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Literature data are reviewed relevant to the decision for a biowaiver of immediate release (IR) solid oral dosage forms containing metoclopramide hydrochloride. In addition, new solubility data, obtained under Biopharmaceutics Classification System (BCS) conditions are presented. Metoclopramide HCl is conservatively assigned to BCS Class III. Taken also into consideration excipient interactions reported in metoclopramide drug products, its pharmacokinetic properties and therapeutic use and therapeutic index, a biowaiver can be recommended when: (a) the test product contains only excipients present also in metoclopramide HCl containing IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) in amounts in normal use in IR solid oral dosage forms, and (c) the test product and the comparator both comply with the criteria for very rapidly dissolving. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3700–3708, 2008 [ABSTRACT FROM AUTHOR]

Chitosan, a biodegradable and biocompatible polymer, has attracted great attention in the pharmaceutical and biomedical fields especially due to its properties to reversibly open the tight junctions of the epithelial tissues and to allow for paracellular transport of hydrophilic macromolecules. However, chitosan exhibits low solubility at pH values above 6 that may prevent its enhancing effects at the sites of intestinal absorption. Hence, a number of alkylated chitosan salts have been synthesized and characterized. These derivatives have been shown to have good solubility at neutral pH and act as effective permeation enhancers. In this study, two new derivatives of chitosan, C2-C6 trimethyl 6-amino-6-deoxy chitosan and C2-C6 triethyl 6-amino-6-deoxy chitosan were synthesized and characterized using 1H-NMR and FTIR spectra. Moreover, the zeta potential and the antibacterial properties of these polymers were compared to chitosan, trimethyl chitosan (TMC) and triethyl chitosan (TEC). Our results suggest that both C2-C6 trimethyl and triethyl 6-amino- 6-deoxy chitosan, as highly water soluble polymers, have higher positive surface charge than chitosan, TMC, and TEC. Moreover, the new synthesized polymers show higher antibacterial activity against Gram-positive Staphylococcus aureus bacteria. Consequently, these polymers with substitution degrees of 50-60% may be good candidates for the enhancement of peptides in mucosal drug delivery. [ABSTRACT FROM AUTHOR]

N,N-dimethyl N-ethyl chitosan (DMEC), a quanternized derivative of chitosan was synthesized based on a modified two-stop method via a 2² factorial design to optimize the preparative conditions. The degree of deacetylation of the starting chitosan was determined by FTIR and NMR methods and was 95%. In the first step of the synthesis, mono-ethyl chitosan was prepared by introducing an ethyl group onto the amine group of chitosan via a Schiff base and in the next step methyl iodide was added to produce DMEC which was water soluble in a pH range of 4–8. The DMEC polymers with different degrees of quaternization were obtained and fully characterized using FTIR and ¹H-NMR spectroscopic methods. Based on ¹H-NMR calculations, the degree of quaternization was 52% by optimizing the two-step process. [ABSTRACT FROM AUTHOR]

Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1389–1395, 2005 [ABSTRACT FROM AUTHOR]

Differentiated, human submucosal-gland carcinoma, Calu-3 cell monolayers were used as in vitro model for the airway epithelium. Internalised phage were selected from a recombinant pComb8 phage library by repetitive cycles of bio-panning on Calu-3 monolayers, protease K degradation, cell-lysis and amplification. After four selection rounds, sequence analysis of 15 enriched phage colonies revealed two clones of 73 and 27% abundancy, named IB1 and IB2, respectively. The IB2 sequence was eliminated due to a frame shift. IB1-phage internalisation at 4°C was significantly lower ( P <0.05) than at 37°C, suggesting involvement of a receptor-mediated endocytosis pathway. The IB1 peptide was synthesised, biotinylated and complexed to streptavidin. IB1/streptavidin-complexes co-administrated with PEI/DNA-polyplexes, enhanced polyplex transfection efficiency, dose dependently, by 6- and 4-fold in Calu-3 cells. IB1/Alexa488-streptavidin complexes were used for confocal laser-scanning microscopy (CLSM) visualisation and showed basolateral localisation in membrane associated and internalising vesicles. This study demonstrates the potential of phage display technology for identification of internalising peptide-epitopes that can enhance gene delivery efficiency in differentiated airway epithelial cells. [ABSTRACT FROM AUTHOR]

