Current Drug Delivery - Volume 1, Issue 2, 2004

The purpose of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2%w / w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v / v ethanol-water as solvent system. The flux of nimodipine was markedly increased from 35.51 μg / cm2 / h to 167.53±3.69 μg / cm2 / h with the addition of 8%w / w menthol to HPMC drug reservoir. There was an increase in the flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane with an increase in vinyl acetate content (9 to 28%w / w) of the copolymer. The permeability flux of nimodipine from the chosen EVA 2825 (with 28%w / w vinyl acetate content) was 152.05±2.68 μg / cm2 / h, and this flux decreased to 132.69±1.45 μg / cm2 / h on application of a water-based acrylic adhesive (TACKWHITE A 4MED®) coat. However, the transdermal flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MEDa / rat skin composite was found to be 116.05±2.39 μg / cm2 / h, which is about 1.4 times greater than the required flux. Thus a new transdermal therapeutic system for nimodipine was designed using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED®, and 2%w / w HPMC gel as reservoir containing 8%w / w of menthol as a penetration enhancer. The in vivo evaluation of nimodipine TTS patch was carried out to find the ability of the fabricated mentholbased TTS patch in providing the predetermined plasma concentration of the drug in human volunteers. The results showed that the menthol-based TTS patch of nimodipine provided steady plasma concentration of the drug with minimal fluctuations with improved bioavailability in comparison with the immediate release tablet dosage form.

To determine the association form of indomethacin in nanocapsules prepared with poly(ε-caprolactone) as polymer and a triglyceride as oil, two methods were studied. The indomethacin ethyl ester was prepared as control, which showed a higher affinity for the oil than the indomethacin. Two differently loaded nanocapsule formulations were prepared. For both formulations, a burst effect was detected using ethanol as release medium. Light scattering (PCS) and NMR analyses suggested the ethanol diffuses through the nanocapsule polymeric wall promoting the total release of indomethacin and its ester. The results showed the inability of this approach to determine the association form of indomethacin. On the other hand, the alkaline hydrolysis of indomethacin and its ester, followed by their disappearance (HPLC), were evaluated. The nanocapsule suspensions containing indomethacin or its ester were treated with 50 mM NaOH. The total disappearance of indomethacin associated with nanocapsules was determined after 2 min, whereas the ester associated with colloids was consumed during 24 h. The constant particle sizes (264 and 259 nm) during the hydrolysis reactions showed that neither the nanocapsules were dissolved nor the polymer sorbed water during the contact with NaOH aqueous solution. The ester rate hydrolysis was determined by its diffusion from the nanocapsules to the interface particle / water. Finally, the indomethacin association model considers the burst release of drug after the addition of NaOH by the formation of its carboxylate, followed by its hydrolysis in aqueous solution promoted by the excess of NaOH. The adsorption was the mechanism of indomethacin association with nanocapsules.

Various polyamide microcapsules were prepared via an inverse emulsion system (water in oil) by interfacial polycondensation of terephthaloyl dichloride with the aliphatic diamines ethylene diamine (EDA) and 1,6-hexane diamine (HMDA), and the aromatic diamine 1,4-phenylene diamine (PDA). Three types of polyamide microcapsules were thus obtained and labeled: CAPS EDA, CAPS HMDA, and CAPS PDA, respectively. The influence that the various substitutions had on particle size distribution, membrane microstructure, porosity and specific surface area and water content of the polyamide microcapsule was investigated. The roughness, porosity and porous volume of the polyamide membrane increased in the order: CAPS EDA < CAPS HMDA < CAPS PDA. Sodium chloride permeation experiments were performed to obtain an insight into the impact of structural changes on the permeability of the microcapsules to ionic species. The NaCl diffusion and permeability coefficients through the microcapsules were found to be in the order of 10-8 cm2 / s and 10-5 cm / s, respectively.

Galactoside-containing cluster ligands have high affinity for asialoglycoprotein receptors (ASGP-r), which are found in abundance in mammalian parenchymal liver cells. These ligands may be conjugated with a therapeutic drug to improve the efficiency of delivery to diseased liver cells. This report describes a new synthetic route towards clustering glycopeptides containing N-acetyl-D-galactosamine (GalNAc). The building block Fmoc-α-(ah-Ac3GalNAc)-Lglutamate allowed access to the target compound YEEE(α-ah-GalNAc)3, a structural mimic of YEE(ah-GalNAc)3, via solid phase peptide synthesis (SPPS). Fatty acid, poly-lysine, fluorescein and biotin conjugates further demonstrate the facility of the described method. Using fluorescein labeling and 131I labeling, in vitro and in vivo assays confirmed that YEEE(a-ah-GalNAc)3 possesses both specificity and affinity to the liver, similar to the agent YEE(ah-GalNAc)3, which targets liver lesions. The synthesis described in this report represents a considerable improvement in synthesizing a ligand for ASGP-r by simplifying both the preparation of the starting material and the procedure for conjugating the galactosidase cluster to drugs.

