Chapter 2

Controlled-Release Oral Delivery Systems

2
Joseph A . Fix1, Kazuhiro Sako2, and Toyohiro Sawada

1Yamanouchi Shaklee Pharma, 1050 Arastradero Road, Palo Alto, CA 94304

2
Novel Pharmaceutical Laboratories, Yamanouchi Pharmaceutical
Company, Ltd., 180 Ozumi, Yaizu-shi, Shizuoka-ken 425, Japan

The advantages of controlled-release oral delivery systems,

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particularly those achieving once-a-day efficacy, have long been

Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch002

recognized. Outcomes can include better therapeutic efficacy via

improved control of plasma drug levels and reduced peak-
-associated side effects. Oral controlled-release dosage forms can
also afford advantages in drug stability, patient compliance, and
reduced total drug exposure. Applications for once-a-day
administration must balance release kinetics, dosage form and in
vivo drug stability, absorption kinetics and variable physiologic
parameters such as g.i. transit, enzymes, pH, motility and fluid
level. In spite of major efforts to develop once-a-day oral dosage
forms, relatively few products have been introduced. In many
cases, once daily therapeutic efficacy cannot be easily achieved due
to poor control of drug release or poor drug absorption in the colon.
Food effects can also introduce significant variability. O C A S is an
oral controlled absorption gel matrix system that exhibits pH-
-independent, pseudo-zero order drug release with minimal food
effects. The rapid hydration and formation of a rigid gel leads to
effective drug release in the colon. Future advances in once-a-day
oral delivery systems must address improving drug absorption in
the colon and may extend applications of controlled-release
technology to biomolecules.

Controlled-release oral delivery systems have been an integral part of

pharmaceutical technology for several decades (I). Within the pharmaceutical
industry, delivery systems and formulations have been developed which can provide

14 © 2000 American Chemical Society

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ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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a wide variety of drug release profiles, including systems designed for immediate,
continuous, pulsatile, and delayed administration (2-4). For most traditional small
molecule drug candidates, delivery systems can be designed which will release the
candidate drug in the desired profile. In recent years, much of the focus in oral
controlled-release technology has been directed toward site specific delivery in the
gastrointestinal tract, chronobiology as related to oral delivery systems (5), and the
development of technology to control the release and delivery of non-traditional drug
candidates, i.e. peptides and proteins. Included in these various technologies are
osmotically-controlled devices, matrix tablets, hydrogels, polymeric systems,
multiparticulates, and erosion systems regulated by geometric design. Figure 1
depicts illustrative plasma profiles that can be achieved with existing oral technology.
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In spite of the availability of numerous technologies to achieve up to 24 hour

controlled drug release, relatively few products that are efficacious for once-a-day
dosing have reached the market. Table I, although not inclusive, lists some of the
products currently available where the recommended dose and administration
guidelines indicate once-a-day efficacy.
In some cases, controlled-release dosage forms that provide up to 24 hour in
vitro drug release do not achieve the same release profile in vivo due to influences
from the milieu of the gastrointestinal tract. Also, poor colonic drug absorption can
effectively limit the once daily efficacy of dosage forms that otherwise afford 24 hour
drug release.

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ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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Table I: Representative Once-a-Day O r a l Products

Indocin SR® (Merck) Verelan® (Lederle)

DynaCirc CR® (Novartis) Glucotrol XL® (Pfizer)
Toprol XL® (Astra U S A ) Calan SR® (Searle)
Adalat CC® (Bayer) Theo-24® (UCB Pharma)
Prelu-2® (Boehringer Ingleheim) Dilacor XR® (Watson)
Cardizem CD® (Hoechst Marion Roussel) Lodine XL® (Wyeth Ayerst)
Theo-Dur® (Key)
nd
SOURCE: Physician's Desk Reference, 5 2 Edition, 1998, Medical Economics
Co., Inc., Montvale, NJ
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Physiologic Influences

Once-a-day controlled release dosage forms are subject to numerous physiologic

influences in the gastrointestinal tract, including pH, bile salts, fluidity, motility,
enzyme activity, and absorption windows. Ideally, a once-a-day dosage form should
function independent of variations in the parameters shown in Figure 2.

Figure 2: Quantitative trend analysis of gastrointestinal parameters that effect the

performance of once-a-day dosage forms.

During transit from stomach to lower colon, the p H exposure can range from p H
1.0 to p H 7.5 or greater. Bile salts and degradative enzymes are present in relatively
high concentrations in the small intestine. Fluid content and gastrointestinal motility

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are high in the upper intestine and diminish in a distal direction. In order to reliably
control drug release in an extended release product, the formulation would ideally
function independent of these changing variables. Additionally, the decrease in fluid
content in the colon, which is a water re-absorption site, can lead to altered drug
release profiles (normally a decrease in the release rate if the release mechanism is
dependent on the continued presence of high water content). The osmotically driven
delivery systems pioneered by Alza have been quite effective in performing in a
uniform fashion even in the presence of limited water availability (6). Other types of
dosage forms do not always perform as well. Two examples are shown in Figure 3
where prospective once-a-day dosage forms do not achieve continuous drug release
once the formulation reaches the colon.
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Figure 3: A: Plasma nicardipine levels after oral dosing of controlled-release

nicardipine hydrochloride to dogs and humans. B: In vitro and in vivo
acetaminophen release from HPMC matrix sustained release tablets.

