Marija Bogataj

The influence of stirring rate on biopharmaceutical properties of Eudragit RS microspheres

Eudragit RS microspheres containing pipemidic acid, as a model drug, were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The aim of the work was to evaluate the influence of stirring rate on the average particle size, particle morphology, drug content and release kinetics, as well as the influence of particle size on microsphere morphology, drug content and release kinetics. Stirring rate has been found to significantly influence the average diameter of microspheres. The average diameter decreases as the stirring rate increases. This can be explained by production of a finer dispersion of droplets when higher stirring rates are applied and, consequently, by the formation of smaller microspheres. With increasing stirring rate and increasing fraction particle size the drug content also increases. It is assumed that this dependence is a consequence of an uneven diffusion of the drug from the inner to the outer emulsion phase, and an uneven encapsulation of drug particles during the preparation. Drug release follows the Higuchi model. As seen from SEM photographs, larger microspheres are more porous and the microspheres produced at higher stirring rates are more porous than those produced at lower stirring rates. This explains the unexpected finding that the release rate increases as the fraction particle size and the stirring rate increase.

Shape optimization and characterization of polysaccharide beads prepared by ionotropic gelation.

The shape of drug loaded polysaccharide beads produced by ionotropic gelation has been optimized, with the aim of producing spherical beads suitable for further technological operations, such as coating. The optimization was performed on a model system sodium alginate/theophylline by inclusion of various fillers. Incorporation of excipients markedly influenced the morphological characteristics of the beads. The undesired irregular shape of beads caused by incorporation of the drug could only be improved by incorporating a combination of polycarbophil (PK) and polyvinylpyrrolidone (PVP). The spherical shape of these beads was stabilized mechanically by numerous air bubbles trapped inside the beads, which prevented the collapse of the beads during drying. The optimized method was shown to be applicable to a target system of pectin and an anti-inflammatory drug, LK-423.

Influence of chitosan and polycarbophil on permeation of a model hydrophilic drug into the urinary bladder wall.

Influence of dispersions of mucoadhesive polymers chitosan and polycarbophil on permeability properties of urinary bladder was investigated in vitro on isolated porcine urinary bladder. Pipemidic acid as a model hydrophilic drug was used. Its distribution in the bladder wall was determined from actual tissue concentrations by a method based on sectioning of frozen tissue and extraction of tissue slices. Pipemidic acid tissue concentration versus tissue depth profiles were evaluated by a diffusion model assuming constant diffusion coefficient. Increase in bladder wall permeability was observed in the presence of both polymers. Apparent permeability (mean+/-S.D.) of urinary bladder wall was increased 2.7+/-2.9 and 2.8+/-2.0 times for chitosan, and 2.3+/-2.0 and 4.3+/-4.2 times for polycarbophil at 0.5 and 1.0%, w/v polymer concentration, respectively. This increase is a consequence of the increased permeability of urothelium. These findings support investigations on application of chitosan and polycarbophil in development of mucoadhesive intravesical drug delivery systems. Experimental model may be applied to evaluate the results of experiments with drugs used in intravesical therapy.

The study of drug release from microspheres adhered on pig vesical mucosa

The object of our work is the preparation of a mucoadhesive drug delivery system intended for intravesical application. In the present work, microspheres with Eudragit RS matrix polymer and different mucoadhesive polymers, i.e. chitosan hydrochloride (Ch), sodium salt of carboxymethyl cellulose (CMC) and polycarbophil (PC) were prepared to evaluate their influence on the mucoadhesive properties of microspheres. Different parameters were determined and their influence on pipemidic acid release from microspheres adhered on intact and damaged pig vesical mucosa was evaluated: swelling of polymers, mucoadhesion strength of polymeric films and drug dissolution according to USP XXIV method. The dissolution rate from microspheres containing different mucoadhesive polymers decreases as follows: PC>Ch>CMC. PC swelled to the largest volume among all polymers and as a result the fastest release of the drug from PC microspheres was obtained. The release rate of pipemidic acid from microspheres adhered on intact mucosa followed the order PC>CMC>Ch. These results show that both drug dissolution and mucoadhesion strength strongly influence drug release from adhered microspheres. The slowest release from Ch microspheres could be interpreted by the largest mucoadhesion strength of Ch polymeric films. The release rate of pipemidic acid from microspheres adhered on damaged mucosa followed the order PC=Ch>CMC. The results obtained on pathologically changed mucosa model support the indication of the role of glycosaminoglycans and polymer charge in the mucoadhesion process on vesical mucosa. Analysis of release data shows that the drug dissolution profiles follow the Higuchi kinetics better than the release profiles from adhered microspheres and different kinetics might be a consequence of different release mechanisms.

