The characterization of aprotic polar liquids and percolation phenomena in DMSO/water mixtures.

In the previous papers of our research group it was shown, that the Clausius-Mossotti-Debye equation for the quasi-static dielectric constant (epsilonr) can be extended to liquids if the parameter Ei/E is introduced. Thus, it is possible to characterize polar liquids with the easily accessible parameter Ei/E. This property is also reflected by the fact that the parameter Ei/E can be directly related to the empirical ET(30) and the normalized ETN parameter to describe the polarity of liquids proposed by Reichardt (Chem. Rev. 94, 2319-2358) Ei corresponds to the local mean field due to close molecule-molecule interactions after the application of an external electric field E. In a recent work of our research group it was also demonstrated that the modified Clausius-Mossotti-Debye equation and the study of the relaxation time can be related to percolation phenomena in binary solvent mixtures leading to a valuable insight of the structure of polar liquids and to a better understanding of binary systems. In the present paper it is demonstrated that percolation phenomena for binary DMSO/water mixtures, become visible due to changes of parameters describing the dielectric spectrums. The interpretation of the percolation effects leads to the following conclusion: DMSO/water mixtures seem to have in the whole range of miscibility the same microscopic structure like water with a coordination number z approximately between 4 and 6 which could be the reason for the high permeability of DMSO through biological membranes.     

Detection of percolation phenomena in binary polar liquids by broadband dielectric spectroscopy

In the previous papers [Stengele, A., Rey, St., Leuenberger, H., 2001. A novel approach to the characterization of polar liquids. Part 1: pure liquids. Int. J. Pharm. 225, 123-134; Stengele, A., Rey, St., Leuenberger, H., 2002. A novel approach to the characterization of polar liquids. Part 2: binary mixtures. Int. J. Pharm. 241, 231-240], it was shown that the Clausius-Mossotti-Debye equation for the quasi-static dielectric constant (epsilon) can be extended to liquids if the parameter Ei/E is introduced. Ei corresponds to the local mean field due to close molecule-molecule interactions after the application of an external electric field E. In the present paper it is demonstrated that the Ei/E parameter and the relaxation behavior of the dipole moment of the polar molecule in binary mixtures of water, respectively, methanol or benzylalcohol with 1,4-dioxane can be used for the detection of percolation phenomena. As 1,4-dioxane has no intrinsic dipole moment but can form hydrogen bonds and is completely miscible with water, respectively, methanol or benzylalcohol, percolation phenomena can be related to the relaxation behavior of the dipole moment of the polar co-solvent. The relaxation behavior of the binary mixtures can be modeled by applying the Debye equation, and the Cole-Davidson distribution function. Superpositions such as the Debye equation and the Cole-Davidson distribution function or a sum (Sigmai) of Debye equations are also considered.     

Compaction behaviour and new predictive approach to the compressibility of binary mixtures of pharmaceutical excipients.

The compressibility of three pharmaceutical excipients (microcrystalline cellulose, lactose and anhydrous calcium phosphate) and their binary mixtures was studied. The aim of this work was to observe the impact of the mass composition of the mixture on the compressibility. The single-compound materials and their mixtures were compacted using instrumented presses. It allowed obtaining compression cycles (i.e., force-displacement curves) which were associated with energy measurements (specific compaction energy, Esp cp and specific expansion energy, Esp exp). It was observed that for the mixtures studied, the change of Esp cp with the mass composition could be fitted using a linear relationship (it was not the case with Esp exp). A linear relationship between the porosity of mixture's compacts and the mass composition was also obtained. Heckel's plots were then obtained for the three excipients and the mixtures. The mean yield pressure was calculated with the "in-die-method" and the "out-of-die method". A proportional relationship was not valid for the mean yield pressures. But, a predictive approach was proposed in order to obtain indirectly the mean yield pressure of a binary mixture if the data of the single materials were known. It used the linear mixing rule observed with the porosity. The validity was verified and compared with the experimental values. This comparison showed that it was possible to predict the mean yield pressure of binary mixtures from the accessible data of the single excipients.     

Novel approach to estimate quality of binary random powder mixtures: samples of constant volume. I: Derivation of equation.

