Design and optimization of a new self-nanoemulsifying drug delivery system

https://doi.org/10.1016/j.jcis.2008.10.077Get rights and content

Abstract

To improve the dissolution rate of ibuprofen, a model poorly water soluble drug, self-nanoemulsifying drug delivery systems (SNEDDS) were developed. Various surfactants and oils were screened as candidates for SNEDDS on the basis of droplet size of the resulting emulsions. The influence of the constituent structure, concentration and the composition of SNEDDS formulations, and the emulsifier HLB value, on the properties of the resulting emulsions was systematically investigated. Several SNEDDS formulations were employed to study the relationship between the emulsion droplet size and the dissolution rate of ibuprofen. The dissolution rate was accelerated by decreasing the nanoemulsion droplet size, and was significantly faster than that from a conventional tablet. The optimal SNEDDS formulation had a mean nanoemulsion droplet diameters of 58 nm in phosphate buffer, pH 6.8 (simulated intestinal fluid), and released ibuprofen more than 95% within 30 min. Therefore, these novel SNEDDS carriers appear to be useful for controlling the release rate of poorly water soluble drugs.

Graphical abstract

In-vitro release of ibuprofen from a conventional tablet and SNEDDS indicates the release of ibuprofen SNEDDS is related to the nanoemulsion droplet size.

  1. Download : Download full-size image

Introduction

Due to the convenience and improved patient safety, oral administration is the preferred method of drug administration. For any orally-administered drug, the pharmacological effect relies on involved mechanism of transport from the site of entry into the body to the site of action [1]. The oral delivery of poorly water soluble drugs presents a major challenge because of the low aqueous solubility of such compounds. For such compounds, the absorption rate from the gastrointestinal (GI) lumen is controlled by dissolution [2]. Much attention has been used to increase the drug solubility and dissolution properties, such as the use of surfactants, water-soluble carriers, polymeric conjugates and solid dispersions [3], [4]. In recent years, the most popular approach is the incorporation of the active poorly water soluble component into inert lipid vehicles such as surfactant dispersions [5], microemulsions [6], nanoemulsions [7], self-emulsifying formulations [8], self-microemulsifying formulations [9], emulsions [10], [11] and liposomes [12].

Droplet size of the carrier is of key importance for the dissolution rate of low water solubility drugs. It has been reported that the particle size distribution is one of the most important characteristics of the in vivo fate of cyclosporine emulsion [13]. Nicolaos et al. [14] also reported the bioavailability of cefpodoxime proxetil increased from 50 to 98 wt% when using submicronic emulsions for oral administration. Recent investigations show that the dissolution rate of griseofulvin particles with sizes in the range of 200 nm is about two-fold higher than for the conventional micronized material [15]. However, submicron emulsions and particles are very difficult to be produced in solid dosage forms, and particle size reduction may result in handling difficulties and poor wettability. To overcome these drawbacks, a self-nanoemulsifying drug delivery system (SNEDDS) would be an efficient, convenient, flexible and more patient-friendly approach.

SNEDDS are isotropic mixtures of oil, surfactants and co-surfactants that form fine oil-in-water nanoemulsions upon mild agitation, followed by injection into aqueous media, such as GI fluids [16]. SNEDDS can be orally administered in soft or hard gelatin capsules due to the anhydrous nature, typically producing nanoemulsions with droplet sizes between 20 and 200 nm upon dilution. When compared with emulsions, which are sensitive and metastable dispersed forms, SNEDDS are physically stable formulations that are easier to manufacture, and may offer an improvement in dissolution rates and extents of absorption, resulting in more reproducible blood–time profiles due to the nanometer sized droplets present. Although droplet size was widely proposed as being a key factor for the efficiency and of SNEDDS applications [7], [16], [17], [18], the factors influencing the droplet sizes formed in SNEDDS have not yet been studied systematically. The lack of knowledge is addressed by this work which is a systematic study of the effect of emulsifier hydrophile–lipophile balance (HLB), as well as the structure of emulsifiers and oils on the final nanoemulsion droplet size. The results show how it is possible to control the preferred droplet sizes in nanoemulsions generated from model SNEDDS.

