications, including treatment of local conditions such as periodontal disease, bacterial and fungal infections, and aphthous stomatitis and vesiculo bullous diseases. For the treatment of chronic diseases, the mucoadhesive buccal drug delivery system allows easily accessibility and is generally well-accepted for administeringdrugs by systemic action.

Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine

Lamotrigine is a BCS class II drug with pH dependent solubility. The bilayered gastric mucoadhesive tablets of lamotrigine were designed such that the drug and controlled release polymers were incorporated in the upper layer and the lower layer had the mucoadhesive polymers. The major ingredients selected for the upper layer were the drug and control release polymer (either HPMC K15M or polyox) while the lower MA layer predominantly comprised of Carbopol 974P. A 23 full factorial design was constructed for this study and the tablets were optimized for parameters like tablet size, shape, ex vivo mucoadhesive properties and unidirectional drug release. Oval tablets with an average size of 14mm diameter were set optimum. Maximum mucoadhesive bond strength of 79.3±0.91*103dyn/cm2 was achieved with carbopol when used in combination with a synergistic resin polymer. All the tested formulations presented a mucoadhesion time of greater than 12h. The incorporation of methacrylic polymers in the lower layer ensured unidirectional drug release from the bilayered tablets. The unidirectional drug release was confirmed after comparing the dissolution results of paddle method with those of a modified basket method. Model independent similarity and dissimilarity factor methods were used for the comparison of dissolution results. Controlled drug release profiles with zero order kinetics were obtained with polyox and HPMC K15M which reported t90% at 6th and 12th hours, respectively. The “n” value with polyox was 0.992 and that with HPMC K15M was 0.946 indicating an approximate case II transport. These two formulations showed the potential for oral administration of lamotrigine as bilayered gastric mucoadhesive tablets by yielding highest similarity factor values, 96.06 and 92.47, respectively, between the paddle and modified basket method dissolution release profiles apart from reporting the best tablet physical properties and maximum mucoadhesive strength.

Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics

The creation of an oral drug delivery platform to administer chemotherapeutic agents effectively can not only increase patient compliance, but also potentially diminish drug toxicity. A microfabricated device offers advantages over conventional drug delivery technology. Here we describe the development of a multi-layered polymeric drug-loaded microfabricated device (microdevice) for the oral delivery of therapeutics, which offers unidirectional release of multiple therapeutics. The imaging and release of therapeutics from the multi-layered device was performed with three different fluorescently labeled albumins. The release of insulin and chemotherapeutic camptothecin was also observed to be released in a controlled manner over the course of 180 min in vitro. Furthermore, asymmetric delivery was shown to concentrate drug at the device/cell interface, wherein 10 times more drug permeated an intestinal epithelial cell monolayer, compared to unprotected drug-loaded hydrogels. The bioactivity of the released chemotherapeutic was shown with cytostasis of colorectal adenocarcinoma cells. Cytostasis of drug loaded hydrogels was significantly higher than control empty hydrogel laden microdevices. Our results conclude that microfabrication of a hydrogel laden microdevice leads to a viable oral delivery platform for chemotherapeutics.

Design and Evaluation of a New Gastrointestinal Mucoadhesive Patch System Containing Chitosan-Glutathione

Within this study, a novel gastrointestinal patch system was developed and investigated regarding water-absorbing capacity, adhesive properties, in vitro release, unidirectional release and permeation enhancing effect. Water uptake studies revealed that the weight of patch systems with Ch-GSH increased about 44.5 ± 2.3 mg (127%) after 90 min. This patch system remained even after 180 h on the mucosa and released 49.7 ± 0.7% of FD4 within 8 h. A 2.5-fold higher transport of FD4 can be obtained in contrast to control. In conclusion this patch system could be an interesting possibility for the transport through the intestinal mucosa of macromolecules which will normally be degraded in the intestinal tract.

