FDA Report on Phytoceramides
RonaldGUdell
Phyto Derived Ceramides
This New Dietary Ingredient (“‘NDI”) Notification is submitted pursuant to 21 C.F.R. 0 190.6
and Section 8 of the Dietary Supplement Health and Education Act. This Notification concerns the
new dietary ingredient phyto-derived Ceramides, a type of lipids which are constituents of
sphingolipids, and for this Notification, derived from either wheat or rice (henceforth Ceramide or
Ceramides). Currently, in its research and development for a dietary supplement containing this new
dietary ingredient, Soft Gel Technologies, Inc. (“SGTI”) of Los Angeles, California is using
CennamidesTM (a phyto-derived Ceramide, sourced from wheat germ) Cennamidesm is
manufactured by Ennagram of Pantin, France, for SGTI, which intends to use this ingredient in a
dietary supplement to promote and support healthy skin. For a proposed new dietary supplement,
SGTI intends to use as an ingredient Ceramides derived from either rice or wheat germ oil, in
amounts of 30 mg per serving, and 60 mg per day.

The safety evidence presented in this Notification will show that: 1) plant Ceramides are
naturally-occurring in many foods; 2) six forms of &amides are found in the skin, and these and
the various forms of phyto-derived Ceramides are chemically identical or substantially equivalent
(please see below); 3) two LD-50 tests detailed below have been performed, one using
CennamidesTM(1 5% Ceramide in wheat germ oil) and one using rice-derived Ceramide and both
conclude that the LD-50 is more than 5,000 mg per Kg.; 4) other animal studies also show no
toxicity; 5) human efficacy studies using orally-administered Ceramides have been done, and they
show no reported adverse events; 6) Ceramides are similar to plant sterols, which the FDA accepts as
GRAS in foods; and 7) nutritional supplements and functional foods containing Ceramide (derived
from plant sources, e.g., rice bran and wheat) are currently on the market in Japan and have been for
approximately 5 years. This Notification is intended to meet the standard of safety for a new dietary
ingredient of rice-derived Ceramides as well as for CennamidesTM (wheat-based), collectively
Ceramides. In this Notification, SGTI will present the scientific evidence and substantiation on
which it bases its conclusion that a dietary supplement containing Ceramides (in amounts up to 60
mg per day) is reasonably expected to be safe.

Ceramides Found in and Derived from Foods, Plants
Ceramides are found naturally in many foods, especially wheat flour. 1 (Copies of all articles
and reported cited or referenced in this Notification are attached.) The amounts of Ceramides in
food vary considerably, but considering all the food sources, the per capita Ceramide consumption in
the United States is estimated to be 0.3 to 0.4 grams per day.2”74 Sphingoiipids, which contain
Ceramides, as shown below, are found in large amounts in dairy products, eggs and soybeans.5
Ceramides are also found in rice, millet, and spinach.6 By one estimate, sphingolipids account for
.Ol to .02% of the human diet.

Currently there are many types of Ceramides on the market (e.g., in Europe and Japan) and
virtually all of them are commercially derived from plant sources. Ceramides derived fiorn plants
(Phyto-Derived Ceramides) are the focus of this Notification, specifically those derived fkom wheat
and rice. Originally Ceramides were derived from soybeans and bovine sources. However, unlike
bovine-derived animal Ceramides, which can carry the problematic risk of viral infection or of
conditions such as mad cow disease, plant-based Ceramides are attractive from a safety and low risk
standpoint.* Now, fermentation processes from yeast and glycerol are available. Two popular
sources are brown rice and wheat germ extracts. These are the two common sources of
commercially available Ceramide for dietary supplement and cosmetic applications.’
Specifically, the subject of this Notification is Ceramides derived f&m wheat germ, other
wheat sources, and from rice; regardless of derivation, these Ceramides are chemically very similar
and are substantially equivalent for purposes of safety analysis.!o The complex plant sphingolipids
which make up the ceramide have glucose, galactose, and inositol backbones. Wheat derived
ceramides are structurally similar to rice derived ceramides because they share common sugar
components and only differ in the placement of the fatty acid component along the chain. This
makes these two forms of plant ceramides interchangeable as functional components of a specific
sphingoloid (ceramide) class.”

Recommended Conditions of Use in the Proposed Product

There are no special requirements for use in dietary supplements containing Ceramides, such
as the need to take it on an empty stomach. No suggested conditions for use are required or
recommended by SGTI. Most probably, SGTI will place the following,Caution on the label of the
dietary supplement containing Ceramides:

However, this would be purely as a precaution; as shown herein, Ceramides are naturally-occurring
in many foods. Again, sphingolipids account for .Ol to .OZ% of the human diet;12 and Ceramides
account for .3 to .4 mg per day in the human diet. Ceramides are neither hormones nor stimulants.
Furthermore, there are no limits on the duration of use. Ceramides can be taken for a long term
supplementation regimen to keep the skin moist and healthy.

