More Than The Sum of Ingredients: Interactive Vehicles in
Advanced Cosmeceuticals
Enhanced
performance of ingredients in topical formulations can be facilitated by:
q
incorporation of ingredients into interactive
vehicles that modulate
q permeability,
q transport,
q concentration,
q proximity,
q orientation,
and
q accessibility
to their target biological sites;
q
synergistic combination of ingredients that expands
their end effects beyond their individual activity ranges.
Disclaimer
The
following text and statements are not legal or medical advice nor are they
intended to reflect the ideas of or represent the Food and Drug Administration.
The sole purpose is to stimulate a discussion and point out issues of concern
in this field.
The Following Pages are Provided to Clarify Terminology
1.
What are “topical formulations”?
2.
What are “cosmeceuticals”?
3.
What are “active ingredients”?
4.
What are “vehicles”?
a.
What is “facilitated transport”?
b.
What is “diferential concentration”?
c.
What is “proximity”?
d.
What is “orientation”?
e.
What is “accesibility”?
5.
What are “synergistic effects”?
6.
What are “side effects”?
7. What are “interactive vehicles”?
1. What are “topical formulations”?
Topical
formulations (TF) include liquids, creams, lotions, pastes, that are formulated
to be applied onto the skin.
Legal definitions
of drugs and cosmetics.
TF
can be divided into two legal categories: pharmaceutical preparations and
cosmetic preparations. The legal categories are defined by the Food and Drug
Administration (FDA). Cosmetic preparations are sub-categorized as preparations
that have brief contact with the skin, such as soaps and detergents, and
preparations that are made for a prolonged stay on skin, such as skin care
products.
After
TF are applied onto skin they can penetrate into the skin or remain on top of
the skin. TF claiming to be trans-dermal will most likely be treated as a drug.
TF claiming to remain on top of the skin or penetrate into dead skin layers can
be treated as cosmetics.
TF that remain on top of the skin after application may not be different than protective clothes or sun glasses and won a court case against the FDA which was then overturned on appeal.
Actual performance
of preparations categorized as
“cosmetics”
Legal
definitions of pharmaceutical and cosmetic preparations relate to claims and
label regulations and not to actual performance of TF as long as the TF does
not include any ingredient that is specifically categorized as a drug.
Statistically significant, well-designed studies on TF therapeutic performance
can be regarded as scientifically valid. However, scientific validation is not
sufficient ground for legal acceptance of a TF as a drug unless FDA protocol
was applied.
The discrepancy between “actual performance” and “legal performance” of TF is the creative space in which “cosmeceuticals” flourish.
2. What are “cosmeceuticals”?
Cosmeceuticals
are TF containing non-restricted active ingredients similar to those in
medicinal preparations, or TF that are beneficial in categories where
medicinals are also beneficial. Cosmeceuticals may be one of the few industries
where product performance is routinely understated by its claims.
Cosmeceuticals
are the most innovative, daring, and pioneering category in TF. Cosmeceutical
formulations are the most dynamic testing ground for future medicines,
exploring botanicals and other natural and synthetic ingredients. Exploring the
same for new drug discovery would be non-feasible for even major drug
companies. Many ingredients are incorporated and tested in TF cosmeceuticals
before there is a solid body of scientific evidence in support of their
medicinal performance. This activity “cuts to the chase” and introduces ample
new data on many ingredients many years before “step by step” research pays
attention to them.
How
is that done? Being a “non-category” by the FDA (cosmeceuticals are legally
categorized as cosmetics) they proliferate with budgets and regulations as skin
care products. In testing different ingredients and formulations, some may
emerge that perform as medicinals. When they do, they can be readily
incorporated into drug development programs.
3. What are “active ingredients”?
Active
ingredients are ingredients that have specific and desirable activities when
incorporated in TF and applied onto skin.
Labels
of medicinal TF have to specify the type and amount of active ingredients.
Non-active ingredients are considered as a “mere filler”.
Active
ingredients often:
q
are immiscible in the media in which they are
intendent to be formulated;
q
are too poisonous if they are distributed throughout
the body;
q
have a short circulation life time in the body and
are readily expelled or biodegraded or metabolized after application;
q
have little or no ability to cross bio-membranes,
skin, or other biological obstacles.