Buccoadhesive drug delivery system of isosorbide dinitrate: Formulation and evaluation

Buccoadhesive buccal delivery systems for isosorbide dinitrate in the form of unidirectional buccal films were developed and characterized for improving bioavailability. The films were formulated by solvent casting method using different bioadhesive polymers like Carbopol 934P and polyvinyl pyrrolidone by using two different plasticizers propylene glycol and diethyl phthalate. Unidirectional release was achieved by preparing composite films with backing membrane. The films were characterized on the basis of their physical characteristics, bioadhesive performance, and other parameters. In vitro studies revealed that release rate of isosorbide dinitrate was higher from carbopol films containing ratio of Eudragit RL100 and polyvinyl pyrrolidine in proportion of 1:2 and 2:1, respectively by using both plasticizers. Drug diffusion from buccal films showed apparently zero order kinetics and release mechanism was diffusion controlled after considerable swelling. All the films exhibited sufficient in vitro bioadhesion strength. Promising formulations were further studied for temperature dependent stability studies. Results of our preliminary experiments indicate that, therapeutic level of isosorbide dinitrate can be achieved using this buccaladhesive formulation.

An oral delivery device based on self-folding hydrogels

A self-folding miniature device has been developed to provide enhanced mucoadhesion, drug protection, and targeted unidirectional delivery. The main part of the device is a finger like bilayered structure composed of two bonded layers. One is a pH-sensitive hydrogel based on crosslinked poly(methyacrylic acid) (PMAA) that swells significantly when in contact with body fluids, while the other is a non-swelling layer based on poly(hydroxyethyl methacrylate) (PHEMA). A mucoadhesive drug layer is attached on the bilayer. Thus, the self-folding device first attaches to the mucus and then curls into the mucus due to the different swelling of the bilayered structure, leading to enhanced mucoadhesion. The non-swelling PHEMA layer can also serve as a diffusion barrier, minimizing any drug leakage in the intestine. The resulting unidirectional release provides improved drug transport through the mucosal epithelium. The functionality of this device is successfully demonstrated in vitro using a porcine small intestine.

Micromachined Polymeric Devices for Applications in Targeted Drug Delivery

Advances in microelectromechanical systems (MEMS) have allowed the microfabrication of polymeric substrates and the development of a novel class of controlled delivery devices. In contrast to the traditional microsphere delivery vehicle, microfabricated devices may be specifically designed flat and thin to maximize contact area with the intestinal lining. This flat design may also minimize the side areas that are exposed to constant flow. The devices can be microfabricated to incorporate single or multiple drug reservoirs to provide unidirectional release for any number of drugs/biomolecules of interest. Furthermore, specific areas of the device can be targeted for surface modification. These specifically tailored three-dimensional physical and chemical features, together, provide a micromachined vehicle with the capacity to target cells, promote unidirectional controlled release, and enhance permeation across the intestinal epithelial barrier (Figure 1).

Design of a novel hydrogel-based intelligent system for controlled drug release

The present work focused on the design of an assembled drug delivery system (DDS) to provide multifunctions, such as drug protection, self-regulated oscillatory release, and targeted uni-directional delivery by a bilayered self-folding gate and simple surface mucoadhesion. In this device, a pH-sensitive hydrogel together with a poly(hydroxyethyl methacrylate) (HEMA) barrier was used as a gate to control drug release. In addition, poly(HEMA) coated with poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO–PPO–PEO) surfactant was utilized to enhance mucoadhesion on the device surface. The release profiles of two model drugs, acid orange 8 (AO8) and bovine serum albumin (BSA) were studied in this assembled system, which compared with the conventional drug-entrapped carriers and enteric-coating systems. Furthermore, targeted uni-directional release was demonstrated in a side-by-side diffusion cell. In conclusion, for such an assembled device, the poly(HEMA) layer not only affects the folding direction but also serves as a barrier to protect the model drugs. The release time can be controlled by the thickness of the bilayered gate and the drug reservoir. Due to the reversible swelling behavior of poly(methyacrylic acid-g-ethylene glycol) (p(MAA-g-EG)) gels, the bilayered gate can sense the environmental pH change and achieve an oscillatory release pattern. Moreover, the local targeting and uni-directional release have been successfully demonstrated in vitro.

