INTRODUCTION

As drug discovery continues to advance into new therapeutic frontiers, pharmaceutical formulators are increasingly challenged by the poor solubility, permeability, and absorption of modern APIs. From complex small molecules to the promise of oral biologics, the demand for safe, effective formulation strategies has never been greater.

Amidst the uncertainty of novel ingredients and formulation techniques, lipid excipients provide a safe, proven platform for enhancing in vivo formulation performance, enabling innovation without sacrificing scalability or regulatory confidence.

This whitepaper explores three areas where lipid-based systems are transforming oral drug development: synergistic lipid–polymer combinations, lifecycle management through reformulation and food effect mitigation, and oral delivery of peptides and biologics.

LIPID EXCIPIENTS ENHANCE IN VIVO PERFORMANCE

Lipid excipients leverage the body’s natural digestive processes to enhance the solubility, permeation, and absorption of many active pharmaceutical ingredients (APIs).

SOLUBILITY & SUPERSATURATION MAINTENANCE

The lipid digestion process, involving gastric lipase, bile salts, and pancreatic enzymes, creates colloidal carriers and mixed mi­celles that maintain API solubility and prevent drug precipitation. Lipid excipients also maintain drug supersaturation in vivo, allow­ing for greater absorption across the intestinal epithelium.

Formulations leveraging self-emulsifying drug delivery sys­tems (SEDDS) are especially effective at promoting solubilization. These systems utilize combinations of lipid excipients (oily vehi­cles, surfactants, or cosurfactants) to form emulsions in GI fluids that enhance solubility and bioavailability.

PERMEABILITY ENHANCEMENT VIA TIGHT JUNCTION MODULATION

Excipients with high medium-chain fatty acid ester content (C8, C10) are known for their ability to modulate tight junctions, enhancing both transcellular and paracellular permeation for challeng­ing APIs (Figure 1).^1-3

Medium-chain fatty acid esters found in excipients like Capryol^® 90, Labrasol^® ALF, and Labrafac™ MC60 can:

• Enhance transcellular absorption through the lipid digestion and super­saturation process (BCS Class II and IV)
• Enable paracellular permeation by safely and reversibly modulating tight junctions (BCS Class III and IV)
• Improve absorption of drugs subject to P-gp inhibition through the combination of supersaturation and tight junction modulation

These interactions make lipid ex­cipients effective tools for delivering both poorly soluble and poorly permeable compounds while offering consistent, scal­able performance in vivo.

INCREASED ABSORPTION VIA LYMPHATIC UPTAKE

For highly lipophilic compounds, lipid excipients can further enhance absorption by leveraging lymphatic uptake. This effect is observed in formulations containing un­saturated, long-chain fatty acids (C16, C18) such as those found in Maisine^® CC, Peceol™, and Labrafil™ M 1944 CS.

Following digestion, long-chain fatty acids are re-esterified into triglycerides within enterocytes and packaged into chy­lomicrons, which carry lipophilic drug mol­ecules into the lymphatic system (Figure 1).

The lymphatic route not only en­hances systemic exposure but also allows drugs to bypass first-pass hepatic metab­olism, a major barrier for many APIs with low oral bioavailability.

IMPROVED DOSING VIA FOOD EFFECT MITIGATION

Food is a well-known source of vari­ability in oral drug absorption, leading to reduced drug absorption (negative food effect), delayed absorption rate, or in­creased absorption (positive food effect).⁴ This “food effect” can lead to inconsistent dosing, reduced patient adherence, and additional regulatory hurdles. Lipid-based formulations offer a proactive solution by building the physiological benefits of di­etary lipids into the dosage form itself.

In lipid-based formulations, oily vehi­cles, surfactants, and/or cosurfactants are combined to create SEDDS that mimic the fed state, stimulating lipolysis and trigger­ing the release of lipase, bile salts, and pancreatic enzymes. As a result, orally ad­ministered drugs formulated with lipid ex­cipients show more consistent exposure in both fed and fasted states (Table 1).⁵

LIPID-POLYMER SYNERGIES: PRACTICAL INNOVATION FOR CHALLENGING SMALL MOLECULES

Modern APIs, including bRo5 com­pounds like molecular glues and PRO­TACs, often exhibit poor solubility and limited absorption. To formulate these molecules, scientists must balance solubi­lization and drug loading with in vivo per­formance and stability.

Traditionally, binary amorphous solid dispersions (ASDs) consisting of API in a polymer carrier have been the go-to strat­egy for solubility enhancement. While scal­able, they may fall short in vivo, as high drug loading can trigger recrystallization, and polymers alone may not overcome poor permeability.

To address these limitations, ternary ASDs incorporate a third functional excip­ient — often a surfactant — into the poly­mer–drug system.^12-14 These surfactants may act as precipitation inhibitors, disso­lution enhancers, and/or processing aids.