Uptake of particulate antigen carrier systems by specialized M-cells of the gut-associated lymphoid tissue is still a limiting step in inducing efficient immune responses after oral vaccination. Although transport of soluble drugs over the epithelial barrier of the gut is extensively studied in vitro by using the Caco-2 cell model, this was for long time not possible for particles due to the absence of M-cells. By co-culturing Caco-2 cells with cultured human B-lymphocytes (Raji-cells), cells which are morphologically and functionally similar to M-cells can be induced. This human M-cells model makes it possible to study the uptake of microparticles for oral vaccine delivery. In this way, chitosan microparticles, which have demonstrated to target the Peyer's patches efficiently in vivo , could be tested in vitro . The development of this M-cells model facilitates the optimization of the microparticles in order to target them even more efficiently to the M-cells in the gut. In this study, the integrity of the human M-cell model was investigated by determining the transepithelial electrical resistance (TEER), 14 C-mannitol transport and morphology using scanning electron microscopy. The uptake of particles was investigated by measuring transport of both fluorescently labeled microspheres (Fluospheres ® ) and chitosan microparticles using flowcytometry. No discontinuities or abnormalities could be found in the co-culture. Scanning electron microscopy showed that morphologically different cells were present in the human M-cell model. Both commercially available Fluospheres ® (size 0.2 μm) and chitosan microparticles (size 1.7 μm) for oral vaccine delivery were transported at a significantly higher amount by the human M-cell model compared to the transport by the Caco-2 cell monoculture. Since chitosan microparticles were proven to be taken up by Peyer's patches in mice as well, this human M-cell model is able to predict the M-cell uptake of microparticles for oral vaccine delivery. This M-cell model is a new tool, which can be used to scan, develop and optimize microparticles for oral vaccine delivery. Since the M-cell uptake can now be studied in vitro , the targeting of these cells can be studied more efficiently and can now be done in cells from human origin. [ABSTRACT FROM AUTHOR]

The interactions between three liposomal formulations and human stratum corneum were visualized using freeze fracture electron microscopy. A new replica cleaning method was introduced. Human stratum corneum was submerged for 48 h in liposome suspensions prepared from commercially available phospholipid mixtures. The size, lamellarity and lipid moieties of the liposomes were similar. The main difference between the three phospholipid formulations was the hydrophilicity of the headgroups. The composition dependence of the interactions between these vesicles and human stratum corneum was investigated. In essence. two types of interaction were observed: adsorption of the liposomes on to the outer surface of the stratum corneum, and ultrastructural changes in deeper layers of the stratum corneum caused by mixing of the liposomal constituents and the stratum corneum lipids. The electron microscopic observations were verified wit Ii small-angle X-ray scattering. It was found that liposomes composed of phospholipids containing relatively small hydrophilic headgroups showed a marked interaction with the skin lipids of human stratum corneum in vitro. The complexity of she phospholipid mixtures. however, made it very difficult to determine the exact effect each of these headgroups has on the interactions between these vesicles and human stratum corneum. [ABSTRACT FROM AUTHOR]

We have studied the skin irritation produced by the prolonged application of transdermal therapeutic systems. The systems were applied to the skin of the back of male volunteers for 120 hours, and sweat accumulation and bacterial growth were studied. In some cases hydrogel discs were attached to the systems. The results showed that sweat accumulation contributed more to the skin irritation than the bacterial overgrowth. The incorporation of hydrogels in the transdermal delivery system may help to reduce skin irritation by absorbing water. [ABSTRACT FROM AUTHOR]

The time dependent changes of the lamellar gel structure in a nonionic O/W cream were studied. It appeared that the changes were connected with alterations in the hydrophilic layers of this lamellar gel structure. The structure of the hydrocarbon layers did not change. The alterations were induced by an increasing hydration of the surfactant molecules on cooling from the preparation temperature to room temperature. Ageing of the cream involves a decrease of the thickness of the hydrophilic layers and a change of the distribution of the surfactant molecules, resulting in, among other things, a decrease of the release rate of a hydrophilic drug. Ageing of the cream can be prevented by using the appropriate amount of starting materials or by the use of polymerizable surfactants. In the former case a cream, from which a drug is slowly released, is obtained. On the other hand, creams containing polymerized surfactants can release drugs at a relatively high rate. [ABSTRACT FROM AUTHOR]

