Lipid-Polymer Synergies: Enhancing Tablet Performance for New Drug Modalities

The Oral Drug Delivery Landscape

As drug discovery pushes into new therapeutic frontiers, the task of developing effective, patient-friendly oral medicines has become increasingly challenging. Modern APIs such as targeted protein degraders and peptides are plagued by more than just poor solubility—they often suffer from limited permeability, poor in vitro-in vivo translation, and complex stability or compatibility issues.^1–3

For decades, lipid-based formulations, such as self-emulsifying drug delivery systems (SEDDS) delivered in liquid-filled soft and hard capsules, have been the gold standard for overcoming in vivo barriers. However, the market preference for oral solid dosage (OSD) forms such as tablets remains strong.

Consider the data on non-generic FDA approvals for new oral drugs from 2014 to 2023 (Figure 1). As the chart shows, solid formats (e.g., tablets, powder-filled capsules, granules) represented around 80% of approvals during this timeframe. Many of these products rely on polymeric formulations to solubilize and stabilize APIs.

Figure 1: Oral Non-Generic FDA Approvals from 2014 to 2023

This reality exposes a significant missed opportunity in drug development. The unique, multi-functional in vivo benefits of lipids are vastly underutilized in the industry’s most preferred dosage forms.

In this article, we look beyond traditional lipid-based formulations, offering ways to enhance the performance of polymeric systems and improve oral tablet formulations.

Why Consider Lipid Excipients for Oral Solid Dosage Forms?

Lipid excipients are fatty acid esters derived from naturally occurring fats and oils by combining different fatty acid chains (e.g., C8, C10, C18) with various polar head groups (e.g., glycerol, PEG, propylene glycol, polyglycerol). This modularity allows for a diverse portfolio of amphiphilic excipients with a wide range of melting points, functionalities, and properties.

Lipid-based formulations not only improve solubility but work with the body’s natural digestive processes to overcome key absorption barriers (Figure 2). For example, medium-chain fatty acid esters based on C8 and C10 chemistry form colloidal structures and mixed micelles in the gastrointestinal tract that solubilize drugs and improve transcellular absorption while also enabling tight junction modulation for paracellular uptake. This allows excipients such as Labrasol® ALF, Capryol® 90, and Labrafac™ MC60 to improve delivery of BCS Class II, III, and IV APIs, including both small molecules and peptides.

Figure 2: In Vivo Benefits of Lipid Excipients

By incorporating lipid excipients into modern OSD development, formulators can introduce unique benefits, including:

Enhanced in vivo solubility and intestinal supersaturation via lipid digestion
Improved dosing consistency via food effect mitigation
Enhanced intestinal permeability via safe, reversible tight junction modulation
Increased bioavailability via lymphatic transport, avoiding first-pass metabolism

These benefits are utilized in several commercial products today, and they will be critical to enabling the next generation of oral drug products. It is no longer sufficient to focus solely on solubility and dissolution rate—new drug modalities demand the functionalities of lipid excipients to maximize permeation, prevent in vivo recrystallization, and ensure therapeutic effect.

Lipid-Polymer Synergies: Improving In Vivo Oral Tablet Performance

Over the past 20 years, amorphous solid dispersions (ASDs) consisting of API in a polymer carrier have been the dominant strategy for solubility enhancement, translating to 48 FDA-approved products from 2012 to 2023.⁴ While proven and scalable, ASDs may fall short in vivo, as high drug loading can trigger recrystallization, and polymers alone may not overcome poor permeability. While the addition of surfactants can help improve wetting and dissolution rate, clinical translation remains a challenge for the growing pipeline of poorly permeable compounds.

Table 1: Examples of Lipid-Polymer Synergies

API	Key Lipid Excipients	Polymer	Key Result
Felodipine	Hydrogenated castor oil Medium chain triglycerides Glyceryl monocaprylocaprate	HPMC-AS	1.6-fold increase in AUC (rat PK study)
Ritonavir	Glyceryl monolinoleate Polyoxyl hydrogenated castor oil	PVP-VA	3-fold increase in AUC (rat PK study)
Novel PROTAC	Caprylocaproyl polyoxyl-8 glycerides Glyceryl mono and dicaprylocaprate PEG-40 hydrogenated castor oil	PVP-VA	4-fold increase in permeation (PAMPA study)

Because of this trend, new research has emerged around combining lipids and polymers to access formulation synergies. Co-dosing lipid excipients alongside polymers or ASDs has been shown to increase drug loading and boost exposure, as demonstrated in rat pharmacokinetic studies of felodipine, ritonavir, and a novel PROTAC compound (Table 1).^5–7

