Special Delivery

Originally Published NO April 2010

An increasing number of manufacturers are successfully leveraging novel delivery systems for their dietary supplements in response to consumer demands for more convenience. These new delivery systems include bottled drinks, bars, and chewable products, and serve as alternatives to more-traditional tablets and capsules.

When considering any dietary supplement delivery system, you should evaluate, at minimum, four important criteria, which are discussed in this article. When possible, examples are given of a New Dietary Ingredient (NDI) notification whose failure resulted from a lack of consideration of one or more of these factors.

History

Despite the rather strongly held belief by the general public that the dietary supplement industry and its products are largely unregulated, this assumption is far from true. Admittedly, the volume of text, otherwise known as the Dietary Supplement Health and Education Act (DSHEA), which was added to the Federal Food Drug and Cosmetic Act (FFDCA) to permit the use of dietary supplements, is fairly modest. Likewise, the regulations in 21 Code of Federal Regulations 190 is not extensive.

However, the wording defining a dietary supplement is very specific and limiting, versus the broad wording used to describe food ingredients. For instance, DSHEA specifically prohibits the use of tobacco, and specifically defines a dietary supplement as vitamins, minerals, herbs, extracts, or metabolites of food ingredients. Comparatively, the original definition of food, according to FFDCA section §201(f), is broad: "…articles used for food or drink for man or other animals..."

While there are many reasons that Congress established specific wording for dietary supplements, in the context of this discussion, the primary reason involved thwarting the Food and Drug Administration's (FDA) previous efforts to keep supplements off the market. By declaring dietary supplements a subset of foods, FDA cannot declare them as drugs-a strategy FDA had previously used to keep dietary supplements off the market. Secondly, with dietary supplements considered a subset of foods, FDA is prevented from declaring dietary supplements as unapproved food additives. Instead, dietary supplements are considered to have a presence in the diet of man, and therefore are a food.

As the agency charged with overseeing the safety of the food supply, FDA has developed a regulatory regimen that complies with Congress's wish to keep dietary supplements in the food arena. At the same time, it also incorporates demands that excipients or inactives-the ingredients comprising the delivery system for a dietary supplement-also be compliant with regulations governing food. Below are four criteria to consider when determining whether your dietary supplement delivery system complies with FDA's rules.

Intended for Ingestion

The delivery system must support the use of a substance as a dietary supplement, and not as a drug, device, cosmetic, or food.

The FFDCA clearly states that a dietary supplement is "intended for ingestion."¹ This would rule out any delivery system for intravenous, other injectable, or intranasal use. (The possible exception is a naso-gastric tube, although FDA has not yet ruled on the legitimacy of such a delivery system.) Clearly, administration of a product to or within any orifice other than the mouth, even via the opposite end of the alimentary canal, would not be regarded as "ingestion."

LET'S GET TOGETHER

As demand continues to grow for pre- and probiotics, Capsugel's (Greenwood, SC) capsule-in-a-capsule technology may offer dietary supplement marketers a unique solution. Introduced last year, the Pre-Pro Combo capsule was especially designed to house a combination of prebiotic and probiotic ingredients.

When the Pre-Pro Combo was first introduced, Mark Vieceli, director of sales, marketing, and business development for Capsugel, said, "Prebiotics and probiotics can work together to improve the ultimate nutritional effectiveness of probiotic ingredients...The Pre-Pro Combo gives manufacturers a distinctive way to efficiently offer consumers additional benefits within one unique product."

The Pre-Pro Combo's inner capsule, which is designed to house a freeze-dried probiotic, is suspended in a liquid-prebiotic formula in an outer capsule. The capsules can be customized to house the probiotic strain and prebiotic of a manufacturer's choice, says Vieceli.

"This delivery technology has the greatest benefit for those probiotics that are more sensitive to activation by moisture, but certainly it is a good way to deliver all probiotics," he adds.

The vegetarian hypromellose (HPMC) that's used to make both capsules is a low-moisture material. That, combined with the use of excipients with low water activity, helps to protect moisture-sensitive probiotics. Low water activity in the capsule also allows probiotic formulas to remain stable at room temperature.

The capsule-in-a-capsule technology also offers delayed release of the probiotics that may help to protect the probiotic until its capsule can pass from the stomach into the upper intestinal tract. The outer capsule must first rupture and dissolve before the inner capsule can be exposed to water and start to dissolve.

