One of the many challenges for supplement manufacturers is consistently ensuring that the products they bring to market are safe, innovative, and aligned with practitioner and consumer preferences, while optimizing production efficiency, productivity, and profitability.
That’s no easy feat. From the choice of bioactive ingredients, through the encapsulation or tableting process, and ultimately to the packaging and shipping, there are dozens of decisions to be made. Each choice has a potential impact on overall product quality, stability, and efficacy.
We know from numerous consumer research studies that, despite nuances between age groups and regions, the safety and quality of supplement products are the top two overriding concerns among consumers when asked about what influences their supplement purchasing decisions (Natural Marketing Institute, Supplements, OTC, Rx Database (SORD) Proprietary Report for Capsugel, 2018).
The concerns are, understandably, very similar among physicians and other healthcare professionals (see How Practitioners Define Dietary Supplement Quality). Practitioners who recommend or dispense supplements need a high level of confidence that the products are safe, and likely to deliver on their stated benefits.
Most major supplement brands recognize customers’ concerns about quality, and take them very seriously. They work with raw materials suppliers that have extensive expertise and experience in supplement technologies and manufacturing processes. There is a science to producing good quality supplements, and ingredient suppliers and other solution providers offer a wealth of support throughout the product development process. They can help with guidance on R&D, formulation, manufacturing processes, and regulatory compliance.
As one of the world’s largest raw materials and capsule suppliers for both the supplement and pharmaceutical industries, Lonza is committed to helping our customers produce safe, efficacious, high-quality products to address consumers’ health needs and preferences. We do this by building quality into all stages of product development, across our science-backed ingredients and functional dosage forms.
One important area of focus for Lonza has been on joint health, a product category in which there is high consumer demand for science-backed supplement solutions. Consumers want to maintain their mobility as they age, and they’re seeking products that not only alleviate symptoms of joint pain, but also truly support healthy joints.
One such ingredient, supported by multiple clinical studies, is Lonza’s UC-II® undenatured type II chicken collagen. This innovative ingredient has been shown to support joint comfort, flexibility, and mobility. One small 40mg dose, taken daily, enables healthy people to remain active for longer periods. UC-II® collagen has also been shown to help improve joint comfort, mobility, and flexibility in people with osteoarthritis (Lugo JP, et al. Nutr J. 2016. Crowley DC, et al. Int J Med Sci. 2009).
In a head-to-head comparison with a combination of glucosamine and chondroitin, UC-II® was found to be significantly more effective, as measured by the industry standard for mobility, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
UC-II® has a unique mode of action; it initiates cell-signaling cascades that turn on the body’s natural repair mechanisms in the joints, and is thought to play a role in supporting the rebuilding of cartilage.
When taken orally, UC-II reaches specialized lymphoid follicles found in portions of the small intestine. These areas, known as Peyer’s Patches, form a part of the gut-associated lymphoid tissue (GALT). Once UC-II makes contact with the Peyer’s Patches, it starts interacting with regulatory T-cells, which in turn produce cytokines that are transported to the joints.
These molecular signals induce resident chondrocytes to begin producing more type II collagen and other constituents that make up the structural matrix of the joint.
Lonza’s UC-II® undenatured type-II collagen creates the opportunity for supplement manufacturers to deliver high-quality joint health solutions that are backed by science and align with the latest consumer demands.
Delivery is Key
High quality bioactive ingredients are only one part of the quality equation.
The truth is, no matter how good or how pure the ingredients are, they will only be effective if they make it to the end-user intact and undegraded, and then—once consumed—they are released when and where the body needs them.
This is where choices about dose delivery systems—tablets versus capsules, enteric coated versus uncoated, microencapsulation, animal versus vegetable source materials, timed-release mechanisms—come into play.
Unless you work in the supplement or pharma industries, you probably don’t think too much about capsules and tablets. Nonetheless, this is a very important consideration. A lot of thought and expertise goes into the decisions about how best to formulate a product, how to optimize its absorption and pharmacokinetics, and how to protect it on its long journey from the manufacturing facility to your patient’s hands.
Today’s delivery systems are quite sophisticated. There are more choices than ever, each offering a spectrum of properties, advantages, and drawbacks. Committed companies strive to match their delivery system choices with their ingredient profiles and also with consumer preferences.
