Alfred Fahr

Sustained-release injectables formed in situ and their potential use for veterinary products.

The controlled drug delivery of hydrophilic and lipophilic drug substances via the parenteral route has gained increasing importance in the development of pharmaceutical dosage forms. In particular, the animal health industry has generated strong interest in long-term drug delivery for both companion and farm animals during the past few years. At present sustained-release injectables formed in situ for s.c./i.m. administration have become an attractive alternative to common slow release technologies such as microspheres or standard implants. In this context, technologies based on PLA/PLGA, sucrose acetate isobutyrate (SAIB) and the amphipathic molecules Poloxamer, glycerol monooleate or PEG-PLA-PEG copolymers, are discussed. Release periods from hours to months can be obtained by choosing one of these drug delivery technologies. The release times are strongly dependent on the biodegradation of the polymers and the physico-chemical properties of the drug substance used. Furthermore, the use of different solvents for the matrix-forming agents and the individual loading capacity are critically assessed. Additionally acceptance of the excipients for parenteral use by the regulatory authorities is closely considered. Scientific articles as well as patent publications are reviewed to give a wide overview of the existing approaches and their future potential for animal health products.

Improvement of intestinal peptide absorption by a synthetic bile acid derivative, cholylsarcosine

The potential of the nontoxic bile salt derivative, cholylsarcosine, to enhance the intestinal absorption of peptides was investigated in vitro and in situ. The permeation of the two model peptides octreotide and vasopressin-[arg(8)CT>/=CS, whereas ursodeoxycholic acid exhibited no absorption enhancement. Determination of the cytotoxic potential of the bile salts revealed the same rank order. In rats, octreotide and desmopressin were absorbed from the gastrointestinal-tract with moderate absorption efficiency. Coadministration of bile salts resulted in an increased absorption efficiency. The effect of CS was similar to that of CT. In conclusion, CS shows absorption enhancement properties and a relatively low cytotoxicity. It offers an alternative as absorption enhancer as compared to conventional bile acids which may have a potential cocarcinogenic risk.

P-glycoprotein- and mrp2-mediated octreotide transport in renal proximal tubule.

Transepithelial transport of a fluorescent derivative of octreotide (NBD‐octreotide) was studied in freshly isolated, functionally intact renal proximal tubules from killifish (Fundulus heteroclitus). Drug accumulation in the tubular lumen was visualized by means of confocal microscopy and was measured by image analysis. Secretion of NBD‐octreotide into the tubular lumen was demonstrated and exhibited the all characteristics of specific and energy‐dependent transport. Steady state luminal fluorescence averaged about five times cellular fluorescence and was reduced to cellular levels when metabolism was inhibited by NaCN. NBD‐octreotide secretion was inhibited in a concentration‐dependent manner by unlabelled octreotide, verapamil and leukotriene C4 (LTC4). Conversely, unlabelled octreotide reduced in a concentration dependent manner the p‐glycoprotein (Pgp)‐mediated secretion of a fluorescent cyclosporin A derivative (NBDL‐CS) and the mrp2‐mediated secretion of fluorescein methotrexate (FL‐MTX). This inhibition was not due to impaired metabolism or toxicity since octreotide had no influence on the active transport of fluorescein (FL), a substrate for the classical renal organic anion transport system. The data are consistent with octreotide being transported across the brush border membrane of proximal kidney tubules by both Pgp and mrp2.

Permeation enhancement of octreotide by specific bile salts in rats and human subjects: in vitro, in vivo correlations.

1 The potential of bile salts to improve the enteral absorption of octreotide, an orally active somatostatin analogue, was investigated by a combination of in vitro, in situ and in vivo experiments. 2 Incorporation of octreotide into lipid monolayers (as measured by area increase of the monolayer at constant surface pressure using a Langmuir‐Blodgett trough set‐up) depended on the type of bile salt used for monolayer pre‐treatment. Addition of 20 μm octreotide to the subphase containing 20 μm of the dihydroxylated bile salt ursodeoxycholate (UDCA) causes a 9% increase in area, whereas addition of octreotide to the subphase containing the 7α‐enantiomer of UDCA, chenodeoxycholate (CDCA), resulted in an area increase of the lipid monolayer of 20%. Area increase by octreotide alone was not significantly different from the increase of octreotide and UDCA in combination. 3 CDCA and UDCA in combination with octreotide increased the permeability of liposomal membranes for rubidium ions, whereas octreotide alone did not significantly change the permeability. This indicates membrane distortion as a possible cause for the enhanced absorption of octreotide by bile salts. 4 In polarized Caco‐2 cell monolayers octreotide exhibited a permeation coefficient of 0.008 ± 0.004 cm h−1. Addition of 0.2 − 1% of UDCA to the apical incubation medium had no significant effect upon the permeation coefficient. In contrast, 0.2 − 1% CDCA in the incubation medium resulted in a significant increase (P < 0.05) of the monolayer permeability of octreotide (0.015 − 0.037 cm h−1). 5 Octreotide was absorbed as the intact peptide from the gastrointestinal tract in rats with an absorption efficiency of 0.26%. Coadministration of bile salt resulted in a dose‐dependent increase in absorption efficiency of the peptide up to 20.2%. The observed effect was more pronounced for CDCA than for UDCA. 6 The effect of CDCA and UDCA on octreotide absorption in vivo was assessed in a pharmacokinetic study with healthy volunteers. After oral administration of 4 mg octreotide in the presence of 100 mg bile salt, an average bioavailability of the peptide of 1.26% was achieved in the presence of CDCA, whereas in the presence of UDCA a bioavailability of only 0.13% was reached. This difference was statistically significant (P < 0.01). 7 In conclusion, the co‐administration of CDCA is able to enhance the enteral absorption of octreotide. The in vitro and in situ experiments were predictive for the observed effect in human subjects.

Liposomal Formulations of Cyclosporin A: Influence of Lipid Type and Dose on Pharmacokinetics

AbstractPurpose. Liposomal formulations of Cyclosporin A (CyA)3 have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics.nMethods. A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood.nResults. Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood.nConclusions. These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.