Evolution of Pharmaceutical Oral Dosage Forms

Author(s): William H. Helfand and David L. Cowen

Source: Pharmacy in History , 1983, Vol. 25, No. 1 (1983), pp. 3, 5, 7-18
Published by: American Institute of the History of Pharmacy

Stable URL: https://www.jstor.org/stable/41109385

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 Evolution of
Pharmaceutical
Oral Dosage Forms
by William H. Helfand* and David L. Cowen**

0ÍBOUT one hundred years ago, on June 24, 1884, to be exact, Dr. Paul G.
Unna, a dermatologist of Hamburg, Germany, dramatically passed among his
audience at a meeting of the Hamburg Medical Society four reagent glasses.1
Perhaps he had an inkling that he was ushering in a new age of drug therapy
as he did so. In two of the reagent glasses, Unna had placed salicylic acid pills
coated with Hornstuff; in the other two keratinized (keratinirte) iron chloride
pills. He demonstrated to his colleagues that these pills were impervious to a
mixture that simulated stomach fluids and that both were highly activated
and broken up by fluids simulating those of the small intestine. He suggested
that in the healthy human -such keratinized pills would pass through the
stomach unchanged and not release their medication until they reached the
intestine.2
Although he had been interested in the problem for six years,3 Unna did
not claim to be alone in the concept of enteric coating or treating of drugs.
One C. A. Ewald had proposed, at the Allgemeine Deutsche Ausstellung auf
dem Gebiete der Hygiene und des Rettungswesens, held in Berlin in
1882-1883, the coating of pills with sodium silicate, for the same purpose, but
Unna had found this ineffective. Unna himself had tried treating pills with
collodion before he hit on kératine.4 Such pills had been exhibited at the same
Hygiene Exhibition5 and indeed apparently had been in use for some time. As
early as 1867, for example, the Pacific Medical and Surgical Journal,
editorially distressed by a resurgence of the gilding and silvering of pills, com-
mented that "collodion protects the pill from solution in the stomach."6
The therapeutic revolution that Unna was ushering in was an outcome of
the changes already taking place in oral dosage forms in the nineteenth
century. By then, the ancient and rather exotic dosage forms of earlier cen-
turies had virtually disappeared: lohochs, linctuses, electuaries, conserves,
confections and others were no longer part of the materia pharmaceutica. A
few elixirs and troches still continued in use, but pills and powders, solutions,
tinctures and spirits were the common oral dosage forms of the nineteenth
century. Changes in dosage forms, given impetus by the introduction of new

* Senior Vice President, Merck Sharp & Dohme International.

* * Professor Emeritus of History, Rutgers University; Lecturer in the History of Pharmacy, Rutgers College
of Pharmacy.

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remedies, the vegetable alkaloids, glycosides and synthetic chemicals, involv-
ed essentially the coating of pills and tablets, or placing the drug in a wafer or
gelatin container.
Pill coating had behind it a tradition that went back to the Arabs.
Urdang has placed the coating of pills with gum mucilage as early as the ninth
century by Rhazes (850-923). 7 Silvering and gilding of pills goes back at least
to Avicenna (980-1037), 8 and, as has been noted, was a technique still being
practiced well into the nineteenth century. Presumably the gold and silver
was thought to have a medicinal effect and undoubtedly did enhance the
appearance of the pills, but pill coatings had for their main purpose the mask-
ing of the taste of the medicine.
In the nineteenth century, improvement in dosage forms reflected not
only these desires to make medication more palatable and more elegant in
appearance, but also the desire to make the pills easier to swallow, to protect
the pills against the environment and from each other (uncoated pills tended
to get stuck together), and, finally, to provide a way of standardizing and con-
trolling dosage.9 Sugar-coating of pills, which had its origin in France in the
late 1830's, gained immediate popularity and spread quickly to other coun-
tries. By 1856 or 1857, William R. Warner was manufacturing such pills in
bulk in Philadelphia. 10 Sugar-coating was usually a combination of sugar and
gum, and it did not take long for ingenious pharmacists to develop other
coatings. Mohr, in 1848, listed, in addition to sugar and gum, and gold and
silver leaf, magnesia, starch, licorice powder, lycopodium and gelatin.11 In
fact, in 1862, Bernard Proctor in England listed 45 processes for coating pills
using a wide range of coating materials.12
One such process was that of pearl coating -the application of a talc
coating that gave the pill a resemblance to pearls. It gained considerable
popularity, no one at the time showing concern over the insoluble and water-
repellent character of the talc.13
During these years, the coating that gained widest popularity as
"elegant and efficient" was gelatin.14 The gelatin-covered pill was an
interesting off-shoot of the gelatin capsule. In 1838, when the latter were no
longer made available empty to pharmacists by Dublanc, one of the
pharmacist-inventors of the capsule, another pharmacist, Garot, produced
gelatin-coated pills as a substitute.15 Pill coating, not surprisingly, was for the
most part still in the hands of the pharmacist, and the art of the apothecary,
among other admonitions, required him to be ready to touch up each hole left
by the wire which had held the pill in the gelatin with "the point of a camel's
hair pencil previously dipped into the solution of gelatin."16
There were dosage forms other than coatings introduced in the nine-
teenth century. Most important was the gelatin capsule which was introduced
in France by the pharmacists F. A. B. Mothes and J. G. A. Dublanc and
patented in 1834. 17 These capsules came into wide use in the United States,
especially after Parke, Davis & Company undertook to manufacture them on
a large scale in 1875. 18 The same idea of a digestible drug container was the
cachet (konseal, wafer capsule), a unit consisting of two concave pieces of
wafer made of flour and water. Medication was placed between two wafers
which were then sealed by moistening the margins. When moistened, the
cachet became soft, elastic, slippery and easily swallowed.19 These cachets

