Home About us Contact
|
Home About us Contact | ||
|
|
||
Drug Molecules (drug + molecule)
Selected AbstractsControlling the Association of Adamantyl-Substituted Poly{N -[tris(hydroxymethyl)methyl]acrylamide} and a , -Cyclodextrin/Epichlorohydrin Polymer by a Small Drug Molecule , NaproxenCHEMISTRY & BIODIVERSITY, Issue 1 2007Danica Mislovi Abstract Two polymeric substances, a poly{N -[tris(hydroxymethyl)methyl]acrylamide} (THMMA) substituted with adamantyl moieties and a , -cyclodextrin/epichlorohydrin polycondensate, formed a host,guest type complex, which resulted in the gel formation upon mixing of these two compounds at appropriate conditions. Introduction of a drug molecule, i.e., naproxen, that was able to fill the , -cyclodextrin cavities, thus expulsing adamantyl moieties, led to disruption of such association and inhibition of gel formation. The conditions required for the association of the two polymeric components and formation of the gel, as well as the dynamics of its inhibition by addition of naproxen was established. The procedure of using solutions of two associating polymers and an appropriate drug competitor can be used at targeted viscosupplementation. [source] Strength of C,H Bonds at Nitrogen , -Position:Implication for Metabolic Stability of Nitrogen-containing Drug MoleculesCHINESE JOURNAL OF CHEMISTRY, Issue 4 2008Xiang-Ming MENG Abstract The available experimental ,C-H BDEs of a variety of amine-containing molecules were examined by using the G3B3 and CBS-Q methods. The verified values were employed to benchmark and calibrate the density functional theory methods. It was found that the (U)BHandH/6-311++G(2df, 2p)//(U)B3LYP/6-31G(d) method was a fast and accurate method for calculating C,H BDEs at nitrogen , -positions. By using the newly benchmarked BHandH method, the ,C,H BDEs in a number of nitrogen-containing drug molecules were calculated, where a dramatic variation of the ,C,H BDEs was discovered. To understand this variation, the effects of mono- and double-substitution at both carbon and nitrogen atoms on the ,C-H BDEs were systematically studied. The origin of the substitution effects was thoroughly discussed in terms of four categories of substituents. [source] Ab initio computational study of positron emission tomography ligands interacting with lipid molecule for the prediction of nonspecific bindingJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 14 2008Lula Rosso Abstract Nonspecific binding is a poorly understood biological phenomenon of relevance in the study of small molecules interactions in vivo and in drug development. Nonspecific binding is thought to be correlated in part to a molecule's lipophilicity, typically estimated by measuring (or calculating) octanol,water partition coefficient. This is, however, a gross simplification of a complex phenomenon. In this article, we present a computational method whose aim is to help identify positron emission tomography (PET) ligands with low nonspecific binding characteristics by investigating the molecular basis of ligand,membrane interaction. We considered a set consisting of 10 well-studied central nervous system PET radiotracers acting on a variety of molecular targets. Quantum mechanical calculations were used to estimate the strength of the interaction between each drug molecule and one phospholipid molecule commonly present in mammalian membranes. The results indicate a correlation between the computed drug,lipid interaction energy and the in vivo nonspecific distribution volume relative to the free tracer plasma concentration, calculated using standard compartmental modeling for the analysis of PET data. Significantly, the drugs whose interaction with the lipid molecule more favorably possessed, in general, a higher nonspecific binding value, whereas for the drugs taken in consideration in this study, the water-octanol partition coefficient, log P, did not show good predictive power of the nonspecific binding. This study also illustrates how ab initio chemical methods may offer meaningful and unbiased insights for the understanding of the underlying chemical mechanisms in biological systems. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] In vitro transdermal iontophoretic delivery of leuprolide,mechanisms under constant voltage applicationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2003Charu Kochhar Abstract The transdermal iontophoretic delivery of Leuprolide, a nonapeptide LHRH agonist was studied with the aim of understanding the mechanisms of iontophoresis. Permeation studies were carried out at pH 4.5 and 7.2, at which the average ionic valence of the drug molecule was roughly 2 and 1, respectively. Heat-separated human epidermal membrane was subjected to constant voltage within the range of 250 to 1000 mV during the iontophoretic phase. Iontophoretic enhancement at pH 7.2 was greated than at 4.5. A model for iontophoretic enhancement was developed that takes into consideration the membrane alterations caused by iontophoresis depicted as increased porosity and the permeation through lipid pathways of the stratum corneum. Model-based evaluation yielded that first, the porosity increased with the applied voltage to as much as three times the original at 1000 mV. Second, the lipid pathways contributed approx. 20% to the total permeation during the passive phase. Third, the electro-osmotic flow contributed significantly to the enhancement and its direction was from anode to cathode at pH 7.2 and the opposite at pH 4.5. The magnitude of the electro-osmotic flow was at pH 4.5 somewhat lower than at pH 7.2. Addition of a negatively charged water soluble peptide, Acetyl leucine leucinolyl phosphate as an adjuvant led to twofold increase in the enhancement factor at pH 4.5 and a decrease in the magnitude of the electro-osmotic flow from cathode to anode. Repeated iontophoretic applications of 250 mV on the same skin specimen resulted in same enhancement every time and did not cause any barrier alterations when applied for 1 h every 24 h, which was not the case if the duration between the two iontophoretic applications was only 3 h. