Lipids for Self-Emulsifying Drug Delivery Systems

MICHAEL TIECK - STOCK.ADOBE.COM

With the majority of APIs under development considered poorly soluble and/or poorly permeable, formulators have been forced to develop new solutions for overcoming these key issues. Lipid-based drug delivery is one of only a few methods effective for increasing both the solubility and permeability of APIs.

Formulations that are designed to spontaneously emulsify upon contact with aqueous media, including self-emulsifying drug delivery system (SEDDS) and self-microemulsifying drug delivery system (SMEDDS), are often preferred because they are relatively easy to formulate, can potentially decrease first-pass metabolism, minimize food effects (minimize the difference in API absorption in the fed and fasted states), and can protect APIs sensitive to degradation in aqueous environments. In addition, because the API is dissolved in a pre-concentrate and not subject to amorphous-to-crystal transitions, which can occur over time with other technologies, SEDDS formulations are relatively more stable.

The key to successful SEDDS formulation is the choice of the right combination of lipid excipients for the particular API and route of administration.

Some basic SEDDS properties

Lipid-based formulations are generally classified into four categories, according to Philippe Caisse, scientific director pharmaceuticals at Gattefossé. Type I are composed 100% of lipids. Type II are SEDDS without water-soluble components that consist of 40–80% oils and 20–60% surfactants with low hydrophilic-lipophilic balance (HLB) values, have a turbid oil-in-water dispersion aspect, and are easily digested.

Type III lipid formulations are SEDDS/SMEDDS composed of <20–80% oils, 20–50% high-HLB surfactants, and 0–50% hydro cosolvents that have water-soluble components, form clear of bluish dispersions, and are less easily digested. Type IV systems are composed of 0–20% low-HLB surfactants, 30–80% high-HLB surfactants, and 0–50% hydro cosolvents and able to form clear micellar solutions but may not be digested.

Typically, SEDDS are isotropic and kinetically stable (SMEDDS are thermodynamically stable) formulations of functional lipids containing one or APIs for systemic delivery, according to John K. Tillotson, pharmaceutical technical business director (Americas) for ABITEC. SEDDS compositions, adds Nitin Swarnakar, North America Application Laboratory manager within BASF Pharma Solutions, comprise precise combinations of oil, surfactant, and cosurfactants to yield low-viscosity, isotropic mixtures.

The nature and selection of each of these components will, Swarnakar says, significantly affect properties such as droplet size, speed of dispersion, digestibility of the droplets, and API absorption.For example, he notes that a less digestible mixture can be formulated by including a lipid with a long carbon chain or by increasing the concentration of a less digestible surfactant.“Depending on the goals of the formulation, an optimal composition can be targeted,” he states.

Several common lipids

As of 2019, there were at least 15 commercially available small-molecule drugs formulated as SEDDS (1,2). The relatively simple need to make a small-molecule API soluble to improve drug delivery—rendering it orally available or capable of getting across the lining of the gut—involves differences in lipid structure, according to Jamie Grabowski, vice president, portfolio and sourcing at Curia (formerly AMRI).

The most common classes of lipids employed are solubilizers, emulsifiers, surfactants, and potentially co-surfactants, Tillotson comments.Medium-chain triglycerides serve as solubilizers; mono- and di-glycerides as solubilizers and emulsifiers; and pegylated esters, polysorbates, and ethoxylated oils as surfactants and co-surfactants.

Surfactants can be water-insoluble (e.g., propylene glycol esters), water-dispersible (e.g., linoleyl polyoxyl-6 glycerides), or water-soluble (e.g., polyoxyl-based esters), according to Caisse. Diethylene glycol monoethyl ether is the most common hydrophilic cosolvent.

“These functional lipids are preferred based on their efficacy with regard to solubilization and emulsification capabilities,” says Tillotson. For example, medium-chain triglycerides have a high solubilizing capacity for lipophilic drugs and are especially easy to emulsify using suitable surfactants, such as castor oil derivatives, according to Swarnakar.