Influence of physicochemical and biological parameters on drug release from microspheres adhered on vesical and intestinal mucosa.

The object of our work is to develop mucoadhesive microspheres to be applied into the urinary bladder. In the present study the microspheres were prepared and the release of a model drug after their adhesion to mucosa was evaluated. The microspheres were prepared by solvent evaporation method using Eudragit RL or hydroxypropylcellulose as matrix polymers and one out of five different polymers as mucoadhesives or non-mucoadhesive references. A method for the evaluation of the drug release from microspheres adhered on guinea pig urinary bladder and small intestine mucosa was developed and the influence of the following parameters on this process was followed: mucoadhesion strength of polymeric films, swelling of polymers and the drug release from microspheres. The results showed that the detachment forces were decreasing in the following order: CMCNa > Carbopol 934P > HPC > EE.HCl = PVP/VA. Carbopol swelled to the largest volume among all polymers and the drug release from microspheres was more retarded when Eudragit RL was used as matrix polymer. When comparing the results of pipemidic acid release from microspheres adhered on intestinal mucosa with detachment forces, similar ratios among the mucoadhesive polymers can be seen. On the other hand, differences between two mucosae were observed. These differences are due to the amount of mucus on mucosa and might also be influenced by the charge of mucus. The goal of our work at this point of investigation was achieved by microspheres containing carboxymethylcellulose as mucoadhesive and Eudragit RL as matrix polymer because they provide the longest release time from microspheres adhered on vesical mucosa and sufficient high strength of mucoadhesion.

Eudragit E microspheres containing bacampicillin: Preparation by solvent removal methods

Eudragit E microspheres containing bacampicillin hydrochloride were prepared by solvent evaporation and solvent extraction methods. Three different systems of solvents were used: methyl acetate, acetone and methanol/liquid paraffin. The success of the procedures depended mostly on the lipophilicity of the solvent. The particle size of microspheres was determined by sieve analysis. The results showed that the average size of microspheres is influenced greatly by the type of solvent. Scanning electron microscopy was used for observation of the shape of microspheres. Microspheres prepared by the solvent evaporation method in systems with acetone and methyl acetate were all of a regular spherical shape. The surface of all other microspheres were folded. The influence of magnesium stearate content in microspheres was also studied in terms of different methods, solvents and processing conditions.

Optimal Lotsizing Within MRP Theory

MRP Theory combines the use of Input-Output Analysis and Laplace transforms, enabling the development of a theoretical background for multi-level, multi-stage production-inventory systems together with their economic evaluation, in particular applying the Net Present Value principle (NPV) In this paper we concentrate our attention on the question of optimal lotsizing decisions within the MRP Theory framework. MRP Theory has mainly dealt with assembly structures by which items produced downstream (on a higher level in the product structure) contain one or more sub-items on lower levels, but at each stage, the assembly activity produces only one type of output. This enables the input matrix, after enumerating all items suitably, to be organised as a triangular matrix, with non-zero elements only appearing below its main diagonal. The introduction of a diagonal lead time matrix capturing the advanced timing when required Inputs are needed, enables compact expressions to be obtained, explaining the development of key variables such as available inventory and backlogs in the frequency domain. Central in this theory is the generalised input matrix showing when and how much the internal (dependent) demand amounts to for any production plan. Previously has been demonstrated that in a one-product case, inner-corner conditions for an optimum production plan in continuous time reduce the number of possible replenishment times to a finite set of given points at which either a replenishment is made, or not. The dynamic lotsizing problem is thus turned into choosing from a set of zero-one decisions with 2(m-1) alternatives, of which one (or possibly several equivalent) solution(s) must be optimal, where m is the number of requirement (demand) events. Given these points in time and the corresponding staircase function describing cumulative demand, the optimal plan may be obtained, for instance by employing the Triple Algorithm of dynamic lotsizing. This applies either an Average Cost approach, or the Net Present Value principle is applied In this paper, we extend this analysis to a general multi-item system of the assembly type. Among other issues, it is shown how the number of internal demand events depends on product structure and number of external demand events. Also the inner-corner condition is proven still to be valid in this somewhat more complex situation, when demand for lower-level items no longer is given from the outset, but instead depends on decisions concerning production of items on higher levels in the product structure. A simple dynamic program procedure is provided offering a solution to maximising the NPV for any general assembly system. To solve for the optimal production plan, the Triple Algorithm may be applied to each stage.

