Contribution to the rheological testing of pharmaceutical semisolids.

Rheological behaviour of pharmaceutical semisolid preparations significantly affects manufacturing process, administration, stability, homogeneity of incorporated drug, accuracy of dosing, adhesion in the place of application, drug release, and resulting therapeutic effect of the product. We performed test of consistency by penetrometry, rotational, oscillation and creep tests, and squeeze and tack tests of model samples to introduce methods suitable for characterization and comparison of semisolids in practice. Penetrometry is a simple method allowing sorting the semisolids to low and high stress-resistant materials but deficient for rheological characterization of semisolids. Value of yield stress, generally considered to be appropriate feature of semisolids, is significantly influenced by the method of testing and the way of evaluation. The hysteresis loops of model semisolids revealed incomplete thixotropy, therefore, three-step thixotropy test was employed. Semisolids showed nonlinear response in the creep phase of tests and partial recovery of structure by storing energy in the recovery phase. Squeeze and tack tests seem to be convenient ways for comparison of semisolids. Our study can contribute to a better understanding of different flow behaviour of semisolids given by different physicochemical properties of excipients and can bring useful approaches to evaluation and comparison of semisolids in practice.

[Measurement of adhesive properties of polymers in vitro]. / Merení adhezivních vlastností polymeru in vitro.

Adhesive force of branched oligoesters under the in vitro conditions was studied by measuring the maximal force necessary to separate the tested sample from the base (F(max)) under different testing conditions. Branched oligoesters were synthesized from lactic and glycolic acids in the molar ratio 1:1, and from mannitol or dipentaery thritol as the branching components in concentrations of 3%, 5% or 8%. To decrease viscosity and thus to facilitate the workability and administration, triethyl citrate (TEC) in a concentration of 30% was employed. Polymeric systems for adhesive force measurements were prepared by melting oligoesters in a micro oven and by homogenization with TEC. Adhesive force was measured on a material testing device T1-FR050TH.A1K Zwick/Roell at the set rate of separation 10 mm/min or 100 mm/min, contact force 10 N or 20 N, and a period of contact of the sample with the base of 5 s or 10 s. The adhesive force of branched oligoesters was found to be significantly higher than the adhesive force of gelatine gels, methylcellulose, carmelose sodium salt or sodium carbomer salt. Dipentaerythritol-branched oligoesters exerted higher adhesive force than mannitol-branched oligoesters. The value of adhesive force was increased with growing concentration of the branching component in the oligoester. Of the experimental parameters tested, a statistically significant influence of the separation rate of the sample from the base on the magnitude of F(max) was observed. The influence of different periods of contacts was manifested only in some samples, and the influence of different contact forces on F(max) value was not demonstrated in any sample.

Albendazole repeated administration induces cytochromes P4501A and accelerates albendazole deactivation in mouflon (Ovis musimon).

Adult mouflon ewes (Ovis musimon) were treated repeatedly with therapeutic doses of albendazole (ABZ, p.o. 7.5 mg/kg of body weight/day, for five consecutive days). Animals (treated or control) were sacrificed 24 h after the fifth dose of ABZ and liver and small intestine were collected to prepare microsomes. The activities of several biotransformation enzymes were measured in both hepatic and intestinal microsomes. A significant increase in the activity and amount of cytochromes P4501A (CYP1A) was observed in both tissues of ABZ treated mouflons compared to control animals. No other biotransformation enzymes tested were affected by five ABZ doses. The in vitro biotransformation of ABZ was studied in hepatic and intestinal microsomes from ABZ treated and control mouflons. Concentrations of two main ABZ metabolites - pharmacologically active ABZ sulfoxide and pharmacologically inactive ABZ sulfone were analysed using HPLC. A significant increase in rate of formation of ABZ sulfone (which is catalysed by CYP1A) was observed in hepatic as well as in intestinal microsomes from ABZ treated animals. The enhancement of ABZ deactivation by its repeated administration may affect the anthelmintic efficacy of this drug and may contribute to the development of parasite resistance.

[Effect of sodium chloride on elasticity of silicone matrices]. / Vliv chloridu sodného na elastické chování silikonových matic.

An increase in the availability of the active ingredient from silicone matrices can be achieved by using sodium chloride as the filler. An addition of sodium chloride also influences the mechanical properties of silicone systems. The temperature dependence of real Young's model E' of addition silicone systems with sodium chloride was measured. With increasing NaCl concentration in the silicone system, the values of Young's module E are increased. The increase is also influenced by the particle size of NaCl. The values of the module are moderately increased also with increasing temperature, which corresponds to the kinetic theory of caoutchouc elasticity. A significant increase in E takes place at NaCl concentrations higher than 20%. With a 50% NaCl content in the system, E is increased approximately 3.5 times in comparison with an unfilled sample. Various theories of elastic behaviour of composites can be employed for the description of the effect of the filler on the mechanical properties of silicone systems under small deformations. The effect of chloride is best described by the relation proposed by Nielsen. The value of the constant A in Nielsen's relation, dependent on the shape of the filler particles and Poisson's constant of the unfilled matrix, decreases with increasing particle size. With a change in particle size, a certain change in particle shape takes place. Hydrodynamic theory provides good results for sodium chloride particle size of 102.5 microns, but for particle sizes of 20 microns and 60 microns it is less successful than Nielsen's relation.

[Effect of fillers on the strength of silicone systems]. / Vliv plniv na pevnostní chování silikonových systému.

The present paper examines the strength behaviour of addition silicone systems composed of Lukopren A 6200 and three inorganic fillers (Skron SF 600, Cab-O-Sil LM 150, sodium chloride) in different concentrations and particle sizes. The tensile strength sigma (MPa) and the relative lengthening of samples on rupture epsilon (%) were measured. With increasing concentration of the filler in the system relative lengthening of matrices is decreased. This trend corresponds with the theoretical hypotheses and it is understandable also with regard to the fact that the filler, in comparison with silicone rubber, possesses very low ductility. An addition of Sikron increases tensile strength of samples. Dependence of tensile strength on the amount of Sikron in the system is linear. This behaviour is typical of fibrous composites and the composites with high adhesion between the filler and matrix. Concentrations of Cab-O-Sil up to 5% did not exert an effect on tensile strength. An important increase in strength was shown only by the systems containing 10% of Cab-O-Sil. Experimental dependence of tensile strength on the amount of Cab-O-Sil in the system can be described by the equation for composites with Hookean behaviour till destruction. The effect of sodium chloride on tensile strength is more complicated. In the systems with NaCl particles of 20 microns, strength is not practically changed up to a content of 40% of NaCl in the system. In larger size fractions, tensile strength is decreased, and with a change in particle size, shape is probably changed as well.