BAS 420

Robert Amo, Director Global OTC and Health & Nutrition Marketing, Capsugel Inc.

DRcaps® Capsules
Achieve Delayed Release
Properties for Nutritional
Ingredients in Human
Clinical Study
A gamma-scintigraphy study confirms delayed release
properties of DRcaps capsules in human subjects
 introduction
More consumers are addressing their digestive health as a cornerstone of
optimizing the nutritional benefits of their diets and overall health, including
immune support, cardiovascular health, joint health, and more. As a result,
they are driving healthy growth in probiotics and nutritional enzymes,
especially those in convenient supplement delivery forms.

Probiotics and enzymes are sensitive to acid and run the risk
of being rendered less effective while crossing the low pH of
the stomach on their way to the intestinal tract.

Global sales of probiotic supplements were $3.3 billion in 2013 and are
poised to nearly double to $5.5 billion by 2018, with North America,
Europe and Asia Pacific leading the growth.1,3

Sales in digestive enzymes have been accelerating at a slower pace, but

are expected to gain speed as a growing number of consumers embrace
systemic enzymes to address other health issues, including inflammation,
skin care, wound healing, joint health, and cardiovascular health. In the
United States, the world’s number 1 supplement market, sales of enzyme
products and digestive formulas through both conventional and natural
channels combined continue to grow.2

But the industry has concerns about delivery methods that can help support
maximum effectiveness of probiotics and nutritional enzymes. Both work
best in the intestines. However, both probiotics and enzymes are also
sensitive to acid and run the risk of being rendered less effective while
crossing the low pH of the stomach on their way to the intestinal tract.
Additionally, probiotics – as living bacteria – can easily be prematurely
activated by variations of temperature, oxygen, and humidity before they are
consumed, whether delivered in yogurts, vials, capsules, or tablets.

Supplement manufacturers have turned to a range of dosage delivery

solutions for the purpose of enhancing protection of moisture and
acid-sensitive ingredients. Some environments, especially the low pH of the
stomach, can destroy some acid-sensitive strains. Additionally ingredients

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that are very hygroscopic and need protection in the packaging from early
activation due to environmental moisture or water content of the capsule or
coating create specific challenges. Occasionally taste masking is required.
Many ingredients target release to the upper gastrointestinal tract where
the ingredient action is optimized, thus a delayed or targeted release
delivery is important. Unfortunately, many of these attempted solutions
might solve one issue but not others. They offer variable shelf life for the
ingredients but limited proof of delivery to the intestines while increasing
manufacturing time and costs.

Enteric coatings are often applied to tablets to provide protection and delay
release. Conventional film coatings for acid-resistance involve costly
manufacturing processes that are complex and may lead to waste, delays
and yield loss. Coating techniques require use of chemicals and solvents
that do not fit many consumers’ preference for ‘healthy and natural’
products. Coatings have variable moisture levels, variable bulk density and
variable compressibility. The incremental costs, multi-step preparation and
potential yield issues can be operationally challenging.

Vegetarian capsules with a three-fold lower moisture content

than gelatin, have provided an excellent alternative.

Encapsulation is one of the standard technologies for oral dosage delivery

forms. However, for some ingredients gelatin capsules may not provide
sufficient protection against moisture (leading to early activation or
ingredient degradation) or may become brittle (leading to capsule
breakage). In addition, some consumers prefer supplements that do not
contain any animal ingredients such as gelatin. Therefore, vegetarian
capsules made of plant derived cellulose such as Vcaps® and Vcaps® Plus
capsules with a three-fold lower moisture content than gelatin, have
provided an excellent alternative.

Made of plant-based hydroxypropyl methylcellulose (HPMC), both Vcaps®

and Vcaps® Plus capsules have low water content of 3% to 9% at ambient
conditions, with an average of less than 6%, and maintain their mechanical
stability under stressed condition of temperature and low relative humidity.
Ideally suited for moisture sensitive and hygroscopic ingredients, both
capsules were designed for immediate release applications such as the
majority of vitamins, minerals and supplements.

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 Introducing DRcaps Capsules
A third HPMC option, DRcaps® capsule, was developed to effectively address all of
the various challenges and shortcomings of delivering acid-sensitive ingredients.
The revolutionary dosage form offers unique polymer properties formulated within
the capsule itself to slow the capsule opening after swallowing without adding
coating ingredients that increase manufacturing time and costs. With moisture
content of 4% to 6% in 50% relative humidity, low moisture DRcaps capsules
inherently enhance stability for moisture-sensitive probiotics. The innovative
polymer properties also mask the taste and odor of ingredients; therefore, by
protecting against early disintegration, DRcaps capsules actually reduce the
DRcaps Caspule potential for unpleasant odors, aftertaste and reflux from supplements. In
particular, the unique polymer properties were designed to resist acid in order to
Advantages
protect nutritional ingredients from full release and disintegration in the stomach
• Acid resistance protects and allow for complete dissolution in the intestine.
nutritional ingredients without
the need for film coatings.

• Plant-based, vegetarian With moisture content of 4% to 6% in 50% relative humidity,

capsule designed to release low moisture DRcaps capsules inherently enhance stability for
when you need it.
moisture-sensitive probiotics.
• Enhanced stability for
moisture sensitive and
hydroscopic ingredients.

