Characterization of Prototype Self-Nanoemulsifying Formulations of Lipophilic Compounds

doi:10.1002/jps.20673

Journal of Pharmaceutical Sciences

Volume 96, Issue 4, April 2007, Pages 876-892

https://doi.org/10.1002/jps.20673 Get rights and content

Abstract

This study describes the evaluation and characterization of a self-nanoemulsifying drug delivery system (SNEDDS) consisting of a nonionic surfactant (Cremophor RH40), a mixture of long chain mono-, di-, and triacylglycerides (Maisine 35-1 and Sesame oil) and ethanol. Compositions containing 10% (w/w) ethanol, 40%-60% (w/w) lipid content, and 30%-50% (w/w) Cremophor RH40 were identified as pharmaceutically relevant, robust, and self-nanoemulsifying when dispersed in aqueous media. The influence of adding three different lipophilic model drug compounds (danazol, halofantrine, and probucol) to the SNEDDS was evaluated. While danazol precipitated from the SNEDDS after dispersion in aqueous media, halofantrine and procubol remained solubilized. Halofantrine- and procubol-loaded SNEDDS were evaluated in both saline and in media simulating fasted and fed-state intestinal fluid (FaSSIF and FeSSIF) using dynamic light scattering and small-angle X-ray scattering (SAXS) techniques. Stable nanoemulsions with droplet sizes in the range of 20-50 nm were formed in all media and with and without drugs. The mean size of the droplets was neither affected significantly by being dispersed into the media simulating gastro intestinal fluid, nor by addition of the drug.

Section snippets

INTRODUCTION

The high-throughput screening approach in drug discovery within the pharmaceutical industry has lead to drug candidates with increasing lipophilicity.¹ A typical characteristic for these compounds is low and variable oral bioavailability from solid dosage forms due to their poor water solubility. One increasingly popular approach to overcome this problem, is the use of a self-emulsifying drug delivery system (SEDDS).2., 3., 4. The bioavailability enhancing properties of SEDDS compared to solid

Materials

Cremophor® RH40 (Cr RH40) (polyethoxylated hydrogenated castor oil obtained by ethoxylating hydrogenated castor oil with 40 mol ethylenoxide per mol) was obtained from BASF-BASIS Kemi, Copenhagen, Denmark and Maisine® 35-1 (obtained by partial alcoholysis of maize oil and contains a mixture of monoacylglycerides (MAG), diacylglycerides (DAG), and triacylglycerides (TAG) (39.7% MAG, 44.6% DAG, and 14.9% TAG)), was from Gattefosse, Saint-Priest cedex, France. Sesame oil was from Apoteket AB,

RESULTS AND DISCUSSION

The evaluated system was composed of the nonionic surfactant Cremophor RH40 (Cr RH40), a lipid phase consisting of a 1:1 w/w mixture of Maisine 35-1 and sesame oil, and ethanol. The system has previously been found to include self-emulsifying compositions giving resultant emulsions with particle size in the nanometer range, designated SNEDDS in the following.¹⁴,³⁰

CONCLUSION

We have used turbidity measurements for rapid screening of different combinations of excipients in the development of robust SNEDDSs. Drug solubilization capacity of the preconcentrates were found to be compound dependent and upon dispersion precipitated danazol, for which the solubility was governed by ethanol. In the identified SNEDDS, the inclusion of a lipophilic drug compound had no profound effect on dispersion properties and particle size in saline. The droplet size of the identified

ACKNOWLEDGEMENTS

This work is part of the project “Explorative Pharmaceutical Formulations” and financially supported by VINNOVA in Sweden and VTU—Ministry of Science, Technology and Innovation in Denmark. Linda Söderberg, Camurus AB are acknowledged for excellent technical assistance.

REFERENCES (42)

C.A. Lipinski
Drug-like properties and the causes of poor solubility and poor permeability
J Pharmacol Toxicol Methods
(2000)
A.J. Humberstone et al.
Lipid-based vehicles for the oral delivery of poorly water soluble drugs
Adv Drug Deliv Rev
(1997)
T. Gershanik et al.
Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs
Eur J Pharm Biopharm
(2000)
C.W. Pouton
Formulation of self-emulsifying drug delivery systems
Adv Drug Deliv Rev
(1997)
C.J. Porter et al.
In vitro assessment of oral lipid based formulations
Adv Drug Deliv Rev
(2001)
P.C. De Smidt et al.
Intestinal absorption of penclomedine from lipid vehicles in the conscious rat: Contribution of emulsification versus digestibility
Int J Pharm
(2004)
G.A. Kossena et al.
Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems: A phase diagram approach
J Pharm Sci
(2004)
C.W. Pouton
Lipid formulations for oral administration of drugs: Non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems
Eur J Pharm Sci
(2000)
C.W. Pouton
Self-emulsifying drug delivery systems: Assessment of the efficiency of emulsification
Int J Pharm
(1985)
S.M. Khoo et al.
Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine
Int J Pharm
(1998)

E.I. Taha et al.

