Louis Cartilier

Cross-linked high amylose starch for controlled release of drugs: recent advances.

Cross-linked high amylose starches have been developed as excipients for the formulation of controlled-release solid dosage forms for the oral delivery of drugs. Advantages of this new class of excipients include cost-effectiveness, readily accessible industrial manufacturing technology, high active ingredient core loading and the possibility of achieving a quasi zero-order release for most drugs. In addition to the latter, other features distinguish cross-linked high amylose starches from other excipients used to prepare hydrophilic matrices. Among these are the absence of erosion, the limited swelling and the fact that increasing cross-linking degrees results in increased water uptake rate, drug release rate and equilibrium swelling. Thus the goal of the present study was to gain some insights into the mechanism of drug release control by matrices of cross-linked high amylose starch. Water transport kinetics and dimensional changes were studied in matrices placed in water at 37 degrees C by an image analysis technique. The results show that in the first 5 min, a gel layer is formed at the surface of the tablet, after which the gel front seems to halt its progression toward the center of the tablet. Water continues to diffuse through the front and to invade the core. As a consequence, this latter swells, with a predominance for radial swelling. Equilibrium swelling is reached over 3 days, when the water concentration in the tablet becomes homogeneous and the whole tablet gelifies. Solid-state 13C-NMR were acquired on cross-linked high amylose starch powders, tablets and hydrated tablets with varying cross-linking degrees. They show a predominance of the V-type single helix arrangement of amylose in the dry state irrespective of the cross-linking degree. Upon hydration, the homologues with a low cross-linking degrees show a transition from the V to the B-type double helix arrangement. It is therefore hypothesized that the capacity of amylose to undergo the V to B transition is an important factor in controlling water transport and drug release rate. Finally applications to different drugs are reviewed briefly. They illustrate the versatility of this technology as generic versions of zero order OROS drug (Efidac) and Fickian release conventional matrices (Voltaren SR) were developed and successfully tested in pilot clinical studies to be bioequivalent to the references. These studies further showed that cross-linked high amylose starch matrices have the lowest inter-subject variability among the systems tested and show a total absence of food effect.

The modified box-counting method: Analysis of some characteristic parameters

Abstract One of the most popular ways of estimating fractal dimension (Df) is the box-counting method (BCM). The major problem with this method is that it leads to results with a very high percentage of error. The modified box-counting method (MBCM) was developed as a methodic procedure to set sequence and range. The procedure eliminates two problems of the computerized BCM, the border effect and noninteger values of e. The MBCM is a new, powerful tool, very simple to use, allowing accurate estimation of Df.

New methods characterizing avalanche behavior to determine powder flow

AbstractPurpose. To characterize the avalanche behavior of different powders and to compare the results of the strange-attractor and novel characterization approaches. Methods. The following nine different materials were tested: three lactoses, maltodextrin, two microcrystalline celluloses, sodium chloride, sucrose, and glass beads. Morphology, size, and size distribution, true density, bulk and tap density, angle of repose, flow index, and avalanching behavior were quantified for each excipient by scanning electron microscopy, laser time-of-flight analysis, helium pycnometer, graduated cylinder, fixed-height funnel, Flodex (Hanson Research Corp., Chatsworth, California) method, and AeroFlow (TSI, Inc., St. Paul, Minnesota), respectively. Environmental factors were controlled, and the avalanches were studied at various speeds. Results. The strange-attractor graph obtained at 1 rotation per 120 s showed that it was difficult to appreciate the flowability differences among 3-mm glass beads, lactose 100, and lactose 325. However, plotting the raw data as a relationship of the time between each avalanche and the inverse of speed revealed a characteristic linear slope for each sample. Furthermore, a new flowability index based on the SD calculated from the raw data gave results that were consistent with Carrs index. A cohesive index also can be determined by avalanche behavior, and it reflects the stability of the rapid particular rearrangements of powder. Conclusion. A novel method of evaluating avalanche measurements makes it possible to better characterize powder flowability and to predict powder behavior under working conditions.

Substituted amylose as a matrix for sustained drug release

AbstractPurpose. Amylose derivatives form an important group of polymers, and many of them can be used as drug sustained-release systems. Methods. Substituted amylose can be prepared in a 1-step reaction with substituent(s) in a basic medium. The substituents can be represented as (A—R), where (A) serves an epoxy, halide or suitable organic or inorganic function reacting with hydroxyl groups located on the amylose chain, and (R) is an organic radical. Results. The present work shows the synthesis of different polymers and the effect of different (A) and/or (R) and their different degrees of substitution (n) on the sustained drug release from matrix tablets prepared by direct compression. Conclusions. SA polymers are interesting excipients for the preparation of controlled drug release tablets.

Cross-linked amylose tablets containing α-amylase: an enzymatically-controlled drug release system

An oral controlled release system based on direct compression of cross-linked amylose (CLA) and drug powders was previously introduced. For drugs with limited solubility or for some drugs for which solubility can be influenced by variation of gastro-intestinal pH, a system is required to accelerate drug release. This paper describes a novel enzymatically-controlled drug release (ECDR) system based on the addition of alpha-amylase to CLA tablets, which can modulate the release kinetics of drugs. The alpha-amylase within the tablets is able to hydrolyze alpha-1-4-glucosidic bonds present in the CLA semisynthetic substrate. Increasing amounts of alpha-amylase (5 to 25 EU) within the tablets induced a significant decrease in release time from 24 to 6 h. High amounts of external alpha-amylase (300-6000 EU/l) had a slight effect on the release rate. Drug release from the ECDR system seems to be controlled by two sequential mechanisms: (a) hydration and swelling of CLA tablets followed by (b) internal enzymatic hydrolysis of the hydrated gel phase.