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A konseal apparatus, based on the cachet idea of Stanislas Limousin, used in the mid-1800's.

were invented by the noted French pharmacist Stanislas Limousin, and

enjoyed wide use, but did not, of course, offer the convenience of a capsule.
An interesting innovation was the gelatin lamel introduced by Savory &
Moore in London in the 1870's. Accurate quantities of a medicament were
incorporated into thin pliable sheets of gelatin. The sheets were cut into single
dose squares and later into discs, and Savory & Moore issued no fewer than 70
different types of drugs in these "lamellae." The British Pharmacopoeia of
1885 included a method of preparing such laméis and several of them were
still to be found in the Pharmacopoeia of 1948. 20
Later in the century, two dosage forms directed largely to the idea of
quantitatively controlling dosage came on the market. These were the
"Parvules" introduced by Warner in 1879, and the "dosimetrie granules"
which Abbott Laboratories first marketed in 1891. The latter were an old
French invention, the work of Adolph Burggraeve, and the French were
already seeking an American market when Abbott entered the picture.
"Dosimetry," as the use of dosimetrie granule was called, was based on the
contention that medication should consist of chemically pure, stable and
precisely manufactured dosages, uniform in quality and quantity.21
Thus, against this broad background, the revolutionary aspect of Unna's
introduction of keratin was the idea that the form of the medication could be
used as a device to influence, if not to determine, the disposition of the

