Impact of octreotide counterion nature on the long-term stability and release kinetics from an in situ forming depot technology.

The generation of acylated impurities has represented an important hurdle in the development of long acting injectables for therapeutic peptides using biocompatible polymers with a polyester moiety. We investigated here an in situ forming depot (ISFD) technology that uses polyethylene glycol - polyester copolymers and a solvent exchange mechanism to promote depot formation. This technology has shown promise in formulating small molecules as well as therapeutic proteins. In the present work, using the well-known somatostatin analog octreotide acetate (OctAc) as a model molecule, we evaluated this delivery platform to release therapeutic peptides. Peptide acylation was found to be pronounced in the formulation, while it was very limited once the depot was formed and during the release process. The octreotide acylation pattern was fully characterized by LC-MS/MS. Moreover, it was demonstrated that exchanging the acetate anion with more hydrophobic counterions like pamoate or lauryl sulfate allowed to greatly improve the peptide stability profile, as well as the formulation release performance. Finally, the in vivo evaluation through pharmacokinetics studies in rat of these new octreotide salts in ISFD formulations showed that octreotide was quantifiable up to four weeks post-administration with a high bioavailability and an acceptable initial burst.

Diurnal variations in personal care products in seawater and mussels at three Mediterranean coastal sites.

The presence of personal care products (PCPs) in the marine environment is of major concern. PCPs, UV filters, and musks can enter the marine environment indirectly through wastewater or directly via recreational activities. We conducted this study to document patterns in the occurrence of seven PCPs at three coastal sites impacted by recreational activities during 1 day. The study focused on diurnal variations in these seven PCPs in seawater and indigenous mussels. In seawater, UV filters showed diurnal variations that mirrored variations in recreational activities at the sites. Ethylhexyl methoxycinnamate (EHMC) and octocrylene (OC) water concentrations increased from under the limit of quantification in the morning to 106 and 369 ng/L, respectively, when recreational activities were the highest. In mussels, diurnal variations in OC were observed, with the lowest concentrations recorded in the morning and then increasing throughout the day. As Mytilus spp. are widely used as sentinels in coastal pollution monitoring programs (mussel watch), our findings on diurnal variations could enhance sampling recommendations for recreational sites impacted by PCPs.

Exposure of marine mussels to diclofenac: modulation of prostaglandin biosynthesis.

Human pharmaceuticals, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are an emerging threat to marine organisms. NSAIDs act through inhibition of cyclooxygenase (COX) conversion of arachidonic acid into prostaglandins. One experiment was carried out whereby marine mussels were exposed for 72 h to 1 and 100 µg/L diclofenac (DCF). A specific and sensitive method using liquid chromatography high-resolution tandem mass spectrometry was developed to quantify DCF in mussel tissues. The developed method could also clearly identify and quantify COX products, i.e., prostaglandin levels, and be used to assess their modulation following DCF exposure. Prostaglandin-D2 (PGD2) was always found below the detection limit (20 µg/kg dry weight (dw)). Basal prostaglandin-E2 (PGE2) concentrations ranged from below the detection limit to 202 µg/kg dw. Exposure of 100 µg/L resulted in a significant reduction in PGE2 levels, whereas a downward trend was observed at 1 µg/L exposure. No difference was observed for prostaglandin-F2α (PGF2α) levels between controls and exposed organisms.