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Formulation and cytotoxicity evaluation of new self-emulsifying multiple W/O/W nanoemulsions.

Sigward E, Mignet N, Rat P, Dutot M, Muhamed S, Guigner JM, Scherman D, Brossard D, Crauste-Manciet S - Int J Nanomedicine (2013)

Bottom Line: The multiple emulsion stability was found to increase from 24 hours to 2 and 6 months with Labrasol, glycerol, and Cremophor, respectively.The formulation including glycerol, investigated between 1 and 100 mg/mL concentration of nanoemulsion, did not affect cell viability.This last formulation would therefore be of major interest for further developments.

View Article: PubMed Central - PubMed

Affiliation: Chemical, Genetic and Imaging Pharmacology Laboratory; INSERM U1022, CNRS UMR8151, Chimie ParisTech, Faculty of Pharmacy, Paris Descartes University, Sorbone Paris Cité, Paris, France.

ABSTRACT
Three multiple water-in-oil-in-water (W/O/W) nanoemulsions have been designed for potential inclusion of either lipophilic or hydrophilic drugs using a two-step emulsification process exclusively based on low-energy self-emulsification. The W/O primary emulsion was constituted by a blend of oil (medium chain triglyceride), a mixture (7:3) of two surfactants, and a 10% water phase. The surfactants were a mixture of Polysorbate-85/Labrasol(®), Polysorbate-85/Cremophor(®) EL or glycerol/Polysorbate-85. The final W/O/W nanoemulsions were obtained by the addition of water, with a weight ratio nanoemulsion/water of 1:2. The multiple emulsion stability was found to increase from 24 hours to 2 and 6 months with Labrasol, glycerol, and Cremophor, respectively. Cytotoxicity was found for formulations including Labrasol and Cremophor EL. The concentration of emulsion inhibiting 50% cell viability (IC(50)) was determined using the alamarBlue(®) test, giving after 24 hours of incubation, IC(50) = 10.2 mg/mL for the Labrasol formulation and IC(50) = 11.8 mg/mL for the Cremophor EL formulation. Corresponding calculated IC(50) values for surfactants were 0.51 mg/mL for Labrasol and 0.59 mg/mL for Cremophor EL. In both cases, cytotoxicity was due to an apoptotic mechanism, evidenced by chromatin condensation and P2X7 cell death receptor activation. The formulation including glycerol, investigated between 1 and 100 mg/mL concentration of nanoemulsion, did not affect cell viability. Moreover, neither chromatin condensation nor P2X7 activation was found between the 10 and 30 mg/mL final concentration of the emulsion. This last formulation would therefore be of major interest for further developments.

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Schematic representation of W/O/W multiple emulsion.Abbreviation: W/O/W, water-in-oil-in-water.
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f1-ijn-8-611: Schematic representation of W/O/W multiple emulsion.Abbreviation: W/O/W, water-in-oil-in-water.

Mentions: Nanoemulsions have been developed over the last decade for their particular interest for drug delivery through different routes.1–3 Multiple emulsions, such as water-in-oil-in-water (W/O/W), have been less developed as drug carriers. These systems, also called double emulsion, are emulsions within an emulsion and consist of a primary water-in-oil (W/O) emulsion of water droplets dispersed in oil droplets, which are themselves dispersed in an external water, giving the W/O/W multiple emulsion (schematically represented in Figure 1). The first major advantage of the multiple system is that it allows the absorption, via the enteric route, of poorly absorbed hydrophilic compounds, such as insulin.4 The second advantage is its potential for the co-delivery of drugs, giving the opportunity to carry hydrophilic and lipophilic compounds simultaneously in one single vehicle.5 The main drawback is the poor stability of the multiple systems due to their thermodynamic instability, but this can be enhanced by alteration in the size of the micrometer droplets. Nevertheless, multiple nanoemulsion systems have been recently developed as drug carriers6 and have shown better stability to particle aggregation, due to small droplet size.7 However, these later systems still exhibited short-term stability, with quick enhancement of their mean droplet size within 7 days of observation.


