Oil-in water-emulsion gels: determination and mathematical treatment of flow properties.

Flow properties of oil-in-water (o/w)-emulsion gels are determined for two experimental designs using common Searle-type rotating viscometers. Samples were characterized after preparation as well as real time and stress stability testing. Model emulsions contained Newtonian oil phases and cross-linked acrylic acid polymers and carboxymethylcellulose sodium as aqueous thickener. Varying two factors, concentration of gelling agent in the aqueous phase and amount of phase fraction phi, a series of formulations was obtained ranging from liquid o/w-lotions to semi-solid o/w-emulsion gels. Robust data evaluation is done applying Herschel, Bulkley, Van-Wazer (HBW) power law function and determination of rheological area under the curve (AUC) parameters. Factors were calculated by means of a power law function and a modified Taylor-series. Second order multiple regression and the method of Kriging were applied to describe summarized response surfaces. O/w-emulsion gels are (pseudo)plastics without rheotropic effects. Flow properties can be assessed by choosing an appropriate concentration and type of gelling agent. The influence of the Newtonian oil phase vanishes in a dominant thickened aqueous phase. Consistency of liquid o/w-lotions on the other hand is primarily controlled by phi.

Determination of (pseudo)plastic flow properties of pharmaceutical semisolids using rheological AUC parameters.

The purpose of this study was to develop a simple and unique method of data reduction for pharmaceutical semisolids. Application and accuracy of different regression models for rate-controlled rotating cylinder and T-shaped spindle data was compared in a conventional analysis of variance. Methods employed to determine area under the flow curve (AUC) parameters included integration of fitting function, planimetration, and calculation of trapezoids. Complex rheological behavior such as structure breakdown at low rates of shear (D) and deflocculation of particle aggregates at high values for D is not sufficiently described by conventional fitting functions. Iterating the nonlinear power law function tau = tau 0 + k2. Dn0, however, gives the best fit of data for pharmaceutical samples, estimating a yield value, tau 0.1 calculated for D = 0.1 s-1 following double logarithmic transformation. Alternatively, rheological AUC parameters are determined for D: 0 < or = D < or = 98 s-1. Validating models, maximum deviation for different methods of determination is smaller than Srel of 5 consecutive planimetration experiments. In case of sufficient fit of experimental data, integration of a nonlinear power law function is acceptable. Convenient fitting parameters tau and n0 can be substituted by area parameters such as AT, Arel, or R for all liquids, and hydrophilic and lipophilic gels, as well as o/w and w/o emulsions being investigated. The new AUC method offers robust data reduction and universal pharmaceutical application for different Newtonian and (pseudo)plastic materials. The approach is, however, limited to instrumental conditions and the range of D.

Micellization and solubilization behavior of sucrose laurate, a new pharmaceutical excipient.

The micellization and solubilization properties of sucrose laurate have been investigated. Solubilization experiments showed that numerous poorly water-soluble drug substances could be solubilized by aqueous sucrose laurate solutions; the solubilization was uncomplicated and the maximum solubilizate concentration was high. Laser light scattering investigations proved that solutions containing pure sucrose monolaurate formed spheroidally shaped micelles with a hydrodynamic radius of 29.2 A, which behaved like ideal particles, showing no solute-solute interactions. Surprisingly, the hydrodynamic radii of the sucrose monolaurate micelles were hardly changed by the introduction of 0.20% cyclosporin-A. The addition of sucrose dilaurate, the main impurity of the sucrose laurate product, however, resulted in large and polydisperse structures. Considering the critical packing parameters, the light scattering results could be explained by assuming a transformation of the spherical micelle into a disk with rounded edge.

Bubble bed reactor: A reactor design to minimize the damage of bubble aeration on animal cells.

A new bubble aeration system was designed to minimize cell killing and cellular damage due to sparging. The residence time of the bubbles in the developed bubble bed reactor was prolonged dramatically by floating them in a countercurrent produced by an impeller. The performance of the new reactor bubble aeration system, implemented in a laboratory reactor, was tested in dynamic aeration experiments with an without cells. An efficiency up to 95% in oxygen transfer could be achieved, which enables a much lower gas flow rate compared with conventional bubble aeration reactors. The low gas flow rate is important to keep cell damage by bubbles as low as possible. A laser light sheet technique used to find the optimal flow pattern in the reactor. The specific power dissipation of the impeller is a good measure to predict cell damage in a turbulent flow. Typical values for the power dissipation measured in the bubble bed reactor were in the range of 0.002 to 0.013 W/kg, which is far below the critical limit for animal cells. The growth of a hybridoma cell line was studied in cell cultivation experiments. A protein-free medium without supplements such as serum or Pluronic F68 was used to exclude any effect of cell-protecting factors, No difference in the specific growth rate and the yield of the antibodies was observed in cell grown in the bubble free surface aeration in the spinner flask. In contrast to the spinner flask, however, the bubble bed reactor design could be scaled up. (c) 1994 John Wiley & Sons, Inc.

