Influence of glucosamine on the bioactivity of insulin delivered subcutaneously and in an oral nanodelivery system.

The aim of the work reported herein was to study the effect of glucosamine HCl (GlcN·HCl) on the bioactivity (BA) of insulin, administered via subcutaneous (SC) and oral routes, in adult male Sprague Dawley rats. The oral insulin delivery system (insulin-chitosan reverse micelle [IC-RM]) was prepared by solubilizing insulin-chitosan (13 kDa) polyelectrolyte complex in a RM system consisting of oleic acid, PEG-8 caprylic/capric glycerides, and polyglycerol-6-dioleate. The BA of insulin in vivo was evaluated by measuring blood glucose level using a blood glucose meter; the results revealed that the extent of hypoglycemic activity of SC insulin was GlcN·HCl dose dependent when they were administered simultaneously. A significant reduction in blood glucose levels (P<0.05) was found for the insulin:GlcN·HCl at mass ratios of 1:10 and 1:20, whereas lower ratios (eg, 1:1 and 1:4) showed no significant reduction. Furthermore, enhancement of the action of SC insulin was achieved by oral administration of GlcN·HCl for 5 consecutive days prior to insulin injection (P<0.05). For oral insulin administration via the IC-RM system, the presence of GlcN·HCl increased the hypoglycemic activity of insulin (P<0.05). The relative BA were 6.7% and 5.4% in the presence and absence of GlcN·HCl (ie, the increase in the relative BA was approximately 23% due to incorporating GlcN·HCl in the IC-RM system), respectively. The aforementioned findings offer an opportunity to incorporate GlcN·HCl in oral insulin delivery systems in order to enhance a reduction in blood glucose levels.

Influence of glutathione on the bioactivity of subcutaneously or orally administered insulin to rats.

The effect of reduced (GSH) and oxidized (GSSG) glutathione on the bioactivity of insulin was studied. A polyelectrolyte complex (PEC) of insulin with low molecular weight chitosan (13 kDa) was prepared and characterized. The PEC was then solubilized, in the presence and absence of GSH and GSSG, in a reverse micelle consisting of oleic acid and two surfactants (PEG-8 caprylic/capric glycerides and polyglycerol-6-dioleate). The in vitro and in vivo performances of the reverse micelle formulations (RMFs) were evaluated in rats. At pH 6.5 the association efficiency of the PEC was 76.2%. In vitro insulin release from the RMs was negligible at pH 1.2 and was markedly increased at pH 6.8. The hypoglycemic activity of insulin in the PEC was reduced when administered via the subcutaneous route, regardless of the GSH content. On the other hand, the presence of GSSG significantly enhanced hypoglycemia. When the RMF was administered via the oral route, the presence of GSH had no effect on the hypoglycemic activity of insulin compared with the GSH free system. However, the presence of GSSG in the oral preparation increased the hypoglycemic activity of insulin; probably by inhibiting insulin degradation, thereby prolonging its effect. Thus, incorporation of GSSG in the RMF reduces blood glucose levels in rats and protects insulin from degradation.

Low molecular weight chitosan-insulin polyelectrolyte complex: characterization and stability studies.

The aim of the work reported herein was to investigate the effect of various low molecular weight chitosans (LMWCs) on the stability of insulin using USP HPLC methods. Insulin was found to be stable in a polyelectrolyte complex (PEC) consisting of insulin and LMWC in the presence of a Tris-buffer at pH 6.5. In the presence of LMWC, the stability of insulin increased with decreasing molecular weight of LMWC; 13 kDa LMWC was the most efficient molecular weight for enhancing the physical and chemical stability of insulin. Solubilization of insulin-LMWC polyelectrolyte complex (I-LMWC PEC) in a reverse micelle (RM) system, administered to diabetic rats, results in an oral delivery system for insulin with acceptable bioactivity.

Co-processed chitin-mannitol as a new excipient for Oro-dispersible tablets.

This study describes the preparation, characterization and performance of a novel excipient for use in oro-dispersible tablets (ODT). The excipient (Cop-CM) consists of chitin and mannitol. The excipient with optimal physicochemical properties was obtained at a chitin: mannitol ratio of 2:8 (w/w) and produced by roll compaction (RC). Differential scanning calorimetry (DSC), Fourier transform-Infrared (FT-IR), X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) techniques were used to characterize Cop-CM, in addition to characterization of its powder and ODT dosage form. The effect of particle size distribution of Cop-CM was investigated and found to have no significant influence on the overall tablet physical properties. The compressibility parameter (a) for Cop-CM was calculated from a Kawakita plot and found to be higher (0.661) than that of mannitol (0.576) due to the presence of the highly compressible chitin (0.818). Montelukast sodium and domperidone ODTs produced, using Cop-CM, displayed excellent physicochemical properties. The exceptional binding, fast wetting and superdisintegration properties of Cop-CM, in comparison with commercially available co-processed ODT excipients, results in a unique multifunctional base which can successfully be used in the formulation of oro-dispersible and fast immediate release tablets.