The structure of a nonionic O/W cream and its separate components were investigated by X-ray diffraction and microscopic methods. The results presented in this paper are combined with the results obtained with DSC in order to elucidate these structures. The very important role of water with respect to the formation of the colloidal structures is discussed. The influence of water on the polymorphic behaviour of cetylstearylalcohol is attributed to a good structural fit of its α-modification and water. Hydration induces a tilt of the alkyl chains of poly(oxyethylene)glycerylmonostearate (PGM). For this surfactant an antiparallel arrangement of the molecules is proposed. The lamellar structures present in mixtures of cetylstearylalcohol, PGM and water are discussed extensively. [ABSTRACT FROM AUTHOR]

The structure of a simple O/W cream and its separate components were investigated by differential scanning calorimetry. The results obtained for cetylstearylalcohol agree with those cited in literature. The thermal behaviour of the component poly(oxyethylene) glycerolmonostearate (= PGM) was also investigated. It is pointed out that the thermal history of the PGM batch may play an important role in a study concerning the structure of this surfactant. To both components water was added to study the effects of hydration. Hydration affected the transition temperatures of either component. The melting enthalpy per unit mass of cetylstearylalcohol was not influenced, in contrast with the melting enthalpy of the hydrocarbon fraction in PGM/water mixtures. It is supposed that hydration induces a tilt of the hydrocarbon chains with respect to the lattice plane in lamellar PGM/water mixtures. Cooling experiments indicated that, in samples containing sufficient water, 2 water molecules were tightly bound to the polyoxyethylene chains of the surfactant. The properties of simple creams containing cetylstearylalcohol, PGM and water can be explained regarding their structure and considering the behaviour of the separate components. [ABSTRACT FROM AUTHOR]

As a part of a study of the colloidal structures present in nonionic ointments, the interaction between polyoxyethylene and water is investigated. A series of mixtures of polyoxyethylene 1550 and water is studied using differential scanning calorimetry. Heating as well as cooling experiments are performed. The effects of the heat of mixing, supercooling and melting point depression on the measured enthalpy changes are discussed. From the non-freezing water fraction it is concluded that 2 water molecules per oxyethylene unit are tightly bound to the polymer chain. The observed differences between the cooling and the heating curves lead to a possible explanation for the alterations in the samples occurring at low temperatures. A hydrate structure of polyoxyethylene at low temperatures is proposed. Finally, comment is made on the phase diagram of the system polyoxyethylene/water. [ABSTRACT FROM AUTHOR]

The structure of systems containing equal weights of cetylalcohol, stearylalcohol and the nonionic surfactant poly(oxyethylene)-glycerolmonostearate is studied as a function of the water concentration. In this paper mainly results are presented obtained by small angle X-ray-diffraction. Up to ± 22% (w/w) water several coexisting phases were observed. From ± 22% to ± 55% water a lamellar structure is found. This structure consists of lipophilic bilayers formed by the hydrocarbon tails of cetylalcohol, stearylalcohol and the surfactant, alternated by hydrophilic layers formed by the polyoxyethylene glycerol chains, the hydroxyl groups of cetylalcohol and stearylalcohol and water. From the swelling behaviour the density of the gel structure (0.9 g/cm) and the cross sectional area of the molecules in the bilayers (0.19 nm) have been calculated. It is concluded that the hydrocarbon chains are in a crystalline, state and are placed perpendicular to the lattice plane. Upwards of ± 55% water the lamellar phase disperses in the excess of water. [ABSTRACT FROM AUTHOR]

A simple model is described, in which the influence of two parallel Brillouin zone faces on the electron phonon coupling parameter λ can be studied. In this model it is observed that λ, considered as a function of the Fermi energy E, has a peculiar structure when the Fermi body just passes through the two Bragg planes. Both an enhancement as well as a reduction of the more familiar density of states effect on λ and therefore on the critical temperature T of superconductors appears to be possible. In this respect approaching a Brillouin zone face turns out to be very favourable. The structure in λ is due to a combination of Umklapp, wave function mixing, and density of states effects. The calculations indicate that it is worthwhile to study these effects in detail in actual systems. [ABSTRACT FROM AUTHOR]