betadex and carbitol

Potential new drugs are assessed in pre-clinical in vivo studies to determine their safety profiles. The drugs are formulated in vehicles suitable for the route of administration and the physicochemical properties of the drug, aiming to achieve optimal exposure in the test species. The availability of safety data on vehicles is often limited (incomplete data, access restricted/private databases). Nineteen potentially useful vehicles that contained new and/or increased concentrations of excipients and for which little safety data have been published were tested. Vehicles were dosed orally once daily to HanWistar rats for a minimum of 28 days and a wide range of toxicological parameters were assessed. Only 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes (AST, ALT and GLDH), urinary volume and the kidneys (tubular vacuolation and tubular pigment). 20% (v/v) oleic acid caused increased salivation and hence this vehicle should be used with caution. As 40% (v/v) tetraethylene glycol affected urinary parameters, its use should be carefully considered, particularly for compounds suspected to impact the renal system and studies longer than 1 month. There were no toxicologically significant findings with 10% (v/v) dimethyl sulphoxide, 20% (v/v) propylene glycol, 33% (v/v) Miglyol®812, 20% (w/v) Kolliphor®RH40, 10% (w/v) Poloxamer 407, 5% (w/v) polyvinylpyrrolidone K30 or 10% (v/v) Labrafil®M1944. All other vehicles tested caused isolated or low magnitude effects which would not prevent their use. The aim of sharing these data, including adverse findings, is to provide meaningful information for vehicle selection, thereby avoiding repetition of animal experimentation.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Dimethyl Sulfoxide; Ethylene Glycols; Female; Kidney; Male; Organ Size; Pharmaceutical Vehicles; Poloxamer; Propylene Glycol; Rats; Triglycerides

The objective was to develop a ternary skin targeting system for ketoconazole (KET) using a combined strategy of microemulsion (ME) and cyclodextrin (HP-β-CD), i.e., KET-CD-ME, which exploits both virtues of cyclodextrin complex and ME to obtain the synergetic effect. KET-CD-ME was formulated using Labrafil M 1944 CS as oil phase, Solutol HS 15 as surfactant, Transcutol P as cosurfactant, and HP-β-CD solution as aqueous phase. The formulation of KET-CD-ME was optimized and the optimal formulation was characterized in terms of particle size, size distribution, pH value, and viscosity. Long term stability experiment showed that HP-β-CD could increase the physical stability of ternary system and KET chemical stability. Percutaneous permeation of KET from KET-CD-ME in vitro through rat skin was investigated in comparison with KET microemulsion (KET-ME), KET HP-β-CD inclusion solution (KET-CD), KET aqueous suspension, and commercial KET cream; the results showed that the combination of ME with HP-β-CD exhibited significantly synergistic effect on KET deposition within the skin (29.38 ± 1.79 μg/cm(2)) and a slightly synergistic effect on KET penetration through the skin (11.3 μg/cm(2)/h). The enhancement of the combination on skin deposition was further visualized by confocal laser scanning microscope (CLSM). In vitro sensitivity against Candida parapsilosis test indicated that KET-CD-ME enhanced KET antifungal activity mainly owing to the solubilization of HP-β-CD on KET in the ternary system. Moreover, the interactions between HP-β-CD and KET in the ternary system were elucidated through microScale thermophoresis (MST) and 2D (1)H NMR spectroscopy. The profiles from MST confirmed the host-guest interactions of HP-β-CD with KET in the ternary system and a deep insight into the interactions between KET and HP-β-CD were obtained by means of 2D (1)H NMR spectroscopy. The results indicate that the ternary system of ME combination with HP-β-CD may be a promising approach for skin targeting delivery of KET.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Cutaneous; Animals; Antifungal Agents; beta-Cyclodextrins; Candida; Chemistry, Pharmaceutical; Drug Carriers; Emulsions; Ethylene Glycols; Glycerides; Hydrogen-Ion Concentration; Ketoconazole; Kinetics; Microscopy, Confocal; Particle Size; Permeability; Polyethylene Glycols; Proton Magnetic Resonance Spectroscopy; Rats, Wistar; Skin; Skin Absorption; Solubility; Stearic Acids; Surface-Active Agents; Technology, Pharmaceutical; Viscosity