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medicament in the body. Unna's work was followed by a series of publications
concerned with convenient prescriptions for compounding keratin pills22 and
opened up a whole new avenue of pharmaceutical research -the search for an
enteric coating that would be effective as well as safe.
Keratin was a long-lived development and was still in use in the 1950's,23
even though its effectiveness had been questioned as early as 189724 and a
1943 study found it to be the least efficient of a group of substances tested.25
It sometimes disintegrated in the stomach and at other times did not break up
until it reached the region of the colon.26 It gave way to salol, phenyl
salicylate, introduced in 1890 by Ceppl.27 Almost sixty years later, combina-
tions of salol and tolu were said to be "largely used,"28 yet both were
sometimes found unreliable. Perhaps the most important of the particulars
leveled against salol (in 1938) was that upon hydrolysis it yielded phenol and
salicylic acid and its physiological action could not be ignored.29 As early as
1935, tolu was found "resistant to the process of digestion" and providing no
medication, in almost two-thirds of the cases studied.30
One enteric coating procedure in use for many years was capsules
hardened by formaldehyde. Called "glutoid" capsules, they were of Swiss
origin, the brain-child of a Dr. Weyland and developed about 1897. (It is
interesting to note that pharmacists were still directly concerned in the
development of dosage forms -the application of keratin to capsules was the
work of Pohl, an apothecary of Danzig; Dr. Weyland worked on the glutoid
capsule with Hausmann, a Swiss apothecary of St. Gallen).31
The search for effective enteric coatings accelerated in the first half of
the present century. To illustrate, the United States Patent Office issued
patents for a variety of fat and fatty acid coatings starting in 1906, for
cellulose nitrate lacquer in 1928, for shellac coatings in 1930, for wax coatings
in 1931, and for cellulose acetate phthalate in 1937.32 (The last, an industrial
contribution to pharmaceutics, was developed by the Kodak Company.)33
Other synthetic polymers were patented in Germany in the 1930's. In 1938,
Thompson and Lee listed no fewer than 34 substances for enteric coatings
named in the literature and 12 "auxiliary substances."34
In 1951, Remington's Practice of Pharmacy (10th ed.) published a list of
substances used for enteric coating which included, in addition to keratin,
salol and tolu; shellac; casein; stearic acid; a good number of compounds of
salol, of shellac, and of castor oil; cetyl alcohol; cellulose acetate phthalate;
carboxymethyl cellulose, and polyvinyl alcohol.35 The 13th edition, 1965, listed
60 coatings (some generic, e.g., "various copolymers") and indicated the
favorable references in the literature for each. For 24, however, unfavorable
references were also listed; the cellulose acetate phthalates, for example,
presented 13 favorable, 3 unfavorable and 5 mixed references.36
Ingenious procedures were devised to test the effectiveness of enteric
coatings. About 1930, for example, one technique was to coat a pill consisting
of calcium sulfide, méthylène blue, starch and sugar. If the subject
regurgitated hydrogen sulfide, which was readily recognized, the enteric
coating had broken down in the stomach; if this did not occur and the urine
was blue, the coating had broken down in the intestine; if neither phenomenon
occurred, the coating had passed through the system unscathed.37 Yet the
enteric dosage form was not always reliable and successful, as Carl Dragstedt

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pointed out in 1958. 38 Alec Williams has described the United States patents
of the 1950's and 1960's pertaining to timed-release Pharmaceuticals; almost
half of them involved coatings.39
A great deal had been learned since the time of Unna about the
physiology of the alimentary system. The old rule-by-thumb of an acid
stomach and a basic small intestine gradually gave way to more precise
understanding of the fluids, enzymes, motions, and absorption processes. All
of this affected the search for enteric coatings, of course, but the most impor-
tant scientific development that was to point the direction for the develop-
ment of new drug dosage forms was the new science of pharmacokinetics.
Although there had been some interest in what was to be called phar-
macokinetics in the last century, "There were few triumphs in this field until
well into the 20th century."40 John G. Wagner, himself an important partici-
pant in the events, in his brief chronology of the development of pharmaco-
kinetics, noted some earlier activity, but placed the beginning of the discipline
in 1937 with activities of the Swedish workers E. M. P. Widmark and Torsten
Teorell (separately) and the American Rafael Dominguez.41 This is not the
place for a history of pharmacokinetics, but in the process of studying the
movements and the time relationship in the absorption, distribution,
metabolism and excretion of drugs, some very basic concepts were learned
that could be translated into practical new dosage forms. Drug therapy had to
respond to the challenge of such new concepts as blood levels (in 1930, "there
was little knowledge of the concentration in blood or tissues of drugs other
than some of the inhalation anesthesia and alcohol," and, it might be added,
narcotics),42 biologic half -life (which was first demonstrated experimentally in
1953), 43 dissolution-rate control absorption (introduced in 1959 and really the
starting point of the study of biopharmaceutics),44 as well as certain other con-
siderations such as concentration, duration, zero order, pH, particle size,
ionization, solubility, and crystallization. Not until the 1960's could phar-
macokinetics have been said to have "caught on."45 The drug itself had become
but one arm of drug therapy; the other was what became known as the drug
delivery system.
The success of therapy using injectables -even before the principles of
distribution were understood - helped renew the interest in finding oral
dosage forms46 that would perform functions beyond merely delaying dissolu-
tion until the medication reached the small intestine. A great deal of attention
turned to dosage forms which incorporated principles of timed-release far
more sophisticated than the common enteric coated tablet. No longer were
medical and pharmaceutical sciences to be satisfied with ordinary delivery,
which, to quote the pungent remark of T. Higuchi, "is like shipping drugs from
Basle to Rotterdam by pouring them into the Rhine."47 The pharmaceutical
industry rushed to meet the new challenge. "The market is now more or less
deluged with preparations purporting to have delayed action, repeat action,
and sustained action," said the noted pharmacologist Carl Dragstedt in
1958. 48 In 1959 there were said to be 180 products in oral timed-release
dosage forms in the United States, only 20 of which were from large research-
based pharmaceutical companies. In that year, it was estimated that the value
of such products was $87 million, or 4% of the total pharmaceutical market.49
In the 1950's and 1960's, three major types of oral dosage forms were