Novel analytical approaches for the study of mobility and relaxation phenomena in positional isomers of GABA.

γ-Aminobutyric acid (GABA), and its positional isomers DL-α-aminobutyric acid (AABA) and DL-ß-aminobutyric acid (BABA) have been analysed, in the solid state, using thermally stimulated current (TSC) spectroscopy. Secondary relaxations in these molecules have been detected for the first time. GABA displays two secondary relaxations at 77 ± 2 °C and 114 ± 2 °C, whilst AABA and BABA each display a single secondary relaxation at 109 ± 1 °C and 104 ± 1 °C, respectively. Analysis (decoupling of molecular mobilities) of secondary relaxations using thermal windowing (TW) and relaxation map analysis (RMA) show that the dipole relaxation associated with secondary transitions observed for the aminobutyric acids requires activation energies of 189.9 ± 3.2 kJ mol(-1) (GABA), 142.4 ± 1.4 kJ mol(-1) (AABA) and 195.7 ± 0.8 kJ mol(-1) (BABA). However, the ΔH(≠) values observed were found to exhibit negligible deviations from the zero entropy line. This indicates that the relaxation processes are localised, non-cooperative rotational motions that have a negligible influence on entropy changes of detected molecular mobilities. Furthermore, RMA analysis revealed that AABA and BABA display compensation behaviour i.e., entropy and enthalpy are linearly related to each other, whereas GABA did not demonstrate such behaviour. The coordinates of the compensation point (compensation temperature (Tc) and the compensation relaxation time (τc)) were found to be 214 ± 6 °C and 0.051 ± 0.024 s, respectively for AABA and 153 ± 3 °C and 0.025 ± 0.011 s for BABA. For the molecules investigated the compensation points coincide with the starting temperature of the higher temperature thermal events i.e. sublimation, melt/decomposition, and indicate a correlation between secondary relaxation processes and the main thermal transitions, found via TGA and DSC studies.

Raman and IR spectroscopic studies of fenamates--conformational differences in polymorphs of flufenamic acid, mefenamic acid and tolfenamic acid.

Solid-state Raman and IR spectra of two polymorphic forms of each of three fenamates (flufenamic acid, mefenamic acid and tolfenamic acid) display subtle but highly reproducible differences. Many of these spectral differences can be ascribed to different conformations of these molecules, involving two of four possible orientations of one substituted benzene ring with respect to the other. Interpretation of the vibrational spectra in terms of conformational differences has been facilitated by DFT calculations at the B3LYP/cc-pVDZ level for each conformer. The calculated spectra are compared with the experimental spectra in order to identify the conformers present in two polymorphic forms in each case, and detailed band assignments are obtained from the DFT calculations.

A novel multifunctional pharmaceutical excipient: modification of the permeability of starch by processing with magnesium silicate.

A directly compressible excipient has been developed by co-processing starch with magnesium silicate. The foregoing was achieved either by co-precipitation of magnesium silicate onto different types of starch or by dry granulation of maize starch with magnesium silicate. A variety of techniques (permeability, water retention/swelling, compression analysis, scanning electron microscopy, tensile strength and disintegration/dissolution studies) were used to characterize these systems. The permeability of the formulations produced using the two methods was evaluated experimentally using Darcy's permeability law. Magnesium silicate, as an anti-adhering agent, increases the permeability of both maize and partially pregelatinized starch, resulting in compacts of high mechanical strength, short disintegration time and low lubricant sensitivity. Such advantages are evident when the properties of the physical mixture of maize starch with magnesium silicate are compared with the co-precipitation and dry granulation techniques. Formulation with this novel excipient system, using paracetamol as a model drug, indicated its suitability as a single multifunctional excipient.

Vibrational spectra and structures of the anions of urazole and 4-methylurazole: DFT calculations of the normal modes and the influence of hydrogen bonding.