Formulation and cytotoxicity evaluation of new self-emulsifying multiple W/O/W nanoemulsions.

Sigward E, Mignet N, Rat P, Dutot M, Muhamed S, Guigner JM, Scherman D, Brossard D, Crauste-Manciet S - Int J Nanomedicine (2013)

Schematic representation of W/O/W multiple emulsion.Abbreviation: W/O/W, water-in-oil-in-water.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569110&req=5

f1-ijn-8-611: Schematic representation of W/O/W multiple emulsion.Abbreviation: W/O/W, water-in-oil-in-water.
Mentions: Nanoemulsions have been developed over the last decade for their particular interest for drug delivery through different routes.1–3 Multiple emulsions, such as water-in-oil-in-water (W/O/W), have been less developed as drug carriers. These systems, also called double emulsion, are emulsions within an emulsion and consist of a primary water-in-oil (W/O) emulsion of water droplets dispersed in oil droplets, which are themselves dispersed in an external water, giving the W/O/W multiple emulsion (schematically represented in Figure 1). The first major advantage of the multiple system is that it allows the absorption, via the enteric route, of poorly absorbed hydrophilic compounds, such as insulin.4 The second advantage is its potential for the co-delivery of drugs, giving the opportunity to carry hydrophilic and lipophilic compounds simultaneously in one single vehicle.5 The main drawback is the poor stability of the multiple systems due to their thermodynamic instability, but this can be enhanced by alteration in the size of the micrometer droplets. Nevertheless, multiple nanoemulsion systems have been recently developed as drug carriers6 and have shown better stability to particle aggregation, due to small droplet size.7 However, these later systems still exhibited short-term stability, with quick enhancement of their mean droplet size within 7 days of observation.

Bottom Line: The multiple emulsion stability was found to increase from 24 hours to 2 and 6 months with Labrasol, glycerol, and Cremophor, respectively.The formulation including glycerol, investigated between 1 and 100 mg/mL concentration of nanoemulsion, did not affect cell viability.This last formulation would therefore be of major interest for further developments.

View Article: PubMed Central - PubMed

Affiliation: Chemical, Genetic and Imaging Pharmacology Laboratory; INSERM U1022, CNRS UMR8151, Chimie ParisTech, Faculty of Pharmacy, Paris Descartes University, Sorbone Paris Cité, Paris, France.

ABSTRACT
Three multiple water-in-oil-in-water (W/O/W) nanoemulsions have been designed for potential inclusion of either lipophilic or hydrophilic drugs using a two-step emulsification process exclusively based on low-energy self-emulsification. The W/O primary emulsion was constituted by a blend of oil (medium chain triglyceride), a mixture (7:3) of two surfactants, and a 10% water phase. The surfactants were a mixture of Polysorbate-85/Labrasol(®), Polysorbate-85/Cremophor(®) EL or glycerol/Polysorbate-85. The final W/O/W nanoemulsions were obtained by the addition of water, with a weight ratio nanoemulsion/water of 1:2. The multiple emulsion stability was found to increase from 24 hours to 2 and 6 months with Labrasol, glycerol, and Cremophor, respectively. Cytotoxicity was found for formulations including Labrasol and Cremophor EL. The concentration of emulsion inhibiting 50% cell viability (IC(50)) was determined using the alamarBlue(®) test, giving after 24 hours of incubation, IC(50) = 10.2 mg/mL for the Labrasol formulation and IC(50) = 11.8 mg/mL for the Cremophor EL formulation. Corresponding calculated IC(50) values for surfactants were 0.51 mg/mL for Labrasol and 0.59 mg/mL for Cremophor EL. In both cases, cytotoxicity was due to an apoptotic mechanism, evidenced by chromatin condensation and P2X7 cell death receptor activation. The formulation including glycerol, investigated between 1 and 100 mg/mL concentration of nanoemulsion, did not affect cell viability. Moreover, neither chromatin condensation nor P2X7 activation was found between the 10 and 30 mg/mL final concentration of the emulsion. This last formulation would therefore be of major interest for further developments.

Show MeSH
Related in: MedlinePlus