Delivery and dosage technologies continue to enable today’s finished products to break yesterday’s rules about formulation, ingredient combinations, storage conditions, applicability to food and beverage formats, and more.
 
There’s plenty to keep up with when it comes to optimizing an ingredient’s bioavailability, capacity to survive digestion, efficacy at small dosages. There are also many factors to consider when evaluating which kinds of technologies may best suit a given finished product.
 
“Selecting the right dosage and delivery format is a vital consideration for brand owners and manufacturers seeking to develop supplements that stand out from the crowd,” said Brian Garrett, global senior director of dosage form solutions and health ingredients at Lonza.
 
According to a survey conducted by Lonza, capsules remain the preferred dosage form among consumers, with 68% of oral solid dosage form (OSDF) consumers reporting they’ve used capsules within the past year, Garrett noted, with a significant portion of them using multiple OSDF.
 
Compared to other formats, capsule users tend to seek out additional information at greater rates than users of other formats, demonstrating that this core consumer base is where to find higher engagement, Garrett said.
 
“Convenience is also a key consumer priority when choosing between dosage forms,” he added. And while certain observers note consumer complaints about conventional formats and “pill fatigue,” the relative ease of swallowing and resistance to breakage within packaging are two convenient attributes capsule users seek out. They’re also potentially the most suitable ingredient to mask aftertastes and odors associated with botanicals or other plant-based ingredients, Garrett noted.

Storage Concerns

Proving that all vitamins meet claimed potency by the end of shelf life requires an assay for every active ingredient present within a product, and that’s generally quite expensive.
 
Studies, such as a GAO report from late January which found inconsistencies across leading prenatal supplements, highlight the challenge supplement companies face in creating products that maintain potency to the end of shelf life.
 
Meanwhile, e-commerce rapidly gained a substantial share of the dietary supplements market since COVID-19, and it’s hard to pick out from the sea of online retailers and shipping companies which have the best storage and handling procedures in place.
 
“More manufacturers have needed to consider supplement degradation, particularly for e-commerce sites where hundreds if not thousands of products will sit in storage, hopefully temperature-regulated, until sold,” said Maggie McNamara, marketing director at Gencor. In addition to advantages like bioavailability and compatibility with other formats, certain delivery technologies can help to extend the lifespan of certain ingredients, she said.
 
Products by Gencor and its sister company Pharmako Biotechnologies which could be used for this purpose include Aquacelle micellar delivery technology, LipiSperse cold water dispersion technology, and Compressible Powdered Oils (CPO).
 
Containers are also crucial to shelf-life considerations. “The best protection is offered by amber glass,” said Tanja Kokkinis, international business coordinator of Pharmako Biotechnologies. “Once you decide on a container type, you then need to run a controlled study at the storage conditions on the label and in real time.”
 
“Accelerated” models of storage conditions are usually misleading in studies, Kokkinis said, resulting in both false failures and passes.
 
As demand for sustainable products grows, so too does the use of alternative packaging, noted McNamara. Manufacturers of both supplements and packaging will be up to the task of ensuring stable storage in new kinds of packages, such as recyclable packaging, biodegradable capsules, water-soluble film technology, refillable or reusable containers, and minimalist packaging.
 
Delivery trucks mostly aren’t climate controlled for the protection of sensitive dietary ingredients, and products might sit in loading docks or ports for extended periods regardless of the weather. There may also be huge differences regarding the in-house quality control efforts of a store specializing in dietary supplements versus a massive fulfillment center.
 
“The whole supply chain needs to cater and to protect against the conditions stated on the label to improve product stability,” Kokkinis said.
 
For both e-commerce and brick-and-mortar, there are no stringent regulations for how a retailer handles dietary supplement inventory, and it’s difficult to verify that good quality control measures are in place at any given location. The widely recognized third-party certifications utilized by the industry usually only cover manufacturing, and not quality control measures for finished products once exchanged to retailers.
 
On the supply side, raw material supplies and contract manufacturing services are still being stretched thin, resulting in companies opting for a just-in-case rather than a just-in-time model of manufacturing more than ever before, adding to the challenge of predicting how long products and their contents will spend in storage before reaching an end user.
 
Altogether, these changes in supply chain dynamics might warrant a second look at one’s product stability performance. 

Customization and Optimizing Release

There are plenty of routes by which one can protect ingredients from harsh digestive conditions and optimize where along the digestive tract they are released for maximum benefit.
 
For conventional delivery formats like capsules, tablets, and softgels, this means constant innovation in what encapsulation materials are composed of.
 
For instance, Lonza has been working with DRCaps designed-release capsules, a plant-based line of capsules created for increased protection against stomach acid. Suitable for ingredients that are highly sensitive, the capsules release ingredients approximately 45 minutes later than a standard gelatin-based capsule.
 
In the softgel space, gelatins are not all one in the same. Rousselot recently introduced a specialized gelatin which can improve the stability of softgels by the prevention of crosslinking, called StabiCaps. Crosslinking occurs when molecular bonds are formed as a result of poor storage conditions, or interactions with a certain kind of active ingredient, and can prevent capsule dissolution, resulting in slower or incomplete release of nutrients.
 