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:84,96, 2003 [source] Preparation and Properties of Cyclodextrin/PNIPAm MicrogelsMACROMOLECULAR BIOSCIENCE, Issue 5 2009Yu-Yang Liu Abstract A two-stage precipitation polymerization in aqueous solution was used to prepare , -cyclodextrin/poly(N -isopropylacrylamide) (, -CD/PNIPAm) core,shell microgels. At the first stage, core microgels with CD moieties were synthesized by precipitation copolymerization of N -isopropylacrylamide (NIPAm) with a monovinyl , -CD monomer. At the second stage, using the core particles as seeds, PNIPAm shell were further added onto the seeds by NIPAm polymerization. The microgels were characterized by means of Zetasizer Nano-ZS dynamic light scattering, TEM, IR, NMR, DSC, and TGA measurements. Using paeonol as a model drug molecule, the release behaviors of the microgels were investigated. The result indicates that the core,shell microgels could respond to change in temperature. Furthermore, the release of paeonol was related to supramolecular inclusion behavior of , -CD and temperature sensitivity of PNIPAm. [source] Controlling the Association of Adamantyl-Substituted Poly{N -[tris(hydroxymethyl)methyl]acrylamide} and a , -Cyclodextrin/Epichlorohydrin Polymer by a Small Drug Molecule , NaproxenCHEMISTRY & BIODIVERSITY, Issue 1 2007Danica Mislovi Abstract Two polymeric substances, a poly{N -[tris(hydroxymethyl)methyl]acrylamide} (THMMA) substituted with adamantyl moieties and a , -cyclodextrin/epichlorohydrin polycondensate, formed a host,guest type complex, which resulted in the gel formation upon mixing of these two compounds at appropriate conditions. Introduction of a drug molecule, i.e., naproxen, that was able to fill the , -cyclodextrin cavities, thus expulsing adamantyl moieties, led to disruption of such association and inhibition of gel formation. The conditions required for the association of the two polymeric components and formation of the gel, as well as the dynamics of its inhibition by addition of naproxen was established. The procedure of using solutions of two associating polymers and an appropriate drug competitor can be used at targeted viscosupplementation. [source] Synthesis of Magnetic, Up-Conversion Luminescent, and Mesoporous Core,Shell-Structured Nanocomposites as Drug CarriersADVANCED FUNCTIONAL MATERIALS, Issue 7 2010Shili Gai Abstract The synthesis (by a facile two-step sol,gel process), characterization, and application in controlled drug release is reported for monodisperse core,shell-structured Fe3O4@nSiO2@mSiO2@NaYF4: Yb3+, Er3+/Tm3+ nanocomposites with mesoporous, up-conversion luminescent, and magnetic properties. The nanocomposites show typical ordered mesoporous characteristics and a monodisperse spherical morphology with narrow size distribution (around 80,nm). In addition, they exhibit high magnetization (38.0,emu g,1, thus it is possible for drug targeting under a foreign magnetic field) and unique up-conversion emission (green for Yb3+/Er3+ and blue for Yb3+/Tm3+) under 980,nm laser excitation even after loading with drug molecules. Drug release tests suggest that the multifunctional nanocomposites have a controlled drug release property. Interestingly, the up-conversion emission intensity of the multifunctional carrier increases with the released amount of model drug, thus allowing the release process to be monitored and tracked by the change of photoluminescence intensity. This composite can act as a multifunctional drug carrier system, which can realize the targeting and monitoring of drugs simultaneously. [source] Hierarchic Nanostructure for Auto-Modulation of Material Release: Mesoporous Nanocompartment FilmsADVANCED FUNCTIONAL MATERIALS, Issue 11 2009Qingmin Ji The preparation of mesoporous nanocompartment films composed of both hollow silica capsules and silica particles by using layer-by-layer (LbL) adsorption is described. The resultant nanocompartment films exhibit stepwise release of encapsulated water molecules without application of external stimuli. The hollow hierarchic pore structure of the silica capsules, including their internal void and mesoporous walls, is a key factor for the regulation and stepwise release of water, and is probably caused by the non-equilibrated concurrent evaporation of material from the mesopore and capillary penetration into the mesopores. The number of release steps and rate of release can be tuned by variation of several parameters including water content, ambient temperature, layer multiplicity, and co-adduct particle size. Application of the mesoporous nanocompartment films for the release of substances, including therapeutic agents and fragrances, indicates that the stepwise material release can be applied for a wide range of liquid substances. The films should lead to a novel material release system useful even for biomedical applications capable of controlled and sustained delivery of drug molecules. [source] Solvent effect on the reactivity of CIS -platinum (II) complexes: A density functional approachINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 8 2008Pubalee Sarmah Abstract The structure and chemical reactivity of some selected cis -platinum(II) complexes, including clinically used drug molecules, cisplatin, carboplatin, and oxaliplatin are investigated using density functional theory (DFT) calculations. Calculated geometries of the complexes are in agreement with their available X-ray data. The global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity are calculated to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the complexes. Inclusion of solvent effect shows that both global and local descriptors change the trend of reactivity with respect to their trend in the gas phase. The stability of the complexes increases with the inclusion of water molecules. Simple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on DFT derived electrophilicity index for the Pt(II) complexes against A2780 human ovarian adenocarcinoma cell line to establish the importance of the descriptor in predicting cytotoxicity. