LIPID-BASED EXCIPIENTS - Misconceptions About Lipid-Based Drug Delivery

INTRODUCTION

For decades, lipid-based drug delivery systems (LBDDS) have been studied, developed, characterized for improving uptake of poorly soluble compounds, found to be safe and effective in de­livering a multitude of compounds of diverse chemistries, and present in pharmaceuticals across the globe, including dozens of FDA-approved products.¹ Yet, the viability of LBDDS as a platform for modern drug development is still a concern to some due to lingering misconceptions about their functionality, stability, han­dling, and toxicology. Many of these concerns may be easily ad­dressed by broadening our understanding of oleochemicals’ strengths and sensitivities.

The following aims to provide formulators confidence in using LBDDS as part of formulation development programs, by demonstrating their benefits and key functional mechanisms when used and addressing commonly misrepresented, misinter­preted, and misunderstood LBDDS topics.

UNDERSTANDING MECHANISMS OF ORAL BIOAVAILABILITY ENHANCEMENT FOR LBDDS

Among the mechanisms attributed to lipid-based formula­tions for enhancing oral bioavailability is natural lipid metabolism in the gut. Known as lipolysis, this metabolic process initiates on contact with stomach fluid thereby releasing gastric lipase. Sub­sequently, pancreatic lipase and bile salts further break down lipids into micellar structures that are absorbed by enterocytes that line the intestinal tract. Pharmaceutical actives are then sol­ubilized within these lipid formulations and absorbed through the gut in a bioavailable (solubilized) state. This process can be op­timized by using digestible surfactants/co-surfactants and oils to create self-emulsifying drug delivery systems (SEDDS) that form fine dispersions on contact with stomach fluid, thereby helping to maintain drug solubility within the emulsion particle.

There are other key mechanisms for enhancing oral bioavail­ability of actives associated with lipid-based formulations. These include targeting lymphatic absorption to bypass liver metabolism as well as reversable modulation of tight junctions to enhance permeation through the gut lining.

Starting with lymphatic absorption, long chain fatty acids (LCFAs) that are absorbed into the enterocytes can be selectively transported via the lymphatic system. Drugs solubilized within the lipid particles will then avoid first-pass metabolism and will eventually be diverted into the blood stream via lymphatic ente­rocytes.² Lipid-based formulations containing esters of LCFAs can also be used to target lymphatic absorption of lipophilic drugs having Log P >5 and solubilities >50 mg/mL in the LCFA based oil as demonstrated in several studies.³

For low-permeability actives including peptides, the re­versible opening of tight junctions may assist in the peptide ab­sorption, and with certain lipid-based chemistries, promote the increased uptake of model compounds via the same mechanism. For example, increasing the concentration of materials like Labrasol^® (caprylocaproyl polyoxylglycerides) and Labrafac^® MC60 (glyceryl mono and dicaprylocaprate) has shown to induce transient opening of intestinal tight junctions to allow the transport of insulin and FITC-Dextran across the epithelial barrier.^4,5 Other lipids with medium chain fatty acid chemistries like Capryol 90 (propylene glycol monocaprylate), can enhance the uptake of orally administered model drugs as well.⁶

OUTDATED CONCEPTS OF INTESTINAL EFFLUX INHIBITION

Given the variety of uptake-enhance­ment mechanisms inherent in lipid chem­istry, LBDDS have historically been evaluated as possible inhibitors of active transport. Previous studies and their con­clusions based on antiquated analytical methods that P-gp inhibition occurred with model drugs formulated with permeation enhancers like Labrasol (caprylocaproyl polyoxylglycerides), have recently been shown to be inapplicable as they were based on models no longer considered to be representative of such systems.⁷

A more recent study suggested that conclusions claiming LBDDS are possible P-gp inhibitors may have misinterpreted other lipid excipient-induced penetration-enhancement mechanisms with P-gp inhi­bition.⁸ This study compared the gold standard model from older studies with a more modern version that considered ad­ditional parameters, highlighting irregu­larities between the two. With so many possible mechanisms of bioavailability en­hancement intrinsic to lipid-based formu­lations: participation in the lipolysis process, avoidance of liver metabolism, targeting lymphatic uptake, and reversible modulation of tight junctions, it is difficult to attribute permeation enhancement just to efflux inhibition.