Pectin, a plant-based biopolymer first popularized as a plant-based alternative to gelatin, is now often used in various combinations with gelatin in order to help customize the timing of nutrient release.
 
With the rise in the popularity of precision nutrition, plenty of brands are offering consumers customized formulations. This “calls for adaptable dosage forms capable of containing diverse constituents in accurate quantities,” McNamara noted. “The production of customized formulations requires sophisticated manufacturing techniques, while delivery technologies play a vital role in guaranteeing these unique combinations’ stability and efficient transportation.”
 
Encapsulation, controlled-release systems, and micro-dosing can all help to improve dose precision in customized formulations, where excesses and insufficiencies are more likely during manufacturing, McNamara continued.
 
Expect improvements in tailoring release profiles as well. “To accommodate physiological requirements of each individual, personalized supplements may necessitate specific release profiles,” McNamara said. “Controlled-release technologies, including targeted delivery systems and time-release capsules, can be implemented to enhance the gradual or targeted release of nutrients within particular digestive tract segments.
 
To further the push for personalization, novel ingredients and ingredient combinations should be compatible with more innovative delivery options, including transdermal gels and patches, dissolvable tablets, and liquid formulations, McNamara said.
  
Separation

“Recent technology innovations can enable brands to incorporate separate, non-compatible ingredients in one dose,” Garrett said. “This gives the opportunity to develop a bespoke nutritional supplement for consumers.”
 
Capsule-in-capsule designs offer formulators the opportunity to package both powdered and liquid ingredients in the same dose, with different respective release profiles which can be tailored to both the liquid and solid contents.
 
“Lonza’s Capsugel Duocap technology supports brands looking to formulate with ingredients that are traditionally challenging to combine,” said Garrett. “For instance, in the case of probiotics, the Capsugel Duocap consists of a smaller probiotics pre-filled capsule which is inserted into a larger liquid-filled capsule, alongside other active ingredients.
 
Beadlet-filled capsule designs are also growing in popularity among contract manufacturers in the supplements space, and certain specialists are now able to offer brands turnkey solutions for another eye-catching means of separating both liquid and solid ingredients that would be reactive with one another.
 
Double-encapsulation has become an eye-catching way to differentiate products, especially as consumers invest more time looking into what makes certain supplements outperform others. Many brands choose to have transparent outer capsules in order to showcase the double-encapsulation within, such as Ritual, Wholier, First Person, Orb, and more.
 
Startup company Rootine skips capsules altogether, instead offering sachets filled with beadlets that can be sprinkled into a beverage. This enables the company to customize the blends of beadlets that go into each sachet, which are uniquely formulated based on DNA, blood, and lifestyle data gathered through a range of tests that the company offers.
 
While most are still in the prototype phase, center-filled gummies have been introduced to the market from manufacturers like Sirio and Rousselot, enabling a liquid core formulation which contains certain active ingredients, and an outer gummy formulation which can both protect the liquid interior and contain other ingredients which can’t interact with those on the inside. Another advantage of liquid center-filled gummies is that the liquid interior contents don’t need to be exposed to heat, enabling manufacturers to include sensitive ingredients like probiotics.

Improving Palatability

New methods of encapsulation and emulsion are enabling more palatable dietary supplements, both in conventional formats as well as in gummies, chewables, and more.
 
Omega-3 fatty acids, specifically fish oils, are one of the most challenging ingredients to work with from a palatability perspective. But microemulsion to create smaller droplet sizes, or even powders, can reduce the amount of odor-causing contact with air, resulting in reductions in fishy burps, odor, and aftertaste.
 
Catalent, for instance, recently launched OmegaZero technology, which is a micro-emulsified formulation designed to emulsify omega-3 oils within the gut so that they don’t form a layer on the surface of gastric juice, with additional masking thanks to the presence of essential oils. While initially launched for omega-3s, the technology is applicable to plenty of other ingredients with less-than-favorable organoleptic properties as well.
 
For those of the plant-based persuasion, dsm-firmenich offers life’sOMEGA, a branded algal oil which uses a double-shell system to create a powder suitable, from both a performance and palatability standpoint, for applications like gummies. The format also helps to improve potency several fold compared to conventional omega-3 gummies. 
 
Additionally, Nuseed Nutritional, the company behind Nutriterra, recently partnered with Connoils to form a powdered version of its DHA-rich oil sourced from genetically-engineered canola, enabling its incorporation into food and beverage formats. The neutral taste of Nutriterra, relative to other sources of omega-3, makes integration into foods and beverages all the more seamless, the company noted.

Plant-Based and Clean Label

Plant-based alternatives in supplement formats continue rising in popularity, so innovation with pectin, carrageenan, HPMC, pullulan, and other gelatin alternatives for gummies, capsules, and more is due.
 
“According to Lonza’s proprietary research, 40% of supplement users cite the importance of ‘vegan’ as a purchasing factor,” said Garrett. “There has also been an increase in supplement users who state that ‘plant-based’ is important to them when making a purchase.”
 
