When considering a lipid-based system to enhance solubility and bioavailability, formulation services buyers as well as practitioners often focus on the use of self-microemulsifying or even self-nanoemulsifying delivery systems, the so-called SMEDDS and SNEDDS. This designation suggests a relationship between particle size of the emulsified formulation and bioavailability-enhancing potential. This conception is misleading and generally not helpful in the context of predicting lipid formulation in vivo performance. This article provides an overview of the factors that do affect performance and how lipid formulations may be assessed in a biopredictive manner in vitro.
When considering a lipid-based system to enhance solubility and bioavailability, formulation services buyers as well as practitioners often focus on the use of self-microemulsifying or even self-nanoemulsifying delivery systems, the so-called SMEDDS and SNEDDS. This designation suggests a relationship between particle size of the emulsified formulation and bioavailability-enhancing potential. This conception is misleading and generally not helpful in the context of predicting lipid formulation in vivo performance. This article provides an overview of the factors that do affect performance and how lipid formulations may be assessed in a biopredictive manner in vitro.
These dispersions commonly exhibit particle sizes below 100 nm and have been shown to enhance the oral bioavailability of lipophilic compounds. The ease of dispersion and the small particle size of the resultant colloidal emulsion have historically been viewed as the principal reasons for the utility of SEDDS, SMEDDS and SNEDDS in the delivery of lipophilic compounds. Consequently, most of the commercially available lipidic formulations are complex mixtures of lipids, surfactants and co-solvents/co-surfactants constructed to both improve API solubility in the formulation (and therefore increase API payload and decrease pill burden) and also to maximize dispersion of the dose form on exposure of the capsule fill to the GI contents.
The design, development, and testing of these formulations is often still based entirely on these formulation endpoints - namely API solubility in the formulation and rapid and complete dispersion in a simple in vitro dispersion test, commonly coupled with a particle size measurement to characterize the resulting dispersion.
However, the understanding of the mechanisms that underpin lipid-based formulation performance has evolved tremendously in the last decade, and it is now abundantly clear that the particle size formed after self-emulsification is not predictive for absorption potential.
The adage that “smaller is better” has been responsible to a large degree for the use of SMEDDS and SNEDDS. In turn, the addition of relatively large amounts of surfactants to facilitate rapid and effective in vitro dispersion into a micro- or nanoemulsion has been used to provide for this perceived improvement in formulation performance.
Current knowledge indicates that the following factors drive lipid formulation performance:
- Avoidance of API precipitation on dispersion (usually on capsule rupture in the stomach)
- Stimulation of secretion of endogenous solubilizing lipids present in bile (bile salt, phospholipid, cholesterol)
- Supply of exogenous (formulation-derived) lipids, lipid digestion products, surfactants, and cosolvents
- Generation of mixed colloidal species from endogenous and exogenous solubilizers with the solubilization capacity to prevent API precipitation during GI transit
To properly assess the impact of all these effects on the likely pattern of in vivo solubilization, in vitro digestion tests are very valuable tools. These tests involve the addition of enzymes to simulate digestion and include a centrifugation step to separate collected samples into an aqueous dispersed phase (from where API absorption occurs), a pellet phase (containing precipitated API) and an undigested/undispersed lipid phase (which acts as an API-rich reservoir).
Consensus exists among experts that the endpoints obtained via these digestion tests provide a much better estimate of in vivo performance than particle size of the dispersed formulations. While there may be use cases where lipid formulation dispersibility is crucial to product quality (for example in the nutritional supplement space where lipid-based formulations may be mixed with beverages directly prior to consumption to create an optically clear nanoemulsion), we believe that the designation of formulations as either SMEDDS or SNEDDS isn’t very helpful in the context of predicting lipid formulation in vivo performance.
In our view, the focus during lipid formulation design should be on maximizing API solubilization and minimizing API precipitation following digestion. While optimization for these endpoints requires case-by-case evaluation, formulation design options that are generally effective in this regard are i.) to increase the lipid content in the formulation and ii.) to use glycerides that intercalate effectively with endogenous biliary- secreted bile salt, phospholipid and cholesterol species.