Safe Use of Ceramides

As far back as 1853, scientific papers were published explaining the role of internal lipids
(fats) in the skin.‘4 Nearly twenty years later, classes of lipids named Sphingolipids were
discovered. Specifically, the presence of ceramides as a category within Sphingolipids was “first
detected in the animal (human) brain by the German physician L.T. W. Thudichen in 1884, and
subsequently these substances were extracted from sources such as the bovine brain for use in
cosmetics, etc.“‘* Over a century later, much of the biochemistry of lipids in the skin has received
significant attention and is much better understood. As discussed below, Ceramides are a special
class of sphingolipids and are found in the stratum comeum, the outermost skin layer. They account
for about 40-65% of lipids in the stratum comeum. There are six kinds of Ceramides found in the
skin, all serving different purposes. Ceramides are not very soluble, thus making them difficult to
manufacture. They work when absorbed into the stratum comeum, and that mechanism necessitates
special processing procedures to derive a viable product for human ingestion and topical use. I6
Much has been written about “anti-aging“ creams and lotions, and more have been sold in
recent years based on the current marketing of beauty creams, which promise youthful skin.
Aggressive marketing and promising cosmeticf ormulas have characterizedm uch of this salesb oom.
The term “anti-aging” is important in establishing the market for Ceramide products. In the early
1990’s, major cosmetic companies such as Elizabeth Arden formulated and branded products based
on the safe and effective use of Ceramides for treating aging problems such as fine lines, wrinkles,
and dryness. These were often in the form of expensive topical creams and potions. Because of its
moisture retaining properties, Ceramides were eventually included in cosmetic products such as
foundations and lipsticks to increase outer moisture and to provide a benefit to the skin while
protecting it from damaging elements.i7 For the same purpose, but via a different route-ingested-
SGTI is developing Ceramide-containing dietary supplements.

Ceramides, SPhingoliPids and Glvcosphiwolipids

Ceramides are a type of sphingolipids, which are lipid substances present in all cell
structures. C&amides are constituents of cells in the cytoplasmic membranes. Thus, they are
naturally found in the skin, central nervous system, and spinal marrow.” As shown above,
Ceramides are also present in the plant world, with the main sources being wheat, rice, soy, and
spinach. These compounds are the result of the formation of an amide bond between a fatty acid and
sphingosine, or phytosphingosine.

Glycosphingolipids (GSLs) are a varied and diverse class of molecules which consist of a
sugar attached to Ceramide moieties. More than 400 species are known, though only seven
monosaccharides are found in vertebrates. Distributed mainly at the surface of the cell, they
participate in the regulation of the interactions ofcells with their environment.‘” These lipids serve
as distinguishing markers for cells and mediate cell-to-cell recognition and communication. They
are essential for the development and growth of organisms, and their decrease has been implicated in
skin disease,20a nd in a number of serious diseasess uch as cancer and viral infections.2”2y23
The separation of GSLs into groups and subgroups is made according to the different kinds
of carbohydrates, acyl, or sphingosine structures which can attach to forqa variety of compounds.
GSLs are commonly divided into two main groups, Neutral GSLs and Acidic GSLs. Acidic GSL
compounds reflect the type of structures which form the basis ofthe Ceramide compounds which are
the subject of this ND1 Notification.

Ceramides are the simplest sphingolipids and situated at the center of sphingolipid
metabolism. Thus, the transfer of a phosphorylcholine head group from phosphatidylcholine to
Ceramide yields another phospholipid, sphingomyelin (also sphingolipid); and the addition of
carbohydrate groups fkom the sugar donor, UDP-hexose, yields complex Glycosphingolipids
(cerebrosides, sulfatides, gangliosides). These compounds can be converted back to Ceramide by the
removal of sugars (glycosidases) or phosphorylcholine by sphingomyelinases. An enzyme
(ceramidase) is able to cleave the amide-linked fatty acid of ceramide and free sphingosine.
Free ceramides are separated with the neutral lipid fraction on a silica column; and the
minute amounts present in cell extracts are best analyzed after derivatization before HPLC. Their
chromatographic behavior is not very different from that of diacylglycerols which are also
structurally similar. The amide linkage is resistant to hydrolysis but is disrupted by prolonged
heating in an alkaline medium (although better with an acidic reagent). Ceramide can be prepared
conveniently from complex Glycosphingolipids by chemical degradation.24
The stratum comeum of the skin (the upper-most layer made of dead cells) has a unique lipid
composition which comprises mostly free fatty acids, cholesterol and ceramides (0-acylceramides).
These are different molecular species, differing by the head group architecture and by the mean fatty
acid chain length. The fatty acid esterified to the amide of the (phyto)sphingosine head group can be
either a-hydroxy or nonhydroxy fatty acids. The fatty acid chain length varies from 16 to 34 carbon
atoms.