Capsugel has its sights set on even-more-advanced delayed-release technology, which the company says is still going through research and development. "We will continue to work on polymers for delaying release," says Vieceli. "Combination products, such as capsule-in-a-capsule and beadlets-in-a-capsule, offer a creative opportunity for dietary supplement developers."

Likewise, for dietary supplements, FDA has prohibited delivery systems whose instructions for use include application to the external surface of the body. This would theoretically exclude "cosmeceuticals" from being considered dietary supplements-unless, of course, the beautifying result came from within, as the result of ingesting the product.

"Intended for ingestion" would also rule out delivery systems such as an eye patch, or even an object that, although it is taken through the mouth, serves as an appetite suppressant by expanding in the stomach to provide a sensation of fullness. FDA considers such delivery systems to be medical devices.

FDA has also declared that a substance intended to be held in the mouth followed by expectoration is not a dietary supplement because it is not intended for ingestion.

Interestingly, a product such as Ginsana-a chewy square that is not chewing gum but rather a rubbery sponge with a hollow cavity in the center that, when chewed, releases the product for swallowing-is a unique delivery system that is considered "ingested" by FDA because the system allows the contents therein to be made available for swallowing. Products such as a lozenge, a fabric pouch (such as a pouch for tobacco snus), or even a "breath strip" are permitted, as long as the dietary ingredients emanating from such products are intended to be swallowed.

Does Not Resemble Food

The delivery system must comply with lawful restraints on type, form, and volume of an appropriate system, and may not resemble a food or meal replacement.

FFDCA's definition of a dietary supplement explicitly refers to the particular form in which a dietary supplement can be ingested. FFDCA says that a dietary supplement, a) is intended for ingestion in tablet, capsule, powder, soft gel, gel cap, or liquid form, and, b) is not represented as conventional food nor as a sole item of a meal or the diet.²

Clearly, there is no disputing that the intent of the law was to avoid the concept of a "meal in a pill." It also reinforces to the consumer that "supplements are not foods" by banning the use of delivery systems that emphasize gustatory hedonics or a pleasurable organoleptic sensation.

However, despite the law's good intention, soon after the passage of DSHEA, it became obvious that the coarse delivery systems used for dietary supplements were a turn-off to consumers. Some customers had difficulty swallowing pills, especially large ones, or felt that consumption of supplements in a drug-like format such as pills is psychologically unacceptable and/or sets a poor example for observant children.

Recognizing the problem, FDA allowed the addition of supplements to snack bars and beverages-but under the condition that such products be clearly labeled as supplements. To its credit, FDA is careful to prevent abuse of this flexibility by forbidding obvious conventional foods, such as soups, juices, and cereals, from containing added herbs or other products that are clearly supplements in a meal vehicle.

Recently, however, FDA has called into question the wisdom of allowing supplements to be marketed in larger-volume delivery systems, such as beverages.³ However, we believe that the addition of supplements to a standard-serving-size liquid (e.g., 8 to 12 oz) is an effective method for portion control. Banning supplements administered in standard liquid-serving sizes, such as in flavored waters or drinks, could be problematic because consumers might purchase supplements as powders or small-volume liquids, and add several doses to a single bottle of liquid, teeing the consumer up for a possible overdose. The larger volume confers an added layer of safety.

The fact that standard-serving-size beverages or energy bars are flavored is a product of necessity, as many supplements are not palatable. The use of a large-volume or pleasant-tasting delivery system does not in and of itself make a dietary supplement a meal replacement.

Excipients: Approved for Food?

If the delivery system is a functional food or beverage, it must only use ingredients that are approved as food additives or have generally recognized as safe (GRAS) status. Also, the delivery system may not use excipients that are only approved for drug use.

Until recently, FDA had only considered excipients as a category of substances in the context of pharmaceuticals (i.e., the inactive non-drug or non-pharmacologically active components of drugs). Most often, the excipients used in drugs, including bulking agents, preservatives, buffering agents, and even the inks used on tablets and capsules, have already been approved as food additives or have GRAS status.

Some excipients, such as methyl cellulose derivatives, are only approved for use as excipients in drugs. A few substances have no specific approval for drug use but have been regarded as "innocuous" by FDA and thus have been permitted to be used in pharmaceuticals.

Recently, FDA decided that if a dietary supplement is a food, its delivery system must logically comprise ingredients approved for food use. Therefore, recent New Dietary Ingredient notification approvals have required that a supplement be delivered in a food-compliant format.