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developed: the repeat action, the prolonged action and the sustained-release.
The first was designed to release an immediate dose and an additional dose or
doses after the lapse of a calculated period of time. The second provided a
slow release of the drug at a rate which would give a longer duration of action
than a normal single dose. The sustained-release type provided an initial
therapeutic dose immediately, followed by a gradual release of the medication
over a prolonged period of time.50 The terminology has never been completely
clear: phrases such as extended action, sustained action, oral repository,
timed disintegration, timed release, oral depot therapy, prolonged release,
control release and protracted release are terms that have been used in addi-
tion to the three noted.51 Here we shall use, generically, the term "timed-
release" to cover all the various forms.
Behind these forms is a search for a rational pharmacology: phar-
maceutical researchers involved with them have sought not new compounds
or analogs, but ways to make a known medication most effective. The variou
kinds of timed-release forms thus have had a long list of objectives and claim-
ed a long list of advantages. Most important, they attempted to maintain a
steady drug concentration at therapeutic drug levels and to eliminate defi-
ciencies in drug concentration due to divided or improperly spaced doses.
They could also provide opportunities to use powerful drugs too toxic for
single-dose use, and to diminish the chances of side effects. Additionally, they
could reduce the total amount of the drug needed, possibly lessen the hazard
of the patient's defaulting from prescribed treatment, on occasion provide
adequate all-night therapy that would not interfere with sleep and, finally,
they could reduce the time and cost of frequent drug administration by
hospital and other nursing personnel.52 There were, of course, certain disad-
vantages to this type of dosage form. They were not recommended for drug
which required precision of dosage (e.g., digitalis glycosides), nor for drugs
normally erratically absorbed (e.g., some of the ganglionic blocking agents)
and not for drugs whose dose index (the difference between effective an
toxic doses) was too narrow. Sometimes, too, as we shall see, the timed
release dosage form did not live up to expectations, but as Munzel declared in
1960, "The question whether such drug forms are necessary is idle . . . Three
times daily' will be replaced by 'one time daily.' "53
The idea of time-controlled dosage forms was carried over into
therapeutics other than oral. Inserts for the eye releasing pilocarpine,
intrauterine contraceptives releasing progesterone, topical discs to be attach-
ed to the skin behind the ear for the transdermal release of scopolamine, are
only a few of the more recent developments.54 Beyond these, current
approaches include the implantation of devices releasing drugs; these offer
great opportunities in cardiovascular studies,55 contraception,56 narcotic
antagonists57 and antibiotic delivery58 among others.
Not surprisingly, the oral dosage forms remained the center of phar-
maceutical development activities. We cannot here attempt to go through the
myriad of ideas and devices that flourished in the development of the timed
release dosage form. We can point only to some of the major concepts an
outstanding contributions. The turn from enteric coated pills and tablets to
timed-release dosage forms derived from the simple notion that coatings

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could be devised that would slow up the processes of dissolution in the
intestine. If one coating could delay the release of the drug, two or more
coatings, thicker coatings or variants of the coatings could prolong that
release. One early application of this first notion was that of Boyd Welin who,
in 1939, patented the coating of granules with a vegetable gum that would
slow or retard the hydration of the body of the granules. When the finely
divided partieles of the exterior coating came in contact with moisture they
would hydrate quickly and form a rather impervious hydrated coating around
the body of the granules. This would retard the hydration of the body portion
of the granules.59 Much earlier (1918) Fantus had worked on the coating of
tiny granules, but he was interested only in disguising their taste rather than
developing a timed release form.60
More significant for future developments was the idea of Israel
Lipowski, who received Australian and British patents on coated slow-release
beads. In his studies, beads or pellets of a drug were divided into ten groups,
each of which was given an ascending number, from one to ten, of enteric
coating materials.61 Presumably the release of the drug would be prolonged
more or less evenly over ten intervals.
It was, however, the research efforts of pharmaceutical scientists at the
Smith, Kline & French Laboratories in Philadelphia that gave the real
impetus to the further development of the timed-release dosage form. SK&F
researchers began to work on the problem in 1945; their efforts culminated in
the marketing of the first Spansule® in 1952. 62 (It is interesting to note that
three of the four researchers involved at an early date in this activity were
pharmacists: Rudolph Blythe, Harold Clymer, and Donald McDonnell, and the
fourth, Wesley Scull, was a biochemist.) A sympathomimetic preparation in a
Spansule was first patented in 1956. 63 A "Spansule" is best described in the
words of Rudolph Blythe, to whom the patent was granted:
The basic process consists of placing the proper amount of drug on sugar pellets
or other nuclei. Some of the pellets are uncoated to release an initial dose immediately.
The rate at which the rest of the drug is to be released over a prolonged period is
achieved by coating the remaining hundreds of medicated pellets with various
thicknesses of a selected coating. The amount and the composition of the coating, as
well as the solvent used for its application, will depend upon the amount of solubility of
the drug being formulated. Various certified colors are added to give distinctiveness to
the product, but of no other significance. The proper blend of coated and uncoated
pellets is then placed into capsules.64