Orgretmen explains how endogenous ceramide found in skin mediates the action of
exogenous ceramide. This action is thought to work via a recycling process where the sphingosine
backbone of Ceramide is thought to be recycled. This provides the link which allows phyto-derived
ceramide compounds to be used to replace degraded ceramide which is depleted in the stratum
corneum2’ As stated above, Ceramides are commercially extracted from rice bran or wheat germ.
These plant sources naturally contain a large amount of glycosphingolipids. The glycosphingolipids
of rice bran are similar to the animal glycosphingolipids, in which the backbone of the Ceramide
including sphingoid bases with fatty acids is an amide linkage, and the terminal hydroxyl group is
substituted by glucose. Glycosphingolipids have a great variety of molecular species because of the
partial structure of sphingoid bases.

Ceramide Functionalitv

Ceramides are also natural components of human skin.2g There are six Ceramide species or
structures commonly found in skin.3o These Ceramides are formed via a biosynthetic mechanism in
the epidermis. The four layers of the epidermis contain Ceramides, and they play an important role
by creating a barrier which reduces infection and helps to retain the skin’s moisture.31 Reduction in
the amount of Ceramides in the epidermal layers results in dry skin, dermatitis, and is believed to be
a major cause of wrinkles.32 Studies have shown that a proper amount of Ceramides in the internal
epidermal layer is necessary to maintain healthy skin.

The stratum corneum is the outermost layer of mammalian skin. This layer primarily acts as
a barrier to protect us from external environmental stresses and to prevent excessive transcutaneous
water loss. The cells of the stratum comeum, comeocytes, and the lipids between them, Ceramides,
accomplish this important function. Disruptions of this barrier, through either physical trauma
caused by dermatitic conditions like eczema or by simple aging, results in this important function
being compromised. The result is decreased elasticity, increased susceptibility to infection, and
increased water loss which can lead to aging conditions such as wrinkles and fine lines, as well as an
overall dullness to the skin’s texture.

Plants contain structures which are chemically similar to human Ceramides. These plantderived,
or phyto-derived, Ceramide products can aid in creating the protective barrier in the
epidermis. Supplementation with an oral agent of Ceramide replaces the components lost through
aging, and has hydration effects.38 The moisturizing effect comes fi-om the Ceramides being carried
directly to the stratum comeum via the blood. This direct method improves the functionality of the
Ceramides and produces results not seen in cosmetic topical applications3’
Ceramides have become an important compound for skin protection. Lipid depletion and
replenishment studies have shown that Ceramides play an essential role in establishment and
maintenance of the water-retaining properties of skin. Since it is known that Ceramides decrease
with age, it has been suggested that increased transepidermal water loss is the result of their reduced
presence in the skin. In short, Ceramides play an important role in preventing moisture loss which
can be caused by physical trauma or aging.

It is also known that Ceramides inhibit Melanogenis and are thought to promote a pigment
lightening effect. Melanogenis is a process by which the skin produces pigments that give our skin its
unique tone and color. This is particularly helpful for hyper-pigmentation which causes age spots
and other discolorations of the skin. In an in vitro study using B-16 melanoma cells, the
melanogenic effect of Ceramides was observed. Ceramides exhibited a stronger whitening effect
when compared to ascorbic acid, arbutin, and ellagic acids.

The moisturizing effect of Ceramide was established in several. clinical studies. These
studies show that C&amide is absorbed via the digestive system and carried to the stratum comeum
by blood, where it circulates, and produces a significant effect in promoting a water barrier in the
layers of the skin. Therefore, Ceramides in the stratum comeum of the skin play important roles for
maintaining a barrier function and protecting the skin from harm.

Ceramide Toxicitv and Safetv Data and Animal Studies

There have been numerous toxicology and animal studies of ingested Ceramide. The
available toxicology and safety profile of this product offer ample assurances of the safety of
Ceramide in clinical, ingested use. This conclusion can be drawn from the work of several
researchers who examined both acute and chronic toxicity in animals.

Acute Toxicity

This wheat Ceramide safety brochure also contained toxicity toward those who are allergic to wheat
data, and the results were very similar to the rice-derived Ceramide studies because of the similarity
between the components.

