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by Aftab J. Ahmed, Ph.D. Therapeutics
Therapeutics and Excipients: More Than Meets The Eye
Tablets and capsules are the most common, efficient,
and convenient forms for oral delivery of
nutritives and pharmaceuticals. It is intriguing to
note how much it is taken for granted that
ingesting a tablet, say, would “do the job” effectively
and in a timely fashion. Surprisingly, however,
a cottage industry seems to have recently
evolved around the notion that a tablet comprised
only of an active ingredient(s) would be a
more acceptable form to deliver nutritives and/or
correctives.
That this counter-intuitive argument has
apparently assumed the status of an urban
legend is evidenced by the fairly esoteric claims
about nutritives adducing properties to them
that cannot possibly be achieved by the actives if
administered alone. A nutraceutical or pharmaceutical
product is the actual dosage form of
active(s)—such as a tablet, capsule, suppository,
transdermal patch, or a solution—and usually
consists of the active(s) combined with other
ingredients. For oral intake, the admixture of
actives and inactives is mixed and compressed
into a tablet form. The type and amount of additives
and the degree of compression determines
how quickly a tablet dissolves. As will be discussed
later, dissolution, or disintegration, of
tablets is an important issue, especially in
delivery of natural products, as it determines how
efficiently an active becomes bioavailable.
Bioavailability implies that the “actives” must be
solubilized in order for them to be taken up in the
bloodstream. This is the case as much with therapeutic
actives as with nutriment derived from
foodstuffs. This was clearly recognized as early as
the 1870s by the German pharmacist August
Oetker, who became an avid proponent of
making nutritives bioavailable first and foremost.
Practically speaking, then, these and other variables variables
are adjusted during manufacturing to optimize
the rate and extent of an active’s absorption.
After all, benefits of a formulation depend
upon how effectively the actives are absorbed.
Orally administered correctives are absorbed
through the gastrointestinal (GI) tract, whereby
the process begins already in the mouth and
stomach, but is completed fully in the small
intestine. As such, actives must first pass
through the intestine and then the liver, where
they are also chemically altered (metabolized),
before they reach the general circulation (Fig. 1).
It is in this apparently straightforward sequence
of events that both the art and science of formulation
in pharmaceuticals and nutraceuticals
become apparent. In fact, the combination of
actives with inactives has been the norm for centuries,
of which Galen was the most vocal proponent.
In the 2nd century AD, he advocated the use
of “poly-pharmaceutical” preparations, arguing
that the body would pull out of a complex formulation
substances needed to heal itself.
Formulation technology is also critical in regulating
the release of actives. For instance, if a
tablet dissolves and releases the active(s) too
quickly, its levels in the blood could provoke an
excessive, occasionally undesirable, response.
Conversely, if a tablet does not dissolve and
release its payload quickly enough, it may pass
through the body without being absorbed.
Hence, its benefits are not experienced.
Accordingly, some products are specially formulated
to release their active ingredients slowly,
usually over several hours. These controlledrelease
dosage forms slow or delay the rate at
which active ingredients are dissolved or emulsified
in the GI tract for optimal absorption, as
noted above. Thus, in such formulations, active
particles may be coated with binders of varying thicknesses designed to dissolve at different
times in the GI tract.
Some tablets and capsules have protective
(enteric) coatings intended to prevent
irritants (for example, aspirin) from
causing damage to the stomach lining or
from decomposing in the acidic milieu of
the stomach. These dosage forms are
usually coated with a material that does
not begin to dissolve until it comes in
contact with alkaline environs of the small
intestine. Likewise, the intended site of
absorption of actives may also dictate
enteric coating, as is the case with
enzymes intended to function systemically.
If such enzymes were not enterically
coated, they would be less likely to survive
unscathed the GI environment. Equally,
enteric coatings stabilize enzymes and
preserve their biological activity and
potency.
It should be clear from these cursory
considerations that specifications suchlike
require more than mere actives.
First and foremost, however, the actives
must be stabilized for the rigors of the
manufacturing process. These and
other goals are achieved with the addition
of inactive ingredients in a formulation
for it to be manufactured to provide
dosage, to stabilize the actives and to
ensure safe levels of an active becoming
uniformly bioavailable. In light of the
foregoing, then, the assertion that an
active could be delivered without the
addition of inactives is odd, if not plain
outlandish.
What are these inactives? Ordinarily
referred to as excipients, (interchangeably
and synonymously) inactives are a varied
group of substances that make a formulation
work. In some circles, the word excipient
is a dreaded word that conjures up
unnecessary chemical “pollution” of otherwise
pristine actives. A better understanding of what excipients do, however, yields insights as to how necessary they are in the delivery of therapeutics, and how they are a challenge common to both pharmaceuticals and nutraceuticals. For even a rudimentary formulation must seek compatibility between excipients and the actives. This means a detailed knowledge of each active, and excipients used as well as their properties. This is the reason the
development of a commercial drug or a
nutritional supplement seldom, if ever,
conforms to the proverbial slam dunk.
Excipients are usually categorized by
the function they perform in a formulation,
and they may belong to two broad
groups: One, excipients that are used to
process an active into a tablet or capsule
may be fillers, binders, disintegrants and,
among others, lubricants; and, two,
excipients that affect the bioavailability,
stability, marketing, and consumer
acceptance of a product. Implicit in the
second group is the centrality of excipients
to make actives bioavailable. If an
active cannot be absorbed properly and
becomes bioavailable, it would be a futile
exercise to ingest it in the first place. In
and of itself, this should explain that
excipients are integral components of formulations,
especially nutraceuticals.
