Lifecycle Management and Reformulation Opportunities with Lipid Excipients

Over the past decade, technological advances in drug discovery have combined with enhanced regulatory frameworks to reshape the landscape of new drug approvals. 

On one hand, improvements in modeling, computational approaches, and API synthesis have spurred growth in drug pipelines. Globally, the number of compounds in active development has doubled in the past decade, spanning small molecules, peptides, and biologics.^1,2 While these compounds offer significant therapeutic potential, they are also increasingly difficult to formulate, with molecular weights and logP values beyond Lipinski’s rule-of-five (bRo5).^3,4 

In parallel, accelerated approval pathways, such as fast-track designation and priority review, have allowed novel drugs for cancer and rare diseases to reach patients faster than traditional routes. A study of accelerated approvals from 1992 to 2022 concluded that these programs reduced time to market for serious and life-threatening disease treatments, especially in oncology.⁵

While increased output from drug discovery provides more opportunity for innovation, the competitive pipeline coupled with increased speed to market puts a significant burden on formulation scientists. Balancing funding runways, complex molecules, and regulatory pressures is a daunting task. 

While drugs may get to market faster under this current environment, they may not always be fully optimized. An analysis of FDA approvals from 1995 to 2010 showed that tablet or capsule formulations granted accelerated approval were 5.5 times more likely to be reformulated.⁶ 

Reformulation is driven by a number of factors, both commercial and technical. Common challenges with first-generation drug products include: 

• Positive food effect: approximately 20% of FDA-approved oral products from 2019-2023 exhibited a positive food effect, requiring patients to take medicines with a high fat meal^7,8
• Inefficient dosing regimens: poor in vivo exposure can result in oral drug products with frequent daily dosing requirements or higher doses, leading to increased side effects^9,10
• Inconvenient formats: while injectable dosage forms are becoming more common, patients with chronic diseases still benefit from the convenience of oral or topical dosing
• Non-optimized administration for pediatric/geriatric populations: pediatric dose adjustments in first-generation medicines often require manipulating adult forms (e.g., splitting/crushing tablets)

These challenges create opportunities for companies to develop more effective, patient-friendly medicines through lifecycle management and 505(b)(2) reformulation strategies. 

To keep up with project timelines, formulators need access to effective, proven tools that allow them to innovate and improve upon first generation medicines without extending their development timelines. Lipid-based formulations offer technical versatility and global precedence of use, enabling value-added reformulations without additional regulatory risk.

One of the primary obstacles in patient-centric drug delivery is the food effect, where orally-administered drugs exhibit variable absorption in the fed and fasted states. 

Lipid-based formulations offer a proactive solution by building the physiological benefits of dietary lipids into the dosage form itself, stimulating lipolysis and triggering the release of lipase, bile salts, and pancreatic enzymes. This process not only helps to keep the drug solubilized throughout the gastrointestinal tract, but it also promotes consistent exposure regardless of the patient's meal timing.

The “holy grail” of patient-centric drug delivery remains the transition of injectable therapies to oral dosage forms, a move that drastically improves patient compliance and overall quality of life.

Lipid excipients are strong solubilizers that work with naturally occurring enzymes, bile salts, and phospholipids to maintain drug solubility throughout the gastrointestinal tract. However, these excipients also offer key in vivo functionalities that overcome oral absorption barriers and allow legacy parenteral products to find new life as oral dosage forms (Figure 1).

Figure 1: Enhanced Absorption Mechanisms of Lipid Excipients

Permeation Enhancement via Tight Junction Modulation

Excipients with high medium-chain fatty acid ester content (C8, C10) such as Labrasol® ALF, Labrafac™ MC60, and Capryol® 90 are known for their ability to safely and reversibly modulate tight junctions.^13–15 This well-documented effect increases exposure for otherwise impermeable compounds, such as BCS Class III/IV small molecules and oral peptides (e.g., octreotide).

Increased Absorption via Lymphatic Uptake

For compounds suffering from first-pass metabolism (e.g., testosterone), lipid excipients can enhance absorption by promoting 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.

Developing age-appropriate formulations for pediatric populations is a critical area of patient-centric reformulation. However, tailoring medicines to the preferences and safety requirements of various age groups can be challenging. 

In 2022, the World Health Organization published a pediatric quality product profile assessment tool (PQPPAT), which highlights key dosing and safety attributes of medicines for patients 12 years and younger.¹⁸ The PQPPAT addresses considerations such as dose flexibility, patient acceptability, ease of administration, and excipient safety. 

Using this framework, researchers performed a review of over 200 FDA-approved oral pediatric medicines and found several formulation-related gaps:¹⁹

• Traditional tablets and capsules still make up 58% of oral pediatric formulations, despite often being unsuitable for younger children
• Non-conventional, child-friendly formats such as multiparticulate systems and solids for reconstitution remain vastly underutilized

Lipid excipients offer a long history of use across all pediatric age groups (Table 2), and many lipid chemistries are included in the EuPFI Safety and Toxicity of Excipients for Pediatrics (STEP) database. Using lipid-based approaches, formulators can safely overcome several common challenges for pediatric/geriatric dosing, including:

• Pediatric medicines
• Taste-masking
• Excipients for modified release
• Excipients for solubility and bioavailability enhancement 

Table 2: FDA-Approved Lipid-Based Formulations for Pediatric Medicines

While oral delivery remains the first choice for many formulators, topical and transdermal dosage forms present unique opportunities for patient-centricity. 