In a 1996 report, Richeux discusses administering CENNAMJDE CERO 15, a product name
for a vegetal ceramide produced by Ennagram, to a group of 6 Sprague Dawley rats (3 males and 3
females) at a single dose of 5,000 mg/kg body weight per day for a week. This study was petiormed
according to the experimental protocol established on the basis of the official method as defined in
the O.E.C.D. guideline No. 423 dated March 22”d, 1996 and the test method B. 1 ter of the Directive
No. 96/540X dated July 30th, 1996. The animals were administered the product by force-feeding
under a volume of 5 ml/kg body weight using a suitable syringe (graduated), fitted with an
oesophageal metal canula. No mortality occurred during the study. The conclusion was: LD50 of
the product fREF.03.749 CENNAMIDE CERO 15) is higher than 5 g/mg by oral route in the rat. 47
In 1989 Merrill reported the digestion and absorption of sphingomyelin, ceramide, and
sphingosine using an in vivo intestinal loop technique with rats. This abstract reports that essentially
no sphingomyelin or ceramide was hydrolyzed or lost from the small intestinal segments; however,
digestion and uptake from the colon was evident. In addition, later work by Merrill, in 1997,
confirmed and refined these results.

Schmelz, in 1994, reported that radio-labeled sphingolipids were placed in isolated intestinal
segments of female mice, and the metabolism and distribution of the radiolabel were followed. 4g
The aim of the study was to determine if sphingomyelin can be digested and taken up by different
regions of the intestine, with particular interest in determining if ceramide and sphingosine are
formed. The study documents that a substantial portion of the sphingomyelin was cleaved to
ceramide and sphingosine. Similar to information presented at the beginning of this Notification,
this study reports that sphingomyelin is present in substantial amounts in milk (123 ymol/L), salmon
(160 nmol/g), pork and beef tissue (350-390 nmol/g), and chicken (530 nmol/g). The study reports
that there was substantial metabolism of sphingomyelin throughout the intestine. Ceramide was the
primary breakdown product of sphingomyelin found in almost all regions of the intestine, accounting
for up to 9.5% of the administered dose. No safety data is reported in the study.
Most recently, in 2002, Berm reports that sphingomyelin is hydrolyzed by a
sphingomyelinase in response to extracellular stimuli, generating the lipidmoiety ceramide and the
water-soluble moiety choline-phophate. The study also reports that milk (lyophilized) contains
several species of glycospingolipids, such as Mono-hexosylceramide, Lactosylceramide, and Tetrahexosylceramide.
No safety data is reported in the study, but its import lies in the careti
documentation of the ubiquitous nature of Ceramides, in various forms, in conventional foods.”

Clinical Trials and Safety

Human clinical trials have been conducted on Ceramides as well. A double-blind placebocontrolled
study was conducted at Osaka City University to evaluate the effmts of oral
administration of supplements containing rice ceramides in 33 patients with a habitual tendency
toward dry, rough skin. The 33 patients were comprised of 6 men and 27 women, and the study was
performed in keeping with the tenets of the Helsinki Accord, with written Informed Consent forms.
This study was performed as a double-blind tial involving 6-week oral administration of
“functional supplements” containing rice-derived Ceramides or a placebo.”

The test supplement was given in the form of soft capsules provided by Oryza Oil & Fat
Chemical Co., Ltd., with a daily consumption of rice-derived Oryza Ceramide, 40 mg/day,
containing rice-derived sphingolipids of 1.2 mg/day. Placebo capsules were administered that were
identical in appearance and smell, but containing 0 mg/day of rice-derived Oryza Cerarnide and 0
mg/day of rice-derived sphingolipids. After the (i-week trial period, no subjects had dropped out and
no adverse events were reported. Other evidence of the safety of ingested Ceramides is also
presented in this study:

Experiments have shown that after oral administration plant-based ceramides are
absorbed unchanged in the small intestine or are broken down into, sphingosine and
fatty acids for absorption and are then reconfigured as ceramides. The substance is
then transported by the capillaries into the horny layer and the keratin intercellular
spaces. The supplements containing rice ceramides as used in this study, in contrast
to the ceramide substances distributed in animal brains, provide superior
supplementation that can be exnected to be both safe and effective for oral
administration. [Emphasis added.]

Confirming this assessmenits Lati, who as early as 1995 wrote about the useo f ceramidesi n
functional foods:

Ceramide has been highly appraised in the field of functional foods because
of its hydration characteristics and vectorization of vitamins (vitamin C and E).
Presently phytoceramides by INOCOSM [Laboratories] are used as
ingredients for various functional and cosmeceutical foods.
Because of its hydration characteristics, ceramide is most extensively used in
this field, and it is generally used together with vitamins.