Solid state IR and Raman as well as aqueous solution state Raman spectra are reported for the anions of urazole and 4-methylurazole, and their N-deuterated derivatives. DFT calculations, at the B3-LYP/cc-pVTZ level, established that the structures and vibrational spectra of both anions can be interpreted using a model that incorporates hydrogen-bonded water molecules, in conjunction with the polarizable continuum solvation method. In the case of the urazole anion it is shown that deprotonation occurs primarily at N1 rather than N4, but there is also evidence for the second tautomer both in the solid state and in aqueous solution. The vibrational spectra were computed at the optimised molecular geometry in each case, enabling normal coordinate analysis, which yielded satisfactory agreement with the experimental IR and Raman data. Computed potential energy distributions of the normal modes provided detailed vibrational assignments.

Chitin.

A comprehensive profile of chitin with 61 references is reported. A full description including nomenclature, formulae, elemental analysis, and appearance is included. Methods of preparation for chitin and its derivative, such as chitosan, are discussed. Physical properties, analytical methods, uses and applications, stability, biodegradability, and toxicity of chitin are also reviewed.

Magnesium silicate.

A comprehensive profile of magnesium silicate with 80 references is reported. A full description including nomenclature, formulae, and appearance is included. Methods for magnesium silicate preparation including precipitation, hydrothermal precipitation, and mechanochemical dehydration are reviewed. Physical characteristics, compendia and non-compendia analytical methods, uses, stability and incompatibilities, biodegradability, toxicity, and substances related to magnesium silicate are also discussed.

Preparation and characterization of a novel co-processed excipient of chitin and crystalline mannitol.

A co-processed excipient was prepared from commercially available crystalline mannitol and α-chitin using direct compression as well as spray, wet, and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size, on the properties of the prepared co-processed excipient has been investigated. α-Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol-chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol-chitin (2:8, w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength, and friability of tablets, produced from Cop-MC using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, high-strength, and low-strength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient.

Surface-enhanced Raman scattering studies of rhodanines: evidence for substrate surface-induced dimerization.

The surface-enhanced Raman scattering (SERS) spectra of rhodanine adsorbed on silver nanoparticles have been examined using 514.5 and 632.8 nm excitation. There is evidence that, under the experimental conditions used, rhodanine undergoes a nanoparticle surface-induced reaction resulting in the formation of a dimeric species via the active methylene group in a process which is analogous to the Knoevenagel reaction. The experimental observations are supported by DFT calculations at the B3-LYP/cc-pVDZ level. Calculated energies for the interaction of the E and Z isomers of the dimers of rhodanine with silver nanoparticles support a model in which the (intra-molecular hydrogen bonded) E isomer dimer is of lower energy than the Z isomer. A strong band, at 1566 cm(-1), in the SERS spectrum of rhodanine is assigned to the nu(C double bond C) mode of the dimer species.

Characterization of chitin-metal silicates as binding superdisintegrants.

When chitin is used in pharmaceutical formulations, processing of chitin with metal silicates is advantageous, from both an industrial and pharmaceutical perspective, compared to processing using silicon dioxide. Unlike the use of acidic and basic reagents for the industrial preparation of chitin-silica particles, coprecipitation of metal silicates is dependent upon a simple replacement reaction between sodium silicate and metal chlorides. When coprecipitated onto chitin particles, aluminum, magnesium, or calcium silicates result in nonhygroscopic, highly compactable/disintegrable compacts. Disintegration and hardness parameters for coprocessed chitin compacts were investigated and found to be independent of the particle size. Capillary action appears to be the major contributor to both water uptake and the driving force for disintegration of compacts. The good compaction and compression properties shown by the chitin-metal silicates were found to be strongly dependent upon the type of metal silicate coprecipitated onto chitin. In addition, the inherent binding and disintegration abilities of chitin-metal silicates are useful in pharmaceutical applications when poorly compressible and/or highly nonpolar drugs need to be formulated.

Novel inclusion complex of ibuprofen tromethamine with cyclodextrins: physico-chemical characterization.