The days of compromise are over, and brands are now showcasing the advantages that certain plant-based compounds have over all others, including gelatin.
 
For instance, pullulan, a water-soluble polymer made from fermented tapioca, offers a particularly high oxygen barrier for vegetarian or plant-based supplement formulations, such as those which utilize Lonza’s Capsugel Plantcaps, Vcaps, and Vcaps Plus HPMC.
 
On a broader level, consumers want natural ingredients and clear labels, said McNamara. “Manufacturers are tasked with identifying delivery technologies that preserve the ‘natural’ qualities of these compounds while preserving their stability and efficacy.

Next-Gen Bioavailability

“Bioavailability enhancement is a formidable obstacle that can yield numerous advantages when approached with appropriate delivery technology. For many manufacturers, enhancing the bioavailability of specific nutrients continues to be a challenge,” said McNamara. “Efforts are underway to investigate novel delivery technologies, including nano-emulsions, liposomes, and other sophisticated encapsulation techniques, intending to augment the absorption of particular compounds.”
 
There are four common reasons why a given compound isn’t bioavailable. One is limited water solubility, commonplace for many vitamins and plant compounds. Some nutrients have extremely low stability compared to others in light, heat, and oxidation. Plenty of compounds are mostly metabolized hepatically (first pass metabolism), which diminishes how much is accessible for utilization within the body. Lastly, nutrients larger in size will have diminished intestinal permeability, McNamara noted.
 
Todays’ technologies to solve these challenges include nanoparticles and nanocarriers (including nano-emulsions, liposomes, and the more nascent solid lipid nanoparticles and polymeric nanoparticles); micelles (assemblages of amphiphilic molecules which can make hydrophobic substances soluble); microencapsulation; self-emulsifying drug delivery systems (an integration of oil, surfactant, and co-surfactant to create a stable emulsion); and coating technologies.

“The primary objective of these sophisticated delivery technologies is to enhance the physicochemical characteristics of nutrients in order to optimize their solubility, absorption, and stability, thereby maximizing their bioavailability for therapeutic purposes,” said McNamara.
 
“Micelles are structures formed naturally in the human GI tract to enable the absorption of lipophilic ingredients. Micelles allow the nutrient to emulsify in watery environments such as the GI tract, increasing the surface area to positively impact absorption,” said Kokkinis. “Liposomes are tiny structures that due to their size are able to pass through the buccal membrane of the mouth and enter directly into the cells, bypassing the stomach and subsequent metabolism by the liver. They provide the most targeted method of nutrient delivery. Factoring the use of novel coatings and carriers that are used in their production, they not only support protection of ingredients from harsh digestive conditions but help to promote controlled release. These systems contribute to maximizing the effectiveness of dietary supplements and functional foods and beverages.”
 
While liposomal technology has been used by the pharmaceuticals industry for a long time to enhance bioavailability and absorption of drugs, only more recently have manufacturers started creating liposomes that contain vitamins, minerals, herbs, and other dietary ingredients, thanks to recent improvements in processing equipment.
 
Liposomes are hollow sub-microscopic spheres made of lipid bi-layers with an aqueous core, which can carry nanoparticles of active ingredients in order to give them both fat- and water-soluble characteristics. This improves absorption rates and helps protect ingredients even further as they pass through the digestive tract.
 
“Their structure encapsulates hydrophilic ingredients in their core, or lipophilic ingredients in the bilayer membrane, or both,” Kokkinis said. “As liposomal membranes are similar in structure to cell membranes, together with their tiny size, they help boost bioavailability to significantly maximize the ingredient’s nutrient benefits.
 
It’s important to note that the standards and methods of validation for liposomes have been developed for pharmaceutical ingredients, which are extremely pure and uniform in particle size, unlike dietary ingredients.
 
There is no single validated testing protocol in order to prove the proper liposomal encapsulation of dietary ingredients, which are by nature much more technically challenging to encapsulate with this emerging technology. Most working in the field consider a combination of transmission electron microscopy (TEM) Cryo-TEM imaging, zeta potential, and dynamic light scattering analysis to be standard operating procedure.
 
Some key trailblazers within the liposomal space include: Specnova, with its line of ingredients utilizing LipoVantage, a proprietary liposomal technology that produces liposomes which can be further shielded with DualHydrogel; Indena, with its Phytosome technology tailor-made for the creation of botanical liposomes; Pharmako, with its PlexoZome liposomal technology which enables customizable particle size for targeted delivery; and more.
 
“Many liposomal supplements are nothing more than phospholipid emulsions, which cannot offer the true absorption benefits of genuine liposomal formulations,” Kokkinis said. “The saying ‘you get what you pay for’ rings true, and for this reason there are several important factors that consumers should consider.
 
“The efficacy and safety of a product relies not only on the attention to specific ingredients being used, but the manufacturer’s expertise, a sound production process, and strong quality assurance measures,” she continued. “As liposomes are a highly customizable delivery system that can be tailored to meet the specific needs and preferences of a consumer, the concentration, particle size, and efficiency of a formula can vary, influencing the overall bioavailability and effectiveness of a product.”