Also importantly, the ingredient may not be used at a level or concentration in the final dietary supplement product that exceeds the approved use level for food. It may also not exceed the aggregate acceptable daily intake level-that is, the level of use approved in food, plus the level of use approved in supplements. Lastly, the ingredient must adhere to any standards or specifications cited in the original approval.

The "Catch 22" of this guideline is that there is no approval pathway for excipients for food use. However, this is where the "safe and suitable" rule would come into effect. That is, if an ingredient is approved as, for example, a preservative or bulking agent for food, it could also be used for the same technical effect in a dietary supplement at a level no higher than necessary to achieve its intended effect.

Technically, a "safe and suitable" substance should not be a food additive with specific limitations on its use. However, FDA has apparently applied regulatory discretion on this point and not demanded precise compliance with the regulation. Keep in mind that the "safe and suitable" option and reliance on regulatory discretion are best looked upon as temporary measures. Visionary excipient manufacturers are putting their products through the GRAS process to ensure future regulatory compliance.

Note: In regard to the use of colors, although many of the colors used in drugs are also approved for food use, some are only approved for drug or cosmetic use and are called D&C (drug and cosmetic) colors. By contrast, FD&C (food, drug, and cosmetic) colors can be used in all three product classes. Again, the "safe and suitable" rule would apply.

Must Be Safe

The delivery system must not compromise the safety of an otherwise safe product.

There are those rare instances when a delivery system changes the nature of a substance or the grounds on which the original concept of safety for the substance was based.

One example is the use of nanotechnology, which can lead to enhanced absorption of a substance. The gut wall serves as a natural protective barrier against the absorption of some substances, either by blocking absorption entirely or by slowing absorption so that only small amounts of the substance are absorbed over a prolonged period of time-and are therefore better tolerated.

However, nanosized particles (less than 100 nanometers in at least one dimension) may gain the ability to bypass these traditional barriers and pass through, or even between, gut wall cells, regardless of the physiology in place to prevent passage of larger particles made of the same substance. Therefore, a substance that may have been regarded as safe as a "macro" particle may exhibit toxicity as a nanosized particle.

A second example of a delivery system enabling a substance to bypass traditional barriers would be encapsulation of probiotic bacteria. Probiotic bacteria are often encapsulated to allow them to escape the rigorous physical barriers of stomach acidity and bile acid. Stomach acid and bile are two traditional, protective barriers against bacteria that enter the alimentary canal via the food we eat.

The concern in this instance is that use of a delivery system to preserve the probiotic may allow a large volume of bacteria to enter the lower alimentary canal, which could overwhelm the system, suddenly upsetting the ecology of the intestine and wreaking havoc on the balance of the resident bacterial players, many of which are beneficial. Comparatively, if such a protective encapsulation system were not used, the few bacteria that survive the physical barriers of stomach acid and bile have an opportunity to grow and proliferate at a rate that is less of a potential shock to the system, and would allow a more natural, progressive change of the bacterial ecosystem.

Looking Forward

Despite FDA's original resistance to dietary supplements, the agency is still charged with implementing DSHEA and permitting the marketing of dietary supplements, which are often unusable without a sophisticated delivery system. While DSHEA is very prescriptive in some ways, its implementation must be reconciled with the conceptual landscape concerning foods and their ingredients.

Ironically, while many people feel that dietary supplements are not regulated, dietary supplements are actually subject to more prescriptive regulatory oversight than food ingredients. While dietary supplements are held to a lower proof-of-safety threshold than food ingredients are, the excipients comprising the delivery system are held to the higher standard for food.

One of the issues unforeseen by Congress when framing DSHEA was the need for a directive to FDA to allow for delivery systems for supplements. However, the judicious use of regulatory discretion by the agency, and thoughtful application of the regulations by manufacturers-or, optimally, a GRAS determination for a delivery system's components-can overcome potential barriers to marketing safe and effective dietary supplements to the public.

References

1. §201(ff)(2)(A)(i)
2. §411(c)(1)(B)
3.www.fda.gov/food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/ucm192702.htm

George Burdock, PhD, is president of Burdock Group (Orlando, FL), a safety- and regulatory-consulting company. E-mail him at gburdock@burdockgroup.com. Ray Matulka, PhD, is the company's director of toxicology. Reach him at rmatulka@burdockgroup.com.