Ceramide has shown numerous benefits as a food additive because of its very
unique characteristics, and it is effective not only for the tissuesbut also for the
stabilization of foods in some cases. If a certain amount of phytoceramide is
ingested every day, the following benefits could be attained.

* Because ceramide suppressesfr ee radicals, ceramide can enhancet he protection
of tissues from external harmful effects (pollution, sunshine, and stress).
l Ceramide moisturizes the skin by its hydration capability.
l Ceramide achieves wrinkle prevention by its elastase suppression and collagen
protection.

. . . On the other hand, if ceramide is added to drinks for the benefit of the tissues,
ceramide can also stabilize hydrophobic flavoring ingredients and hydrophobic
molecules (vitamins) by vectorization.

These conclusions are based in part on Lati’s 1995 study which concludes that phytoceramides
taken orally improve the hydration of the skin. The phyto-ceramides were given at an
amount of 20 mg/day for a month. No adverse effects or events were reported.

Ceramide Use Topicallv Moves to Ceramide Use Invested

Ceramides have been traditionally found in topical formulas such as creams and lotions.
Possibly the oldest exponent of an emulsifier free cream is the cold-cream. “Cold creams” contain
structures which are similar to the bi-layers of the stratum corneum. Therefore Ceramide integrates
in the skin barrier layers and it is very resistant against exogenous substances, It is recommended to
avoid occlusive components on mineral oil base for this concept as they slow down the formation of
the skin’s own protective substances. .This can be shown by artificially damaging the skin with
adhesivet ape strips (stripping). While the skin regeneratesu nder normal conditions within 24 hours,
the regeneration process is considerably delayed if the skin is artificially covered. 56
Internal ingestion of Ceramide is a concept which takes the benefits of Ceramides for skin
health and beauty to a new level. While a topical cream can provide only so much of a moisture
layer, an internal formula can carry or transport Ceramides to the cell level, thereby increasing the
potential for a Ceramide product to be absorbed into the layers of the skin. One common sense
indication that Ceramides are safe when ingested is that they have been included in semi-ingested
products such as lipsticks for many years. Lipstick is a cosmetic used by millions of women in the
U.S. that is gradually and eventually ingested throughout the day (because of the natural
phenomenon of licking one’s lips) and is reapplied continuously during tlie day as well. Although
very hard to calculate, some amount of Ceramides in the “ingested” lipstick is consumed every day,
assuming at least four re-applications per day.

A reasonable expectation of safety for ingested ceramides also may be deduced from at
least three patents, two concerning lipsticks. A patent for a “Long wearing lipstick” includes a
wax and “a phytosphingosine type ceramide.“57 In the detailed description of the invention, we
learn that the invention calls for the phytosphingosine-type ceramide to be present in the lipstick,
preferably from .20 to .50% by weight. According to the inventors, improved wear of the
lipstick, without sacrificing gloss, increased from .l % of Ceramide 3B to .2 and .5 %
respectively. Human clinical trials were performed, in which the experimental ceramidecontaining
lipsticks were applied twice a day. While lipsticks are semi-ingestible, there are two
other patents describing uses of ceramides in fully ingested products, and even pharmaceutical
products, as well as topically-applied cosmetics.

In patent 6,136,301, “Lipid mix for lip product,” one application is for an OTC drug lip
bahn5* This invention relates to a mixture of less than about 5% by weight of sphingolipids
(including ceramides), for both cosmetic and pharmaceutical formulations for topical use on the
lips. One claim is for a method of treating or preventing damage to the lips, and other
therapeutic embodiments are described.

Finally, in patent 5,s 17,646, “Polar lipid composition of plant origin,” the composition is
comprised of “an injectable, intra-articular, topical or ingestible aqueous emulsion of a polar
lipid mixture rich in phospholipids, in glycolipids and in ceramides. . .7’59 (emphases added).

This mixture is obtained from cereal flour or an extract such as bran or lipids extracted from
cereals, and thus is similar to the wheat-derived Ceramides discussed above, which is one type of
Ceramide being the subject of this Notification. The mixture in this invention is 90% ceramides
by weight, and the concept is to create a polar lipid mixture of plant origin essentially identical to
the composition of the constituents of the target cells. The detailed description of the invention
explicitly states (at page 7 of 14) that this polar lipid mixture can be used as a dietary
supplement, in addition to uses for pharmaceuticals or cosmetics. It also notes that ceramides
help with retention of water and thus aid in hydration of the skin. In addition, this invention
may be applied to drug treatment: “as a vehicle for the delivery of a vaccine component”; and
other tests were performed at the laboratories of the Faculty of Pharmacy of Chatenay Malabry
(France).60 This invention highlights the safety and efficacy of a ceramide product for targeting
cells with a specific composition. (Copies of all patents attached.)