Characterization of moving fronts in cross-linked amylose matrices by image analysis

Abstract The purpose of this work was to characterize swelling and solvent concentration gradients in large matrices by image analysis. Tablets prepared by direct compression of cross-linked amylose (CLA), a polymer used for controlled release of drugs, with 10% diltiazem HC1 were studied. Matrices corresponding to 3 different degrees of cross-linking were compared. The technique was simple and precise. It permitted the characterization of the changes occurring at the surface as well as inside the tablets during water sorption. The solvent penetrated all sides of the tablets. Three-dimensional swelling was recorded. Axial swelling was more pronounced than radial swelling for the 3 types of CLA. Augmenting the degree of cross-linking from 6 to 11 significantly increased the degree of swelling and solvent transport kinetics in CLA tablets. The equilibrium swelling state was attained much after the solvent penetration fronts had met.

Measurements of fractal dimension by box-counting: a critical analysis of data scatter

The multifractal concept was introduced in the 1980s by Mandelbrot. This theory arose from the analysis of complex and/or discontinuous objects. In this study, we analyzed the data scatter obtained by a modified box-counting method. Considering the curved shape of the data scatter, it is noticeable that there is more than one slope corresponding to different fractal behavior of an object. In this work, to discriminate different fractal dimensions from data scatter obtained by box counting, we suggest a rigorous selection of data points. The results show that large ϵ’s usually characterize the embedding surface of the whole object and that small ϵ’s approximate the dimension of the substructure for discontinuous objects. They also show that a dimension can be associated with a density distribution of singularities.

Insights into the Role of Electrostatic Forces on the Behavior of Dry Pharmaceutical Particulate Systems

PurposeUnder different charging conditions, particles can be either attracted or repulsed by each other, causing powder agglomeration or segregation. Such behavior can be detrimental in many processes aimed at achieving particulate mixture homogeneity. Consequently, the effects of electrostatic charges on mixing kinetics must be well understood to insure a high level of process control, product quality, and reproducibility.MethodsIn Part 1, an electrostatic charger is used to evaluate the ability of the studied particles to develop and retain an induced charge at the surface for a fixed period of time. Part 2 assesses the natural electrostatic charge developed by powders sliding across a stainless steel, plastic, or Tyvek chute. In Part 3, 2 binary systems were formed according to an experimental design under different charging conditions, and their behavior was quantified by measuring the degree of agglomeration attained.ResultsThis work has shown that each raw material develops a different charge according to its physico-chemical properties and the type of contact surface. Electrostatic charges influence the creation of agglomerates under certain conditions.ConclusionsThe presence of electrostatic charges must be accounted for in any effort to maximize mixing efficiency.

A model of growing vascular structures

Increasing attention is being paid to the configuration and development of vascular structures and their possible correlations with physiological events. The study of angiogenesis in normal and pathological states as well as in embryo and adult has provided new insights into the mechanism of vessel growth and organization of the vasculature. Various mathematical branching models have been developed. These constructions are mainly geometrical and only involve a branching phenomenon. We propose the use of a deterministic non-linear model based on physiological laws and hydrodynamics. Growth, branching and anastomosis, the three actual main events occurring in vascular growth, are included in this model. Space growth, including cells and vessels, is defined by a decreasing transformation. Space density and the length of new sprouts are controlled by a set of parameters. The conditions on these parameters are well established, which allows the production of realistic patterns.

High-amylose sodium carboxymethyl starch matrices for oral, sustained drug-release: formulation aspects and in vitro drug-release evaluation.

High-amylose sodium carboxymethyl starch (HASCA), produced by spray-drying (SD), was previously shown to have interesting properties as a promising pharmaceutical sustained drug-release tablet excipient for direct compression, including ease of manufacture and high crushing strength. This study describes the effects of some important formulation parameters, such as compression force (CF), tablet weight (TW), drug-loading and electrolyte particle size, on acetaminophen-release performances from sustained drug-release matrix tablets based on HASCA. An interesting linear relationship between TW and release time was observed for a typical formulation of the system consisting of 40% (w/w) acetaminophen as model drug and 27.5% NaCl as model electrolyte dry-mixed with HASCA. Application of the Peppas and Sahlin model gave a better understanding of the mechanisms involved in drug-release from the HASCA matrix system, which is mainly controlled by surface gel layer formation. Indeed, augmenting TW increased the contribution of the diffusion mechanism. CFs ranging from 1 to 2.5 tonnes/cm(2) had no significant influence on the release properties of tablets weighing 400 or 600 mg. NaCl particle size did not affect the acetaminophen-release profile. Finally, these results prove that the new SD process developed for HASCA manufacture is suitable for obtaining similar-quality HASCA in terms of release and compression performances.