(524g) Mechanistic Studies of Self Emulsifying Drug Delivery Systems for the Oral Delivery of Lipophilic Drugs

Oral drug delivery is a $35 billion dollar industry [1] and the most preferred way of drug administration. However, the oral route is not possible for 50% of currently marketed drug compounds due to their low solubility in water. Forty percent of prospective drugs coming out of discovery pipelines are lipophilic compounds, which leads to difficulty in achieving acceptable oral bioavailability. Lipid based drug delivery systems, and in particular self-emulsifying drug delivery systems (SEDDS), show great potential for enhancing oral bioavailability of lipophilic drugs, as well as offering the advantage of minimal processing and inherent stability, but have not been broadly applied, largely due to lack of general formulation guidance and lack of knowledge of how these systems function to enhance bioavailability [2, 3]. SEDDS are oil in water emulsions that typically have droplet sizes ranging from a few nanometers to hundreds of nanometers and consist minimally of oil, surfactant, and the drug to be delivered dissolved in oil (Figure 1). SEDDS are spontaneously formed in the gently mixed aqueous gastrointestinal (GI) environment [4]. 

To gain a better understanding of the dependence of emulsion drug delivery function in the GI tract on formulation composition, a quantitative study of properties central to emulsion function was conducted utilizing representative self-emulsifying formulations based on a 3³ factorial experimental design. Formulations have been studied as follows. Oils from three different structural classes (long chain triglyceride (Soybean oil), medium chain trigylcerides (Neobee M5), propylene glycol dicaprylate/dicaprate (Captex 200)) and surfactants with hydrophilic-lipophilic balance (HLB) values ranging from 10-15 (Cremophor EL, Tween 80, a mixture of Capmul MCM and Labrasol) were combined at three different oil-to-surfactant weight ratios (9:1, 5:1, 1:1). A model drug, Naproxen, was included in formulations to test the influence of drug incorporation on emulsion properties. One of the proposed mechanisms by which SEDDS are believed to influence oral bioavailability of water insoluble drugs is by diverting drug absorption to the lymphatic pathway. Another major mechanism is the formation of complex colloidal structures due to digestion of the oil component of the formulation in the intestine, which alters the overall drug solubility. Upon reaching the intestine, SEDDS begin to be hydrolyzed by lipase. Upon inception of digestion, digestion products are released from the surface of SEDDS emulsion droplets into the aqueous medium, forming complex colloidal structures. Meanwhile, drug compounds are released from SEDDS into intestinal fluid, and a portion of released drug further partitions into colloidal structures.

In this study, the influence of formulation composition on lymphatic drug transport was assessed in vitro by quantifying secretion of Apolipoprotein B (Apo B), a lipoprotein secretion marker, which is proportional to the increase of lymphatic drug transport, in intestinal epithelial Caco-2 cells exposed to formulations. Lipophilic drug associates with the triglyceride lipid core of the lipoproteins, and it has been suggested that amount of drug transported through the lymphatic pathway is proportional to the amount of lipoprotein secreted by intestinal cells. In vitro tests for Apo B secretion require 20 hour incubation of formulations with Caco-2 cells. Therefore, along with the Apo B test, MTT toxicity tests were carried out to assess the possible cytotoxicty of formulations due to the long incubation period. Low dilution formulations in biorelevant media (1:100, 1:200, 1:500) resulted in low levels of cell viability. 1:1000 dilution formulations, on the other hand, resulted in reasonably high viabilities; only formulations containing Captex 200 had low (30%) viabilities. 1:1000 dilution formulations therefore were used for Apo B secretion tests. Quantification of Apo B secretion with an enzyme-linked immunosorbent assay suggested the influences of certain formulation parameters on lymphatic transport. Formulations of Cremophor EL at high surfactant ratios showed a trend of inhibiting ApoB secretion compared to negative control of biorelevant media. In general, results did not indicate enhancement of lymphatic transport by the formulations tested.

Secondly, in an effort to perform real time quantitative tracking of drug partitioning and drug release into colloidal phases during in vitro digestion, electron paramagnetic resonance (EPR) was used to track a model drug (spin probe: Tempol Benzoate). In vitro lipolysis experiments were conducted in fasted state biorelevant simulated intestinal fluid. Formulations including Tempol Benzoate were added to 20 ml digestion buffer at 1:100 ratio, and digestion was started with the addition of 2.2 ml pancreatin extract. Samples were collected at specific time intervals (0, 5, 20, 50 minutes), and the digestion process was terminated by the addition of enzyme inhibitior, 4-BPB (4-bromophenacyl bromide). Samples were analyzed with EPR. Differences in peak to peak distances (a_N) and peak widths among EPR spectra give information related to probe distribution among different phases (oil vs. vesicles and micelles vs. water). For the formulations studied, results indicate a release of the probe from oil phase into biorelevant micellar phase over 15 minutes in the absence of digestive enzymes and an increased partitioning of the probe into the micellar phase over a 30 minute time period in the presence of digestion enzymes. Correlation of quantitative results on drug partitioning and lymphatic transport with formulation design parameters will be ultimately incorporated in an overall mechanistic mathematical model to predict and optimize oral absorption of a drug administered with SEDDS.  

 

 

References

[1] Drug Deliver Markets. Edition 2 Volume I: Oral Delivery, Jan. 2007 

[2] A.J. Humberstone, W.N. Charman, Lipid-based vehicles for the oral delivery of poorly water soluble drugs. Adv. Drug Deliv. Rev 25(1) (1997) 103-128.

[3] R. Neslihan Gursoy, S. Benita, Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed. Pharmacother. 58(3) (2004) 173-182.

[4]  J. Yamamoto, H. Tanaka, Transparent nematic phase in a liquid-crystal-based microemulsion. Nature 409(6818) (2001) 321-