An internal formula containing Ceramide provides a cost effective way to get more Ceramide
into the skin without the barrier of creams and lotions. Ceramides designed for ingestion work from
the inside out rather than the traditional outside in methods of topical creams.
Plant Sterols, Chemicallv Similar to Ceramides, are GRAS for Foods
Another indication of the reasonable expectation of safety for a Ceramide supplement is by
analogy to the safety profile of plant sterols. Plant Sterols are in the same chemical “family” as
phyto-derived Ceramides. Fundamentally similar to Ceramides, which are a type of lipid or natural
fat found in many foods, plant sterols or “plant fats” are present in virtually all fruits and vegetables.
Indeed, plant sterols are substantially equivalent in their natural occurrence in conventional foods,
and in the way in which they occur and are metabolized in the human body. Recently, the Food and
Drug Administration (“FDA”) has accepted a GRAS (Generally Recognized As Safe) petition from
Cargill, Inc. for use of plant sterols in foods, and also has approved a health claim linking 1.3 g of
plant sterols per day with a reduced risk of coronary heart disease. (See the FDA’s Final Rule, 21
C.F.R. sec. 101.83.) Given the close chemical relationship between plant sterols and Ceramides,
SGTI’s Technical Department has concluded that this GRAS status of plant sterols and the FDA’s
official, pre-approved health claim logically indicates that if 1.3 g per day of plant sterols are
considered safe (indeed beneficial) by the FDA, then 60 mg per day of Ceramides has a reasonable
expectation of safety.

A Historv of Safe Use of Ceramides in Dietarv Suaplements in Japan

Two dietary supplements containing Ceramides derived from rice (=Oryza sativa) are
produced by Oryza Oil & Fat Chemical Co. Ltd. (“Oryza”). Again, by comparison to all the numbers above,
of Ceramide per day is the maximum recommended use of Ceramide in this Notification. Oryza
Ceramide-P and Oryza Ceramide -L have been sold in Japan for approximately 5 years, and to our
knowledge no adverse events have been reported.

In several JapaneseIn ternet websitess elling nutritional supplements,m any different products
containing phyto-ceramides are advertised.62 Among these products is one called “Honen Ceramide
& Cysteine,” which contains ceramides extracted from the Konjac tuber, where a 4-capsule serving
contains 24 mg of ceramide powder. The ceramide is extracted from Konjac tubers, a food that has
been eaten by the Japanese since as far back as the Heian Period (794-t 1921, and that reportedly
contains 7 to 15 times more ceramides than found in rice or wheat. The manufacturer of this
particular ceramide nutritional supplement reports that the acute toxicity (LD50) is
Also, the advertisement reports a survey in which Konjac ceramides are taken for 4 weeks.
Finally, part of the promotion includes that the company’s research has been presented at a Food
Science conference:

Unitika Ltd. ranks its Life Health business as one of its most important areas
of business. At the end of last year, Unitika succeeded in extracting ceramides
contained in the konjac tuber and is expecting to move into new markets with the
commercialization of this highly purified, pure plant ceramide as a product with
cosmetic and dietary applications.

At the August 2002 Conferenceo f the JapaneseS ociety for Food Sciencea nd
Technology, [Ceramide’s] function as a new beauty food material was announced,
and that it is a beauty ingredient that is attracting attention.
Indeed, the “collaborative campaign” by Honen Corporation and Unitika Ltd. launched its Ceramide
product on November 17,2002. The Unitika Ltd. brochure for the Konjac Ceramide Supplement
stressesit s safetya nd seemst o imply use as a food additive as well:
“PhytoCeramide” which is an extractf rom Konjac . . . is an edible beauty-carep roduct
richly containingG lucosylceramide,a Glycosphingolipid.

Being natural products from Konjac, “Phyto-&amide” is a highly safe food, and
continuous intake will gain high performance.

As Phyto-&amide take on varied appearancesi,t s usage is suitable to any kind of
food.