When lipid excipients are incorpo­rated into ternary ASDs, they not only maintain drug solubility, but they bring added in vivo performance and processing benefits.^15-18 This allows formulators to combine the advantages of lipid excipients with existing polymer-focused manufactur­ing infrastructure.

CASE STUDY: AN ENHANCED ORAL TABLET FORMULATION OF TICAGRELOR USING PVPVA & GELUCIRE^® 48/16

Recent Gattefossé research has demonstrated the impact of incorporating Gelucire lipid excipients into amorphous solid dispersions (ASDs) using ticagrelor (BCS Class IV) as a model compound.

In a 2024 study, Gelucire 48/16 (Polyoxyl-32 stearate (Type I) NF) and Gelucire 50/13 (Stearoyl polyoxyl-32 glyc­erides) were incorporated into ticagrelor–PVPVA dispersions via hot melt extrusion. This study demonstrated that both Gelucire excipients acted as plasticizers, reducing the required extrusion temperature by as much as 70°C. The addition of Gelucire 48/16 also significantly improved in vitro drug release over a binary ASD.

Building on this work, a 2025 study incorporated the most promising formula­tion into an oral tablet. A ternary ASD con­taining 14.3% ticagrelor, 21.4% Gelucire 48/16, and 64.3% PVPVA was successfully incorporated into a tablet formulation (Table 2).

Three key findings were observed:

1. The addition of Gelucire 48/16 re­duced processing temperatures by nearly 40°C relative to the binary ASD (115°C vs. 153°C).
2. The ternary system containing Gelucire 48/16 showed a significant increase in dissolution, with API release reaching 92% compared to only 18% for the bi­nary ASD (Figure 2).
3. Dissolution performance was main­tained after three months of storage at 25°C/60% RH (Figure 2).

These studies highlight the value of combining polymer carriers and lipid ex­cipients to improve both ASD manufac­turability and performance.

REFORMULATION & LIFECYCLE MANAGEMENT: MITIGATING THE FOOD EFFECT

Food effect is a well-documented ob­stacle in oral drug delivery.⁴ Drugs that depend on dietary fat for solubilization often exhibit variable absorption and bioavailability, complicating dosing sched­ules and patient adherence.

From a regulatory standpoint, the food effect also adds uncertainty. In June 2022, the FDA published an updated guidance document that recommended “conducting food effect studies early in de­velopment” to identify and mitigate risk associated with variable absorption.^19,20 And this is not a niche issue — an analysis of FDA and EMA approvals from 2010 to 2017 showed that >40% of orally admin­istered drugs exhibited a positive food ef­fect, and a similar analysis of oncology drug approvals from 2003-2016 showed that anywhere from 55% to 69% of com­pounds exhibited fed and fasted differ­ences in AUC or Cmax.^21,22

The food effect is often viewed as a barrier in oral drug development, compli­cating clinical translation and patient use. However, it also presents an innovation opportunity. Reformulating an existing molecule to reduce or eliminate its food ef­fect can unlock significant value as part of a broader lifecycle management strategy or 505(b)(2) program. Lipid-based sys­tems offer a proactive approach by repli­cating the physiological benefits of dietary lipids without relying on the patient’s meal timing or content.

CASE STUDY: MITIGATING FOOD EFFECT FOR VENETOCLAX WITH SEDDS

Venetoclax (Venclexta^®/ Venclyxto^®) is a BCL-2 inhibitor, indicated for the treat­ment of adult patients with chronic lym­phocytic leukemia or small lymphocytic lymphoma. It has a MW of 868.44, low aqueous solubility with LogP 5.5, and it is classified as BCS IV. According to the FDA approved product label (Venclexta tablet), there is a 5-fold Cmax and AUC increase with a high fat meal.

A 2022 study showcased a self-emul­sifying drug delivery system (SEDDS) con­taining a lipophilic salt of the API (venetoclax docusate) to mitigate the food effect.23 The formulations are shown fur­ther:

1. Long Chain SEDDS

-30 % Peceol^® (Glyceryl monooleate, Type 40)

-70% surfactant mix (Kolliphor^® RH40: Tween^® 85, 1:1)

2. Medium Chain SEDDS

-30% Capmul^® MCM (Glyceryl mono­caprylate)

-70% surfactant mix (Kolliphor RH40: Tween 85, 1:1)

3. Surfactant-Only SEDDS

-100% of surfactant mix (Kolliphor RH40: Tween 85, 1:1)

The bioavailability of these formula­tions in the fasted state were compared with the bioavailability of the commercial product (Venclyxto tablet) in fed and fasted states in male landrace pigs (Figure 3).

The SEDDS formulations showed an increase in oral bioavailability of veneto­clax docusate up to 2.4-fold compared to the commercial amorphous solid disper­sion in the fasted state. All SEDDS formu­lations in the fasted state showed a similar bioavailability compared to Venclyxto in the fed state.