• Taste and odor masking Human Clinical Study

of herbal or mineral
To clinically assess the efficacy of DRcaps capsules for resistance to stomach
ingredients which can
increase digestive comfort. acids for delayed delivery properties of ingredients, Capsugel commissioned the
independent laboratory, Bio-Images Research, in Glasgow, Scotland, to conduct a
gamma scintigraphic in vivo study. The human clinical study was designed to
evaluate the disintegration behavior of unbanded DRcaps capsules in human
subjects. Completed in spring 2013, the study documents through images and
data the success of unbanded DRcaps capsules’ resistance to stomach acids for
delivery of ingredients.

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Study Protocol and Execution DRcaps capsule administered

The study was designed to investigate the in vivo behavior of DRcaps capsules
using qualitative and quantitative scintigraphic methods to assess the
gastrointestinal transit of the capsules and release of capsules based on the
scintigraphic images obtained. Gamma scintigraphy is an established technique in
which a radio label is swallowed and the disposition in the gut is photographed
externally over time.

In this study, DRcaps capsules were filled with 290 mg of cold lactose
monohydrate and approximately 10 mg of lactose monohydrate radiolabeled with
99mm Tc-DTPA. The capsules were closed and stored in individual, labeled plastic Intact DRcaps capsule reaches the stomach

bijous in lead pots.

After meeting eligibility requirements, eight subjects were enrolled. Each subject
consumed a light breakfast comprising one slice of crisp bread, five grams of jam,
and 200 mL apple juice. Approximately 30 minutes later, each subject swallowed
whole one DRcaps capsule filled with the radio label with 150 mL of room
temperature water.

Scinitigraphic images were taken following the dosing until complete capsule
radiolabel release, i.e. capsule disintegration, was confirmed. Anterior and posterior
abdominal images of 25-second duration each were acquired after dosing and
DRcaps capsule starts to release the contents
then every five minutes up to four hours after dosing, then every 10 minutes to a
maximum of 10 hours after dosing.

Trained personnel analyzed the images with Weblink software relating to the
position of the capsule in the gastrointestinal tract and onset and complete
radiolabel release from the capsule.

Three scenarios of capsule disintegration were noted: begun and completed in the
stomach, started in the stomach and finished in the small intestine, and
commenced and completed in the small intestine.

DRcaps capsule has left the stomach

and releases its contents in the intestine

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 Study Results and Conclusion
• DRcaps unbanded capsules displayed delayed release properties.
• Disintegration started approximately 45 minutes later than a typical immediate release capsule of about 5 minutes.
• For the majority of subjects, complete release took place in the intestine.
• Complete release occurred 20 minutes after the onset of release.
• DRcaps unbanded capsules significantly reduced opportunity for nutritional ingredient degradation compared with
standard immediate release capsules.
The results of this in vivo human clinical trial presents empirical evidence of successful acid-resistance and delayed release
properties of DRcaps capsules. The innovative DRcaps capsule targets release after a certain time period, protecting
ingredients from full disintegration in the stomach.

Data and images showed radiolabeled release began at a mean time of 52 minutes when the capsules were about to leave the
stomach and a full 45 minutes later than a typical immediate release capsules. While the lactose ingredients in the capsules
were inert and didn’t require moisture protection from premature activation like probiotics, the delayed release properties can
be applied to any ingredient. This gives confidence that DRcaps capsules are an excellent choice for delivery of acid-sensitive
ingredients, in particular probiotic and enzyme ingredients that work best in the intestines, where complete release of
ingredients was observed in the majority of subjects.

The fact that the polymer exhibits delayed release properties without the use of costly coatings is a major bonus, allowing for
economical and quick product launches and vegetarian product with great appeal to this fast-growing lifestyle market.

Radiolabel release parameters and gastric emptying times (DRcaps capsule A)

Time from Gastric

Subject Onset of Completion of Site of
Site of onset onset to emptying
Number release (min) release (min) completion
complete (min) time (min)
001 52.5 S 67.5 S 15.0 N/A
002 57.5 S 97.5 S 40.0 N/A
003 47.5 S 102.5 SI 55.0 97.5
004 37.5 SI 42.5 SI 5.0 37.5
005 32.5 SI 42.5 SI 10.0 32.5
006 47.5 S 57.5 SI 10.0 55.0
007 87.5 SI 97.5 SI 10.0 87.5
008 52.5 S 67.5 SI 15.0 55.0
Mean 51.9 71.9 20.0 60.8

St Dev 16.6 24.6 17.7 26.3

S – stomach; SI – small intestine; N/A – not applicable

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References
1. NBJ/Engredea Monograph, Probiotics Forecast 2013-2014: An in-depth look at the latest
news, innovations and market trends.

2. “New Frontiers in Nutritional Enzymes,” by Lisa Olivo, Nutraceuticals World, October 1, 2012,
www.nutraceuticalsworld.com/issue/2012-10/view-features/new-frontiers-in-nutritional-enzymes/.

3. Euromonitor International database 2014, Fixed Exchange Rates.

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