Lipid-based formulations are widely used to enhance the oral bioavailability of poorly water-soluble compounds. Self-emulsifying delivery systems (SEDDS, SMEDDS and SNEDDS) are a subset of lipid-based formulations that have enjoyed particular interest from academicians and industrialists alike. These formulations consist of an isotropic mixture of API, lipid, surfactant and typically a co-surfactant or co-solvent. When exposed to the fluids of the gastrointestinal (GI) tract, these systems spontaneously emulsify to form highly dispersed micro- or nanoemulsions.
These dispersions commonly exhibit particle sizes below 100 nm and have been shown to enhance the oral bioavailability of lipophilic compounds. The ease of dispersion and the small particle size of the resultant colloidal emulsion have historically been viewed as the principal reasons for the utility of SEDDS, SMEDDS and SNEDDS in the delivery of lipophilic compounds. Consequently, most of the commercially available lipidic formulations are complex mixtures of lipids, surfactants and co-solvents/co-surfactants constructed to both improve API solubility in the formulation (and therefore increase API payload and decrease pill burden) and also to maximize dispersion of the dose form on exposure of the capsule fill to the GI contents.
The design, development, and testing of these formulations is often still based entirely on these formulation endpoints - namely API solubility in the formulation and rapid and complete dispersion in a simple in vitro dispersion test, commonly coupled with a particle size measurement to characterize the resulting dispersion.
However, the understanding of the mechanisms that underpin lipid-based formulation performance has evolved tremendously in the last decade, and it is now abundantly clear that the particle size formed after self-emulsification is not predictive for absorption potential.
The adage that “smaller is better” has been responsible to a large degree for the use of SMEDDS and SNEDDS. In turn, the addition of relatively large amounts of surfactants to facilitate rapid and effective in vitro dispersion into a micro- or nanoemulsion has been used to provide for this perceived improvement in formulation performance.
Unfortunately, these dispersion optimization measures detract from in vivo solubilization potential, as water-miscible excipients rapidly leach from the formulation into the aqueous environment with a concomitant loss of solvent capacity and the risk of API precipitation into a less soluble form. The current state of the art indicates that the in vivo performance of lipid-based formulations is much more sensitive to the physicochemical properties of the lipid digestion products, formed after interaction of the formulation with the endogenous systems that normally act to digest dietary lipid, rather than the dispersion characteristics of the formulation. Digestion results in the loss of the initial physical form of the formulation, and the solubilizing power of the colloidal phases that result dictates the pattern of API absorption far more avidly than the particle size of the dispersed formulation.
Current knowledge indicates that the following factors drive lipid formulation performance:
- Avoidance of API precipitation on dispersion (usually on capsule rupture in the stomach)
- Stimulation of secretion of endogenous solubilizing lipids present in bile (bile salt, phospholipid, cholesterol)
- Supply of exogenous (formulation-derived) lipids, lipid digestion products, surfactants, and cosolvents
- Generation of mixed colloidal species from endogenous and exogenous solubilizers with the solubilization capacity to prevent API precipitation during GI transit
To properly assess the impact of all these effects on the likely pattern of in vivo solubilization, in vitro digestion tests are very valuable tools. These tests involve the addition of enzymes to simulate digestion and include a centrifugation step to separate collected samples into an aqueous dispersed phase (from where API absorption occurs), a pellet phase (containing precipitated API) and an undigested/undispersed lipid phase (which acts as an API-rich reservoir).
Consensus exists among experts that the endpoints obtained via these digestion tests provide a much better estimate of in vivo performance than particle size of the dispersed formulations. While there may be use cases where lipid formulation dispersibility is crucial to product quality (for example in the nutritional supplement space where lipid-based formulations may be mixed with beverages directly prior to consumption to create an optically clear nanoemulsion), we believe that the designation of formulations as either SMEDDS or SNEDDS isn’t very helpful in the context of predicting lipid formulation in vivo performance.
In our view, the focus during lipid formulation design should be on maximizing API solubilization and minimizing API precipitation following digestion. While optimization for these endpoints requires case-by-case evaluation, formulation design options that are generally effective in this regard are i.) to increase the lipid content in the formulation and ii.) to use glycerides that intercalate effectively with endogenous biliary- secreted bile salt, phospholipid and cholesterol species.