LIPIDS VS. POLYMERS: DIFFERENT CHEMISTRIES, COMPOSITIONS, FORMULATION PROCESSES

While some lipids, specifically those of the chemically modified variety, have overlapping applications with polymeric materials, it is important to understand these chemical families are indeed differ­ent. One key distinction is lipids consist of fatty acids, naturally occurring (organic) moieties abundant in plants and seeds, while polymers are composed of chains of repeated units generally derived from syn­thetic sources. Simple lipids (eg, glyc­erides) are composed of alkyl heads esterified to fatty acid tails and have well-defined molecular weights, ranging from 8 to 24 pairs of -CH2. Lipid-based mate­rials also generally have lower melting ranges than high molecular weight poly­mers.

Physico-chemical properties of poly­mers, on the other hand, are quantified by their molecular weights and highly de­pendent on the number of repeated units. For example, PEG-1000 and PEG-4000 are both composed of 1000 and 4000 re­peat units of ethylene glycol and have dif­ferent properties due to their vastly different molecular weights.

Also, because lipids are derived from natural and botanical sources, they can range in homogeneity depending on their raw materials (ie, whole natural oil vs. fractionated oil vs. purified fatty acids) and manufacture process design. For example, Labrafil M 1944 CS conforms to the USP monograph for oleoyl polyoxylglycerides and is derived via alcoholysis of apricot kernel oil with PEG to form PEG esters and glycerides of mostly oleic acid, and con­trolled quantities of stearic, palmitic, and linoleic acids. This is compared to Capryol 90, which conforms to the USP mono­graph for propylene glycol monocaprylate that is derived via direct esterification of propylene glycol and caprylic acid and distilled to contain >90% monoesters of the raw materials therein. Even though lipid materials have diverse components, this does not make their composition or specifications less consistent than poly­mers. Like polymeric materials, lipid sys­tems can also have a range of purity depending on manufacturing process and extent of purification (eg, distillation). Lipid-based materials like all pharmaceu­tical-grade materials in the US must still conform to strict USP/NF monographs.

Lipids’ melt properties and diverse chemistries allow them to be easily incor­porated into processing techniques that traditionally use polymer-based systems. Due to the lower melting point ranges of lipid excipients, generally <75°C, they do not require diluting or dispersing in sol­vents in hot melt processes (eg, melt gran­ulation). They can instead be melted and applied directly onto a substrate without the need for solvents. This means an evaporation step is not required to achieve diverse functionalities like modified release, taste masking, and powder lubrica­tion.⁹

As another example, lipid excipients can be incorporated into hot-melt extru­sion processes but do not undergo a glass

transition like polymer-based materials. Due to lower melting point ranges, lipid-based HME processes do not require the addition of plasticizers because the low viscosities of the melted lipids reduces the need for material shear and leads to re­duced energy while maintaining a high throughput.¹⁰ Lastly, lipid-based emulsions can undergo lyophilization to form semi-solids that will disperse on contact with aqueous media.¹¹

THE IMPORTANCE OF DRUG SOLUBILITY IN LIPID VEHICLES

There are several potential ways in which lipid-based chemistries can be har­nessed to enhance bioavailability of orally dosed compounds. API solubility in lipids, for example, can be used as an indicator of a formulation’s final performance be­cause compounds solubilized in the lipid vehicle can fully participate in the lipolysis process. In an internal study carried out by the Gattefossé Technical Center of Excel­lence, Cinnarizine solubilized in SEDDS maintained better solubility in biorelevant gastrointestinal media than Cinnarizine in a suspended state (Figure 1). In other words, a larger percentage of Cinnarizine was in a state that can be absorbed by the body when pre-dissolved in a SEDDS than when dosed suspended in the same vehi­cles.¹² This is a fundamental rationale be­hind using lipids for oral bioavailability en­hancement. It is for this reason that it is highly recommended to complete a solu­bility screening of actives in an array of lipid vehicles during early stages of devel­opment.

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In another example, Danazol (a well-characterized low-water solubility model compound) was orally administered to rats in both a traditional aqueous suspension and in Labrafil M 2125 (Linoleoyl polyoxyl-6 glycerides NF) based solutions and sus­pensions. Table 1 contains concentrations of Danazol and percentages dissolved in various prepared formulations.