This study highlights the feasibility of SEDDS not only for enhancing the bioavailability of highly lipophilic and BCS class IV compounds but also for mitigating the food effect.

ORAL DELIVERY OF BIOLOGICS: REACHING THE NEXT FRONTIER

Biologics, such as peptides and pro­teins, face formidable barriers in oral de­livery due to their size, hydrophilicity, and enzymatic instability. Consequently, most peptide therapies are currently adminis­tered via parenteral injection, which en­sures bioavailability but sacrifices patient convenience and adherence. The pharma­ceutical industry has long recognized the need for effective oral peptide delivery sys­tems, yet few have reached the market.

This landscape presents an opportu­nity for innovation. Leveraging excipients that enhance permeability, protect against enzymatic degradation, and exploit alter­native absorption pathways can help over­come these barriers, enabling patient-friendly oral peptide medicines. Lipid excipients, particularly those with medium-chain fatty acid ester content, provide a physiologically compatible strat­egy to enhance permeability and protect peptides in the GI tract.^1,2

CASE STUDY: ORAL DELIVERY OF A MACROCYCLIC PEPTIDE WITH LABRASOL^® ALF

In a recent human clinical study, Merck & Co. explored formulation ap­proaches for an orally administered form of enlicitide chloride (MK-0616), a novel macrocyclic peptide designed to treat ele­vated levels of LDL cholesterol. Macro­cyclic peptides sit at the intersection between small molecules and biologics, offering a unique combination of proper­ties that make them attractive as next-generation therapeutics, especially in an oral dosage form.

In the study, Labrasol ALF (Caprylo­caproyl Polyoxyl-8 glycerides) was evalu­ated as a permeation enhancer. A simple mixture of 1800 mg of Labrasol ALF with 200 mg of enlicitide chloride enabled a 2- to 3-fold increase in plasma concentra­tion, showcasing the translational rele­vance of lipid-based approaches for oral delivery of biologics (Table 3).²⁴

LIPID-ENABLED INNOVATION OFFERS SAFETY & REGULATORY CONFIDENCE

Across all these categories, lipid ex­cipients offer more than performance —they offer reliability. In a world where novel excipients continue to face significant reg­ulatory hurdles, the robust safety data and global precedence of use (Figure 4) that accompany lipid excipients make them a low-risk, high-reward option for pharma­ceutical innovation.

Whether driving new product devel­opment or revitalizing existing assets, lipids remain a valuable option in the for­mulation toolkit, and Gattefossé Pharma­ceuticals is committed to the scientific advancement of lipid-enabled drug deliv­ery. Through innovative research, hands-on formulation support at our global technical centers of excellence, and collab­orations across industry and academia, Gattefossé continues to uncover the unique benefits of lipids in drug delivery. When coupled with industry-leading safety and regulatory support, lipid excipients offer a truly streamlined path to innovation.

SUMMARY

Delivering the next generation of poorly soluble and permeable APIs re­quires innovative, reliable formulation strategies. Lipid excipients are a uniquely effective solution, leveraging the body’s di­gestive mechanisms to overcome critical bioavailability barriers. By enhancing sol­ubility through supersaturation, increasing permeability via tight junction modulation, and enabling lymphatic uptake, these ex­cipients provide a multi-faceted approach to improving drug performance.

From creating ternary ASDs that im­prove manufacturability and drug release to reformulating existing drugs to mitigate food effect, lipid-based systems offer tan­gible solutions to today’s formulation chal­lenges. Furthermore, they represent a critical enabling technology in the quest for oral biologics.

Ultimately, the value of lipid excipients lies in their combination of performance and precedent. With a long history of use in globally approved medicines and an es­tablished safety profile, they offer a low-risk, high-reward pathway for innovation. For formulators tasked with developing the next generation of oral therapies, lipid-based systems provide a flexible, scalable, and proven platform to transform chal­lenging molecules into effective, patient-centric treatments.

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Nick DiFranco, MEM, is the Senior Marketing Manager for the Pharmaceutical Division at Gattefossé USA, a well-established supplier of pharmaceutical excipients and drug delivery solutions. In this role, he leads the strategy and marketing efforts for the North American excipients business — seeking opportunities to expand the use of lipid excipients at innovative pharmaceutical companies. Mr. DiFranco has many years of experience coordinating multi-disciplinary teams in the pharmaceutical excipient and contract development and manufacturing (CDMO) industries. He previously led global marketing efforts for solubility/bioavailability enhancement technologies, oral drug delivery portfolios, and long-acting implantable and injectable offerings. Mr. DiFranco holds a BS in Biomedical Engineering (Biomaterials focus) and a Master of Engineering and Management degree from Case Western Reserve University.