Another Japanese product advertised on the Internet is Morishita Jintan’s “Collagen &
Ceramide Concentrate Tablets,” where one daily “pouch” contains 0.6 mg of ceramides. Further,
three additional products are advertised on these websites, namely “Cell E&e” (Product Number
CER-l), “Sup. Ceramide” (Product Number CER-l), and Ozio’s “Ceramide and Cysteine”(Product
No. 010000016023). Promotions for these three products state that they contain ceramides and are
to be ingested. Ozio’s “Ceramide and Cysteine” advertisement states, that it contains 75 mg
ceramides in a daily dose. Clearly, for product liability reasons, if Ceramide supplements were
unsafe at 75 mg of Ceramides per day, then this product would not be able to stay on the market.
Japan does have a counterpart to the Food and Drug Administration in the U.S., and this is
called the Ministry of Health, Labor and Welfare. According to a report by International Business
Strategies,64J apanh as very strict limits on the substancesa llowed in dietary supplements: only 350
synthetic food additives and 490 natural origin additives may be used in food. This appears to
require that dietary supplement ingredients, unlike in the U.S., must be GRAS, or at least officially
on the “safe” list. Any substance not on the list may not be used in supplements. In addition,
additives which have been approved for use in Japan in pharmaceuticals are not permissible for use
in supplements unless they are on the list of350 synthetic food additives. Japan’s regulatory regime
has been termed “both restrictive and opaque” by this report (at p. 5), which explains that many
ingredients or products that may be sold in other countries may not necessarily be legal in Japan.
For example, supplements from the U.S. routinely must be both reformulated and relabeled before
they may be sold in Japan. Finally, it was not until April 1,200l that Japan implemented new
regulations permitting heahh effect claims @f. structure/function claims) on supplement labels. The
main point here is that arguably the Ministry of Health, Labor and Welfare in Japan is much stricter
in regard to nutritional supplements than is the FDA under DSHEA, and yet Ceramides are permitted
as supplement ingredients in Japan, and have been on the market there for approximately five years.
Conclusion of Reasonable Expectation of Safety
Under 2 1 C.F.R. 6 190.6 (a), the standard for a new dietary ingredient premarket Notification
is that the manufacturer presents the basis on which it has concluded that “a dietary supplement
containing such dietary ingredient will reasonably be expected to be safe.” In this Notification, we
have documented a reasonable expectation of safety for a dietary supplement containing phytoderived
Ceramides, at the amount of in five ways:

1) the presence of Ceramides in much larger amounts in ordinary foods that make up the human diet and
that are consumed daily;
2) two toxicity studies showing that the LD 50 is more than 5,000 mg/kg;
3) clinical trials on rats and humans demonstrating no mortality or toxicity, safety, and no adverse
events;
4) a very similar substance (plant sterols) accepted as being GRAS, clearly a much higher
standard of safety; and
5) dietary supplements marketed and consumed in Japan containing
Ceramides at the same or higher levels than for the proposed SGTI product, in a country that
regulates supplements more rigorously than in the U.S. In addition, as stated above, Ceramides are
naturally present in human skin, the central nervous system, and spinal marrow. Copies of all
articles and reports cited herein are attached, pursuant to 21 C.F.R. 0 190.6 (b)(4). Together, these
articles and reports, in conjunction with the facts, data, and analysis above, demonstrate that a
dietary supplement containing phyto-derived Ceramides at the level of , and under the
conditions of use above, will reasonably be expected to be safe.

Confidentiality

In order to present full background on this NDI, this Notification co&@ proprietary tiormation
and bade secrets of SGTI, and thus is the Confidential version of the submission. Pursuant to 21 C.F.R.
set; 190.6 (e), SGTI, through its counsel, Swan Brienza, Esq. of Patton Boggs LLP (Denver Office),
reservesth e right to redacta ll commercialc onfidential,p roprietarya ndt rades ecreti nformationw ithin 90
days of this filing, and to provide that redacted version to this office, before the Notification is publicly
displayed or added to the FDA’s public Docket.

