Fritz Nimmerfall

Significance of the goblet-cell mucin layer, the outermost luminal barrier to passage through the gut wall

Abstract The decisive luminal barrier to the passage of a compound through the gut wall would appear to be the mucin secreted by goblet-cells. The absorption of compounds of different chemical structures, measured in animal experiments, is directly proportional to diffusion through isolated goblet-cell mucin and inversely proportional to retention in the mucin and, with reservation also to molecular weight. The dependence of diffusion through and retention by the mucin on pH and ionic strength are discussed with reference to changes in the electrical charge and structure of the mucus and its ability to form hydrogen bridges.

Poly(ethylene carbonate)s, part I : Syntheses and structural effects on biodegradation

Poly(ethylene carbonate)s (PECs) of different molecular weights (Mws) were synthesized by copolymerization of CO2 and ethylene oxide using different catalyst systems. Et2Zn/ethylene glycol was found to be exceptionally effective as a catalyst for this copolymerization. PECs synthesized using this catalyst were characterized by very high ethylene carbonate content, low polydispersity and high glass transition temperatures. The in vivo biodegradability of PECs was found to be affected by the content of ether functions in the polymer chain, by the Mw of the products and by the catalyst used to prepare them. Surprisingly, the biodegradation of PECs having Mws 130 000 show almost identical in vivo biodegradation by surface erosion.

Poly(ethylene carbonate)s, part II: degradation mechanisms and parenteral delivery of bioactive agents.

The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated in vitro and in rats and rabbits. PEC was found to be specifically degraded in vivo and in vitro by superoxide radical anions O2-*, which are, in vivo, mostly produced by inflammatory cells. No degradation of PEC was observed in the presence of hydrolases, serum or blood. PEC is biodegraded by surface erosion without significant change in the molecular weight of the residual polymer mass. The non-hydrolytic biodegradation by cells producing O2-* is unique among the polymers used as biodegradable drug carriers. The main degradation product of PEC in aqueous systems is ethylene glycol, formed presumably by hydrolysis of ethylene carbonate. The splitting off of a five-membered ring structure from the polymer chain indicates a chain reaction mechanism for the biodegradation. PEC is a suitable drug carrier, particularly for labile drugs. Using human interleukin-3 and octreotide as model drugs, surface erosion of the PEC formulations was indicated by a 1:1 correlation between drug release and polymer mass loss.

Nonparametric analysis of the absorption profile of octreotide in rabbits from long-acting release formulation OncoLAR

Octreotide (octreotide-acetate, Sandostatin(R)) is a somatostatin analogue, used in long-term treatment of acromegaly. The present study describes the absorption profile in rabbits of octreotide after release from the long-acting formulation OncoLAR (denoted as octreotide-LAR). In a first experiment, the disposition kinetics of octreotide was studied for 24 h in six rabbits after intravenous (i. v.) injection of 0.025 mg of a solution of octreotide. In a second experiment, release kinetics was studied in eight rabbits for 49 days after an i.m. injection of 5 mg/kg of octreotide-LAR. Concentrations were determined by radioimmunoassay. After i.v. injection of octreotide, one- and two-compartment models were compared for each rabbit. A typical disposition profile was computed using the mean parameters. After i.m. injection of octreotide-LAR, deconvolution was performed using the point-area method. Individual absorption profiles were characterised using natural splines. The number of breakpoints was selected using the generalised cross-validation criterion. The two compartment model was selected based on the i.v. study. After i.m. administration, octreotide exhibited a triphasic absorption profile, with large interindividual variability. A transient peak followed the initial burst phase. The third phase covered 85% of total drug released. The approach allows a model-independent description of the in vivo absorption profile of octreotide-LAR.

Modified release of drug: a way to its quantification

Abstract Modified release of drug from a delivery system may be quantified by determining the area deviation of an experimental curve from a standard curve; the latter being the transformation of the individual experimental plasma concentration-time profile to a rectangle of equal area (internal standard) or the plasma concentration-time curve required for adequate effect (external standard). The advantage of this method is the precise characterization of the plasma drug profile over any required time interval. Taking an injectable controlled release drug formulation with bromocriptine (= 2-bromo- α -ergokryptine) as an example, it has been shown how controlled release from such delivery system can be quantified satisfactorily.

Modeling the kinetics of release of octreotide from long‐acting formulations injected intramuscularly in rabbits

Long-acting repeatable formulations (LAR) based on polymeric microspheres were manufactured to deliver octreotide, an octapeptide analogue used in acromegaly. We developed a model to describe the complex triphasic concentration versus time profile observed in rabbits after intramuscular (i.m.) injection of these LAR formulations. A 5-mg x kg(-1) dose of octreotide in a reference LAR formulation was given im to eight rabbits; two groups of four rabbits each received a different formulation. In each animal, 26 blood samples were taken over 49 days. Concentrations of octreotide were assayed by radioimmunoassay. A model describing the concentration profile was developed. Octreotide release was described using the succession of an exponential model, a semiempirical non-Fickian model, and a delayed Weibull model. Parameters were estimated using nonlinear regression, first for the eight rabbits that received the reference formulation and then for the other eight animals. The model provides an adequate description of the concentration versus time profile for the three formulations. For the reference phase, erosion accounted for 87% of total drug release. The formulation encapsulating an octreotide-acetate complex showed a prolonged diffusion phase.