Issue:October 2025
EXCIPIENT TECHNOLOGY - Driving Oral Drug Delivery Innovation With Safe, Reliable Lipid Excipients
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:
- The addition of Gelucire 48/16 reduced processing temperatures by nearly 40°C relative to the binary ASD (115°C vs. 153°C).
- 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).
- 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.
REFERENCES
- McCartney F, Jannin V, Chevrier S, et al. Labrasol® is an efficacious intestinal permeation enhancer across rat intestine: Ex vivo and in vivo rat studies. J Controlled Release. 2019;310:115-126. doi:10.1016/j.jconrel.2019.08.008
- McCartney F, Caisse P, Dumont C, Brayden DJ. LabrafacTM MC60 is an efficacious intestinal permeation enhancer for macromolecules: Comparisons with Labrasol® ALF in ex vivo and in vivo rat studies. Int J Pharm. 2024;661:124353. doi:10.1016/j.ijpharm.2024.124353
- App Note: Unveiling the Potential of Labrasol® ALF LabrafacTM MC60 and Capryol® 90 as Permeation Enhancers to Address Low Bioavailability Issues. https://www.americanpharmaceuticalreview.com/615501-App-Note-Unveiling-the-potential-of-Labrasol-ALF-Labrafac-MC60-and-Capryol-90-as-permeation-enhancers-to-address-low-bioavailability-issues/
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- Grove M, Müllertz A, Pedersen GP, Nielsen JL. Bioavailability of seocalcitol: III. Administration of lipid-based formulations to minipigs in the fasted and fed state. Eur J Pharm Sci. 2007;31(1):8-15. doi:10.1016/j.ejps.2007.01.007
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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.
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