An equation of the quality of binary random mixtures that applies to powder samples of constant bulk volume was derived from the binomial distribution. In contrast to the Stange-Poole equation for samples of constant mass, this approach can also be used for constituents with large differences in particle size and in bulk density. The validity of this equation was verified with tablets directly compressed from mixtures composed of equal mass proportions of sucrose [volume-weighted/volume-number mean diameter (dv), 504 microns] as the coarse ingredient (A) and of a microcrystalline cellulose (Avicel PH 101)-talc mixture (dv, 60 microns) as the fine constituent (B). Because of the difference in the bulk densities of A and B, the equation estimated a coefficient of the random content variation, which for A was double that for B. The content variations found with the tablets were in excellent agreement with the calculated values and reflected the differences predicted from theory. The Stange-Poole equation yielded identical values of the content variations of A and B, which is in contrast to the experimental results.     

The granulation of binary mixtures.

Granules have been prepared from blends of lactose and boric acid by the massing and screening method and their properties have been compared with those of granules from the individual materials, granulated separately. Increasing the volume of binder solution used produced granules stronger and of greater mean size in all blends studied. The largest and strongest granules, for any given binder solution volume and massing time, were obtained from a blend, as were the granules with the minimum pore size. The effect of massing time on granule properties was generally similar to those already reported for single component systems; prolonged massing in some blend led to a reduction in mean granule size. Variation in pre-mixing time produced no significant change in the physical properties of granules prepared from a lactose: boric acid blend.     

Novel approach to estimate quality of binary random powder mixtures: samples of constant volume. III: Range of validity of equation.

The validity of an equation developed to determine the quality of binary random mixtures (eq 1) was evaluated with tablets prepared from random mixtures of a coarse constituent A (sucrose) and fine constituent B [microcrystalline cellulose (Avicel PH 101)-talc] with the A:B ratios (w/w) varying from 10:90 to 80:20. With all A:B ratios, superior agreement was established between the random content variations determined with eq 1 and the content variations found in the tablets. The 80:20 ratio, however, was just at the boundary, and random quality was achieved with the 50-mg tablets but not with the 200-mg tablets because of segregation. From percolation theory, this result is a consequence of the small proportion by volume (bv) of B that is almost equal to the precolation threshold (Pcb) of B of 0.3. With bv less than Pcb, the fine constituent B does not form a coherent lattice, and eq 1 is no longer valid. To estimate the volume proportions av and bv from the mass proportions a and b, two methods were established. Method 1 assumed the bulk densities of A and B to be representative and was used when av was higher than the percolation threshold (Pca) of A of 0.3 (a, 0.5). Method 2 used the true particle density of A and was valid with av values of less than 0.1 (a, 0.3), in which case the particles of A were dispersed as individuals in the matrix of B.     

Novel approach to estimate quality of binary random powder mixtures: samples of constant volume. II: Applications of equation to optimize tableting conditions.

In a companion communication, an equation (eq 1) of the homogeneity of binary random mixtures, which applies to constituents differing in particle size and in bulk density, was derived. The present paper demonstrates the practical applications of this equation in optimizing tableting conditions with respect to a high dose uniformity. Tablets of 50:50 (w/w) mixtures of coarse sucrose and of fine microcrystalline cellulose (Avicel PH 101)-talc vehicle were produced on a single-punch machine. Without a spin feeder, the tablets showed variations in content uniformity that were significantly higher than those estimated from eq 1. Correlation analysis between the individual mass and the content of the constituents of the tablets revealed this difference to be due to nonuniformity of the die filling and not due to incomplete mixing. Accordingly, the use of a spin feeder allowed production of tablets with higher dose uniformity, which conformed well with the theoretical optimum predicted with eq 1. Further variation of the processing conditions cannot improve the quality (i.e., varying the tableting speed resulted in equal or in poorer uniformity of dose content).     

A novel flexible approach for evaluating fixed ratio mixtures of full and partial agonists.