The plasma concentration–time pro­files in Figure 2 show a 4-mL/kg solution of Labrafil increased Danazol oral bioavailability nine-fold compared to an aqueous suspension. Note that even lipid-based suspensions of Danazol showed high uptake. It is important to highlight the lipid-based suspensions contained consid­erable percentages of drug in solution cre­ating a combination of lipid-based solution/suspension compared to the aqueous suspension control.¹³

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While the Labrafil solution showed a similar increase in bioavailability compared to the Labrafil suspension with partial solubilization, increases in bioavail­ability tend to be dependent on the chem­istry of the active compound as well as the dosing methodology based on Gatte­fossé’s experience with similar studies.

EFFECT OF EMULSION PARTICLE SIZE ON BIOAVAILABILITY

The notion that emulsion particle size affects the uptake of an active solubilized within a SEDDS formulation is frequently debated, and not surprisingly, any corre­lation made between droplet size and up­take is generally dependent on formulation chemistry and dissolution medium. The emulsion particle size is dy­namic, becoming finer throughout the lipolysis process, and a lipid-based system undergoes intricate physiological progres­sions having many variables.¹⁴ Therefore, concluding particle size by itself correlates to bioavailability can be misleading.

A potential reason for this common misunderstanding could be a historical view that small particle size is directly cor­related to consistent and predictable dis­persions. This idea was perpetuated by the 1994 study comparing Sandimmune, a cyclosporin soft gel capsule that formed a crude emulsion in the gut, to the second-generation Neoral formulation, a soft gel capsule containing a cyclosporin SMEDDS formulation. The latter self-microemulsi­fied upon contact with gastric fluid, while the former required dispersion by digestive enzymes to emulsify. This study concluded the microemulsifying nature of Neoral simplified dispersion, leading to more con­sistent dispersion profiles.¹⁵

A more recent study highlighted the difficulty correlating in-vitro dispersion size to in-vivo uptake. It examined in-vivo per­formances of different self-emulsifying Danazol formulations with varying oil/sur­factant ratios resulting in a range of emul­sion droplet sizes. In this study, uptake decreased with decreasing particle size, while uptake increased with course emul­sions. The emulsion formulas contained three times as much digestible Maisine CC oil (glyceryl monolinoleate) compared to the non-digestible microemulsion contain­ing increased percentages of Cremophor EL and ethanol. The alternative conclusion was therefore digestibility is a better pre­dictor of bioavailability.¹⁶

In-vitro lipolysis is a screening tech­nique used to simulate this mechanism. In-vitro lipolysis has been well documented to be more representative of a lipid formula­tion’s ability to maintain an active’s solu­bility in-vivo as the model accounts for the presence of enzymes that represent the dy­namic conditions that occur in lipid metab­olism.¹⁷

LIPIDS ARE STABLE & EASY TO HANDLE

As with other excipients, there are po­tential pitfalls that can occur when han­dling lipid-based materials. This has led to a misconception that lipids are unstable and difficult to work with, especially in terms of degradation via oxidation or hy­drolysis. Oxidation can occur when sensi­tive moieties are exposed to oxygen. Oxidation reactions form peroxides from these moieties that propagate into addi­tional peroxides that then generate unsta­ble systems. Hydrolysis occurs when ester bonds are exposed to environmental moisture and react with water, cleaving these bonds and leading to formation of free fatty acids and reduction in ester con­tent.

It’s important to keep in mind these sensitivities are prevalent in many excipient chemistries to a far greater extent espe­cially in terms of propensity to oxidation. The omnipresence of oxygen-sensitive ma­terials in pharmaceutical products is a tes­tament to the manageability of oxidative challenges in drug development. Lipid-based excipients are quite easy to work with and can bring drug delivery solutions that greatly outweigh their controllable challenges. It is important to keep in mind when researching potential degradation pathways for lipids that they are often studied using forced experimental condi­tions.¹⁸ Oxidation and hydrolysis are avoidable using simple preventative meas­ures in terms of storage and formulation in a pharmaceutical setting.

Lipid-based materials should be stored in sealed containers under inert conditions by purging headspace with ni­trogen between uses. When melting and processing, dry heat sources should be used. Water baths are to be avoided when applying heat to melt and mix the formu­lation components. Instead, laboratory mi­crowave ovens can be used to heat in short intervals. Commercial packs can be heated in ovens, hot boxes, or drum warmers.