Lipid-polymer synergies are even being explored for oral peptide delivery. Medium chain lipids previously enabled the conversion of octreotide from an injection to a more patient-friendly oral formulation (MYCAPSSA®).⁸ Researchers are now investigating the use of C8- and C10-based excipient chemistries alongside polymers to enhance permeation of peptides.⁹

From Concept to Practice: Incorporating Lipids into Amorphous Solid Dispersions

Combining lipids and polymers offers a relatively streamlined path to innovation. Unlike novel excipients or formulation approaches, which can add years of regulatory hurdles to a program, lipid-polymer synergies rely on IID-listed excipients to significantly improve in vivo performance and maximize stability in a solid format. However, translating these systems into commercial tablet formulations requires integrating common unit operations, such as spray drying, hot melt extrusion, granulation, and tableting.

Figure 3: Potential Benefits of Combining Lipids with ASDs

Fortunately, the growing use of surfactants such as SLS and vitamin E TPGS in commercial ASD formulations provides a blueprint for bringing lipid-polymer synergies into regular practice.^4,10 These additives have been used to form ternary ASDs via both solvent-based and thermal processing techniques. With proper lipid excipient selection, formulators can access a broader range of chemistries and functionalities to further enhance ASD performance (Figure 3).

Hot Melt Extrusion: Proven Results with Semi-Solid Lipids

Hot melt extrusion (HME) is a thermal process which relies on melting and mixing of a polymer (typically PVP-VA) and API to form an ASD. While HME has several benefits, including the possibility of continuous processing, its reliance on elevated temperatures can limit its application for thermally sensitive APIs.

In recent years, Gattefossé has dedicated resources to exploring the use of lipid excipients as both plasticizers and bioavailability enhancers in hot melt extrusion. Water-soluble surfactant chemistries, such as the Gelucire® family of excipients, have been shown to improve processing, enable higher drug loading, and boost release from extruded ASDs.^11–14

In posters published at the 2024 and 2025 CRS Annual Meetings, Gelucire® 48/16 (Polyoxyl-32 stearate (type I) NF) and Gelucire® 50/13 (Stearoyl polyoxyl-32 glycerides) acted as both processing and drug release aids, enabling lower temperatures, higher screw speeds, and improved dissolution performance from extruded ASDs based on PVP-VA.^12,13 Gelucire® 50/13 has also been shown to lower the processing temperature and torque of HPMC-AS dispersions, potentially expanding the toolbox of polymer options for formulators.¹¹

Spray Drying: A New Frontier for Lipid Excipients

While lipid excipients have traditionally been formulated as liquids for the delivery of pharmaceutical actives, other applications such as food and nutrition have long utilized spray drying and related processes to turn liquid lipids into solid, stable powders.^15,16

Medium-chain fatty acid esters, such as Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides), are liquid excipients that can be incorporated directly into the feedstock of a traditional spray drying process. These C8- and C10-based excipients act as both solubilizers and in vivo permeation enhancers, offering the potential to improve translation for challenging BCS Class III and IV compounds.

While the concept of spray drying lipid excipients alongside polymers to improve pharmaceutical ASD performance is relatively new, a pharmacokinetic study in rats demonstrated that spray-dried dispersions containing 10% Labrasol® improved AUC and C_max of resveratrol.¹⁷ Additional details on this study and a deep dive into the use of lipid excipients in oral solid dosage forms are available in our whitepaper, “Beyond the Capsule: Unlocking the Full Potential of Lipid Excipients in Oral Solid Dosage Forms.” Click below to request a copy today.

Advancing Lipid-Polymer Synergies in Pharmaceutical Formulations

While lipid-polymer synergies offer the potential to overcome challenges such as permeability, food effect, and poor in vivo solubilization of APIs, significant work remains to translate these concepts into commercially viable formulations.

Gattefossé is committed to improving guidance around lipid-polymer synergies, offering personalized excipient recommendations from our library of proven, IID-listed chemistries as well as hands-on support at our global Technical Centers of Excellence (TCE labs). Through in-house capabilities and partnerships with leading CDMOs, equipment suppliers, and polymer manufacturers in the ASD space, Gattefossé is actively developing best practices for lipid incorporation alongside polymers.

Figure 4: Twin-Screw Hot Melt Extruder at Gattefossé’s TCE Lab in Paramus, NJ

While all our TCE labs provide customized bioavailability enhancement solutions, specialized hot melt extrusion capabilities in the United States and France can be used to screen lipid-polymer systems for challenging molecules (Figure 4).

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Source: Gattefossé, website Lipid-Polymer Synergies: Enhancing Tablet Performance for New Drug Modalities | Gattefossé