Assessing for interactions among chemicals in a mixture involves the comparison of actual mixture responses to those predicted under the assumption of zero interaction (additivity), based on individual chemical dose-response data. However, current statistical methods do not adequately account for differences in the shapes of the dose-response curves of the individual mixture components, as occurs with mixtures of full and partial receptor agonists. We present here a novel extension of current methods, which overcomes some of these limitations. Flexible single chemical concentration-effect curves combined with a common background parameter are used to describe an additivity surface along each axis. The predicted mixture response under the assumption of additivity is based on the constraint of Berenbaum's definition of additivity. Iterative algorithms are used to estimate mean responses at observed mixture combinations using only single chemical parameters. A full model allowing for different maximum response levels, different thresholds, and different slope parameters for each mixture component is compared to a reduced model under the assumption of additivity. A likelihood-ratio test is used to test the hypothesis of additivity by utilizing the full and reduced model predictions. This approach is useful for mixtures of chemicals with threshold regions and whose component chemicals exhibit differing response maxima (e.g., mixtures of full and partial agonists). The methods are illustrated with a combination of six chemicals in an estrogen receptor-alpha (ER-alpha) reporter gene assay.     

Solubility of drugs in aqueous solutions. Part 2: binary nonideal mixed solvent

As in a previous paper [Int. J. Pharm. 258 (2003) 193–201], the Kirkwood–Buff theory of solutions was employed to calculate the solubility of a solid in mixed solvents. Whereas in the former paper the binary solvent was assumed ideal, in the present one it was considered nonideal. A rigorous expression for the activity coefficient of a solute at infinite dilution in a mixed solvent [Int. J. Pharm. 258 (2003) 193–201] was used to obtain an equation for the solubility of a poorly soluble solid in a nonideal mixed solvent in terms of the solubilities of the solute in the individual solvents, the molar volumes of those solvents, and the activity coefficients of the components of the mixed solvent.

The Flory–Huggins and Wilson equations for the activity coefficients of the components of the mixed solvent were employed to correlate 32 experimental data sets regarding the solubility of drugs in aqueous mixed solvents. The results were compared with the models available in literature. It was found that the suggested equation can be used for an accurate and reliable correlation of the solubilities of drugs in aqueous mixed binary solvents. It provided slightly better results than the best literature models but has also the advantage of a theoretical basis.     

Investigation and modelling approach of the mechanical properties of compacts made with binary mixtures of pharmaceutical excipients.

Three pharmaceutical excipients (microcrystalline cellulose, lactose, anhydrous calcium phosphate) and their binary mixtures were compacted to form compacts of various mean porosities. Some mechanical properties (Young's modulus, tensile strength and Brinell hardness) were studied on these compacts. The mechanical properties of the binary mixtures were not proportional to the mixture composition expressed in mass. More, for all the properties, a negative deviation was always observed from this linear relationship. In reference to a composition percolation phenomenon, critical mass fractions were detected from the graph mechanical property vs. mass composition of a mixture. The results obtained with Brinell hardness differed from the results of the Young's modulus and the tensile strength, i.e. the most plastic material in the binary mixture controlled the mixture behaviour. Secondly, a predictive model based on a statistical approach was proposed for the Young's modulus and the tensile strength. The validity of this model was verified on experimental data, and an interaction parameter used to characterize the affinity of the two compounds was calculated. Finally, the X-ray tomography technique was applied to the compacts of cellulose/phosphate mixtures to obtain cross-sections images of the compacts. The analysis of the cross-sections images allowed explaining the no linear relationship of the different mechanical properties results observed on these binary mixtures.     

Blocking the inflammasome: A novel approach to treat uveitis

Uveitis is a complex ocular inflammatory disease often accompanied by bacterial or viral infections (infectious uveitis) or underlying autoimmune diseases (non-infectious uveitis). Treatment of the underlying infection along with corticosteroid-mediated suppression of acute inflammation usually resolves infectious uveitis. However, to develop more effective therapies for non-infectious uveitis and to better address acute inflammation in infectious disease, an improved understanding of the underlying inflammatory pathways is needed. In this review, we discuss the disease aetiology, preclinical in vitro and in vivo uveitis models, the role of inflammatory pathways, as well as current and future therapies. In particular, we highlight the involvement of the inflammasome in the development of non-infectious uveitis and how it could be a future target for effective treatment of the disease.     

A novel approach to increase oral drug absorption.