Guest-host interactions of ibuprofen tromethamine salt (Ibu.T) with native and modified cyclodextrins (CyDs) have been investigated using several techniques, namely phase solubility diagrams (PSDs), proton nuclear magnetic resonance ((1)H NMR), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffractometry (XRPD), scanning-electron microscopy (SEM) and molecular mechanics (MM). From the analysis of PSD data (A(L)-type) it is concluded that the anionic tromethamine salt of ibuprofen (pK(a)=4.55) forms 1:1 soluble complexes with all CyDs investigated in buffered water at pH 7.0, while the neutral form of Ibu forms an insoluble complex with beta-CyD (B(S)-type) in buffered water at pH 2.0. Ibu.T has a lower tendency to complex with beta-CyD (K(11)=58 M(-1) at pH 7.0) compared with the neutral Ibu (K(11)=4200 M(-1)) in water. Complex formation of Ibu.T with beta-CyD (DeltaG(o)=-20.4 kJ/mol) is enthalpy driven (DeltaH(o)=-22.9 kJ/mol) and is accompanied by a small unfavorable entropy (DeltaS(o)=-8.4 J/mol K) change. (1)H NMR studies and MM computations revealed that, on complexation, the hydrophobic central benzene ring of Ibu.T and part of the isobutyl group reside within the beta-CyD cavity leaving the peripheral groups (carboxylate, tromethamine and methyl groups) located near the hydroxyl group networks at either rim of beta-CyD. PSD, (1)H NMR, DSC, FT-IR, XRPD, SEM and MM studies confirmed the formation of Ibu.T/beta-CyD inclusion complex in solution and the solid state.

The impact of additives found in industrial formulations of TCE on the wettability of sandstone.

The wettability of aquifer rocks is a key physical parameter which exerts an important control on the transport, residual trapping, distribution and eventual fate of chlorinated hydrocarbon solvents (CHSs) released into the subsurface. Typically chlorinated solvents are assumed to be non-wetting in water saturated rocks and unconsolidated sediments. However industrially formulated solvent products are often combined with basic additives such as alkylamines to improve their performance; and the mineral surfaces of aquifer rocks and sediments usually possess a range of acid and hydrogen-bonding adsorption sites. The presence of these sites provides a mechanism whereby the basic additives in CHSs can be adsorbed at the solvent phase/solid phase interface. Given the amphiphilic molecular structure of these additives, this may result in changes in the wetting conditions of the solid phase. The aim of this study was therefore to test this conjecture for two classes of additives (alkylamines and quaternary ammonium salts) that are often encountered in industrial solvent formulations. Wettability assessments were made on sandstone cores by means of measurements of spontaneous and forced water drainage and spontaneous and forced water imbibition and through contact angle measurements on a smooth quartz surface. No solvent/additive combination produced solvent wetting conditions, though dodecylamine and octadecylamine significantly reduced the water wetting preference of sandstone which frequently resulted in neutral wetting conditions. The large volume of spontaneous water drainage observed in wettability experiments involving cetyltrimethylammonium bromide and octadecyltrimethylammonium bromide, suggested that the sandstone cores in these tests remained strongly water wetting. However equilibrium static contact angles of around 60 degrees were measured on quartz suggesting that the sandstone surfaces should be close to neutral wetting conditions. This paradox was finally resolved by noting that contact between the solvent mixture and water in the sandstone core resulted in a final solvent phase which had an extremely low interfacial tension. It is therefore suspected that the observed spontaneous drainage of solvent from the core was driven by gravitational and buoyancy forces rather than strong water wetting conditions. Finally it was noted that the mobilisation of iron oxide coatings from the sandstone surface had a considerable influence in reducing the interfacial tension and in the formation and stabilisation of TCE/water emulsions.

Changes in interfacial tension of chlorinated solvents following flow through U.K. soils and shallow aquifer material.

The interfacial tension (IFT) that arises at the interface between water and an immiscible organic liquid is a key parameter affecting the transport and subsequent fate of the organic liquid in water-saturated porous media. In this paper, data are presented that show how contact between a range of soil types and chlorinated hydrocarbon solvent (CHS) dense nonaqueous phase liquids (DNAPLs) can affect DNAPL/water IFT values. The soils examined are indicative of U.K. soil types and shallow aquifer materials. The solvents investigated were tetrachloroethylene (PCE) and trichloroethylene (TCE). Lab grade, recovered field DNAPL and industrial waste chlorinated solvent mixtures were used. The data from batch and column experiments invariably revealed that water/DNAPL IFT values change following contact with unsaturated soils. In the majority of cases, the IFT values increase following soil exposure. However, after contact with an organic-rich soil, the IFT of the lab grade solvents decreased. The experimental evidence suggests that these reductions are linked to the removal of organic material from the soil and its subsequent incorporation into the solvent IFT increases in the case of lab solvents are shown to be linked to the removal of stabilizers (added by the manufacturers to obviate degradation) that are removed by adsorption to soil mineral surfaces. Similarly, it is conjectured that adsorption of surface-active compounds from the industrial waste samples to soil surfaces is responsible for increases in the IFT in these samples. Finally, it was observed that invading CHSs are capable of dissolving and subsequently mobilizing in-situ soil contaminants. GC/MS analysis revealed these mobilized soil contaminants to be polyaromatic hydrocarbons and phthalate esters.