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [source] QSAR study of ,-lactam antibiotic efflux by the bacterial multidrug resistance pump AcrB,JOURNAL OF CHEMOMETRICS, Issue 5 2004Márcia M. C. Ferreira Abstract AcrAB-TolC is the most important efflux pump system of Gram-negative bacteria, responsible for their resistance to lipophilic and amphilic drugs. In this work, HCA,PCA studies were performed to investigate the relationship between efflux activities (negative logarithm of minial inhibitor concentration, pMIC) of three strains of S. thypimurium with respect to ,-lactams, and to analyze the relationship between lipophilicity parameters calculated by different methods. The analyses demonstrate that pMICs strongly depend on properties of both bacterial strains and drug molecules, and that lipophilicity parameters do not necessarily contain the same information about the drugs. QSAR studies have shown that the calculated lipophilicities, in some cases, are non linearly related to the pMICs originated by active AcrAB-TolC bacterial pumps, due to the existence of ,-lactams with nitrogen- and sulfur-rich substituents. Among the most important ,-lactam molecular properties quantitatively related to pMICs are lipophilicity and electronic and hydrogen,bonding properties. Parameters describing these properties were included in the QSAR study to obtain parsimonius regression models for MICs. ,-Lactams were classified as good, moderately good and poor AcrAB-TolC substrates. Their stereoelectronic molecular properties, especially the Y-component of the molecular dipole moment and hydrogen binding properties, reflected this classification. Copyright © 2004 John Wiley & Sons, Ltd. [source] Synthesis, pharmacology, crystal properties, and quantitative solvation studies from a drug transport perspective for three new 1,2,4-thiadiazolesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2010German L. Perlovich Abstract A novel 1,2,4-thiadiazoles were synthesized. Crystal structures of these compounds were solved by X-ray diffraction experiments and comparative analysis of molecular conformational states, packing architecture, and hydrogen bonds networks were carried out. Thermodynamic aspects of sublimation processes of studied compounds were determined using temperature dependencies of vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation and structural parameters. Solubility and solvation processes of 1,2,4-thiadiazoles in buffer, n -hexane and n -octanol were studied within the wide range of temperature intervals and thermodynamic functions were calculated. Specific and nonspecific interactions of molecules resolved in crystals and solvents were estimated and compared. Distribution processes of compounds in buffer/n -octanol and buffer/n -hexane systems (describing different types of membranes) were investigated. Analysis of transfer processes of studied molecules from the buffer to n -octanol/n -hexane phases was carried out by the diagram method with evaluation of the enthalpic and entropic terms. This approach allows us to design drug molecules with optimal passive transport properties. Calcium-blocking properties of the substances were evaluated. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3754,3768, 2010 [source] Lack of appreciable species differences in nonspecific microsomal bindingJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2010Ying Zhang Abstract Species differences in microsomal binding were evaluated for 43 drug molecules in human, monkey, dog and rat liver microsomes, using a fixed concentration of microsomal protein. The dataset included 32 named drugs and 11 proprietary compounds encompassing a broad spectrum of physicochemical properties (11 acids, 24 bases, 8 neutral, c,log,D ,1 to 7, MW 200 to 700 and free fraction <0.001 to 1). Free fractions (fu,mic) in monkey, dog, rat and human microsomes were highly correlated, with linear regression correlation coefficients greater than 0.97. The average fold-difference in fu,mic between monkey, dog, or rat, and human was 1.6-, 1.3-, and 1.5-fold, respectively. Species differences in fu,mic were also assessed for a range of microsomal protein concentrations (0.2,2,mg/mL) for midazolam, clomipramine, astemizole, and tamoxifen, drugs with low to high microsomal binding. The mean fold species-difference in fu,mic for midazolam, clomipramine, astemizole, and tamoxifen was 1.1-, 1.2-, 1.3-, and 2.0-fold, respectively, and was independent of normalized microsomal protein concentration. For a fixed concentration of microsomal protein, greater than 76% and 90% of drugs examined in this study had preclinical species fu,mic within 1.5- and 2-fold, respectively, of experimentally measured human values. