Assessment of Labrasol®/Labrafil®/Transcutol® (4/4/2, v/v/v) as a non-clinical vehicle for poorly water-soluble compounds after 4-week oral toxicity study in Wistar rats

Delongeas, Jean-Luc; Conchard, G. Vermeil de; Beamonte, A.; Bertheux, H.; Spire, Catherine; Maisonneuve, Catherine; Bécourt-Lhote, Nathalie; Goldfain-Blanc, Françoise; Claude, Nancy

doi:10.1016/j.yrtph.2010.03.008

Cited by 27 publications

(19 citation statements)

References 27 publications

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“…Moreover 0.5% w/w concentration was earlier assessed for cytotoxicity and proved to be safe for human use. 22 Interestingly, 0.5% w/w concentration exhibited profound effects by increasing the solubility of ATR but the particle size obtained with Labrasol ® alone was relatively very large ~600 nm. Also the nanocrystals exhibited slight negative charge with sedimentation after 4 days of preparation due to the Brownian movement; this phenomenon proved that wettability of hydrophobic surfaces of ATR alone is not sufficient to prevent sedimentation or particle size reduction.…”

Section: Effect Of Surfactantmentioning

confidence: 97%

“…A surfactant with HLB 14 is safer for human use. 22 Few non-ionic polymers and surfactants such as poly vinyl alcohol and Tween 40, 80 were also examined initially but resulted in larger particle size and agglomeration. For this purpose and concern, Labrasol ® as newer non-ionic water surfactant (HLB 12) was investigated in the present work.…”

Section: Effect Of Surfactantmentioning

confidence: 99%

“…Earlier, the use of synthetic surfactants were reported with cytotoxicity effects due to high hydrophilic-lipophilic balance (HLB) value (HLB 14), poor biodegradability and immunogenicity. 22 Identifying an ideal biodegradable stabilizer that can aid in the particle size reduction apart from stabilization of a nanocrystal formulation would be a breakthrough. 23 Chitosan is a deacetylated product of chitin.…”

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confidence: 99%

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Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

Kurakula¹,

El-Helw²,

Sobahi³

et al. 2015

IJN

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Cationic charged chitosan as stabilizer was evaluated in preparation of nanocrystals using probe sonication method. The influence of cationic charge densities of chitosan (low CS L , medium CS M , high CS H molecular weights) and Labrasol ® in solubility enhancement and modifying the release was investigated, using atorvastatin (ATR) as poorly soluble model drug. Compared to CS M and CS H ; low cationic charge of CS L acted as both electrostatic and steric stabilizer by significant size reduction to 394 nm with charge of 21.5 meV. Solubility of ATR-CS L increased to 60-fold relative to pure ATR and ATR-L. Nanocrystals were characterized for physiochemical properties. Scanning electron microscopy revealed scaffold-like structures with high surface area. X-ray powder diffractometry and differential scanning calorimetry revealed crystalline to slight amorphous state changes after cationic charge size reduction. Fourier transform-infrared spectra indicated no potent drug-excipient interactions. The enhanced dissolution profile of ATR-CS L indicates that sustained release was achieved compared with ATR-L and Lipitor ® . Anti-hyperlipidemic performance was pH dependent where ATR-CS L exhibited 2.5-fold higher efficacy at pH 5 compared to pH 6 and Lipitor ® . Stability studies indicated marked changes in size and charge for ATR-L compared to ATR-CS L exemplifying importance of the stabilizer. Therefore, nanocrystals developed with CS L as a stabilizer is a promising choice to enhance dissolution, stability, and in-vivo efficacy of major Biopharmaceutical Classification System II/IV drugs.

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Section: Effect Of Surfactantmentioning

confidence: 97%

Section: Effect Of Surfactantmentioning

confidence: 99%

mentioning

confidence: 99%

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Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

Kurakula¹,

El-Helw²,

Sobahi³

et al. 2015

IJN

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“…The animals were weighed every 5 days throughout the treatment period and the percentage weight variation was calculated relative to initial animal bodyweight on Day 0 using the same protocol as previously described. 35 …”

Section: Stability Studiesmentioning

confidence: 99%

“…The reduction in food consumption observed for groups II and III may be related to gastric stasis due to lipid consumption, in addition to GIT irritation induced by high amounts of Table 5 stability of blank seDDs and raV-seDDs (10 mg/ml of raV) after 6 months at room temperature (25°c) 35,50 The latter effect contributed to the presence of more fluid feces, in particular in group II. The overall clinical observations indicate that even a single dose of 25% (w/v) of Labrasol in SEDDS (equivalent to 0.75 g/kg) is toxic for mice.…”

Section: T Cruzi-infected Micementioning

confidence: 99%

Ravuconazole self-emulsifying delivery system: in vitro activity against <em>Trypanosoma cruzi</em> amastigotes and in vivo toxicity

Spósito

Mazzeti

Faria

et al. 2017

IJN

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Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually presented in gelatin capsules. Ravuconazole (Biopharmaceutics Classification System [BCS] Class II) is a poorly water-soluble drug, and a SEDDS type IIIA was designed to deliver it in a predissolved state, improving dissolution in gastrointestinal fluids. After emulsification, the droplets had mean hydrodynamic diameters <250 nm, zeta potential values in the range of −45 mV to −57 mV, and showed no signs of ravuconazole precipitation. Asymmetric flow field-flow fractionation with dynamic and multiangle laser light scattering was used to characterize these formulations in terms of size distribution and homogeneity. The fractograms obtained at 37°C showed a polydisperse profile for all blank and ravuconazole–SEDDS formulations but no large aggregates. SEDDS increased ravuconazole in vitro dissolution extent and rate (20%) compared to free drug (3%) in 6 h. The in vivo toxicity of blank SEDDS comprising Labrasol ® surfactant in different concentrations and preliminary safety tests in repeated-dose oral administration (20 days) showed a dose-dependent Labrasol toxicity in healthy mice. Ravuconazole–SEDDS at low surfactant content (10%, v/v) in Trypanosoma cruzi -infected mice was safe during the 20-day treatment. The anti- T. cruzi activity of free ravuconazole, ravuconazole–SEDDS and each excipient were evaluated in vitro at equivalent ravuconazole concentrations needed to inhibit 50% or 90% (IC 50 and IC 90 ), respectively of the intracellular amastigote form of the parasite in a cardiomyocyte cell line. The results showed a clear improvement of the ravuconazole anti- T. cruzi activity when associated with SEDDS. Based on our results, the repurposing of ravuconazole in SEDDS dosage form is a strategy that deserves further in vivo investigation in preclinical studies for the treatment of human T. cruzi infections.

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Safety data on 19 vehicles for use in 1 month oral rodent pre‐clinical studies: administration of hydroxypropyl‐ß‐cyclodextrin causes renal toxicity

Healing

Sulemann

Cotton

et al. 2015

J of Applied Toxicology

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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.

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Assessment of Labrasol®/Labrafil®/Transcutol® (4/4/2, v/v/v) as a non-clinical vehicle for poorly water-soluble compounds after 4-week oral toxicity study in Wistar rats

Cited by 27 publications

References 27 publications

Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

Chitosan based atorvastatin nanocrystals: effect of cationic charge on particle size, formulation stability, and in-vivo efficacy

Ravuconazole self-emulsifying delivery system: in vitro activity against <em>Trypanosoma cruzi</em> amastigotes and in vivo toxicity

Safety data on 19 vehicles for use in 1 month oral rodent pre‐clinical studies: administration of hydroxypropyl‐ß‐cyclodextrin causes renal toxicity

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