Preparation and in vitro characterization of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate

Int J Pharm

(2004)

S. Nazzal et al.

Preparation and in vitro characterization of a eutectic based semisolid self-nanoemulsified drug delivery system (SNEDDS) of ubiquinone: Mechanism and progress of emulsion formation

Int J Pharm

(2002)

J.Y. Kim et al.

Enhanced absorption of indomethacin after oral or rectal administration of a self-emulsifying system containing indomethacin to rats

Int J Pharm

(2000)

T.R. Kommuru et al.

Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: Formulation development and bioavailability assessment

Int J Pharm

(2001)

K. Kawakami et al.

Microemulsion formulation for enhanced absorption of poorly soluble drugs. I. Prescription design

J Control Release

(2002)

B.J. Boyd et al.

Using the polymer partitioning method to probe the thermodynamic activity of poorly water-soluble drugs solubilized in model lipid digestion products

J Pharm Sci

(2003)

A.M. Abdul-Fattah et al.

A new high-performance liquid chromatography (HPLC) method for the analysis of halofantrine (HF) in pharmaceuticals

J Pharm Biomed Anal

(2002)

H. Ljusberg-Wahren et al.

Enzymatic characterization of lipid-based drug delivery systems

Int J Pharm

(2005)

L. de Campo et al.

Five-component food-grade microemulsions: Structural characterization by SANS

J Colloid Interface Sci

(2004)

A. Taillardat-Bertschinger et al.

Partitioning of halofantrine hydrochloride between water, micellar solutions, and soybean oil: Effects on its apparent ionization constant

J Pharm Sci

(2003)

M.R. Moncelli et al.

The intrinsic pKa values for phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine in monolayers deposited on mercury electrodes

Biophys J

(1994)

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Citation Excerpt :
For lipid-based formulations, we used, as in our previous studies (Gumaste et al., 2017; Prajapati et al., 2012), different ratios of lipid to surfactant, where a 1:1 mixture of medium chain triglyceride (Captex 355) and medium chain monoglyceride (Capmul MCM) served as the lipid and Kolliphor EL acted as the surfactant. Probucol, a virtually non-ionizable drug with logP of 11 and the aqueous solubility of 2–5 ng/mL, was used as a model drug (Nielsen et al., 2007; Yagi et al., 1996). In a recent study, we observed that precoating of a silicate, Neusilin® US2, with polyvinylpyrrolidone (PVP) greatly improved the extent of drug release from formulations stored up to 6 months (Gumaste et al., 2017).
Lipid-based self-emulsifying drug delivery systems (SEDDS) are usually liquids, and they can be converted into solid dosage forms by adsorbing onto silicates. However, most commercially available silicates are mesoporous with small pore sizes of 1 to 50 nm that lead to incomplete emulsification of SEDDS inside the pores and thus incomplete drug release. The objective of this study was to investigate the impact of silica pore size on the extent of drug release from SEDDS solidified by adsorbing onto macroporous silicas with different pore sizes.
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Research ArticlesCharacterization of Prototype Self-Nanoemulsifying Formulations of Lipophilic Compounds

Abstract

Section snippets

INTRODUCTION

Materials

RESULTS AND DISCUSSION

CONCLUSION

ACKNOWLEDGEMENTS

J Pharmacol Toxicol Methods

Adv Drug Deliv Rev

Eur J Pharm Biopharm

Adv Drug Deliv Rev

Adv Drug Deliv Rev

Int J Pharm

J Pharm Sci

Eur J Pharm Sci

Int J Pharm

Int J Pharm

Int J Pharm

Int J Pharm

Int J Pharm

Int J Pharm

J Control Release

J Pharm Sci

J Pharm Biomed Anal

Int J Pharm

J Colloid Interface Sci

J Pharm Sci

Biophys J

Research Articles
Characterization of Prototype Self-Nanoemulsifying Formulations of Lipophilic Compounds