SOFT GEL TECHNOLOGIES, INC.
By: Ronald G. Udell, President
Date: March 26,2004

References

Berra, B. et al., Dietary Snhinnolisids in Colorectal Cancer Prevention, Eur. J. of Cancer
Prev., Vol. 11, pp. 193-197 (2002).
Bouwstra, J.A. et al., Role of ceramide 1 in the molecular organization of the stratum
cornreum lipids. J. Lipid Res., 39(l), pp. 186-96, Jan. 1998 (Abstract from PubMed).
Brochure entitled Orvza Ceramide, Nutritional Sunnlement, from Oryza Oil & Fat
Chemical Co. Ltd, called in the footer: ORYZA CERAMIDE CATALOG ver. l.OEZ.
Chamlin, S.L. et al., Cerarnide-Dominant Barrier Repair Lipids Alleviate Childhood
Atopic Dermatitis: Chances in Barrier Function Provide a Sensitive Indicator of Disease
Activitv, Journal of Am. Acad. Dermatol, Volume 47, pp. 198-208, No. 2, PR 198-208 (2002).
Ennagram’s Vegetal Ceramides: LD-50 Study, dated July 1999; and Ennagram Report
dated November 1997.
Futerman, A., Ceramide Metabolism Compartmentalized in the Endonalsmic Reticulum
and Golti apparatus, Current Topics in Membranes, Vol. 40, p. 93, (1994).
Goldstein, A., Ceramides in the Stratum Corneum: Structure, Function. and New
Methods to Promote Repair, Int. J, of Derma,, Vol. 42, pp. 256-259 (2003).
Gossioux, P. United States Patent 5,8 17,646, “Polar lipid composition of plant origin,”
issued October 6, 1998.
Hoang, T., Suhinnoliuids (a Powerpoint presentation), March 28,2002, p. 12; also citing
to Vesper. (Copy attached.) Tinyee Hoang is a Graduate Student in Food Science at
Washington State University.
Imokawa, G., Strnctures and Functions of Stratum Comeum Lipids& the Skin, Journal
Japan Oil Chem. Society, Vol. 44, No. 10, pp. l-23 (1995).
International Business Strategies, Dietary Supplements in Japan, December 2001.
Japanese promotional websites (excerpts), Winter 2003-2004.
Kajimoto, 0. et aZ., Clinical Jnvestigation of the Skin Beautitin~ Effects of a Beauty
Supplement Containing Rice Derived Ceramides-Obiective Assessment of Drv Skin through
Analvsis of Three Dimensional Microscony Images. Authors are affiliated with the Health
Management Center, Osaka University of Foreign Studies; Dermatology Department, Faculty of
Medicine, Osaka City University; and the Institute of Comprehensive Medical Science (undated
publication).
Kenko Corporation In-House Report for the Manufacturing Process of Cenmmide CERPSO.
(Confidential, Trade Secret information disclosed for the purpose of this Notification to the FDA only.)
190979
- 22 -
Lati, E., New Research and Development in Moisture Retention Mechanism and
Moisturizing Agents, Fragrance Journal, Vol. 23, No. 81 (1995).
Lee, M., Analvsis of Ceramides in Cosmetics bv Revised-Phase Liquid
Chromatomanhv/Electrosnrav Ionization Mass Suectrometrv with Collision-Induced
Dissociation, Rapid Commun. Mass Spectrom, 1764-75 (2003).
Merrill, A.H., Jr. et al., Sphingoliuid &take bv Isolated Segments of the Rat Intestine,
FASEB Journal, P. 3A, 469 (1989).
Merrill, A.H., Jr. et al., Importance of Snhinpolinids and Inhibitors of Snhingolipid
Metabolism as Comnonents of Animal Diets, Journal of Nutrition, Vol. 127, pp. 830% 8338
(1997).
Motta, S. et al., Ceramide Compositions of the Psoratic Scale, Biochimica et Biophysics
Acta, 1182: pp. 147-151 (1993).
Orgretmen, B., Biochemical Mechanisms of the Generation of Endonenous Long: Chain
Ceramide to Exogenous Short Chain Ceramide in A549 Human Lung Adenocarcinoma Cell
&, J. of Bio. Chem., Vo1227, No. 15 (2002).
Oryza Oil & Fat Chemical Co., Ltd., Safetv of Ceramide with oral administrations, [no
date].
Pelle, E. et al., United States Patent 6,136,301, “Lipid mix for lip product,” issued
October 24,200O.
Richeux, F., BioHC Appendix 2, Renort to the Investigator TAO423-PH-03/0307 (1996);
Appendix 2 (1997). [See cover letter of Report.]
Schmelz, E.V., Uptake and Metabolism of Sphinnolinids in Isolated Intestinal Loops of
Mice, J. of Nutrition, 124 (5): 702-712 (1994).
Szweda, J-A. et al., United States Patent 5,667,770, “Long wearing lipstick,” issued Sept.
16,1997.
Unitika Ltd. Health & Amenity Business Dept., CERAMIDE: Clears the skin as YOU eat
(promotional brochure re a supplement with Phyto-Ceramide extracted from Konjac.]
Vesper, H. et al., Sphinnolinids in Food and the Emerging Importance of Sphingolipids
to Nutrition, J. of Nutrition, 129: 1239-1250 (1999).
Yamamura, T. and Tekezuka, T., Change in sphin~omvelinase activitv in human
epidermis during aging;, Journal of Dermatological Science, 1 (2):79-84 (1990).
Zetterstern, E., Optimal Ratios of Topical Stratum Comeum Lipids ,&nprove Barrier
Recoverv in Chronoloticallv Aged Skin, Journal of American Academy of Dermatology,.
Volume 37, Number 3, Part 1 (1997).
Attachments cited in the footnotes and references of the New Dietary Ingredient
Notification for Phyto-derived Cerarnides: These have been ordered alphabetically by author’s
last name, and if there is no author, by the source or title of the article.
Submitted by: Soft Gel Technologies, Inc.
April 2,2004