To avoid potential oxidation from oc­curring during the formulation process, it is highly recommended to incorporate antioxidants into formulations during the ini­tial stages of development. In a recent white paper, evolution of peroxide value, a critical stability parameter and indicator of oxidation of lipid excipients, was exam­ined with and without antioxidants BHT (butylated hydroxyanisole) and BHA (buty­lated hydroxytoluene). In Figure 3, one can see that in each case, peroxide value evolved at a significantly slower rate in the presence of antioxidants.¹⁹

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DOSING IN PRECLINICAL STUDIES

Lipid vehicles are ideal candidates for preclinical screening studies due to their long history of use and ability to achieve high exposure due to bioavailability-en­hancement mechanisms. A common mis­conception is lipid-based vehicles cause inevitable gastric irritation, tolerability is­sues, and toxicity in certain animal models. This belief stems from labs dosing subjects at improper levels or using poor dosing techniques and not from the lipids them­selves.

As an example, rodents suffering from gastric irritation or emesis after hav­ing been orally dosed with Labrasol often arises when drugs are dosed neat in Labrasol at maximum recommended vol­umes for rodents. The rodents are unable to effectively metabolize lipids at this vol­ume, which leads to negative effects. To avoid this, determine the saturation solu­bility of the drug in a volume of Labrasol for dosing of your target drug load to as­sess whether the required volume of Labrasol is within no observed adverse ef­fect limits. If the required use level is too high, reduce the amounts of Labrasol in combination with other vehicles to achieve required solubility targets while remaining within known safety limits.

Dose-escalation studies that push boundaries of preclinical formulations should always refer to safety limit evalua­tions of single lipid excipients in the test species. Like other surfactant chemistries, lipid-based surfactants can cause more gastric irritation due to their surface-active interactions with the gut lining than simple glycerides; therefore, recommended safety dosing levels should be adhered to. The lipid formula can be optimized to achieve uptake targets at later stages and tested for safety once safety limits of the active have been well characterized. Gattefossé has extensive safety studies available on our excipients to assist in optimizing early stage tox formulations.

Having had a high number of lipid-based oral drugs approved by the FDA and available in the market shows how well lipid vehicles are tolerated when de­veloped by formulators who dose the ma­terials correctly. A 2017 review includes 36 examples of FDA-approved lipid-based formulations, including Absorica and Xtandi, which contain high levels of poly­oxylglyceride-based surfactants, demon­strating lipid systems have withstood not only preclinical safety testing but also vig­orous clinical human trials.¹

SUMMARY

Bioavailability enhancement and pro­cessing flexibility are just a few of the fa­cilities lipid-based excipients, due to their diverse physicochemical features and functionalities, can provide. Their chemistries have well-defined tox and safety profiles, and they offer multifunc­tionality, such as solubility, penetration, and bioavailability enhancers. They are also straightforward, easy-to-use, and compatible with solvent-free processes.

LBDDS can advance formulations from early stages through to commercial­ization when basic dosing recommenda­tions and handling protocols, some of which have been previously discussed, are followed, thereby reducing costs and min­imizing the time to market.

Having been used for decades on a global scale, LBDDS are viable platforms that should certainly be adopted into the formulator’s toolbox for use as key com­ponents of pharmaceutical product devel­opment.

REFERENCES

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Rollie Fuller is Technical Service Coordinator at Gattefossé USA, where he is responsible for provision of technical, quality, and regulatory information to customers. He joined the Technical Service Department in 2019 and has since become an integral part of in internal and external tech support initiatives. He earned his BSc in Chemical and Biomolecular Engineering from New York University in 2017.

Ron Permutt is Senior Director, Pharmaceutical Division, at Gattefossé USA, where he oversees the pharmaceutical sales, technical, marketing, and laboratory operations in Paramus, NJ. Prior to joining Gattefossé in 1999, he worked at Cerestar, developing cyclodextrin business in the northeastern United States and prior to that as Plant Research Engineer at JM Huber Ink Division. He earned his MBA from Fairleigh Dickinson University, NJ, and his BSc in Chemical Engineering from Northwestern University, IL.