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3620,3627, 2010 [source] Solubilizing efficiency and in vitro cytotoxicity of Peptoad GJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2010Radhakrishna K. Maroju Abstract A novel non-ionic surfactant, Peptoad G, is evaluated for its solubilizing capacity and cytotoxicity in order to explore its possible use in aqueous formulation of hydrophobic drugs. Solubility studies were carried out using ten model hydrophobic drugs, and cytotoxicity of the surfactant was evaluated in three different cell lines using the MTT assay. It was shown that peptoad G enhances the solubility of the ten model drugs to different extents, ranging from 20- to 1100-fold, which correlated with the number of hydrogen-bonding sites on the drug molecules. The in vitro cytotoxicity studies revealed comparable cytotoxicity of peptoad G to that of cremophor EL. The results suggest peptoad G possesses potential as an alternative to conventional solubilizers in hydrophobic drug formulations. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2196,2198, 2010 [source] Thermodynamic and structural aspects of sulfonamide crystals and solutionsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2009German L. Perlovich Abstract The crystal structures of three sulfonamides with the general structure 4-NH2 -C6H4 -SO2NH-C6H4/3 -R (R,=,4-Et; 4-OMe; 5-Cl-2-Me) have been determined by X-ray diffraction. On the basis of our previous data and the results obtained a comparative analysis of crystal properties was performed: molecular conformational states, packing architecture, and hydrogen bond networks using graph set notations. The thermodynamic aspects of the sulfonamide sublimation process have been studied by investigating the temperature dependence of vapor pressure using the transpiration method. A regression equation was derived describing the correlation between sublimation entropy terms and crystal density data calculated from X-ray diffraction results. Also correlations between sublimation Gibbs energies and melting points, on the one hand, and between sublimation enthalpies and fusion enthalpies at 298 K, on the other hand, were found. These dependencies give the opportunity to predict sublimation thermodynamic parameters by simple thermo-physical experiments (fusion characteristics). Solubility processes of the compounds in water, n -hexane, and n -octanol (as phases modeling various drug delivery pathways and different types of membranes) were investigated and corresponding thermodynamic functions were calculated as well. Thermodynamic characteristics of sulfonamide solvation were evaluated. For compounds with similar structures processes of transfer from one solvent to another one were studied by a diagram method combined with analysis of enthalpic and entropic terms. Distinguishing between enthalpy and entropy, as is possible through the present approach, leads to the insight that the contribution of these terms is different for different molecules (entropy- or enthalpy-determined). Thus, in contrast to interpretation of only the Gibbs energy of transfer, being extensively used for pharmaceuticals in the form of the partition coefficient (log,P), the analysis of thermodynamic functions of the transfer process provides additional mechanistic information. This may be important for further evaluation of the physiological distribution of drug molecules and may provide a better understanding of biopharmaceutical properties of drugs. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4738,4755, 2009 [source] Colloidal soft matter as drug delivery systemJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009Giulia Bonacucina Abstract Growing interest is being dedicated to soft matter because of its potential in delivering any type of drugs. Since hydrophilic, lipophilic, small and big molecules can be loaded into these colloidal systems and administered through the parenteral or nonparenteral route, soft matter systems have been used to solve many biomedical and pharmaceutical problems. In fact, they make possible to overcome difficulties in the formulation and delivery of poorly water-soluble drug molecules, settle some stability issues typical of biological drug molecules, design parenteral sustained release forms and provide functionalized soft particles that are very effective in drug targeting. This review deals with the important role that colloids play in the drug delivery and targeting, with particular attention to the more currently used systems such as microemulsions, organogels, liposomes, micelles, and dendrimers. Though significant progress has been made in drug targeting, some challenges still remain. Further efforts will be required to better understand the characteristics of targets and to discover new ones. In-depth knowledge of the physico-chemical structure and properties of the systems used for targeting is fundamental for understanding the mechanism of interaction with the biological substrate and the consequent drug release. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1,42, 2009 [source] Liposome transport of hydrophobic drugs: Gel phase lipid bilayer permeability and partitioning of the lactone form of a hydrophobic camptothecin, DB-67JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2008Vijay Joguparthi Abstract The design of liposomal delivery systems for hydrophobic drug molecules having improved encapsulation efficiency and enhanced drug retention would be highly desirable. Unfortunately, the poor aqueous solubility and high membrane binding affinity of hydrophobic drugs necessitates extensive validation of experimental methods to determine both liposome loading and permeability and thus the development of a quantitative understanding of the factors governing the encapsulation and retention/release of such compounds has been slow. This report describes an efflux transport method using dynamic dialysis