Whereas previously most excipients
tended to be chemicals, they are increasingly
derived from natural sources now.
Natural fibers and cellulose are but two
examples of that.
How do excipients help with the formulations?
Primarily, the objective is to stabilize
a product. That is attained by the
addition of fillers (diluents), which are also
variously called carriers or bulking agents.
An array of diverse fillers has been used in
the past, but increasingly polyols like mannitol
are used. Mannitol has the advantage
of superb compatibility with actives, good
compressibility, relatively low dissolution
rate, and, importantly, does not quite
retain moisture (low hygroscopicity).
Xylitol, a similar product from wood shavings,
has specialty uses, since it is non-cariogenic,
anti-bacterial, dissolves freely in
water, has sweet taste, and is ideal for the
manufacture of chewable tablets.
The major objective in a multi-component
formulation, specifically in nutritional
supplements, is to hold the various
actives together, and to distribute them
homogeneously in calibrated ratios.
Excipients such as microcrystalline cellulose
(MCC), microcrystalline bamboo fiber
and arabinogalactan are used to accomplish
that. For instance, MCC is a watersoluble
wood fiber that allows
solvent-free manufacturing. It is commonly
used both as a wet and dry binder,
and it increases the tablet hardness in a
compression formulation and reduces its
friability. In addition, the wicking action of
MCC provides faster and more uniform
distribution of the granulating solution.
On occasion, pre-gelatinized plantderived
gums are used as dry binders in
directly compressed tablet formulations.
Dry binders suchlike are indispensable in
those formulations—for instance, of systemic
enzymes—which would otherwise
be susceptible to degradation. Binders for
wet granulation, on the other hand, help
agglomerate (or clumping) of powder
blends. Natural gums are used more frequently
as wet binders, however, and
include acacia, guar and tragacanth, but
they are being replaced with water-soluble
polymers.
Since powders during the manufacturing
process must flow freely, glidants
are added, particularly with actives of natural
origin, since as they do not flow
smoothly. Related to free flow is the issue
of tablet or capsules slugs sticking to the
tooling. This is avoided by the addition of
lubricants to the formulation. The most
commonly used lubricant is magnesium stearate. The use of steraic acid and magnesium stearate has
met stiff opposition in some quarters. As an aside, it should be
noted that stearic acid, a constituent in chocolate, can lower
cholesterol and positively modulates platelet activity. While it is
true that it can make tablets friable, it can also slow down that
release of actives from the tablet. In contrast, stearic acid is
employed in those cases where magnesium stearate proves
incompatible with the actives. A variant of these, sodium stearyl
fumarate, is gradually gaining popularity, however, because it
offsets some of the drawbacks of magnesium stearate.
Once all these considerations are taken into account, the
most important part of formulation comes into play; that is, how
best to disintegrate the tablet or capsule after it is ingested. If a
tablet does not disintegrates or breaks down at a rate inconsistent
with the original intent, it would not “get to work,” as it is
expected to. This is the business end of a therapeutic regimen,
as appropriate dissolution ensures improved bioavailability of
the actives. Disintegrants work essentially by either wicking
water into the tablet or by swelling; however, a combination of
these two mechanisms works best to speed disintegration, if
quick release of actives is the objective. Different excipients
typify disintegration by swelling or by wicking. Parenthetically,
controlled- and extended-release of actives is a variation of this
basic theme, which has spawned innovative and exciting developments
in drug delivery.
As noted previously, nutritives must be absorbed over the
small intestine in order for them to be effective. This is accomplished
by coating the tablets, granules, powders, and pellets for
a number of reasons. As noted at the outset, enteric coatings are
used to avoid the release of actives in the stomach, and are comprised
of pH-dependent, water-soluble compounds that form a
thin film. To control the release of actives, several agents may be
added to the film coating, or into the tablet matrix or granule
itself, to control the release of actives. Natural gums, waxes, fatty
acid esters, and polymers are examples of such inactive ingredients.
This bird’s eye overview of the necessity to use excipients
drives several points home. To begin with, ingredients in
herbs/plants naturally exist as an ensemble rather than as individual
ingredients. These are cushioned in several “inactive”
substances that help to absorb the actives, if used au naturel.
That is, the body extracts active ingredients from this ensemble
those of nutritional or corrective value. That is how, for example,
nutrients are extracted for absorption from the ingested food.
The suggestion, then, that active ingredient(s) alone could be
delivered ready for absorption is both impractical, if not tantamount
to tilting at the windmills. Thus, the active ingredients of
interest must be formulated along with additional substances
(excipients) that facilitate solubilization/emulsification of active
ingredients in the GI tract to enhance their absorption.
Aside from the impracticality of delivering actives alone, for
want of excipients, ambient moisture would quickly compromise
their potency and just as readily support bacterial and fungal
growth, not an uncommon occurrence in working with herb-/
plant-derived materials. Therefore, actives must be stabilized,
since most tablet and capsule products have a shelf life of six to 12
months. Consequently, the products must be protected from
moisture, degradation, and bacterial/fungal growth to preserve
their potency. These considerations are absolutely essential to the
natural health care industry. As the cursory discussion above highlights,
design, development and production of a tiny tablet takes
considerably more effort than meets the eye. Excipients are, hence,
crucial in making the ferment of an idea into a fungible product.
For references, send a SASE to totalhealth.
Aftab J. Ahmed, Ph.D.
Bio-Aging, Inc., CEO. Scottsdale,
Arizona 85254 E-mail:
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