Consumers Prefer Capsules
We know, for example, that 43% of supplement users prefer capsules over any other dosage form (NMI SORD study, 2018). That’s because they’re convenient, clean, and easy to swallow.
Capsules also have a wide range of applicability, from powders, to liquids, to semi-solid ingredients. Many capsules are made of gelatin, which has been in use for decades within the pharmaceutical industry. Gelatin can be either soft or hard. Both types are often used for pungent nutritional oils, like fish and krill oils. Softgels are generally more porous, and may allow ingredient odors to escape. Hard gelatin capsules—especially those nitrogen-flushed upon filling and then hermetically sealed to prevent oxidation—can more successfully protect ingredients and mask odors.
Gelatin has earned its long history of use: it is durable, flexible, and cost-effective. But in today’s market, it has one big drawback: it comes from animals. The gelatin used in supplement or drug capsules is derived from marine, bovine, or porcine sources.
Vegetarian vs Animal-Sourced Capsules
And these days, a large and increasingly conscious market of vegan and vegetarian consumers, are seeking products that are completely free of animal ingredients. The SORD data suggest that nearly 45% of all supplement buyers want vegetarian options. This is especially true among Millennials and younger consumers.
Unless you work in the supplement or pharma industries, you probably don’t think too much about capsules and tablets. Nonetheless, this is a very important consideration. A lot of thought and expertise goes into the decisions about how best to formulate a product, how to optimize its absorption and pharmacokinetics, and how to protect it.
Fortunately, there are many vegetarian and vegan options for supplement capsules.
Through its Capsugel brand, Lonza has been at the forefront of the vegetarian supplement wave, offering the industry a range of vegetable-derived capsules. Our “Plantcaps” capsules, made from pullulan—a polymer derived from naturally fermented tapioca—are ideal for oil-based ingredients with strong smells, especially those prone to oxidation.
Pullulan has a high odor barrier compared to other non-gelatin polymers, and it has a moisture content similar to gelatin, making it a good substitute for animal-sourced gelatin capsules. Plantcaps™ are also verified by the Non-GMO Project, an added plus in today’s health-conscious market. They are free of additives, preservatives, allergens, starch, and gluten as well as certified non-GMO, Kosher, and Halal.
Pullulan is recognized on the US Department of Agriculture’s National List of ingredients that can be used for “made from organic” claims. Pullulan is a product of fermentation, and will now be classified as a “non-agricultural” and “non-synthetic” substance made from food-grade bacteria. Pullulan presents the only vegetarian encapsulation material that is certified by the National Organic Program (NOP).
Lonza also offers DRcaps™ capsules. These are vegetarian hard capsules made of low-moisture hydroxypropyl methylcellulose (HPMC) that offers an alternative to enteric coatings. HPMC is an acid-resistant polymer, which means it does not disintegrate in the stomach but opens immediately at pH levels above 6.8. HPMC capsules are well-suited for delivery of probiotics, enzymes, and many sports nutrition ingredients where a delayed release is preferable.
“Next-Gen” HPMC Capsules
In recent years, there has been a lot of innovation in the production of HPMC-based capsules, leading to great improvements in their physical properties.
The so-called “first-generation” HPMC hard capsules do not dissolve quickly or consistently, potentially delaying the release of the encapsulated ingredients. This can be especially challenging for active ingredients that need immediate release for optimal efficacy.
A new generation of HPMC capsules, produced via a thermos-gelation process, solves this challenge. These capsules can be produced without the problematic secondary gelling agents, and they have a dissolution profile comparable to that of traditional animal-sourced gelatin capsules. They are made solely with HPMC and water, and give consistent and predictable dissolution profiles at a wide range of pH levels.
In one dissolution study comparing Excedrin Extra Strength encapsulated in new-generation HPMC capsules versus the same formula in standard gelatin, both released 95% of their drug contents within 30 minutes, as expected. Based on tests in 24 healthy human subjects, there were no significant differences in pharmacokinetics between the HPMC capsules and the traditional gelatin.
However, when first-generation HPMC capsules are compared with animal-based gelatin capsules, there is a marked difference in onset of drug absorption.