The coated pellets were about 1 to 2 mm. in diameter and several

hundred were enclosed in a single capsule.65 The patent claimed that the cap-
sule would maintain a "substantially consistent body level of the selected sym-
pathomimetic over a period of about 10 to 12 hours."
The basic idea of the coated bead lead to numerous ingenious attempts to
adapt and improve the processes. A 1957 patent put the drug through
repeated mixings, crushings and dryings with an enteric water-insoluble
excipient and promised "slow but continuous and attenuated solubility in the
gastro-intestinal tract" through a leaching process.66 Another procedure,
patented in 1959, prepared pellets by extruding a mixture of the drug and
materials such as "zein, gliadin, hordein, and kafrin."67 Still another patent, in
1963, proposed granulation of the drug into a range of granule sizes, coating

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them with slowly digestible coatings of waxes and fats in thicknesses varying
with the size of the granule, the smallest receiving the thinnest coating.68
Such timed-release products, based primarily on the use of coated or slow-
release beads, were numerous. In 1970, Remington's Pharmaceutical Sciences
listed 50 such products, but ten years later Remington's list had been cut
almost in half to 26. 69
A drug dosage form based on the idea of impregnating tablets contain-
ing a medication with water-soluble, permeable membrane films of cellulose
derivatives which would form a honeycomb structure through which the
medication would leach was patented in 1949, 70 even before the introduction
of the coated beaded medication. But it was an obvious step for the beads to be
encapsulated or tableted, especially since these opened up many new
possibilities. For example, in 1956, there were patented tablets formed by
compression of treated granules into a slow-dissolving core which in turn was
coated with kaolin and again coated with enough of the drug to supply an
initial dose.71 By 1970, there were at least 32 tablets with slow-released cores
on the market, with seven offering a drug (or drugs) at mixed-released rates.72
Ten years later the same authority (Remington's) reduced these lists to four-
teen and two respectively.73 Again no new products were added in the ten
years.
Another approach to solve the same problem consisted of a core contain-
ing the therapeutically active substance interspersed with materials such as
waxes and solid alcohols which allowed slow dissolution or leaching of the
drug, enclosed within an outer layer containing active material and excipients
and binders.74 Still another approach to timed-release forms was the multi-
layered tablet and pill. Here each layer of the tablet could be tailored to
disintegrate slowly or speedily as desired. These laminated tablets were not
new, one of the earliest being patented in 1933, 75 but their use in timed-
release medication dates only from the 1950's. In 1953, SKF developed a con-
tiguous layer compressed tablet that used hydrogenated castor oil and ethyl
cellulose as time-delay materials. One layer contained the sustained-release
material, the other layer was left subject to immediate release.76 This intrigu-
ing idea was later (1960) developed in such a way as to make the use of
tableting machinery and mass production possible.77 Still a further variation
of the multi-layer tablet was the tablet-within-a-tablet arrangement. Not sur-
prisingly, the multi-layered tablet had a counterpart in the multi-layer pill. A
1960 patent, for example, described a pill with six layers of medicament
separated by control coatings.78 In it, careful engineering would control time,
site of dissolution, leaching and related factors.
Perhaps the one tablet that pointed up the scope of the potential
manipulation, if not the actualities, inherent in this kind of dosage form, was
one patented in 1960 that consisted of an outside layer of a tasteless medica-
ment that was immediately released in the mouth for prompt therapeutic
action. Beneath this layer was a "signal" layer with a lemon flavor -a signal to
the patient to swallow the tablet. At the core was a therapeutic material
absorbable in the gastrointestinal tract to offer prolonged relief.79
A somewhat different approach to timed-release medication is the pro-
cess of microencapsulation. Borrowed from The National Cash Register Com-
pany, the process involves "microencapsulating" the medicament into a