Bioadhesive microdevices with multiple reservoirs: a new platform for oral drug delivery

A variety of delivery systems have been devised, in recent years, to improve the oral bioavailability of drugs including enterically coated tablets, capsules, particles, and liposomes. Microfabrication technology may offer some potential advantages over conventional drug delivery technologies. This technology, combined with appropriate surface chemistry, may permit the highly localized and unidirectional release of drugs, permeation enhancers, and/or promoters. In this study, we demonstrate the fabrication of prototype reservoir-containing microdevices and a surface chemistry protocol that can be used to bind lectin via avidin–biotin interactions to these micromachined drug delivery vehicles. The use of microfabrication allows one to tailor the size, shape, reservoir volume, and surface characteristics of the drug delivery vehicle. In vitro studies show enhanced bioadhesion of these lectin conjugated silicon microdevices. This approach may be used to improve the absorption of pharmacologically active biopolymers such as peptides, proteins and oligonucleotides into circulation at targeted sites in the GI system via the creation of a robust hybrid organic/inorganic delivery system. This paper describes one of the first applications of microfabrication to oral drug delivery.

Bioadhesive Microdevices for Drug Delivery: A Feasibility Study

A variety of delivery systems have been devised to improve the oral bioavailability of drugs including enterically coated tablets, capsules, particles, liposomes, and others. Microfabrication technology, however, may offer some potential advantages over conventional drug delivery technologies. This technology, combined with appropriate surface chemistry, may permit the highly localized and unidirectional release of drugs, permeation enhancers, and/or promoters. In this study, we demonstrate the fabrication of prototype reservoir containing microparticles and a surface chemistry protocol that can be used to bind lectin via avidin-biotin interactions to silicon microparticles. In vitro studies show enhanced bioadhesion of these lectin conjugated microparticles. Such an approach can be used to improve the absorption of pharmacologically active biopolymers such as peptides, proteins and oligonucleotides into circulation at targeted sights in the GI system. Moreover, the use of microfabrication allows one to tailor the size, shape, reservoir volume, and surface characteristics of the drug delivery vehicle.

Stat recruitment by tyrosine-phosphorylated cytokine receptors: An ordered reversible affinity-driven process

Herein, we demonstrate that purified Stat1 binds to its tyrosine-phosphorylated docking site on the IFNγ receptor α chain in a direct, specific, and reversible manner. Using surface plasmon resonance, we determine the affinity (K D = 137 nM) and specificity of the interaction and define the minimum affinity needed for receptor-mediated Stat1 activation. In addition, we quantitate the relative ability of purified Stat1 to interact with tyrosine-phosphorylated binding sites on other Stat proteins. Finally, we describe experiments that imply that the unidirectional release of activated Stat1 from the IFNγ receptor reflects the preference of free tyrosine-phosphorylated Stat1 monomers to form high avidity reciprocal homodimere rather than reassociating with the receptor binding site. Our results demonstrate that IFNγ-induced Stat1 activation is an ordered and affinity-driven process and we propose that this process may serve as a paradigm for Stat activation by other cytokine receptors.