The poorly water soluble ibuprofen, which is a nonsteroidal anti-inflammatory drug (NSAID), has been used for decades in the management of a multitude of pain conditions and rheumatic diseases. Because of a longstanding and favorable safety record, as well as proven efficacy in many different populations and indications, the popularity of ibuprofen is ever increasing [19]. Ibuprofen is highly permeable through physiological membranes and its bioavailability is close to 100% because of almost complete absorption, however, the onset of absorption strongly depends on dissolution. Ibuprofen shows low solubility in aqueous acidic media, and thus its dissolution depends on the administered formulation. The vast majority of pain treatment therapies require a fast onset of action, therefore, different approaches have been made to improve ibuprofen dissolution, such as transferring the substance to a salt (lysinate) or designing a pharmaceutical dosage form that favors a quick release of ibuprofen in the GI tract [1]. In this work, ibuprofen is incorporated into the SNEDDS to improve its dissolution rate.

Experimentally, the following were conducted:

  • (a)

    The factors influencing droplet sizes of resulting emulsion diluted from SNEDDS were screened, and optimal SNEDDS for drug loading were obtained.

  • (b)

    Ibuprofen was loaded as a model water poorly drug onto the SNEDDS. Its influence on the droplet size and stability of resulting nanoemulsion was characterized. The relationship between the ibuprofen dissolution rate from SNEDDS and droplet size of resulting emulsion was investigated.

Section snippets

Materials

Ibuprofen (Scheme 1) was a gift sample from Shandong Xinhua Pharmacy Co., Ltd. (China), and the conventional ibuprofen tablet (equivalent to 100 mg ibuprofen) is purchased from Beijing Taiyang Pharmacy Co., Ltd. (China). Methyl decanoate (MD), isopropyl myristate (IPM), methyl oleate (MO) and ethyl oleate (EO) are fatty acid esters with similar structures (Scheme 2). IPM and EO (purchased from Sinopharm Chemical Reagent Co., Ltd., China) are widely used as solvents in pharmaceutical

Effect of HLB value and emulsifier structure on the nanoemulsion droplet size generated from SNEDDS

The hydrophile–lipophile balance (HLB) value has been proven to be very useful in choosing the best type of emulsifier for any given oil phase. Sagitani [21] suggested that a proper surfactant HLB value was a key factor for the formation of emulsion with small droplets. The HLB system predicts the best emulsifier is obtained when the HLB values of the emulsifier and oil are matched [22]. Spans and Tweens are well-known non-ionic sorbitan alkanoates and ethoxylated sorbitan alkanoates, with a

Summary

In this study, new self-nanoemulsifying drug delivery systems (SNEDDS) were formulated in an attempt to improve the dissolution rate of a model poorly water soluble drug, ibuprofen. Chemical and composition factors influencing the mean nanoemulsion droplet size have been studied systematically. An optimal SNEDDS formulation was determined on the basis of nanoemulsion droplet size and was selected for ibuprofen loading and dissolution studies. The research indicates that the ibuprofen release

Acknowledgments

We acknowledge the National Natural Science Foundation of China (NSFC 20573079) and Ministry of Science and Technology (2006 BAE01A07-5 for financial support.

References (34)

  • H.O. Ho et al.

    Int. J. Pharm.

    (1996)
  • S. Okonogi et al.

    Int. J. Pharm.

    (1997)
  • S.H. Park et al.

    Int. J. Pharm.

    (2006)
  • P. Li et al.

    Int. J. Pharm.

    (2005)
  • M. Nakano

    Adv. Drug Deliv. Rev.

    (2000)
  • G. Nicolaos et al.

    Int. J. Pharm.

    (2003)
  • M. Türk et al.

    J. Supercrit. Fluids

    (2002)
  • S. Nazzal et al.

    Int. J. Pharm.

    (2002)
  • A.A. Date et al.

    Int. J. Pharm.

    (2007)
  • E.I. Taha et al.

    Int. J. Pharm.

    (2004)
  • R.P. Gullapalli et al.

    Eur. J. Pharm. Sci.

    (1999)
  • A. Ganem-Quintanar et al.

    Int. J. Pharm.

    (1998)
  • L. Dai et al.

    Colloids Surf. A Physicochem. Eng. Aspects

    (1997)
  • C. Malcolmson et al.

    J. Pharm. Sci.

    (1998)
  • W. Warisnoicharoen et al.

    Int. J. Pharm.

    (2000)
  • S. Lamaallam et al.

    Colloids Surf. A: Physicochem. Eng. Aspects

    (2005)
  • T.R. Kommuru et al.

    Int. J. Pharm.

    (2001)
  • Cited by (0)

    View full text