A balancing act

SEDDS formulations start as isotropic mixtures that contain the API(s) dissolved in the functional oil, solubilizer, and surfactants. When the SEDDS formulation enters an aqueous environment, such as the GIT, the SEDDS forms API-containing droplets, with the API(s) contained in the hydrophobic interior and the emulsifiers, surfactants, and co-surfactants stabilizing the discontinuous oil phase inside the continuous aqueous phase.

For example, Tillotson notes that greater amounts of hydrophobic lipids tend to increase API solubility in the system for some APIs; in contrast, greater amounts of less hydrophobic lipids, such as emulsifiers and surfactants, tend to reduce globule size and generate micro-emulsions.“The challenge is determining the optimum concentrations of each functional lipid in the pre-concentrate with regard to maximizing API solubilization and emulsion performance,” he concludes.

Often SEDDS formulations may include three, four, or five excipients along with the API, according to Caisse. Formulating an optimal SEDDS may thus require numerous trials and formulation variations. He also notes that some all-in-one self-emulsifying excipient systems are available that can simplify the preparation of type II and Type III lipid-based formulations.

Multiple factors influence lipid selection

Generally, lipids with chain lengths of C8 to C18 are reported in the literature as being ideal for SEDDS formulations, according to Swarnakar. She adds that specific lipids are chosen based on the melting point and crystal lattice properties of the API in question.

Most poorly water-soluble drugs are lipophilic, and thus the solubility of the API in the lipid components of the system will be the first parameter considered, according to Caisse. For highly lipophilic drugs, oils or mixed mono, di-, and triglycerides are often used. For APIs with medium lipophilicity, low HLB (≤ 9) surfactants are often preferred, he says. For APIs with low hydrophilicity, high HLB (> 10) surfactants and hydrophilic solvents are often required.

Another very important consideration is the desired emulsion performance and characteristics of the SEDDS formulation, says Tillotson. “The ideal SEDDS formulation optimally balances the overall solubility of the API(s) while realizing the desired emulsion characteristics, such as globule size and dispersibility. The goal is to develop a system that provides for maximal API loading, while also generating a rapidly-dispersing micro emulsion,” he explains.

SEDDS formulations should also take into account the type of API being delivered, according to Tillotson. For example, Biopharmaceutics Classification System (BCS) Class II APIs are poorly soluble but readily permeable.Therefore, the focus in a BCS Class II carrying SEDDS is on lipids that provide the greatest solubility/carrier capacity for the API.In contrast, a BCS Class IV API is both poorly soluble and poorly permeable.In this case, the SEDDS needs to not only address API solubility in the functional lipids, but also, if possible, permeability issues.

For this reason, Tillotson says a BCS Class IV API-carrying SEDDS may include lipids that open tight junctions between enterocytes (functional lipids composed of C8 and C10 fatty acids) or lipids that inhibit the activity of P-glycoprotein (PGP) efflux pumps (certain mono- and di-glycerides and certain macrogolglycerides).

In addition to the nature of the API, lipids for SEDDS formulations are also selected depending on the delivery strategy, Swarnakar adds. With respect to the API, “like-dissolves-like” is the rule of thumb for choosing the lipid. “Generally, very hydrophobic drugs (log P > 5) can be solubilized in more lipophilic lipids with longer carbon chains,” he says.

Specifically, longer and fully saturated carbon chains are more stable and less digestible within the gastrointestinal tract (GT). “This less digestible nature can be beneficial to the absorption profile by providing a secondary, lymphatic route of absorption in addition to the standard portal vein absorption. This additional route of absorption can be used to enhance the bioavailability of specific APIs and increase API absorption times,” observes Swarnakar.

Other factors related to the API in addition to low in vivo permeability may also be of importance, observes Caisse, such as heat sensitivity and a high first-pass metabolism. “Hence the design of a self-emulsifying formulation as an efficient delivery system for a given API is also related to the targeted strategy for its bioavailability enhancement or physical limits of its manufacturing process,” he says.

The final dosage form should also be considered. Caisse notes that for soft-gel capsules and liquid- filled hard capsules, liquid/low-viscosity formulations are best, while for solid-filled hard capsules, semi-solid/solid excipients are preferred as the main components, although up to 20% liquid excipient is feasible.

