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

https://doi.org/10.1016/S0378-5173(99)00367-1Get rights and content

Abstract

A self-emulsifying system (SES), a mixture of an oil and a surfactant which forms an oil-in-water emulsion, is expected to improve the in vitro drug dissolution and enhance the in vivo drug absorption. In this study, a poorly water-soluble drug, indomethacin (IDM) was incorporated into the SES to increase bioavailability. The SES with 30% of Tween 85 and 70% of ethyl oleate, EO (w/w) was selected as an optimized formulation (high drug loading, low surfactant concentration, and small particle size). After an oral administration of the SES containing IDM and IDM suspension, (IDM was suspended in methyl cellulose), 22.5 mg/kg as IDM, to rats, the area under the plasma concentration–time curve from time zero to the last measured time in plasma, 12 h (AUC0–12 h) was significantly greater (57% increase) in the SES, suggesting that oral absorption of IDM increased significantly by the SES. After a rectal administration of gelatin hollow type suppositories, filled with the SES containing IDM and IDM powder physically mixed with the SES, 22.5 mg/kg, to rats, the AUC0–12 h also increased significantly (41% increase) by the SES, suggesting that rectal absorption of IDM also increased significantly by the SES.

Introduction

After an oral administration, absorption of drugs into the circulatory system consists of the following sequential rate processes; (1) disintegration of the drugs in the gastrointestinal tracts; (2) dissolution of drugs in the gastrointestinal fluids; and (3) absorption of drugs across gastrointestinal membrane into the circulatory system. For poorly water-soluble drugs, the rate-determining step in the absorption processes is usually dissolution of the drug (Sekikawa et al., 1983).

An improvement of the dissolution characteristics for poorly water-soluble drugs results in higher plasma peak level and greater area under the plasma (blood, serum) concentration–time curve from time zero to infinity of the drugs. Numerous methods for the improvement of dissolution characteristics for poorly water-soluble drugs have been reported to enhance bioavailability; micronization, salt formation, formation of solid dispersion with water-soluble carriers, emulsions, and formation of micelles. Among them, oil-in-water emulsion dosage forms have been used for lipophilic drugs. However, emulsions, consisting of two immiscible liquids are thermodynamically unstable, therefore, have a tendency for the two phases to separate (Fahelelbom et al., 1993).

In the absence of water, a mixture of an oil and a non-ionic surfactant forms clear and transparent isotropic solution that is known as a self-emulsifying system (SES) used as a vehicle for drug delivery. The SES system was recently being used to improve characteristics of in vitro dissolution and therefore to enhance in vivo absorption of lipophilic drugs (Charman et al., 1992, Shah et al., 1994). This mixture is known to form a fine oil-in-water emulsion with gentle agitation, when exposed to aqueous media. This property makes the SES a good vehicle for oral delivery of hydrophobic drugs having an adequate oil solubility. Soft gelatin capsules containing SES readily disperse in the stomach to form a fine emulsion; in this case, the gastrointestinal motility can provide the agitating effect necessary for emulsification. For drugs having characteristics of dissolution rate-limited absorption, the SES could enhance the rate and extent of absorption, as well as improve the reproducibility of the plasma (serum, blood) level-time profiles (Myles et al., 1990).

In this study, an unsaturated fatty acid (ethyl oleate, EO) and a nonionic surfactant (Tween 85) were used to formulate a SES for indomethacin (IDM), a poorly water-soluble drug. To characterize various SESs (with different mixtures of EO and Tween 85) containing IDM, phase separation studies were conducted and the particle size was measured using photon correlation spectroscopic method. Based on the studies above, the SES containing 30% of Tween 85 and 70% of EO (w/w) was selected as an optimized formulation for IDM. Finally, in order to examine the SES as a potential vehicle for enhancing the absorption of IDM, the SES (30% of Tween 85 and 70% of EO) containing IDM was administered orally or rectally to rats.

Section snippets

Materials

IDM (Whail, Seoul, South Korea), EO (Aldrich Chemical, Milwaukee, WI), Tween 85 (polyoxyethylene 20) and sorbital trioleate (Nikko Chemical, Tokyo, Japan), methanol and acetonitrile (HPLC grade, Merck Chemical, Darmstadt, Germany), and acetic acid (HPLC grade, Fisher Chemical, Pittsburgh, PA) were used in the present study. Other chemicals were of reagent grade, therefore, used without further purification.

Preparation of a SES

Various SESs having different mixtures of EO and Tween 85 (9.5:0.5, 9.0:1.0, 8.5:1.5,

Characterization of SESs

The SESs containing 0–10% (w/w) of Tween 85 did not form an emulsion, however, the SESs containing higher than 15% of Tween 85 rapidly formed an emulsion which was apparently stable (no phase-separation for 2 h). When the Tween 85 concentrations were 25–30%, phase separation did not occur for 24 h.

Solubility of IDM in SESs

The solubility of IDM in various SESs increased with increasing concentrations of Tween 85; the values were 4.42±0.582, 19.5±15.8, 22.6±1.74, 29.1±0.303, 39.7±1.49, 47.9±1.21, and 54.0±1.87 mg/ml for

Conclusions

The SES (30% of Tween 85 and 70% of EO) was selected as an optimized formulation (high drug loading, low surfactant concentration, and small particle size) for IDM, a poorly water-soluble drug. After an oral administration of the SES containing IDM and IDM suspension (IDM powder was suspended in methyl cellulose), 22.5 mg/kg as IDM, to rats, the AUC0–12 h was significantly greater (57% increase) in the SES, suggesting that oral absorption of IDM increased significantly by the SES. After a

Acknowledgements

This study was supported in part by The Ewha Faculty Research Fund, 1995.

References (11)

  • N.H. Shah et al.

    Self-emulsifying drug delivery systems (SEDDS) with polyglycolysed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs

    Int. J. Pharm.

    (1994)
  • S.A. Charman et al.

    Self-emulsifying drug delivery system: formulation and biopharmaceutic evaluation of an investigational lipophilic compound

    Pharm. Res.

    (1992)
  • W.L. Chiou

    Critical evaluation of potential error in pharmacokinetic studies using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve

    J. Pharm.Biopharm.

    (1978)
  • K.M.S. Fahelelbom et al.

    Micellar solubilization of clofazimine analogues in aqueous solutions of ionic and nonionic surfactants

    Pharm. Res.

    (1993)
  • S.H. Kim et al.

    Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition

    J. Pharm. Biopharm.

    (1993)
There are more references available in the full text version of this article.

Cited by (119)

  • Self-emulsifying systems for drug delivery: advances and challenges

    2023, Advanced and Modern approaches for Drug Delivery
  • Polymers in Rectal Drug Delivery

    2020, Applications of Polymers in Drug Delivery
View all citing articles on Scopus
View full text