Interactions between animal cells and gas bubbles: The influence of serum and pluronic F68 on the physical properties of the bubble surface.

We describe a method by which the degree of bubble saturation can be determined by measuring the velocity of single bubbles at different heights from the bubble source in pure water containing increasing concentrations of surfactants. The highest rising velocities were measured in pure water. Addition of surfactants caused a concentration-dependent and height-dependent decrease in bubble velocity; thus, bubbles are covered with surfactants as they rise, and the distance traveled until saturation is reached decreases with increased concentration of surfactant. Pluronic F68 is a potent effector of bubble saturation, 500 times more active than serum. At Pluronic F68 concentrations of 0.1% (w/v), bubbles are saturated essentially at their source. The effect of bubble saturation on the interactions between animal cells and gas bubbles was investigated by using light microscopy and a micromanipulator. In the absence of surfactants, bubbles had a killing effect on cells; hybridoma cells and Chinese hamster ovary (CHO) cells were ruptured when coming into contact with a bubble. Bubbles only partially covered by surfactants adsorbed the cells. The adsorbed cells were not damaged and they also could survive subsequent detachment. Saturated bubbles, on the other hand, did not show any interactions with cells. It is concluded that the protective effect of serum and Pluronic F68 in sparged cultivation systems is based on covering the medium-bubble interface with surfaceactive components and that cell death occurs either after contact of cells with an uncovered bubble or by adsorption of cells through partially saturated bubbles and subsequent transport of cells into the foam region. (c) 1994 John Wiley & Sons, Inc.

[Mucus models for investigation of intestinal absorption mechanisms. 4. Comparison of mucus models with absorption models in vivo and in situ for prediction of intestinal drug absorption]. / Muscusmodelle zur Untersuchung von intestinalen Absorptionsmechanismen. 4. Mitteilung: Vergleich des Mucusmodells mit Absorptionsmodellen in vivo and in situ zur Vorhersage intestinaler Wirkstoffabsorption.

Intestinal absorption with an in vitro model using pig intestinal mucus was examined by means of in vivo and in situ experiments in the rat. With 10 compounds of different structure, in vitro, in situ, and in vivo models were tested. The in vitro model in the present form can only simulate the first step of intestinal absorption, namely diffusion through the mucus layer. Indeed, we found that one function of the intestinal mucus can be described being a molecular sieve with a molecular mass (MM) cut off within the range of about 600 to 700 [g/mol]. Absorption of substances with higher molecular mass remains at a low level. With the mucus model prediction of intestinal absorption of hydrophilic substances with MM < 600 to 700 [g/mol] will be possible, if the mass transport in the mucus layer is rate limiting. Independent of polarity, it is also valid for substances of MM > 600 to 700 [g/mol]. Estimation however, is not valid for lipophilic substances and MM < 600 to 700 [g/mol], when mass transport from the mucus to the adjacent compartments is rate limiting. Further optimization of the mucus model for a more extensive application seems possible and reasonable with respect to saving in vivo experiments with animals.

[Mucus models for investigation of intestinal absorption mechanisms. 3. A mathematical simulation model of drug diffusion through enteral mucus]. / Mucusmodelle zur Untersuchung von intestinalen Absorptionsmechanismen. 3. Mitteilung: Ein mathematisches Simulationsmodell der Wirkstoffdiffusion durch enteralen Mucus.

The diffusion of drug substance in a closed three-compartment model through a mucus layer to equilibrium is simulated by available pharmacokinetic programs. The obtained curves conform very well to the values experimentally found. If mucus is replaced by buffer solution an explicit equation from the literature, the method used and the experimental findings give the same results. Examination of the rate constants k1 for the diffusion in, kD through and k2 from the mucus shows the significance of the relation k1/k2 > 1, = 1, < 1 as a measure for the affinity of the active agent to the mucus. The discussion of the kinetic parameters shows, as in previous results, no criterion for assuming specific mucus binding. Because of its unspecifity the usual term "mucus binding" should be replaced by "mucus retention".

[Mucus models for investigation of intestinal absorption mechanisms. 2. Mechanisms of drug interactions with intestinal mucus]. / Mucusmodelle zur Untersuchung von intestinalen Absorptions-mechanismen. 2. Mitteilung: Mechanismen der Wechselwirkung von Wirkstoffen mit Intestinalmucus.

Using in vitro models previously described [1] mucus retention and mucus diffusion of polar and non-polar drugs were measured. It could be shown that drug interaction with pig intestinal mucus was based on non-specific binding. The pH-dependence of retention by mucus does not confirm electrostatic interaction of drugs with mucus but favour drug distribution to hydrophobic areas within the mucus. High lipophilicity and retention by mucus correlate with low diffusion of drugs through mucus.