Ca2+-dependent unidirectional vesicular release detected with a carbon-fibre electrode in rat pancreatic acinar cell triplets

An amperometric constant-voltage method for detection of serotonin oxidation currents was applied to pancreatic acinar cell triplets to determine the site of release of granular content following an increase in [Ca2+]i. The carbon fibre electrode, fabricated to be compatible with a conventional patch-clamp amplifier, was voltage-clamped at 600 mV exceeding the serotonin oxidation voltage, 300 mV. The electrode was placed on the different regions of cell surface of acinar cell triplets loaded with exogenous serotonin. Transient oxidation currents were detected only when the electrode was placed on the acinar lumen after stimulation with a Ca2+ ionophore, A23187, but never observed on the basal or lateral cell surface, or paracellular clefts. No such current responses were observed in the acinar cells without serotonin loading. The results indicate that the A23187-induced sustained increase in [Ca2+]i discharges serotonin specifically into the lumen, and provides direct evidence for the presence of Ca(2+)-dependent unidirectional release of granular contents in pancreatic acinar cells.

A role for gamma-aminobutyric acid (GABA) in the evolution of delayed neuronal death following ischemia.

A series of putative neuroprotective agents was tested to determine their efficacy in preventing the loss of the CA 1 neurons of the hippocampus at 4 days following 5 min of bilateral ischemia in the gerbil. Agents associated with the GABAergic system were determined to be the most effective, but only when given prior to the ischemic episode, suggesting that there was a gamma-aminobutyric acid (GABA)-related event during ischemia which triggers the delayed neuronal death of these cells. In this report, the unidirectional release of GABA and glutamate from gerbil hippocampal slices was determined under conditions mimicking anoxia and/or ischemia. Pentobarbital, the most effective of the GABAergic agents, had little or no effect on the time-dependent release of glutamate. In contrast, pentobarbital reduced in release of GABA in both anoxia and ischemia, but only after 25 to 30 min of incubation.

Evidence for the renal paratubular transport of glutathione

The catabolism of glutathione in various nonrenal tissues occurs through an interorgan process [ 1,2]. For example, the turnover of glutathione within rat liver is initiated by the unidirectional release of glutathione to the blood plasma [3]. The released glutathione is carried to the kidney where it is nearly quantitatively extracted and degraded to its constituent amino acids [4,5]. The glutathionemia and the pronounced glutathionuria observed in a patient who lacks detectable -r-glutamyltranspeptidase [6] and in mice treated with inhibitors of y-glutamyltranspeptidase [7,8] indicate that this enzyme catalyzes the initial reaction in glutathione catabolism. The transpeptidase is an amphipathic membrane glycoprotein [9] that is found to the greatest extent in the kidney. Within this tissue, the enzyme is primarily associated with the brush border membrane of the proximal tubule cells [lo], where it is asymmetrically orientated on the lumenal surface [ 111. the glomeruli even when the arterial glutathione concentration is increased to a value 200-fold greater than normal [5]. Therefore, the kidney may contain a mechanism for the transport of glutathione across the basolateral plasma membrane. However, small amounts of y-glutamyltranspeptidase may be associated with the glomeruli [13], with the renal microvasculature [14], or with the basolateral membrane of the proximal tubule [ 151. Thus, the apparent extraction of glutathione by the kidney may be due to its catabolism within the post-glomerular paratubular space. In order to resolve these two possibilities, we have used the procedures in [16] to study the renal paratubular handling of glutathione.

Bidirectional movement of gamma-aminobutyric acid in rat spinal cord slices.

The bidirectional movement of GABA (gamma-aminobutyric acid) was studied in slices of rat spinal cord which were incubated in small volumes of medium. The appearance in the medium of endogenous GABA and the disappearance from the medium of [14C]GABA were used to calculate the rates of unidirectional uptake and unidirectional release of GABA. Under these conditions, no net uptake of GABA was observed when slices were incubated in media containing concentrations of gABA as high as 25 microM. Elevated potassium (60 mM) stimulated the unidirectional release of endogenous GABA from spinal cord slices by a calcium-dependent process. Ouabain (0.1 mM) more than doubled the unidirectional release of endogenous GABA in a calcium-independent manner, while unidirectional uptake was inhibited by 44%. Nipecotic acid (1.0 mM) stimulated unidirectional release and inhibited unidirectional uptake of GABA.