The new form of HPMC also solves the challenge of cross-linking.
One of the issues with gelatin capsules is that some bioactive ingredients can crosslink with amino acids in the gelatin, leading to an unwanted delayed release. Since HPMC is a form of cellulose, and does not contain amino acids, cross-linking does not occur.
Further, animal-sourced gelatin has a high moisture content, typically around 13-16%, in order to maintain the flexibility of the capsule shell. This means that gelatin capsules are more sensitive to degradation, and need to be stored in environments between 35% and 65% relative humidity, and at temperatures between 15° and 25°C.
Moisture-sensitive active ingredients—acetylsalicylic acid is a good example—are often incompatible with gelatin capsules because they are susceptible to degradation from the water in the capsule shells. HPMC capsules have a much lower moisture content, between 5% and 8%, making them more compatible with water-sensitive ingredients.
It’s important to realize that moisture-induced degradation can happen inside a sealed product bottle, independent of environmental exposures.
A head-to-head comparison of acetylsalicylic acid encapsulated in gelatin versus HPMC showed that at 18 months, the gelatin capsules had an 8% degradation of the active compound, versus just 2% for the HPMC capsules. In both cases, the capsules remained inside unopened inductively sealed bottles for the full 18 months. The hydrolysis of salicylic acid was attributable solely to the water content in the capsule shells.
Transfer of water from capsule shell to capsule contents also affects the quality and performance of the former. Gelatin capsules that lose moisture to the hygroscopic ingredients they enclose may become brittle and more susceptible to mechanical damage. Desiccants used in supplement bottles can have the same effect, drawing moisture out of gelatin capsules and making them less flexible.
In simple terms, what this means is that choice of capsule type directly affects product shelf life and stability. This is equally true of supplements and pharmaceuticals.
There are many other considerations when it comes to dose delivery systems for dietary supplements. These include:
Enteric Coatings: A very wide range of substances—fatty acids, waxes, shellac, plastics, plant fibers, or film resins—can be applied to tablets, capsules, pellets, and granules (typically delivered in capsule shells) to delay ingredient release. These enteric coatings protect acid-sensitive ingredients as they pass through the stomach, and delay delivery until the pill or capsule reaches the intestines. The US Pharmacopeia stipulates a 2-hour release to qualify for the enteric claim.
Acid-Resistant Capsules: DRcaps™ capsules protect acid-sensitive ingredients for at least 30 minutes in the stomach’s pH of 1.2. They do this without any additional enteric coatings, which can be costly. This approach is ideal for probiotics and enzymes, as well as plant-based powders such as ground valerian root or garlic that can trigger unpleasant burps if released in the stomach. Creatine and amino acid-based ingredients like BCAA, l-glutathione, and l-carnosine also benefit from delivery in DRcaps™ capsules.
Coni-snap® Sprinkle Capsules: Many people have a hard time swallowing pills and capsules, especially infants, young children, and the elderly. This has led manufacturers to develop consumer-centric alternative delivery systems. One important innovation is the “Sprinkle” capsule, containing powders, multi-particulates, or beadlets of active ingredients.
Coni-snap® sprinkle capsules are manufactured to be five times easier to open than a standard capsule, meaning that people who have trouble swallowing capsules can simply open them and sprinkle the contents onto food or into beverages. Since these capsules can be made of either gelatin or HPMC, they can be taken orally, or used as a biodegradable carrier, which makes them an environmentally-friendly alternative to sachets.
Licaps®: Lonza’s Licaps technology fuses 2-piece hard capsules specially designed for the secure containment of liquids, semi-solids, and versatile ingredient combinations.
These diverse capsule choices are only a few of the dosage delivery systems currently being utilized in the manufacture of dietary supplements. Tableting also has many variables that must be carefully considered. The popularity of chewable gummies brings with it yet another set of options and parameters.
It is essential that the dosage form is optimized for product performance, and that the manufacturer has carefully considered the bioavailability and release profiles of its chosen ingredients. Conscientious brands also consider the specific preferences of a product’s intended consumer base. At Lonza, we offer a broad range of delivery forms and technologies to overcome a variety of formulation challenges and to provide tailored solutions in line with specific consumer needs.