Mucoadhesion on pig vesical mucosa: influence of polycarbophil/calcium interactions.

The influence of polycarbophil/calcium interactions on the mucoadhesive properties of polycarbophil has been examined. Polycarbophil dispersions and films with different concentrations of calcium or sodium ions were prepared and the following parameters were measured: detachment force on pig vesical mucosa, zeta potential, pH and viscosity. Polycarbophil detachment force decreased significantly in the presence of calcium but not sodium. Both ions decrease the pH of polycarbophil dispersions. On the other hand, altering the pH of hydrated polycarbophil films in the absence of added ions had an insignificant effect on detachment force. Both ions reduce the absolute values of polycarbophil zeta potential, calcium more efficiently than sodium. We could conclude that decreased mucoadhesion strength of polycarbophil in the presence of calcium is due to the chelation of polycarbophil carboxylic groups by calcium and crosslinking of polymer. The crosslinked polymer chains would be expected to be less flexible, and therefore, interpenetrate to a lesser extent with the glycosaminoglycans of mucus. Additionally, the interactions between functional groups of polycarbophil and mucus glycosaminoglycans are lowered due to the calcium, blocking the carboxylic groups. The mechanism of calcium influence on viscosity of polycarbophil dispersions appears to be different: repulsion between ionised carboxylic groups of polycarbophil prevails over the crosslinking of polycarbophil by calcium.

Supply chain coordination in spatial games

Abstract The notion that economies consist of the systems of cities originates from a theory by Christaller and Beckmann, based on a Lochean framework of retailers having an endogenously determined market area. In 1968 it was completed by Tinbergen, who has suggested production approach. This original theory explains the location pattern of the market and manufacturing centers selling goods to the local populations within given market areas. The theory was based on the idea of the urban area being a trading center. Our paper, influenced by the ideas, presents the quantitative method of building up the model of spatial hierarchy as the result of spatial games. The paper by Girlich: “On the Metric Transportation Problems and Their Solution” (Inventory Modelling, Lecture Notes of the International Postgraduate Summer School, Vol. 2, ISIR, Budapest-Portorož, 1995, pp. 13–24), gives us proper foundations for our present research. In this paper customer traveling problem is described, which helps us to define a market area. A mathematical description of market areas, defines the border between two areas under the assumption of shortages of goods in at least one market area. The study is influenced by Grubbstroms work on MRP optimization (for details see R.W. Gubbstrom, Management Science 13(7) (1967) 558–567; The Mathematical Scientist 16 (1991) 118–129; International Journal of Production Economics, in press; International Encyclopaedia of Business and Management, Routledge, London, 1996; R.W. Grubbstrom, A. Bogataj (Eds.), Storlien, 1997, FPP, Portorož, 1998; R.W. Grubbstrom, A. Molinder, International Journal of Production Economics 35 (1994) 289–311.). In our paper the problem is formulated as a non-constant sum game, which is the case of the total market area being constant and the conditions for lower central places, described for different positions of this central place in an urban hierarchy, in the case of two-level production. Differential games are suggested when the total market area changes over the time.

The influence of magnesium stearate on the characteristics of mucoadhesive microspheres.

Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, xray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differentialMicrospheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, x-ray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential scanning calorimetry. No differences were observed in the physical state of pipemidic acid and in microsphere shape and surface between different size fractions of microspheres, prepared with different amounts of magnesium stearate. Additionally, no correlation between the physical state of the drug in different microspheres and their biopharmaceutical properties was found.