to study the liposomal membrane permeability of hydrophobic compounds. A mathematical model has been developed to calculate liposomal membrane permeability coefficients of hydrophobic compounds from dynamic dialysis experiments and partitioning experiments using equilibrium dialysis. Also reported is a simple method to study the release kinetics of liposome encapsulated camptothecin lactone in plasma by comparing the hydrolysis kinetics of liposome entrapped versus free drug. DB-67, a novel hydrophobic camptothecin analogue has been used as a model permeant to validate these methods. Theoretical estimates of DB-67 permeability obtained from the bulk solubility diffusion model and the "barrier-domain" solubility diffusion model are compared to the experimentally observed value. The use of dynamic dialysis in drug release studies of liposome and other nanoparticle formulations is further discussed and experimental artifacts that can arise without adequate validation are illustrated through simulations. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:400,420, 2008 [source] Cell adhesion molecules for targeted drug deliveryJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2006Alison L. Dunehoo Abstract Rapid advancement of the understanding of the structure and function of cell adhesion molecules (i.e., integrins, cadherins) has impacted the design and development of drugs (i.e., peptide, proteins) with the potential to treat cancer and heart and autoimmune diseases. For example, RGD peptides/peptidomimetics have been marketed as anti-thrombic agents and are being investigated for inhibiting tumor angiogenesis. Other cell adhesion peptides derived from ICAM-1 and LFA-1 sequences were found to block T-cell adhesion to vascular endothelial cells and epithelial cells; these peptides are being investigated for treating autoimmune diseases. Recent findings suggest that cell adhesion receptors such as integrins can internalize their peptide ligands into the intracellular space. Thus, many cell adhesion peptides (i.e., RGD peptide) were used to target drugs, particles, and diagnostic agents to a specific cell that has increased expression of cell adhesion receptors. This review is focused on the utilization of cell adhesion peptides and receptors in specific targeted drug delivery, diagnostics, and tissue engineering. In the future, more information on the mechanism of internalization and intracellular trafficking of cell adhesion molecules will be exploited for delivering drug molecules to a specific type of cell or for diagnosis of cancer and heart and autoimmune diseases. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1856,1872, 2006 [source] Evaluation of solution oxygenation requirements for azonitrile-based oxidative forced degradation studies of pharmaceutical compoundsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2006Eric D. Nelson Abstract AIBN and ACVA oxidative forced degradation models are examined for two drug molecules whose predominant oxidation chemistries arise from different reaction mechanisms (i.e., free radical vs. nucleophilic). Stress was conducted under a variety of initiator concentrations, and under ambient and pressurized oxygen atmospheres. In each case examined, the azonitrile initiator solutions served as a good predictive model of the major oxidative degradation products observed in pharmaceutical formulations. At low to moderate inititator concentrations, the degradation product distributions and degree of reactivity were similar for samples stored in ambient and pressurized oxygen environments. These results are rationalized with reference to the oxygen consumption kinetics of AIBN and ACVA solutions as a function of initiator concentration. The data suggests that ambient air provides sufficient oxygen to enable chain propagation of peroxy radicals in azonitrile solutions of concentrations appropriate to the forced degradation of pharmaceutical compounds. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1527,1539, 2006 [source] Physicochemical interactions between drugs and superdisintegrantsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2008Nelly Fransén We have evaluated the interactions between superdisintegrants and drugs with different physicochemical characteristics, which may affect the in-vivo absorption e.g. after mucosal administration. The binding of sodium salicylate, naproxen, methyl hydroxybenzoate (methylparaben), ethyl hydroxybenzoate (ethylparaben), propyl hydroxybenzoate (propylparaben), atenolol, alprenolol, diphenhydramine, verapamil, amitriptyline and cetylpyridinium chloride monohydrate (CPC) to different superdisintegrants (sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone) and one unsubstituted comparator (starch) was studied spectrophotometrically. An indication of the in-vivo effect was obtained by measuring the interactions at physiological salt concentrations. SSG was investigated more thoroughly to obtain release profiles and correlation between binding and ionic strength. The results showed that the main interactions with the anionic hydrogels formed by SSG and CCS were caused by ion exchange, whereas the neutral crospovidone exhibited lipophilic interactions with the non-ionic substances. The effect of increased ionic strength was most pronounced at low salt concentrations and the ion exchange interactions were almost completely eradicated at physiological conditions. The release profile of diphenhydramine was significantly affected by the addition of salt. It was thus concluded that the choice of buffer was of great importance for in-vitro experiments with ionic drugs. At physiological salt concentrations the interactions did not appear to be strong enough