In
cosmetic TF the entire preparation is very important in delivering its
benefits. There is growing literuture and experience which indicate that active
ingredients do not perform the same when formulated in different preparations.
Many cosmetic TF specify “active ingredients” to appear “medicinal”. However,
cosmetic preparations can only claim to be moisturizers and thus active
ingredients only have moisturizing activity. Any other claim will categorize
the preparation as a drug.
In reality, cosmetic TF have many other un-claimed, beneficial properties for skin. Innovative formulation of active ingredients into TF can result many times in skin care that performs similarly or better than a medicinal but can not make such claim.
4. What are “vehicles”?
Vehicles
are active ingredients’ carriers. Combining active ingredients into vehicles is
the art of encapsulation. Vehicles can:
q
enhance ingredients’ activity,
q
transport them across biological obsticals,
q
increase their active life time,
q
improve ingredients’ solubility in the desired
media,
q
protect the body from possible poisonous effects of
ingredients, and
q
concentrate active ingredients in the desired
biological target area.
Vehicle
performance with a certain active ingredient can be rated by the following
criteria:
q
facilitated transport
q
differential concentration
q
proximity
q
orientation
q
accessibility
a. What is “facilitated transport”?
When
a vehicle enables or significantly accelerates trans-dermal transport of an
active ingredient or its penetration across any other biological obstacle.
b. What is “differential
concentration”?
When
a vehicle enables or significantly increases concentration of an active
ingredient at the biological target organ area while restricting spread of that
ingredient to other areas of the body.
c. What is “proximity”?
When
a vehicle enables or significantly increases concentration of active ingredient
molecules around molecules at the site of action.
d. What is “orientation”?
When
a vehicle enables or significantly increases orientation of active ingredient
molecules so that the active ingredient molecule and the target molecule form a
desired angle for interaction.
e. What is “accessibility”?
When
a vehicle enables or significantly improves the shape or the charge of the site
of action of active ingredients or the target molecule so that large inactive
chemical side-groups will not create steric hindrance preventing the final
interaction.
5. What are “synergistic effects”?
Synergistic
effects are non-linear cumulative effects of two active ingredients with similar or related
outcomes of their different activities, or active ingredients with sequential
or supplemental activities.
Example:
Vitamin E is an anti-oxidant and Vitamin C may help to recycle oxidized Vitamin
E into active Vitamin E and thus a synergistic effect may be possible between
the two.
Vehicles
can change the sterochemistry of an active ingredient site of action. In some
cases this will result in increasing the reactivity of an active ingredients’
site of action and enhance its activity. Vehicles can remove steric hindrance
from the proximity of a site of action of an active ingredient enabling its
activity at molecular targets that are resistant to that same non-encapsulated
active ingredient.
Vehicles may affect active ingredients’ shape and reactivity so that they gain accesability and synergistic activity with molecular sites of action.
6. What are “side effects”?
Side
effects are in the eyes of the beholder. What may be a desirable effect to one
may be an undesirable effect to the other.
Example:
encapsulation of Vitamin A with a vehicle of the cyclodextrin family may
increase Vitamin A activity against wrinkles. At the same time the dark brown
color and the vivid medicinal odor of Vitamin A are great deterrents. Color and odor are important manufacturing
concerns. Less than effective concentrations of Vitamin A in anti-wrinkle or
anti-aging skin care are therefore used in many preparations. Encapsulation of
Vitamin A in that vehicle drastically reduces color and odor of TF enriched
with Vitamin A. The benefits may be triple:
q
increased activity of vitamin A,
q
increased concentration of vitamin A, and
q increased asthetic performance.
7. What are “interactive vehicles”?
Interactive
vehicles are vehicles that can deliver and extract ingredients with their
biological targets. They can interact with different barriers with some
shape-shifting abilities and can effectively cross those barriers.
Example:
very small liposomes (which I trademarked “nanosomes™”) can encapsulate and
carry water-soluble and oil-soluble ingredients. Small liposomes can exchange
entrapped molecules with cell membranes including phospholipids and
cholesterol. When liposomes in water are facing an oil barrier, they can
transport material or even entire liposomes via that media. Complex
morphological and conformational changes of phospholipids as well as liposomal
and cell membrane changes take place during their interactions.
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