Correlating in vitro and in vivo SEDDS performance

Despite the general understanding of how different lipids impact solubility and permeability, formulators have always struggled to predict the best SEDDS formulation prior to costly in vivo and clinical work, according to Swarnakar. “Various reported in vitro methods, such as [United States Pharmacopeia] USP type 2 dissolutions, provide limited discrimination of SEDDS formulation behavior.The interference of turbidity and biphasic media make conventional in vitro screening methods inaccurate for SEDDS formulations,” he explains.

To address this issue, BASF, in partnership with Professor Anette Müllertz at the University of Copenhagen, has recently established a robust in vitro-in vivo correlation of 10 ready-to-use SEDDS compositions using the MacroFlux device from Pion for determining the absorption potential of formulations and finished drug products in vitro. The ready-to-use compositions are categorized based on their compositional HLB values and performance-indicating target product profile attributes, including microemulsion droplet size and enzymatic digestibility.

“Through careful testing and consideration of the chemistries in these formulations, the formulator is able to pre-screen a range of formulations and select according to their preferred API absorption behavior,” says Lindsay Johnson, global technical marketing manager–Pharma Solutions at BASF.She believes this tool will help formulators avoid costly pre-clinical studies and ensure continuity of product quality and performance during product development. “Overall, these tools will enable formulators to choose the best SEDDS formulation based on the API properties for preclinical and clinical trials and accelerate the product development timeline,” she asserts.

Extending efficacy

New developments with SEDDS are focused on extending the efficacy of the dosage form beyond simple improvements in solubility. Areas of research, according to Tillotson, include chylomicron signaling for tissue targeting, long-chain lipid inclusion promoting lymphatic transport and reduced first pass metabolism, and employing lipids as a delivery system for more specific targeting such as conjugated antibody targeting with APIs.

Moving beyond capsules

Liquid SEDDS formulations for oral administration are generally loaded into liquid-filled soft-gelatin or hard-gelatin capsules. “An ongoing challenge is how to administer SEDDS on higher throughput dosage forms, such as tablets,” says Tillotson.

There are many drivers for the development of solid or semi-solid SEDDs formulations in addition to the ability to easily incorporate them into tablets. They may also offer improved stability and enable sustained-release or abuse-deterrent formulations. Liquid SEDDs, according to Caisse, are susceptible to degradation during long-term storage and suffer from in vivo precipitation issues and handling complexity.

Research is ongoing in this application at multiple institutions.“The primary difficulty is generating tablets at industry tableting speeds with minimum or no sticking to the punches that also release the SEDDS formulation,” he observes. Other solid SEDDS technologies are also being developed such as powder and granular SEDDS.

SEDDS compositions formulated as solids can be achieved, according to Swarnakar, using a variety of methods, including adsorption onto solid carriers, freeze drying, spray drying, and melt granulation. Caisse adds that wet granulation and extrusion/spheronization are other solidification techniques used for converting liquid SEDDS into solid SEDDS.

Of these methods, Johnson notes that adsorption onto an inert solid carrier is most common. In this case, a liquid SEDDS solution is mixed onto various solidifying agents such as mannitol, lactose, or calcium carbonate.

The key to this strategy is to retain the solubilization and dissolution enhancing properties of the SEDDS formulations once they are absorbed on the solid carrier materials, Caisse observes.The resulting powders, he says, can be subsequently filled into capsules or formulated as solid dosage forms such as tablets, granules, or pellets in sachets.

The growing role of lipid nanoparticles

Progress has been dramatic in the past few years particularly with respect to the development of lipids that facilitate the absorption of large molecules—notably biologics, according to Grabowski. “Driving the development of these lipids for SEDDS is the need for drug products with expanded methods of administration, notably oral. This is a big challenge for biopharmaceutical companies that want to offer patients the choice of an oral drug instead of an injectable,” he says.

Specifically, Grabowski notes that developers are moving away from relying on off-the-shelf lipids to get hydrophobic drug substances into solution or improve their stability. Instead, they are turning to complex cationic lipids that are actually helping with the functionality and efficacy of biologics by altering their bioavailability and pharmacokinetics, both in SEDDS and lipid nanoparticles (LNPs) such as those used in the formulation of mRNA vaccines against the SARS-CoV-2 virus, he says.