In skin delivery, the texture and sensorial properties of a dosage form directly impact the patient's experience. A formulation that feels excessively greasy, sticky, or unpleasant is unlikely to be applied consistently, undermining the therapy's overall efficacy. Innovation in the topical space is frequently achieved by reformulating existing dosage forms with both improved drug penetration and optimized textural and sensorial features.

As the pharmaceutical pipeline grows increasingly complex and the race to market accelerates, formulation scientists face the dual challenge of rapid development and optimal patient-centric design. While accelerated approval pathways bring life-saving drugs to patients faster than ever before, they also open doors for lifecycle management and 505(b)(2) reformulation opportunities.

Lipid-based drug delivery systems offer a robust, scientifically proven toolkit for capturing reformulation value. As demonstrated across various administration routes, lipid excipients provide tremendous functional versatility. They enable formulators to mitigate positive food effects for consistent oral exposure, facilitate the highly sought-after transition from injectable to oral therapies, design age-appropriate multiparticulate systems for pediatric populations, and engineer elegant, patient-friendly topical products that boost adherence.

Furthermore, utilizing well-characterized IID-listed lipid excipients significantly reduces regulatory risk, particularly when navigating the competitive reformulation space. By leveraging these established technologies, pharmaceutical companies can breathe new life into legacy APIs, generate new intellectual property, and extend product exclusivity. 

Ultimately, lipid-based reformulation empowers developers to deliver value-added, patient-centric medicines that improve quality of life without compromising on tight development timelines.

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2.          Sedo, K. R. & Llc, P. Drug Delivery Pipeline and Technologies, A Year in Review.

3.          Stegemann, S. et al. Trends in oral small-molecule drug discovery and product development based on product launches before and after the Rule of Five. Drug Discov. Today 28, 103344 (2023).

4.          Advancing Cancer Drug Discovery: Bypassing Synthesis Bottlenecks - European Society of Medicine. https://esmed.org/advancing-cancer-drug-discovery-bypassing-synthesis-bottlenecks/ (2026).

5.          Beakes-Read, G., Neisser, M., Frey, P. & Guarducci, M. Analysis of FDA’s Accelerated Approval Program Performance December 1992–December 2021. Ther. Innov. Regul. Sci. 56, 698–703 (2022).

6.          Gupta, R. et al. Approvals and Timing of New Formulations of Novel Drugs Approved by the US Food and Drug Administration Between 1995 and 2010 and Followed Through 2021. JAMA Health Forum 3, e221096 (2022).

7.          PharmaCircle.

8.          The Role of Lipids in Mitigation of Food Effect. https://www.americanpharmaceuticalreview.com/Featured-Articles/612574-The-Role-of-Lipids-in-Mitigation-of-Food-Effect/.

9.          Why Poor Bioavailability Is a Major Drug Development Risk. https://synapse.patsnap.com/article/why-poor-bioavailability-is-a-major-drug-development-risk.

10.        Almawash, S. Oral Bioavailability Enhancement of Anti-Cancer Drugs Through Lipid Polymer Hybrid Nanoparticles. Pharmaceutics 17, 381 (2025).

11.        Roche Laboratories Inc. ACCUTANE® (isotretinoin capsules). (2008).

12.        Galephar Pharmaceutical Research, Inc. ABSORICA® (isotretinoin) capsules, for oral use. (2019).

13.        McCartney, F. et al. Labrasol® is an efficacious intestinal permeation enhancer across rat intestine: Ex vivo and in vivo rat studies. J. Controlled Release 310, 115–126 (2019).

14.        McCartney, F., Caisse, P., Dumont, C. & Brayden, D. J. Labrafac^TM MC60 is an efficacious intestinal permeation enhancer for macromolecules: Comparisons with Labrasol® ALF in ex vivo and in vivo rat studies. Int. J. Pharm. 661, 124353 (2024).

15.        McCartney, F., Caisse, P., Dumont, C. & Brayden, D. J. Capryol® 90 is an efficacious intestinal absorption enhancer for insulin in vivo when combined other excipients. Int. J. Pharm. 686, 126315 (2025).

16.        Tuvia, S. et al. A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms. Pharm. Res. 31, 2010–2021 (2014).

17.        Johns, D. G. et al. Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor. Circulation 148, 144–158 (2023).

18.        Walsh, J. et al. Assessing the Appropriateness of Formulations on the WHO Model List of Essential Medicines for Children: Development of a Paediatric Quality Target Product Profile Tool. Pharmaceutics 14, 473 (2022).

19.        Weiler, H. R., Le, L. M. & Fadda, H. M. Age-Appropriateness of Oral Formulations Authorized for Pediatrics. Pharm. Res. https://doi.org/10.1007/s11095-026-04055-x (2026) doi:10.1007/s11095-026-04055-x.