SMEDDS (self-microemulsifying drug delivery system) is a liquid that a hydrophobic (poor water-solubility) or lipophilic (soluble in fats or oils) drug is dissolved in to increase its oral bioavailability. In fact, SMEDDS are a vital tool in overcoming the formulation difficulties and improving the oral bioavailability of hydrophobic or lipophilic drugs. Most phytochemicals, in fact, most drugs are lipophilic. This is because drugs are typically organic molecules that are designed to bind hydrophobic pockets on a target site. In general, as a drug is optimised, the molecule’s lipophilicity tends to increase as its activity (target binding) increases. Thus, generally, the more lipophilic a drug is, the stronger it is. So SMEDDS are of utmost importance. However, SMEDDS are extremely rare, in fact, I have only found one single company outside of the pharmaceutical industry to use SMEDDS.

SMEDDS are not to be confused with SEDDS (self-emulsifying drug delivery system), phospholipid drug delivery, or a standard DDS (drug delivery system). SMEDDS are microemulsions compared to SEDDS, which are standard emulsions, so as you can imagine SMEDDS have a higher absorption rate. Phospholipid drug delivery is a rare but used drug delivery system in the supplement industry. Ironically, phospholipids are used within SMEDDS as a surfactant, making SMEDDS several tiers up.

Why Do We Need SMEDDS?
To understand why we need SMEDDS we first have to understand how drugs are absorbed. When a drug is taken orally it is absorbed in the GI tract via GI juices. These GI juices are what we call (in chemistry) polar. A polar substance or solution is hydrophilic (water loving; ie. alcohols, acids), as like dissolves like, a drug must have hydrophilic characteristics to first dissolve in these GI juices. The drug must be soluble in the polar aqueous medium of the digestive system. If the drug cannot mix with the digestive juices, then it will never be absorbed. A lipophilic drug will have a hard time dissolving in these GI juices, this is where SMEDDS comes in.

Before we delve into how SMEDDS work let me introduce cellular membranes. Cellular membranes are lipid bilayers in the GI tract that separate what’s being digested from entering the hepatic portal system (liver metabolism). A lipid bilayer consists of phospholipids (hence phospholipid drug delivery system). Warning ⚠️ Chemistry Explanation. Phospholipids are phosphorylated diglycerides. The diglycerides, with their two fatty acid chains, form a non-polar double tail (opposite of polar; ie. fats, oils). The phosphate forms a charged group at the head of the molecule.

Phospholipids can stack together, as sheets, with their polar heads together on one side and the non-polar tails together on the other. In an aqueous environment, two sheets can stack together with their non-polar ends face-to-face. This stacking forms a bilayer that separates the aqueous GI juices from the other side of the bilayer. If a drug doesn’t have lipophilic characteristics it cannot cross the cellular membrane, however, it needs hydrophilic characteristics to first dissolve in the GI juices.

So How Does SMEDDS Actually Work?
SMEDDS dissolve a drug in an oil, then encapsulates the drug via a surfactant (SMEDDS also use a cosurfactant to increase solubility). When SMEDDS (containing our drug) is mixed in with water the hydrophilic characteristics of the drug is drawn to the water, while the lipophilic ends want to stay in our oil. The surfactant (which encapsulates our drug) forms teeny globulars between the two layers. These globulars are referred to as emulsions, and in the case of SMEDDS form microemulsions. These microemulsions are ‘confused’ as to what layer to dissolve in, so to speak. When we ingest these microemulsions they can readily be absorbed by the GI tract. However, if the drug is too polar, it will likely never be able to cross the non-polar bilayer. The drug’s lipophilicity leads to increased permeation across cellular membranes.

As you can see from the below graph. A standard lipophilic drug has 30-40% oral bioavailability. With SMEDDS it has over 98%, thus, increasing bioavailability by 2.5-3 fold.

Chiruta, V. 2009. SMEDDS (Self-Microemulsifying Drug Delivery System). Academia. Article #1903010001