Optimization of placebos for double-blind clinical trials. Experience with a phytopharmaceutical.

The maintenance of double-blind conditions in placebo-controlled trials depends on the quality of the placebo preparation. The placebo should match the active substance-containing preparation as closely as possible, but it must not contain any substances that might themselves be pharmacologically active. Active substances characterized by a particular colour, taste, smell or other easily perceptible properties constitute a challenge to researchers. The way of developing a placebo that matches a phytopharmaceutical to a satisfactory extent is described and discussed.

Transport and metabolic pathway of thymocartin (TP4) in excised bovine nasal mucosa.

Thymocartin (TP4, Arg-Lys-Asp-Val) is the 32-35 fragment of the naturally occurring thymic factor (thymopoietin). Here studies on the nasal transport and metabolism of TP4 were performed. Freshly excised bovine nasal mucosa was taken as a model membrane. For permeation studies typical donor-receiver experiments (side-by-side) and finite-dose experiments with small volumes of highly concentrated solutions were carried out. The metabolic pathway of TP4 in nasal mucosa was found to occur according to a typical aminopeptidase cleavage pattern, stepwise forming Lys-Asp-Val and Asp-Val. TP4 metabolism experiments under reflection kinetics showed a saturation profile above 0.5 mumol mL-1. A non-linear kinetic model consisting of three steps in sequence was sufficient to describe the kinetics: for the first step saturable Michaelis-Meat kinetics, and for the second and the third step first-order kinetics were assured. The model was capable of simultaneously fitting the data for the full range of initial concentrations from 0.1 up to 1.0 mumol mL-1. Saturation kinetics was also found to be the prominent feature of the permeation experiments performed. In the lower concentration range (< 0.4 mumol mL-1), transport of TP4 across nasal mucosa was controlled by metabolism, in the higher concentration range (> 0.85 mumol mL-1) diffusion control became more important. We conclude that enhancement of absorption can be achieved when nasal aminopeptidases are saturated, e.g. at high TP4 concentrations.

[Pharmaokinetics of beta-escin after administration of various Aesculus extract containing formulations]. / Pharmakokinetik von beta-Aescin nach Gabe verschiedener Aesculus-Extrakt enthaltender Formulierungen.

With a specific radioimmunoassay the pharmacokinetics and relative bioavailability of escin was measured after administration of different formulations containing Aesculus-extract. Of special interest was the relative bioavailability of escin after administration of a newly developed film-coated tablet with sustained release in comparison to a reference formulation. In a cross-over steady-state study in 24 volunteers bioequivalence of test and reference preparation could be demonstrated. The 90% confidence interval of the AUC (O-tau) was 98.3 to 120.9%.

Enzymatic cleavage of thymopoietin oligopeptides by pancreatic and intestinal brush-border enzymes.

The intestinal enzymatic degradation of the immunomodulating peptides thymotrinan (TP3), thymocartin (TP4), and thymopentin (TP5), three oligopeptides derived from the naturally occurring thymus hormone thymopoietin, was investigated to evaluate their potential for peroral drug delivery. In the presence of brush-border membrane vesicles, crude pancreas extract and everted rings from duodenum, jejunum, ileum, and colon, all peptides were shown to be degraded both by pancreatic enzymes and brush-border aminopeptidases. Degradation clearances (Cldeg) of TP3, TP4, and TP5 were calculated for a quantitative comparison of peptide stability. In the presence of crude pancreas extract, there was a rapid degradation of TP5 (Cldeg 17.9 ml/min) in comparison with TP3 and TP4 (Cldeg 0.95 and 0.56 ml/min, respectively, at 0.2 mM peptide concentration) caused by the cleavage of the C-terminal tyrosine by carboxypeptidase A, whereas TP3 and TP4 underwent hydrolysis by aminopeptidase N. In the presence of brush-border membrane vesicles, the degradation clearances were 3.9, 3.1, and 2.4 ml/min at 0.2 mM concentrations of TP4, TP5, and TP3, respectively. The clearance of all peptides was lowered with increasing peptide concentrations, indicating saturable degradation processes. The degradation of the thymopoietin oligopeptides in the presence of brush-border membrane enzymes was exclusively catalyzed by aminopeptidase N. The degradation of all peptides was highly dependent on the intestinal segment, with the lowest degradation clearance observed in the colon.

[The solubility kinetics of enteric-resistant tablets using riboflavin test tablets. 6. Pharmaceutic-technologic and analytic studies on gastric juice-resistant dosage forms]. / Untersuchung der Freisetzungskinetik magensaftresistenter Uberzüge in vivo mit Hilfe einer Riboflavin-Testtablette. 6. Mitteilung: Pharmazeutisch-technologische und analytische Untersuchungen an magensaftresistenten Darreichungsformen.

To examine the dissolution kinetics of enteric coatings in vivo a test system with riboflavine was developed. This system allows to realize the beginning of disintegration in the small gut because riboflavine is excreted in urine already within 1 h after ingestion, and to locate the area of dissolution of the tablet in vivo, because riboflavine absorption is reduced in the great gut and colon. Thus the test system allows to examine and improve coating compositions in vivo and to demonstrate changes of drug dissolution in vivo conditioned by storage of enteric coated pharmaceuticals.

[Resistance and disintegration behavior of gastric juice-resistant drug products. 3. Pharmaceutical-technological and analytical studies of gastric juice-resistant commercial preparations]. / Resistenz- und Zerfallsverhalten magensaftresistenter Fertigarzneimittel. 3. Mitteilung: Pharmazeutisch-technologische und analytische Untersuchungen an magensaftresisten ten Darreichungsformen.

Enteric coated commercial dosage forms often do not correspond with acid resistance and disintegration requirements of the Ph. Eur. About 15-20% of 181 tested samples disintegrate during acid resistance test or do not disintegrate in buffer solution pH = 6.8. The percentage was extremely high amongst enteric coated pancreatin or cardiac glycosides (about 30%) preparations. Storage conditions and time influence acid resistance and disintegration time. 80% of 34 products coated with celluloseacetate phthalate, hydroxypropylmethylcellulose phthalate or polymethacrylic acid ester did not change disintegration time after 2 years storage at 20 degrees C. After storage at 40 degrees C the number decreased to 40%. After 5 years at 20 degrees C number of products which were not stable increased.