12 Pharmacy in History

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gelatin or poly synthetic polymer material. The drug is released by diffusion in
the gastro-intestinal tract rather than by disintegration or dissolution. The
gelatin serves as a dialysis membrane and the rate of release is governed by
the diffusion properties of the drug with respect to the membrane. The use of
microencapsulation for drug delivery was patented in 1953, and there remain
a few products on the market that make use of the microencapsulation princi-
ple.80
In addition to these solid forms of time-related medications, there was
also liquid preparations incorporating timed-release principles. These
operated by suspending finely divided timed-release particles in a suitable
aqueous solution. Similarly, it has been found that sulfonamides obtain
enhanced and prolonged action when administered in an oil emulsion.81
There are, however, other approaches that do not depend either on
coatings or on the use of restraining substances. One of these is chemical
modification or the addition of active substances which can induce prolonged
or sustained action. The administration of Benemid* (probenecid, Merck
Sharp & Dohme) with penicillin to prolong the action of the penicillin by delay-
ing excretion is a good example.82 There is also the technique of "complexing,"
the use of salts or complexes of active drugs that are only slightly soluble in
gastrointestinal fluids. Here the physiologically active portion of the molecule
is only gradually released when the complex is split by hydrolysis in the
gastrointestinal tract, thus prolonging the action.83 Another of these
approaches is the binding of medicaments to ion-exchange resins. In these
systems, the resin is attacked by the digestive juices of the gastrointestinal
tract and an exchange of an ion from the juices for the drug brings about the
even release of the drug. A pharmaceutical composition based on this idea was
first patented in 1962. 84 Finally there is the use of a gel barrier. A 1962 patent
provided for a compressed tablet consisting of a medicinal agent and a
hydrophilic gum that rapidly hydrated and swelled in aqueous fluids at body
temperature. This in turn produced a mucilaginous-gel barrier on the surface
of the tablet, the barrier providing a constant rate of release of the medica-
ment.85
This review of the development of a variety of timed-release dosage
forms is but one facet of the heightened activity of the 1950's and 1960's. Alec
Williams, in his 1969 study of Sustained Released Pharmaceuticals86 described
U.S. patents for nine cellulose coatings, eleven lipid coatings and eight gels
for tablets. In addition, he listed nine general coatings for capsules and no less
than eighteen sustained-release forms which were developed to meet the
requirements of specific medicaments. Even this large number of forms is
incomplete.
The timed-release oral dosage forms are not without their disadvan-
tages. Perhaps the most significant in a long list of "intrinsic disadvantages"
is that their design on the basis of the average elimination rate makes possible
either drug accumulation or under-medication.87 Indeed, there was enough
criticism of these dosage forms almost from the time of their introduction to
lead to some controversy.88 As early as 1956, the New England Journal of
Medicine felt that a "reinvestigation of some of the fundamental concepts of
gastrointestinal physiology as related to drugs [was needed] to discover what
procedures can be supported by fact rather than by fancy and habit."89 Studies

