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04/03/2003
Delivering the Goods
I’ve just read a bit of Tom Brokaw’s book “A Long Way from
Home. Growing Up in the American Heartland”. Brokaw
credits his small town South Dakota upbringing as preparing him
well for his very successful career in the news media. Although
born in Denver, Colorado I spent my most formative years in a
small town, Mechanicsburg, Pennsylvania. Last week I received
a letter from Jack, a resident of Mechanicsburg whom I knew as
a kid. Jack has taken upon himself the mission of compiling a
list of all Mechanicsburg High School Alumni who were in the
service during World War II. (I was not in the service. By the
time I passed my draft physical, the war had been called off.)
The letter was a form letter but Jack had added a note: “I
remember that you were a good pitcher in our baseball games in
‘the field’.”
“The field” was an empty, overgrown lot across the street from
Jack’s family’s house and we kids, with some assistance from
parents, had chopped down little trees, bushes and weeds and
made the lot into a quite satisfactory baseball field. I did have a
bit of a curve ball and a knuckleball and could employ overhand
or sidearm deliveries. I carry in my mouth a souvenir of my
pitching days on “the field”. The batter hit a popup that both the
catcher and I went after and his mask hit my jaw, knocking off
part of a tooth. The original porcelain filling is still in that tooth,
almost six decades later! Jack’s letter also brought to mind the
only time I’ve been knocked out. It was a pitched ball that hit
me squarely between the eyes and I was carried over to Jack’s
backyard, where I regained consciousness. The pitch was
delivered by the high school pitcher, who threw an unanticipated
curve ball that just tipped the undersize catcher’s mitt I was
wearing.
Since those early days, other forms of delivery have come to
concern me more. Back in those days, I don’t recall my parents
taking many, if any pills or vitamins. Today I find myself taking
5 pills in the morning (multivitamin, vitamins E and C, CoQ 10
and Hyzaar for blood pressure) and one at night (Zocor for
cholesterol). Some friends take two to three times as many
different medications daily. I imagine that very few of us think
about what happens after we swallow those pills or about the
delivery of their contents to the appropriate areas of our bodies to
do the most good.
I was drawn to the subject of drug delivery by an article by
Robert Langer, Professor of Chemical and Biomedical
Engineering at MIT, in the April 2003 issue of Scientific
American. What caught my attention in the article, titled “Where
a Pill Won’t Reach”, was the opening illustration of someone
popping a pill into his or her mouth. The sex wasn’t clear
because the body was portrayed as one complex maze,
illustrating that finding the right path for drug delivery may not
be easy. I was also taken by the illustrator’s rather unusual
name, Slim Films!
For a drug to be effective, it typically has to find its way into the
bloodstream. To get there, it has get to the intestine. This means
the pill has to survive a trip through the stomach, which is loaded
with acid that could tear up the drug. The pill designer solves
this problem by coating the drug with a material that doesn’t
dissolve in the acid but that does dissolve in the more alkaline
environment of the intestine. Once the coating dissolves, the
drug has to pass through or between the mucosal cells that line
the walls of the intestine. Once they’ve cleared the intestine, it’s
clear sailing into the bloodstream.
Once in the bloodstream, the drug has to go through the liver and
survive the filtering that goes on in that organ. During all this,
the drug also has to avoid being degraded by a variety of
enzymes that like to chop molecules up into little pieces. There’s
also the matter of timing. Some drugs can be toxic if they are too
concentrated in the bloodstream or if they stick around too long
in the bloodstream. With the older drugs, these problems have
been solved with suitable pill coatings and pill design.
In the past, most of the common drugs have been small
molecules that can worm their way through the intestinal walls.
However, the newer drugs emerging from biotechnology
companies are usually proteins. These proteins are large
molecules that not only can’t pass easily through the intestinal
walls but also tend to be degraded by so-called proteases,
enzymes that love to chop up proteins. The answer to this last
problem is to put “bodyguards” in the pill. The bodyguards are
so-called “protease inhibitors”. These protease inhibitors do a
good job of fending off the protein-wrecking enzymes but don’t
help out with the fact that the protein drugs are still large
molecules and have to get through the lining of your gut.