Heat sterilization of bioindicators in propylene glycol and propylene glycol-water mixtures: arrhenius equation, thermodynamic data, and Z values.

Our interest in calculating the thermodynamic data by means of the Arrhenius equation was based on two observation: (a) the thermal death time increases considerably when the bioindicators Bacillus subtilis var. niger and Bacillus stearothermophilus are sterilized in nonaqueous hydrophilic solutions as found in propylene glycol (PG) with low water concentrations; and (b) the inactivation kinetics of Bac. stearothermophilus does not follow a first-order reaction. The frequency factor A and the entropy of activation delta S* have the highest values in water and the lowest value in PG; delta S* for Bac. stearothermophilus in water is 812 J/mol K; however, in PG it is -9.6 J/mol K. A good correlation between delta S* and the enthalpy delta H* is found, indicating possible protein denaturation during thermal inactivation. The moderate positive and negative delta S* values in PG and PG with low water concentrations might be explained by (a) rigid conformation of proteins due to stabilization and (b) slow reaction, making the complex a less probable structure, when the activated complex is built only under considerable rearrangement of the structure of the reactant molecules. The opposite was observed with the Z and Z* values, the latter being defined as Z values of nonlogarithmic survival curves. The Z values increase with increasing concentrations of PG, i.e., for Bac. subtilis of Z = 8 degrees C in water up to Z = 23 degrees C in PG and for Bac. stearothermophilus of Z = 6 degrees C up to Z* = 27 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Solid surfactant solutions of active ingredients in sugar esters.

This paper describes the preparation of solid solutions of ciclosporin as model solubilizate in water-soluble sugar esters, which are solid, biodegradable, and nontoxic surfactants. Sugar esters were found to be excellent solubilizers for poorly water-soluble drugs such as ciclosporin. Such systems are suitable for the preparation of solid dosage forms for the purpose of oral administration. Addition of water to the solid solutions yields clear solutions of the solubilizate.

In vitro model for ciclosporin intestinal absorption in lipid vehicles.

The influence of lipid vehicles on the intestinal absorption of Ciclosporin was studied in vitro. The effect of the intestinal lipid digestion was considered on the partition of the drug from olive oil or middle-chain triglyceride (MCT) into phases of simulated intestinal content. The phases obtained after ultracentrifugation were analyzed for their Ciclosporin content and characterized for their lipid classes. For both lipid vehicles the presence of lipolysis products did not promote the partition of the drug into the aqueous phase. The absorption in vivo was not related to the drug amount in the aqueous phase and in the oil phase. Therefore, phase quantification in vitro cannot simulate the dynamics of in vivo absorption events following application of a poorly water-soluble drug in a lipid vehicle.

In vivo model for ciclosporin intestinal absorption in lipid vehicles.

The influence of lipid vehicles on the intestinal absorption of Ciclosporin was studied in vivo. The model takes into account the effect of the intestinal lipid digestion on the absorption after intraduodenal administration of [3H]Ciclosporin in olive oil or middle-chain triglyceride (MCT) to the bile duct-cannulated rat. Digested vehicles significantly promoted the absorption compared to nondigested vehicles. In the nondigested state, olive oil was a significantly better vehicle than MCT, whereas the difference between both lipids was only a trend in the digested state. Further studies with variants of this in vivo model should determine the influence of abnormalities of fat digestion and absorption on the pharmacokinetics and pharmacodynamics of a drug with a low therapeutical index.

Tissue tolerance of intramuscular injectables and plasma enzyme activities in rats.

The local tissue damage after intramuscular injection caused by various commercially available injection solutions was determined in the albino rat, by measuring plasma activities of creatine phosphokinase, aspartate aminotransferase, and lactic dehydrogenase, the tissue activity of creatine phosphokinase, and macroscopic changes in the muscle at the injection site (gastrocnemius muscle). The plasma enzyme activities were determined 2, 6, 18, and 28 hr after the injection. After 28 hr the animals were sacrificed for macroscopic inspection of the injection site and for the determination of tissue enzyme activity. The tissue injury caused by the test substances correlated well with the elevated creatine phosphokinase activity (2 hr). The elevations of aspartate aminotransferase (18 hr) and lactate dehydrogenase (2 hr) activity as well as the loss of tissue creatine phosphokinase activity were less indicative of differences between test preparations. The i.p. administration of some of the test preparations caused increased enzyme activity without muscle damage, which could interfere with the test results. The creatine phosphokinase determination indicates the damage occurring immediately after the administration of the test solution, and the macroscopic inspection offers the possibility to obtain some information on the evolution of the muscular lesion.