Press Release: 11/20/2025

From Needle to Capsule: How Lipid-Based Softgels Are Making Oral Delivery of Macromolecules a Reality

 



NOV 19, 2025



 



By Karunakar (Karu) Sukuru, R.Ph., Ph.D.

Global Vice President, Pharma Product Development & Head, Scientific Advisory, Catalent Pharma Solutions





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My work in drug product development over the past thirty years has always focused on practical ways to solve challenging drug delivery problems. One of these challenges is: freeing the patients from the needles? Anyone who works with peptides, proteins, or nucleic acids knows how difficult the oral delivery has been. These large, fragile, and hydrophilic molecules rarely survive the gastrointestinal tract, and even when they do, they struggle to cross the intestinal barrier. What did not seem possible even a decade ago is now moving into real clinical territory. Lipid-based formulations inside advanced softgels are playing a major role in that shift.



Why Oral Macromolecules Have Been So Difficult



When people ask me why oral delivery has taken so long, I point to three barriers that appear in every program I’ve ever touched.




  • Stomach acid and proteolytic enzymes destroy unprotected peptides within minutes.

  • Molecules like insulin, at 5.8 kDa, are far too large for passive paracellular transport.

  • Hydrophilic and charged surfaces resist interaction with the lipophilic intestinal membrane.



For years, these issues made oral macromolecules feel out of reach. Lipid-based systems change the equation because they tackle all three barriers at the same time.



How Lipid Formulations and Smart Softgels Create a Pathway



What excites me most is how versatile lipid systems have become. We now have well-characterized mechanisms that give us multiple levers to protect a molecule and guide it toward absorption.































Function Mechanism Key Excipients
Enzyme protection Oil core plus surfactant barrier MCT, Capmul MCM, SNAC, sodium taurocholate
Mucus penetration PEGylated lipids and chylomicron mimicry Polysorbate 80, TPGS, lecithin
Lymphatic uptake Long-chain lipids stimulate chylomicron formation Oleic acid, Maisine CC
Targeted release Enteric or delayed-release shell Gelatin-pectin, polymer-coated OptiGel® DR


When the fill and the shell are optimized as one system, we routinely see bioavailability increase from less than 1 percent to 5–25 percent in preclinical models, and in some cases into double-digit ranges clinically. That type of improvement is meaningful for chronic diseases where injections reduce adherence.



The Softgel Shell: The Unsung Hero



I’ve spent years working on softgel shell technologies, and I can say with confidence that the shell is far more than packaging. It actively controls where and how a formulation releases. Catalent’s OptiGel® DR platform, using gelatin with pectin or selected polymers, holds up in gastric acid and releases the fill only when conditions become favorable in the duodenum or jejunum. If the shell and fill are not compatible, even the most sophisticated lipid formulation loses its advantage. The success of oral macromolecule delivery depends on getting both pieces right.



Real-World Proof Points



One of the strongest signals that this field has turned a corner is the number of approved or late-stage programs already using these principles.




  • Cyclosporine (Neoral®) and Voclosporin (Lupkynis®): SNEDDS formulations reduced variability and improved absorption; Neoral® remains a benchmark decades later.

  • Octreotide (Mycapssa®): A permeation-enhanced enteric capsule now provides an oral alternative for acromegaly maintenance therapy.

  • Sulodexide: A ~6.5 kDa glycosaminoglycan mixture reaching 30–60 percent bioavailability in softgels shows that large polysaccharides can cross the gut with the right design.

  • Salmon Calcitonin: Oral approaches using caprylate derivatives and enzyme inhibitors have progressed as far as Phase III.

  • Oral Insulin: Lipid-enteric capsule technologies continue in clinical evaluation, including new Phase III efforts building on lessons from prior trials.



These are not theoretical exercises. They are real programs demonstrating what becomes possible when formulation science aligns with biological reality.



The Road Ahead: Opportunities and Manageable Hurdles



The momentum behind oral macromolecule delivery is strong, and the next wave of tools is already emerging.



Opportunities




  • New GRAS ionizable lipids, inspired by mRNA vaccine platforms, may offer pH-triggered release and improved protection.

  • AI-guided screening of oil and surfactant ratios is shortening early formulation cycles.

  • Mini-softgels open the door for pediatric and geriatric patients who avoid injections whenever possible.



Hurdles (all solvable)




  • Droplet-size drift during encapsulation requires disciplined process control.

  • High-fat meals can increase exposure three to five times, so administration guidance is essential.

  • Lipid excipients cost more than standard tablet matrices, but improved adherence and reduced cold-chain needs help offset this.



Closing Thought



I’ve watched the industry move past “impossible” many times. Transdermals, implants, and pulmonary delivery all started that way. Oral macromolecules are now advancing along that same path. When a patient with diabetes, acromegaly, or a rare disease can swallow a capsule instead of facing a needle, everything improves: adherence, access, and quality of life. The science is ready, the technologies are in hand, and execution is underway. I’m proud to lead the teams advancing this shift and turning the science into real therapeutic progress.