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that showed that "claims for any physiologic advantage to this type of medica-
tion seem unjustified" appeared in the literature.90 There was a lack of objec-
tivity in the evaluation of timed-release products91 and as recently as 1979
Lancet, although it recognized the genuine advantages of such dosage forms,
nevertheless deplored the fact that "many of the numerous preparations on
the market have no scientific justification; they give less reliable results, and
are often more expensive than plain preparations. Other elaborate delivery
systems are being developed but they have scarcely progressed beyond the
stage of technical wizardry."92
In the face of criticisms and shortcomings such as these, the phar-
maceutical industry came up with a "profusion of research and patent activity
in dosage form technology" in the 1970's.93 Few products have so far resulted
from this activity, but outstanding among them were those that came from
the Alza Corporation of California. These included an infusion pump now in
use in intensive care units for drug administration, the ophthalmic, hormonal
IUD and the transdermal delivery systems already mentioned, and a new and
radically different approach to the delivery of drugs perorally.94
This new approach is resourceful as well as novel. Where earlier systems
relied on solubility of coatings and medicaments, on leaching or erosion, on
ion exchange or on some combination of these, this new system operates on
the principle of osmotic pressure. In the system, the drug module is essential-
ly an osmotic pump in which the core containing the solid drug is surrounded
by a semi-permeable membrane which will permit only the entry of water. A
laser-produced orifice provides the only exit for the drug into the environ-
ment. After administration of the module, water from the environment is con-
tinuously imbibed, drawn into the module by osmotic pressure. The water
begins to dissolve the enclosed drug and since the membrance's structure does
not allow expansion, the dissolving drug leaves the interior at the same rate
as the osmotic pressure has drawn in the water. The fluid medication thus
continues to flow out at a constant precise rate as the tablet moves through
the intestinal system and release can be sustained for any given amount of
time. As a result, release of drug by this system can be controlled by design.
Two significant control factors, the permeability of the membrane and the
solubility of the drug, are readily adjusted. The only physiological limitation
now foreseen on the capability of the system to provide an optimum
therapeutic performance is the time spent in passing through the
gastrointestinal tract.95 This delivery system was patented in 1974 by F.
Theeuwes and T. Higuchi.96
The ability to release medication at a constant rate and the length to
which release time can be extended are accompanied by certain other advan-
tages inherent in the system: it can be applied to drugs with widely different
solubilities and delivery rates, it protects the drug awaiting delivery from the
gut contents and mucosa, and it is independent of pH and motility variations
(thus it is able to circumvent individual variations in physiology). Moreover, it
has been accompanied by the development of a relatively simple and highly
reliable technique for predicting the in vivo release rate from in vitro tests.
This is of significant research value.97
This osmotic system thus presents modern drug therapy with a new tool
of great potential. The proof, however, lies not in theoretical discussion or

14 Pharmacy in History

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 Drug
Solution _ ,.
. _ Delivery ,.
T s' Orifice

N ]^^^^^^^^^^^^^^^Hi^^

Semi-permeable ^ ^ Osmotic Core

Membrane Containing Drug

Cross-section of new precision rel

mathematical formulas regarding the sy

The first of these was a natural conse
Sharp & Dohme in anti-arthritic dru
frequently prescribed for arthritis suff
times daily in capsules which dissolve
levels of the drug which tail off until an
chronic condition which would benef
sustained-release administration. Moreo
characteristics that lend themselves to
effort, then, indomethacin has been ad
delivery system (GITS -Gastro-Intesti
Indos* (Indosmos,* Osmosin,* outside
Indos has been tested in vitro and in a
program in rheumatoid arthritis and ost
ed release of drug delivery was evident
as compared with single or multiple do
It also showed Indos provides more prol
than capsules, and that the bioavailabilit
80% when compared to conventional r
intravenous preparations. Many patie
day and could be maintained at that d
one world-wide on 402 patients, the
States, have substantiated these finding
* Trademark

Vol. 25 (1983) No. 1 15

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patient in terms of ease with which precise therapeutic dosages and times can
be calibrated is evident.98
The new delivery (GITS) formulation is the latest development in the
search for dosage forms that enable the drug to perform its therapeutic func-
tion more efficiently. There are many other drugs which have been studied
and are appropriate for the new delivery system (GITS). Unna could not have
foreseen that his interest in enteric coatings would lead eventually to the
ingenious attempts of pharmaceutical scientists to search for granulations,
membranes, and coatings, to neat mathematical analyses and to precise phar-
maceutical engineering. Gerhart Levy has predicted that "it is now possible,
in principle, to develop drug delivery systems which release medicinal agents
at sites of the body at selected, constant rates and even at variable rates
according to a particular temporal pattern."99 The new delivery (GITS) for-
mulation may well fulfill this prediction; it is certainly a harbinger of the at-
tainment of a rational pharmacology.

References

1. Unna, P. G., "Eine neue Form Medicamentoser Einverleibung," Fortschr. Med (Berlin) 2:507-509, 188
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3. Ibid., p. 509.
4. Ibid., p. 509.
5. Ibid., p. 508 n.
6. Pacific Med. Surg. J., 10:31, 1867.
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Vol. 25 (1983) No. 1 17

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18 Pharmacy in History

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