Drug oral bioavailbility & self-emulsifying SEDDS

Oral bioavailability of over one-half of the drug compounds gets thwarted owing to their high lipophilicity and poor aqueous solubility. The other ostensible causes  for poor and variable bioavailability include stability in GI fluids, intestinal permeability, resistance to metabolism by cytochrome P450 family of enzymes present in gut enterocytes and liver hepatocytes, and interaction with efflux transporter systems like P-glycoprotein (P-gp), as illustrated in Figure 1.

Amongst the several formulation approaches employed for the purpose, lipid-based self-emulsifying drug delivery systems (SEDDS) have proved their enormous potential in improving the oral bioavailability of such drugs. SEDDS, in general, facilitates the formation of solubilized phase, and increases the extent of transportation via intestinal lymphatic system, thereby augmenting drug absorption from the gastrointestinal (GI) tract.

SEDDS is a broad term typically producing emulsions with a droplet size ranging between a few nanometres to several microns. Depending upon the globule size of the diluted microemulsions or nanoemulsions, the SEDDS are specifically referred to as SMEDDS or SNEDDS. Figure 2 specifically portrays the passage of SEDDS through lymphatic pathways, and ultimately into the systemic circulation.

Technological aspects
A typical SEDDS formulation essentially encompasses the lipid and emulsifier, usually accompanied by a co-emulsifier. SEDDS have been classified as Type I, II, IIIA, IIIB and IV, depending upon the relative proportions of lipidic triglycerides (medium chain and/or long chain fatty acid derivatives), water soluble (or insoluble) surfactant emulsifiers and hydrophobic co-emulsifiers or co-solvents.

Solid SEDDS
Solid SEDDS tend to blend the advantages of the conventional liquid SEDDS (i.e., enhanced solubility and bioavailability) with those of solid dosage forms (low production cost, process control convenience, high stability and reproducibility, better patient compliance, etc.).    

Supersaturable SEDDS
High levels of surfactant typically present in SEDDS can invariably lead to severe GI side-effects. Hence, supersaturable SEDDS (S-SEDDS) have been specially designed to reduce the amount of surfactant by incorporating a water soluble polymeric precipitation inhibitor (PPI’s), like cellulosic polymers, which prevents or minimizes drug precipitation, and eventually reduce the side-effects and achieve rapid absorption of drugs like paclitaxel and simvastatin.

Positively charged SEDDS
Of late, owing to enhanced electrostatic interactions of positively charged droplets with the mucosal surface of intestine, drug bioavailability from the cationic SEDDS has been found to be quite higher vis-à-vis the conventional formulations. Invariably oleylamine has been employed as the charge-inducer for the purpose.

Characterization of SEDDS formulations
A number of diverse in vitro, ex vivo and by in vivo techniques are employed to characterize these SEDDS formulations and determine the feasibility of their formulation process.

Equilibrium phase behaviour
Phase solubility and pseudo-ternary phase diagram studies enable the prediction of the phases which are likely to get formed on dilution of SEDDS with water. Phase behaviourr of three-component system can be represented pictorially by ternary phase diagram, plotted manually or using apt computational software like PCP-Disso or Tri-Plot.

Dispersibility test
The efficiency of self-emulsification of oral micro/nanoemulsion is assessed using a standard USP dissolution apparatus II. A grading system is employed based upon the formation of a microemulsion (o/w or w/o), microemulsion gel, emulsion or emulgel.

Size and zeta potential
A Zetasizer uses light scattering techniques, including SAXS, TEM, etc., to measure globule size, zeta potential and molecular weight of nanoparticulate systems.

Rheological studies
Studies are conducted to explore the viscoelastic properties of the intermediate liquid crystalline phases and evaluate their effect on self-emulsification performance during extreme conditions of temperature, humidity, transportation, etc.

Stability studies
To assess the thermodynamic stability, samples are subjected to freeze-thaw cycles between extreme temperatures, usually between -21°C and +25°C. Besides, nanoemulsions must also be robust to dilutions, showing no phase-separation or drug precipitation even after 12 h of storage.

Liquefaction time
The time required by solid SEDDS to melt in vivo is estimated in the absence of agitation in the simulated GI tract conditions.

In Situ Single Pass Intestinal Perfusion  Technique
Herein, perfusion solution is passed through the intestinal segment (i.e., jejunum) by cannulating it at both the ends. Permeability parameters viz. effective permeability, aqueous permeability and wall permeability are calculated from amount of drug unabsorbed from the intestine. Besides providing experimental conditions closer to that occurring in vivo, SPIP predicts the exact mechanism of absorption, i.e., passive absorption or carrier mediated absorption. Figure 3 describes the schematic representation of a typical SPIP technique in rat.

Everted Sac Technique
In this method, a section of the intestine is tied off at one end and everted using a glass rod to determine kinetic parameters reliably using mass balance.

Caco-2 Cells
The cell lines derived from human colorectal adenocarcinoma are the most popular intestinal cellular model in studies on passage and transport of SEDDS.

Bioavailability enhancement
Poor drug absorption can be caused by inadequate rate and extent of drug dissolution and/or low permeation. As per the Biopharmaceutical Classification Scheme (BCS), a drug is classified into four categories (i.e., Class I to IV), on the basis of these solubility and permeability characteristics.

The Class I drugs, being highly soluble and permeable, do not normally pose any problem of rate and extent of bioavailability. Bioavailability of poorly soluble Class II drugs, on the contrary, is dependent on their aqueous solubility/dissolution rate. As these drugs tend to exhibit dissolution-limited bioavailability, the in-vivo physiological performance correlates well with their in-vitro dissolution, resulting eventually in good in vitro/in vivo correlations (IVIVC).

Absorption of Class III drugs is a distinct function of the permeability across GI barriers. Class IV drug compounds have neither sufficient solubility nor permeability for oral absorption to be complete. SEDDS, in this context, offer the unique feature of augmenting the solubility and permeability both of diverse medicinal agents.

Amongst all the constituents of SEDDS formulations, the lipids exert the most remarkable effect on the bioavailability of drugs. The mode of transport of drugs through the lymphatic system, however, depends upon the nature of lipids. Lipids having a carbon chain length shorter than 12 carbon atoms, i.e., medium chain triglycerides (MCTs), enter systemic circulation through the portal blood. On the contrary, the re-esterified fatty acids of long-chain triglycerides (LCTs) are secreted from the intestinal cells by exocytosis into the lymph vessels.

The surfactants, besides increasing the dissolution rate of drugs, disrupt the phospholipid bilayer of intestinal membranes, which along with the unstirred aqueous layer forms the rate limiting barrier to absorption of drugs.

Table 1 enlists a few of the recent literature instances on bioavailability enhancing effect of SEDDS carried out in laboratory animals.

Epilogue
Self-emulsifying formulations offer a practical solution to augment the oral bioavailability through various physicochemical and physiological mechanisms controlling drug absorption. Till date, no other drug delivery technology can match the bioavailability enhancement potential of the SEDDS. Nevertheless, like any other DDS, there have been tangible barriers to the practical applications of these SEDDS formulations. Research efforts, therefore, need to be intensified on these promising DDS directed at surmounting the solubility, permeability and stability issues, improving production methodologies on industrial scale, and refinement of in vitro as well as in vivo models for more dependable prognosis of the formulation performance in man.