Comparison of the Effects of Potential Parenteral Vehicles for Poorly Water Soluble Anticancer Drugs (Organic Cosolvents and Cyclodextrin Solutions) on Cultured Endothelial Cells (HUV-EC)

Abstract

The effect of dilution of parenteral vehicles (organic cosolvent and 0.1 M cyclodextrin solutions) on cultured endothelial cells (HUV-EC) were compared in vitro. Cell morphology was observed by phase contrast light microscopy and cell viability by measuring 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction or intracellular lactate dehydrogenase (LDH) activity and total protein. Disruption of the HUV-EC monolayer was observed at dilutions of 1 in 20 for the melphalan and PEP cosolvents, 1 in 100 for an investigational drug cosolvent, and 1 in 10 for 0.1 M dimethyl-beta-cyclodextrin. In comparison, 0.1 M SBE7M- and HP-beta-cyclodextrin caused only minor disruption at a 1 in 5 dilution. MTT reduction, intracellular LDH, and total protein were decreased following exposure to 1 in 10 dilution of the melphalan cosolvent. For other test solutions, intracellular LDH activity and total protein were measured, and reductions were observed following exposure to 1 in 10, 20, and 50 dilutions of the investigational drug cosolvent and 1 in 5 dilution of DM-beta-cyclodextrin (0.1 M). At a dilution of 1 in 10, no delayed toxicity was observed for cosolvents or cyclodextrin solutions. Hence, 0.1 M SBE7M- or HP-beta-cyclodextrin formulations may be less damaging to the venous endothelium at the site of injection than organic cosolvent formulations.

In-vitro prediction of bioavailability following extravascular injection of poorly soluble drugs: an insight into clinical failure and the role of delivery systems

“…Formulations with CD showed little or no tendency for drug precipitation after intravenous and extravascular injections . These formulations have been shown to be less irritant compared with the drug alone or the co‐solvent formulations, and induce less pain, thrombophlebitis and haemolysis after parenteral administration …”

“…Formulations with CD showed little or no tendency for drug precipitation after intravenous and extravascular injections. [5,21,22] These formulations have been shown to be less irritant compared with the drug alone or the co-solvent formulations, [23][24][25] and induce less pain, thrombophlebitis and haemolysis after parenteral administration. [26] An early appreciation of the potential for PDP has important implications in clinical situations, and a rapid in-vitro screening method would be valuable for parenteral formulation development.…”

Tissue compatibility and pharmacokinetics of three potential subcutaneous injectables for low-pH drug solutions

“…[21] Apart from their effect on solubility enhancement, cyclodextrins (CDs), particularly hydroxypropyl-b-cyclodextrin (HP-b-CD) and sulfobutylether-b-cyclodextrin (SBE-b-CD), have also been used to mask irritation of parenteral formulations through formation of inclusion complexes. [22][23][24][25][26] This approach has an advantage over co-solvency or pH adjustment approaches, as drug precipitation at the injection site is often reduced or absent. [10,[25][26][27][28][29] Ricobendazole (RBZ) is the most active metabolite of albendazole, a benzimidazole anthelmintic used in veterinary practice for the control of gastrointestinal (GI) worms.…”

Excipient–Drug Interactions in Parenteral Formulations

“…Cyclodextrin‐containing formulations (either 0.1 M sulfobutylether‐β‐cyclodextrin or 0.1 M hydroxylpropyl‐β‐cyclodextrin) were shown to cause less damage to venous epithelial cells at the site of injection compared with formulations containing organic co‐solvents 29. PVP (povidone) is a generally compatible polymeric excipient.…”