A comprehensive analytical solution that accounts for many factors and assumptions affecting drug concentration profile in the gastrointestinal tract was presented. A sensitivity analysis approach was utilized in order to investigate the importance of different parameters in the model. The partition coefficient is found to be the key parameter. Hence, for drugs stable in the intestinal wall, increasing partition coefficient only can lead to higher drug absorption. However, for drugs unstable in the intestinal wall, increasing partition coefficient and diffusivity is needed to counteract drug instability. On the other hand, the model is essentially insensitive to degradation in the intestinal lumen for degradation half lives greater than 0.7 min at a given intestinal length. However, a high model sensitivity to the rate of luminal degradation is obtained at higher intestinal length values. The proposed model can be used as a guide for oral drug delivery.     

Patent Evaluation: A novel approach to the quantification of arteriosclerosis

Sepsis is a syndrome of increasing prevalence and accounts for high mortality in the intensive care unit. The search for sepsis therapies in the past decades have been marked by disappointment and failure. More recently however, new insights have been gained in the process of sepsis which have broadened the field of therapeutic approaches. Elucidation of the signal transduction pathways that are involved in innate immunity have begun to link the pathogen-host interaction to the resulting broad host response. Insights into the host response have resulted in a greater understanding of its complexity as an intricate web involving inflammation, haemostasis and the endothelium. This recent explosion in understanding coincides with the first success in sepsis therapy with the advent of activated protein C and may herald a new era for sepsis treatment.     

Binder distribution onto binary mixtures of glass spheres.

Glass spheres (0-8 and 0-4 cm diam.) in differing weight ratios were treated in a rotating pan with four pharmaceutical binder fluids. Binder uptake for a sphere of 1 g was greater onto the smaller spheres irrespective of binder or wt ratio used. There were differences in uniformity of uptake, the solution binders (PVP and gelatin) being more evenly distributed than the mucilaginous binders (starch and methylcellulose). Binder distribution on the basis of unit surface area showed less obvious differences between the sphere sizes. Possible consequences of such binder distribution through powder aggregates are discussed.     

Tolcapone: a novel approach to Parkinson's disease.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of tolcapone are reviewed. Tolcapone is the first drug brought to market from the new class of selective and reversible inhibitors of catechol-O-methyltransferase. Tolcapone is indicated for use in the treatment of Parkinson's disease as an adjunct to levodopa-carbidopa therapy in patients who are experiencing fluctuations in symptoms and who are not responding to or are not appropriate candidates for other adjunctive therapies. The absolute bioavailability of tolcapone after an oral dose is about 65%. Clinical trials have demonstrated that tolcapone 50-200 mg three times daily reduces "off" time in patients refractory to levodopa-carbidopa, Unified Parkinson's Disease Rating Scale scores, and the dosage of levodopa-carbidopa required for symptom suppression. The most frequent adverse effects of tolcapone are dyskinesia, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and hallucinations; also, there is a potential for elevation of liver transaminase concentrations in the blood. To date, three deaths from fulminant hepatic failure in association with tolcapone have been reported. Extensive liver function testing is required of all patients before and during therapy. The recommended starting dosage is 100 mg orally three times daily as an adjunct to levodopacarbidopa therapy; a concurrent reduction in the levodopa dosage of about 30% is suggested. Patient response should be monitored carefully during the first three weeks of therapy; treatment should be discontinued in patients failing to respond during this initial use. Tolcapone is of benefit in fluctuating Parkinson's disease, but benefits must be carefully weighed against risks in individual patients.     

Small-molecule inhibitors binding to protein kinase. Part II: the novel pharmacophore approach of type II and type III inhibition

Background: Protein kinases are essential enzymes propagating cellular signal transduction processes and consequently emerged as central targets for drug discovery against a wide range of diseases with a strong historical focus on oncological disorders. Several high-resolution crystal structures of various ATP-competitive inhibitors in complex with their target protein kinases have been determined and represent a wealth of detailed information about binding modes, inhibition mechanisms, and associated structure– activity relationships of target-bound small molecules. Objective: In this second part of a two-part review, we discuss the binding mode of inhibitors that target protein kinases in their inactive state. Methods: The scope of this review covers inhibitors for which crystal structures in complex with their respective kinases in the inactive state are available. Results: Structural parameters of both inhibitors and kinases contribute to the complexity of designing kinase inhibitors. Kinase inhibitors that target the inactive state of a kinase have become a novel rule in the design of highly active and selective compounds. The combination of high-resolution structures of ligand-enzyme complexes with especially detailed kinetic studies will in the long-term help to develop new low-molecular weight type II inhibitors.