One obvious answer to these problems is simple – change the
mode of delivery by injecting the drug directly into the
bloodstream. Of course, many diabetics have been doing just
that for eight decades, following the publication in1922 of the
discovery of insulin by Sir Frederick Banting and others. In a
remarkably prompt recognition of the importance of insulin’s
discovery, Banting and James Macleod received the Nobel Prize
for medicine in 1923. Clearly, taking a pill is vastly preferable to
having to inject oneself once or more a day with insulin. The
problem is how to usher the insulin and other large molecule
drugs through the lining of your gut.
One approach to this problem is to coat the drug with what’s
known as a “bioadhesive polymer”. This is a polymer that sticks
tightly to the mucosal cells that bar drug’s passage through the
intestine. There’s a lot of chemistry involved but animal tests are
encouraging in that a particular bioadhesive compound can be
combined with insulin and bind to the intestinal wall sufficiently
tightly that the insulin can be released through the wall and sped
on its way to the bloodstream.
Another approach employs some trickery. Certain intestinal cells
have special receptors on them that latch onto vitamin B12 as it
passes through the intestine. The vitamin B12 is then transported
through the wall. A fellow in Australia, Gregory Russell-Jones,
found that he could attach a protein to vitamin B12 and the
receptor would be tricked into taking up the protein along with
the B12. The problem is that there may not be enough of these
receptors in the intestine to sneak in the required dosage of a
drug. Work is now going on to find other, more numerous
receptors for other substances than B12 to target.
A third approach, somewhat along the same lines, is to coat the
protein-based drug with “carrier” molecules. Certain of these
carrier molecules seem to squeeze the proteins into a smaller
shape so the mucosal cells don’t even know the drug is there.
Once the carrier has breached the cell wall it releases the drug,
which resumes its normal, active shape and goes on to do its job.
These approaches are in various stages of development.
However, the oral pill-popping delivery of drugs is not the only
approach. There’s the inhaling, or lung delivery, approach. The
lungs have microscopic sacs, “alveoli”, which are connected
directly to blood vessels. We’re all using these alveoli even as
we speak, breathing in oxygen for delivery to the bloodstream
and exhaling carbon dioxide from the bloodstream. So, why not
inhale aerosols of fine particles of drugs? This is the principle
behind the inhalers for asthmatics. But, there’s a problem.
It’s not easy to get enough sufficiently fine particles of a drug
into the deep recesses of the lungs to do the job. The process is
very wasteful. Asthma inhalers, for example, only deliver 10
percent of their drug content to the lungs. If the particular drug
is very expensive, the cost of a dose might be prohibitively high.
There are at least two approaches to this delivery problem. One
seems intuitively obvious, to decrease the size of the particles in
the mist delivered by the inhaler. Various researchers are
following this approach and some inhaler devices for delivering
insulin are being tested in diabetics.
David A. Edwards of Harvard, a former postdoctoral fellow with
Langer at MIT, took just the opposite approach, based on the
analogy of wet basketballs and wet grains of sand. The wet sand
grains will tend to stick together and agglomerate to form bigger
particles but wet basketballs won’t! His reasoning was that,
instead of a mist of fine particles, make a mist of fewer, larger
and more porous particles. (Most of a basketball’s volume is
air.) There’s another factor I didn’t mention – the lungs also
contain macrophages, cells that go after intruders such as drugs
and destroy them. The reasoning was that the macrophages
wouldn’t go after large particles, but prefer to engulf smaller
intruders, as in a fine mist. In animal tests, a single dose of a
large-particle insulin aerosol has been shown to last four days.
This approach is also being tested in human subjects.
Well, we haven’t even gotten to another form of drug delivery,
the patch. Maybe next week.
Allen F. Bortrum
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