to influence the in-vivo bioavailability of any of the drug molecules. [source] Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a polymeric absorption enhancer: synthesis, characterization and applicationsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2008Jasjeet K. Sahni ABSTRACT In recent years, researchers have been working extensively on various novel properties of polymers to develop increased efficiency of drug delivery and improve bioavailability of various drug molecules, especially macromolecules. Chitosan, a naturally occurring polysaccharide, because of its protonated/polymeric nature, provides effective and safe absorption of peptide and protein drugs. Its transmucosal absorption is, however, limited to acidic media because of its strong intermolecular hydrogen bonds. A new partially quaternized chitosan derivative, N-trimethyl chitosan chloride (TMC), has been synthesized with improved solubility, safety and effectiveness as an absorption enhancer at neutral pH and in aqueous environment. It enhances the absorption, especially of peptide drugs, by reversible opening of tight junctions in between epithelial cells, thereby facilitating the paracellular diffusion of peptide drugs. This derivative thus opens new perspectives as a biomaterial for various pharmaceutical applications/drug delivery systems. This review deals with the potential use of the quaternized chitosan derivative as a permeation enhancer for the mucosal delivery of macromolecular drugs along with its other biomedical applications. [source] Dermal delivery of desmopressin acetate using colloidal carrier systemsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2005Melkamu Getie Recently, the transdermal route has received attention as a promising means to enhance the delivery of drug molecules, particularly peptides, across the skin. In this work, the skin penetration profiles of desmopressin acetate from a colloidal system (water-in-oil microemulsion) and an amphiphilic cream, a standard formulation, were determined using Franz diffusion cells and compared. In the case of the microemulsion, the total percentages of dose obtained from different skin layers (stratum corneum to subcutaneous tissue) were 3.30 ± 0.67, 7.37 ± 2.43 and 15.54 ± 2.72 at 30, 100 and 300 min, respectively. Similarly, 5.19 ± 0.96, 8.04 ± 0.97 and 14.4 ± 5.15% of the dose applied was extracted from the skin treated with the cream. About 6% of the applied dose reached the acceptor compartment from the microemulsion instead of 2% from the cream within 300 min. The concentration of drug that penetrated into the upper layers of the skin was higher from the cream than from the microemulsion at all time intervals. On the other hand, a higher amount of drug was found in the deeper skin layers and in the acceptor compartment from the microemulsion. [source] Dispersion polymerization of vinyl monomers in supercritical carbon dioxide in the presence of drug molecules: A one-pot route for the preparation of controlled delivery systemsJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 22 2008Alessandro Galia Abstract The polymerization of 1-vinyl-2-pyrrolidone in supercritical carbon dioxide in the presence of ibuprofen as a model drug was investigated as a new one-pot process for the preparation of polymer-based drug delivery systems (DDSs). The composites were prepared at 65 °C and P = 31,42 MPa by changing the initial concentration of the drug and the concentration of a crosslinking agent and that of a hydrophobic comonomer. The effects of these parameters on the performances of the polymerization and on the in vitro release kinetics of ibuprofen were studied. In all the experiments, part of the drug was entrapped inside the polymer particles and dissolved more slowly with respect to the pure compound. Copolymerization with methyl methacrylate was the most effective route to obtain a DDS with sustained temporal release of the drug molecule. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7429,7446, 2008 [source] Self-immolative dendrimers as novel drug delivery platformsJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 5 2006Doron Shabat Abstract Self-immolative dendrimers were recently developed and introduced as a potential platform for a single-triggered multi-prodrug. These unique structural dendrimers can release all of their tail units through domino-like chain fragmentation, which is initiated by a single cleavage at the dendrimer core. The incorporation of drug molecules as the tail units and an enzyme substrate as the trigger generates a multi-prodrug unit that is activated with a single enzymatic cleavage. We have demonstrated several examples of self-immolative dendritic prodrug systems and have shown significant advantages with respect to the appropriate monomeric prodrug. We anticipate that single-triggered, dendritic prodrugs will be exploited to further improve selective chemotherapeutic approaches in cancer therapy. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 1569,1578, 2006 [source] Determination of binding constants and stoichiometries for platinum anticancer drugs and serum transport proteins by capillary electrophoresis using the Hummel-Dreyer methodJOURNAL OF SEPARATION SCIENCE, JSS, Issue 2 2005Alexander V. Rudnev Abstract A CE method has been developed to evidence and quantitatively characterize the interaction between platinum-based antitumor drugs and human serum proteins. This method is a variant of affinity CE modified regarding both experimental setup and data treatment so as to measure the peaks (or vacancies) that correspond to the bound drug when it slowly binds to the protein. Using the formalism of the Hummel-Dreyer method and cisplatin and oxaliplatin as test compounds, a protocol for determining albumin and transferrin binding constants and stoichiometries, including (and distinguished by) 48 hours of incubation of the reaction mixture, was elaborated. Relative affinities of drugs toward different proteins in aqueous solution at physiological pH, chloride concentration, and temperature were compared in terms of overall binding constants and numbers of drug molecules attached to the protein. The results indicate that both platinum drugs bind to albumin more strongly than to transferrin, supporting the concept that the albumin fraction is a major drug supply route for chemotherapeutical needs. From a comparison with the binding parameters measured previously for cisplatin by other methods, conclusions were drawn about the validity of CE as a simple and convenient method for assaying protein-drug reactions with slow kinetics. [source] Tailored Albumin-based Copolymers for Receptor-Mediated Delivery of Perylenediimide Guest MoleculesMACROMOLECULAR RAPID COMMUNICATIONS, Issue 17 2010Klaus Eisele Abstract The synthesis of a novel and multifunctional copolymer based on a human serum albumin backbone bearing several folic acid as well as PEO groups was presented. In solution, this side-chain copolymer adopts a globular architecture and about five molecules of the water-insoluble chromophore PDI were successfully incorporated into these micelles for receptor-mediated cell uptake investigations. A significant uptake of these bioconjugates via receptor-mediated endocytosis was detected for cells expressing folic acid receptors in the cell membrane. These novel albumin-based copolymers could serve as efficient and biocompatible carrier systems facilitating the directed delivery of lipophilic drug molecules into cancer cells and they allow investigating vesicle formation and trafficking even at the single molecule level. [source] High-pressure NMR characterization of triacetyl-,-cyclodextrin in supercritical carbon dioxideMAGNETIC RESONANCE IN CHEMISTRY, Issue 2 2009G. I. Ivanova Abstract Cyclodextrins are used in many drug formulations since their cavities provide microenvironments where drug molecules can enter and form inclusion complexes for controlled drug delivery. Supercritical carbon dioxide (scCO2) is an alternative to organic solvents and a very attractive medium for the preparation of these inclusion complexes. The potential ability of triacetyl-,-cyclodextrin (TA-,-CD) to form inclusion complexes in addition to its high miscibility in liquid and scCO2 could offer a chance for an economical and environmental friendly chemical processing. In this work, high-pressure NMR studies were performed in order to obtain information on the molecular structure and dynamics of TA-,-CD in scCO2 at 313.15 K and 20 MPa and its ability to form inclusion complexes under these conditions was studied. The influence of scCO2 on a number of NMR spectral parameters, such as chemical shifts, spin-spin coupling constants, nuclear Overhauser effect (NOE) and spin-lattice relaxation (T1) has been studied. We unequivocally show for the first time structural changes of TA-,-CD in scCO2, like acetyl chain orientation and overall shape distortions that can affect its inclusion capability in this medium. The possibility of cavity self-closure is discussed and the results of two inclusion studies that support cavity self-closure, with the angiotensin-converting enzyme inhibitor, captopril, and the nonsteroid anti-inflammatory drug, flufenamic acid, are presented. Copyright © 2008 John Wiley & Sons, Ltd. [source] Characterisation of indomethacin and nifedipine using variable-temperature solid-state NMRMAGNETIC RESONANCE IN CHEMISTRY, Issue 11 2005David C. Apperley Abstract We have characterised the stable polymorphic forms of two drug molecules, indomethacin (1) and nifedipine (2) by 13C CPMAS NMR and the resonances have been assigned. The signal for the CCl carbon of indomethacin has been studied as a function of applied magnetic field, and the observed bandshapes have been simulated. Variable-temperature 1H relaxation measurements of static samples have revealed a T1, minimum for indomethacin at 17.8 °C. The associated activation energy is 38 kJ mol,1. The relevant motion is probably an internal rotation and it is suggested that this involves the COCH3 group. Since the two drug compounds are potential candidates for formulation in the amorphous state, we have examined quench-cooled melts in detail by variable-temperature 13C and 1H NMR. There is a change in slope for and at the glass transition temperature (Tg) for indomethacin, but this occurs a few degrees below Tg for nifedipine, which is perhaps relevant to the lower real-time stability of the amorphous form for the latter compound. Comparison of relaxation time data for the crystalline and amorphous forms of each compound reveals a greater difference for nifedipine than for indomethacin, which again probably relates to real-time stabilities. Recrystallisation of the two drugs has been followed by proton bandshape measurements at higher temperatures. It is shown that, under the conditions of the experiments, recrystallisation of nifedipine can be detected already at 70 °C, whereas this does not occur until 110 °C for indomethacin. The effect of crushing the amorphous samples has been studied by 13C NMR; nifedipine recrystallises but indomethacin does not. The results were supported by DSC, powder XRD, FTIR and solution-state NMR measurements. Copyright © 2005 John Wiley & Sons, Ltd. [source] Modulation of protein aggregation by polyethylene glycol conjugation: GCSF as a case studyPROTEIN SCIENCE, Issue 5 2006Rahul S. Rajan Abstract Polyethylene glycol (PEG) conjugation to proteins has emerged as an important technology to produce drug molecules with sustained duration in the body. However, the implications of PEG conjugation to protein aggregation have not been well understood. In this study, conducted under physiological pH and temperature, N-terminal attachment of a 20 kDa PEG moiety to GCSF had the ability to (1) prevent protein precipitation by rendering the aggregates soluble, and (2) slow the rate of aggregation relative to GCSF. Our data suggest that PEG-GCSF solubility was mediated by favorable solvation of water molecules around the PEG group. PEG-GCSF appeared to aggregate on the same pathway as that of GCSF, as evidenced by (a) almost identical secondary structural transitions accompanying aggregation, (b) almost identical covalent character in the aggregates, and (c) the ability of PEG-GCSF to rescue GCSF precipitation. To understand the role of PEG length, the aggregation properties of free GCSF were compared to 5kPEG-GCSF and 20kPEG-GCSF. It was observed that even 5kPEG-GCSF avoided precipitation by forming soluble aggregates, and the stability toward aggregation was vastly improved compared to GCSF, but only marginally less stable than the 20kPEG-GCSF. Biological activity measurements demonstrated that both 5kPEG-GCSF and 20kPEG-GCSF retained greater activity after incubation at physiological conditions than free GCSF, consistent with the stability measurements. The data is most compatible with a model where PEG conjugation preserves the mechanism underlying protein aggregation in GCSF, steric hindrance by PEG influences aggregation rate, while aqueous solubility is mediated by polar PEG groups on the aggregate surface. [source] Some fundamental and technical aspects of the quantitative analysis of pharmaceutical drugs by matrix-assisted laser desorption/ionization mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 14 2005Lekha Sleno The purpose of the present paper was to study some of the underlying physical and technical aspects of high-throughput quantitative matrix-assisted laser desorption/ionization (MALDI) of small drug molecules. A prototype MALDI-triple quadrupole instrument equipped with a high repetition rate laser was employed. Initially, the detection limits and dynamic ranges for the quantitation of four drugs (quinidine, danofloxacin, ramipril and nadolol) were determined. Internal standards were carefully chosen for each of these analytes in terms of structure similarity and fragmentation pathways. Three organic matrices were tested for these assays, resulting in different crystallization behaviors and measurement reproducibilities. , -Cyano-4-hydroxycinnamic acid yielded the best results and was subsequently employed for the quantitative determination of all four analytes. Further experiments considered the role of laser energy and pulse rate on the ablated areas as well as ion signals. Light microscope and scanning electron microscope images allowed the examination of the ablated area of the MALDI spots. The images showed convincing evidence that the ablated area was virtually void of crystals after analysis, with no preferential removal of material in the center of the laser's path. Average values for the amount of material ablated were determined to be 3.9,±,0.5% of the total spot size, and as low as 19.5 attomoles of analyte were detectable for our most sensitive analyte, ramipril. It was calculated that, under these assay conditions, it was possible to accurately quantify less than 1 femtomole of all analytes with the use of appropriately pure internal standards. These studies showed very promising results for the quantitative nature of MALDI for small molecules with molecular weights less than 500,Da. Copyright © 2005 John Wiley & Sons, Ltd. [source] Analysis of the composition of immunoconjugates using size-exclusion chromatography coupled to mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 13 2005Alexandru C. Lazar Recombinant monoclonal antibody drug products play an increasingly important role in the treatment of various diseases. Antibodies are large, multi-chain proteins and antibody preparations often contain several molecular variants, which renders them heterogeneous. The heterogeneity is further increased in immunoconjugates prepared by covalently linking several drug molecules per antibody molecule. As part of the product characterization, the molecular weights of the antibodies or their drug conjugates need to be measured. Electrospray ionization mass spectrometry (ESI-MS) is well suited for the analysis of recombinant antibodies and immunoconjugates. Sample preparation is an important element of ESI-MS analysis, in particular samples need to be freed of interfering charged species, such as salts and buffer components. In this paper, Amicon centrifugal filters, reversed-phase high-performance liquid chromatography (HPLC), and size-exclusion HPLC were evaluated for sample desalting. Size-exclusion HPLC, using aqueous acetonitrile as the mobile phase, directly coupled to ESI-MS provided the best performance and was optimized for the study of immunoconjugates. The results showed that antibodies carrying covalently linked maytansinoid molecules generated charge envelope profiles that differ from those of the non-conjugated antibody. For the determination of the distribution of the various conjugate species in an immunoconjugate sample prepared by randomly linking in the average 3.6 drug molecules per antibody molecule, the experimental conditions needed to be carefully selected to allow acquisition of the whole spectrum containing the charge envelopes of all species. Copyright © 2005 John Wiley & Sons, Ltd. [source] | |||||||||||||