Cationic lipids improve the solubility, oral absorption, bioavailability, and pharmacokinetics of biologic drug substances, according to Grabowski. In LNPs, which have a much more complex structure than SEDDS, they are used along with cholesterol, a minor lipid, and one other typically proprietary compound.

Lipid nanoparticles such as cubosomes, adds Tillotson, contain both hydrophilic and hydrophobic regions and are readily absorbed by cells through typical lipidomic pathways.“The amphiphilic nature of these lipid carriers allows for the incorporation of proteins, RNA and both hydrophilic and hydrophobic APIs.For this reason, lipid nanoparticles composed of high-purity, functional lipids are ideal carriers for biologics and small-molecule actives,” he contends.

Increasing focus on lipid design

Across all research regarding lipid-based delivery, the main focus is on the purposeful design of lipids with specific structural and physiochemical properties. “Ultimately,” asserts Grabowski, “the industry will stop using off-the-shelf compounds such as cholesterol for LNPs and switch to carefully designed lipids with improved and diverse structures that enable fine tuning of the intended pharmacological impacts.”

For instance, Grabowski notes that assessing the structures of cationic lipids through structure-activity relationships will help improve the pharmacokinetics of drug delivery. “It will become less about simply being able to form micelles and more about making lipids that allow the drug substance to get across the gut lining and improve pharmacokinetics. That’s going to be the big issue,” he asserts.

Similarly, Tillotson sees emerging research on lipid-based drug delivery as being focused on the design and manufacture of high-purity lipids for specific applications, such as incorporation into LNPs for the systemic delivery of biological therapeutics. He also notes that ongoing lipidomics research seeks to identify novel lipids and lipid metabolites that can be potentially employed in biomarker discovery programs for specific disease states.

Greater expectations for GMP lipid manufacture

In many advanced lipid-based formulations, including SEDDS/SMEDDS, the lipids are not inactive ingredients, but functional excipients that impact the efficacy of the drug product. Both drug manufacturers and regulators are responding by treating these types of functional excipients more like APIs, according to Grabowski.

“Increasingly drug manufacturers want lipids used in their drug formulations to be made according to [current good manufacturing practice] CGMP requirements,” Grabowski says. “While lipids may not need to be produced in a CGMP environment for early-phase research, if regulators potentially consider them to be additional ‘APIs’ because they affect the bioavailability of the drug substance or efficacy of the drug product, the lipid supplier will be expected to have the ability to produce GMP lipids.” As an example, Grabowski notes that there is movement toward treating cationic lipids as APIs.

One of the biggest challenges with CGMP manufacturing of lipids, observes Tillotson, is maintaining both quality and consistency. “This goal is achieved by maintaining consistent raw material stocks and tight specifications on manufacturing unit operations,” he says. That is important for SEDDS in particular, adds Johnson, because across one monographed chemistry, different manufacturer materials may ultimately perform differently in a final
formulation. “For this reason, the sensitivity of formulations needs to be considered as the choice of supplier is weighed,” she comments.

Another challenge for lipid manufacturing highlighted by Caisse is the need to find new ways to manufacture lipids with sustainable raw materials and more eco-friendly processes that leverage new classes of catalysts.

Additionally, suppliers who start from certified sustainably sourced base raw materials, like palm kernel oil, coconut oil, corn oil, and others, can bring value and awareness to ethical and sustainable sourcing in the pharmaceutical industry, according to Johnson. For example, she observes that many of BASF’s lipid-based pharmaceutical excipients come with an external certification for being responsibly sourced.

References

1. I. Pehlivanov, JIMAB 25(2), 2575–2582 (2019).
2. S.P. Kovvasu et al., Asian J Pharmaceutics 13 (2):73–84 (2019).

Article Details

Pharmaceutical Technology
Volume 45, Number 11
November 2021
Page: 20–24

Citation

When referring to this article, please cite it as C. Challener, “Lipids for Self-Emulsifying Drug Delivery Systems,” Pharmaceutical Technology 45 (11) 2021.