The buccal cavity is attractive for noninvasive, controlled transmucosal delivery of both local and systemic therapeutically active compounds. Administering drugs via this route is advantageous due to the rich vasculature of the oral mucosa, and the absence of gastrointestinal and “first-pass” hepatic degradation. Moreover, the barrier properties of the oral mucosa against noxious substances and its role in disease require further investigation. However, the scarcity of sizeable specimens of human oral mucosa for in vitro experimental studies has hampered research on this tissue. For this reason we developed a model in which human vaginal mucosa is used as a substitute for buccal mucosa. In this article the quality and predictive value of the human vaginal / buccal in vitro model with respect to a number of drugs and other chemical compounds differing widely in molecular size and lipophilicity, including water, arecoline, arecaidine, benzo[a]pyrene, 17β-estradiol, sumatriptan, vasopressin and dextrans, are reviewed. In addition some applications of the model for investigating the effect of areca nut extract on epithelial barrier properties, temperature effects on water and 17β-estradiol flux rates, and cyclosporin diffusion through mucosal membranes are described. The permeability characteristics of vaginal mucosa, as a model of buccal mucosa, are compared with those of other human tissue, including mucosae from the small intestine and colon.

The development of a transdermal delivery system for drug molecules of high molecular weight (peptides or proteins) is nowadays a great scientific and commercial challenge. For these molecules, the passive transport through the skin is generally very low and should be enhanced by the application of the electrical current (a method called iontophoresis). A very important component of a transdermal iontophoretic system is the artificial membrane, which acts as the interface between the drug reservoir and the skin. The optimum membrane should (i) provide an effective drug delivery; (ii) have low electrical resistance and (ii) have low drug adsorption. In this work, the selection of membrane(s) for a transdermal iontophoretic salmon calcitonin (sCT, MW ∼3500) system is performed. The passive and iontophoretic transport of sCT through porous artificial membranes, the sCT adsorption to them and the electrical resistance of all porous membranes in iontophoretic experiments is studied. The sCT transport through the membranes is compared with that through human skin, and based on the above three criteria the optimum membranes are selected for the sCT transdermal system.

The aim of this work is to study liposomes as carriers of nutrients and therapeutic agents in aquaculture with Venerupis decussatus and Venerupis pullastra larvae. Multilamellar (MLVs) and large unilamellar (LUVs) vesicles were prepared from a commercial mixture of soy phosphatidylcholine, rich in unsaturated and polyunsaturated fatty acids, cholesterol, and hydrated with a solution of vitamin B1 both in distilled and sea water. Carboxyfluorescein-loaded liposomes were also prepared in order to test the uptake of vesicles by larvae. The stability of formulations was checked by monitoring the size of vesicles and their drug leakage. In order to limit the vitamin loss, liposome freeze-drying was studied. Dried formulations were also prepared by using different amounts of trehalose as cryoprotectant. We found that freeze-dried vesicles, rehydrated after two weeks, had a vitamin retention (R%) equal to 95%, while their diameter significantly increased. By contrast, liposomes freeze-dried in the presence of trehalose displayed a lower R%, but higher bilayer stability. Finally, when CF-loaded vesicles were added to Venerupis decussatus and Venerupis pullastra larvae incubated in filtered sea water, a bright and diffused fluorescence was present in most of the larvae, a fact which can be regarded as evidence of liposome uptake by Venerupis larvae.

The recent rapid development of molecular biology together with the steady progress of genome projects has given us some essential and revolutionary informations of gene to elucidate all the biological phenomena at the molecular level. Under these circumstances, gene transfection has become a fundamental technology indispensable to the basic research of medicine and biology. On the other hand, the technology of gene transfection is also important for gene therapy of several diseases. Some human gene therapies have been performed with a plasmid DNA alone or virus vectors but are clinically limited by the poor gene expression of plasmid DNA and the adverse effects of virus itself, such as immunogenicity and toxicity or the possible mutagenesis of cells transfected. Therefore, several non-viral vectors of synthetic materials have been explored to enhance the transfection efficiency of gene into mammalian cells both in vitro and in vivo. In this paper, the researches about non-viral vectors and recent research trials about the controlled release of plasmid DNA are briefly reviewed to emphasize the significance of gene delivery technology in basic biology and medicine as well as clinical medicine. A new system of gene release based on biodegradable hydrogel is introduced.

DNA can be delivered into the cell nucleus either using physical means or specific carriers that carry the genes into the cells for gene expression). Various carriers for delivering genes have been investigated which can be divided into two main groups: viral carriers where the DNA to be delivered is inserted into a virus, and cationic molecular carriers that form electrostatic interactions with DNA). Successful gene therapy depends on the efficient delivery of genetic materials into the cells nucleus and its effective expression within these cells). Although at present the in vivo expression levels of synthetic molecular gene vectors are lower than for viral vectors and gene expression is transient, these vehicles are likely to present several advantages including safety, lowimmunogenicity, capacity to deliver large genes and large-scale production at low-cost). The two leading classes of synthetic gene delivery systems that have been mostly investigated are cationic lipids and cationic polymers). This review discusses recent developments in viral vectors, physical means and molecular gene carriers). The last part focuses on our recent studies in developing a new series of biodegradable polycations for in vitro and in vivo gene transfection).