In Figure 3 A , the absorptive phase for nicardipine terminates upon arrival of the
dosage form in the colon (as determined by scintigraphic imaging) of both dogs and
humans. In Figure 3B, the in vivo release of acetaminophen (determined by
deconvolution of plasma acetaminophen levels) only correlates with in vitro release
while the dosage form is in the stomach or small intestine. Acetaminophen release
dramatically decreased when the dosage form reached the colon. These data suggest
that the release characteristics of these matrix tablets are not consistently maintained
throughout the entire gastrointestinal tract.
Several reasons may account for the discrepancies between in vitro and in vivo
drug release, including effects of the gastrointestinal milieu on the controlled-release
dosage form. In the colon, very little free water exists since the colon is a water
absorptive region of the gastrointestinal tract. Those once-a-day dosage forms that
are dependent on the continued presence of relatively significant amounts of water
may be expected to experience altered drug release profiles once the dosage form
reaches the colon. The osmotic systems developed by Alza Corporation have been
shown to function well in low water environments, but other sustained release dosage
forms (i.e. certain matrix tablets, hydrogels) are not always so robust in their

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ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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performance characteristics. The future development of once-a-day dosage forms

depends on the ability to design and develop sustained-release dosage forms that will
function independent of influences from the gastrointestinal milieu. Since sustained-
release dosage forms spend the majority of their residence time in the colon, future
once-a-day dosage forms must be designed to release drug in a predictable fashion in
the relatively low water content of the colon.

Oral Controlled Absorption System (OCAS™)

In an effort to design a sustained-release formulation suitable for once-a-day

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dosing that will perform reproducibly whether in the small intestine or colon,
modifications to gel-forming matrix tablets were investigated. The O C A S system
described here contains, as its major components, the active drug, a gel-forming
polymer (polyethylene oxide, PEO), and a gel-enhancing agent (polyethylene glycol,
PEG). The design concept is to achieve rapid gelation, pseudo first-order drug
release, consistent colonic drug release, and ease of manufacturing. A schematic,
shown in Figure 4, describes the basic performance characteristics of O C A S .

Stomach Small Intestine Colon

(Rapid gelation) (Fully hydrated)

Figure 4: Schematic of OCAS hydration and drug release in small intestine and
colon.

The schematic in Figure 4 depicts the design concept of O C A S in that the

formulation achieves nearly complete hydration in the small intestine. Unlike O C A S ,
other gel-forming matrix tablets may only achieve incomplete hydration in the small
intestine, resulting in a dosage form that retains a significant volume of residual non-
hydrated drug/polymer core in the colon. In the absence of significant free water in
the colon, drug release from these formulations may significantly decrease, resulting
in a lack of correlation between in vitro drug release and in vivo drug absorption.

In Controlled Drug Delivery; Park, K., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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The key to sustaining consistent drug release, as designed in the O C A S dosage

form, is very rapid hydration of the gel matrix such that nearly complete hydration
occurs prior to arrival of the dosage form at the colon. In most cases, the transit time
for dosage forms from the stomach to the colon is approximately 3-4 hours, perhaps
longer in the fed state depending on the extent of gastric retention. In order to ensure
nearly complete pre-colonic hydration, fillers that could be combined with the gel-
forming polymer (PEO) were examined for their effects on gelation index (extent of
gelation occuring within 2 hours). The results are summarized in Table II.

Table II: Effect of Fillers on Gelation Index of 1:1 PEO-Filier Matrix Tablets
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Additive Gelation Index (Percent at 2 hours)

Lactose 24.4 + 3.3

D-Mannitol 26.8 + 3.3
PVPK30 82.2 + 4.3
PEG6000 87.1 +0.4
D-Sorbitol 97.0 + 0.8

None 29.7 + 5.0

Tablets were immersed in dissolution media for two hours. Gelation index was
calculated by comparing ratios of the gel layer and non-gelated residual core
thicknesses.
Without added filler, PEO matrix tablets exhibited only 30% gelation within two
hours. This control gelation index was not significantly increased by the addition of
lactose or mannitol. Ρ V P K30, PEG6000 and D-sorbitol each significantly increased
O C A S gelation index, although P V P K30 required 2 ml of water per 1 g of solute
whereas PEG6000 and D-sorbitol required only 1 ml of water per 1 g of solute to
achieve similar results. PEG6000 was chosen as the desired filler because of its high
gelation index and pharmaceutical acceptability.
Utilizing PEG6000 as the filler for the gel-forming matrix tablets, four different
gel-forming polymers were examined for their ability to achieve pseudo zero-order
drug release for 12 hours. Matrix tablets were prepared from
acetaminophen:PEG:polymer (1:1:2) and their in vitro release profiles determined by
the paddle method. In addition, the release mechanism was described according to
the following equation,
n
D = kt

where D is drug release at time t, k is the drug release rate constant, t is time, and η is
the diffusional exponent number. As an approximation, η < 0.66 indicates diffusion
dominated drug release while η > 0.66 indicates erosion dominated drug release (n =

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0.5 for Fickian diffusion control and η = 1.0 for solvent front penetration control).
The results from these studies are summarized in Table III.

Table III: Determination of In Vitro Release Mechanism of Acetaminophen

from Drug:PEG:Polymer (1:1:2) Matrix Tablets

Gel-Forming Polymer Diffusional Exponent Number (n)

Hydroxypropylcellulose (HPC) 0.59

Hydroxyethylcellulose (HEC) 0.61
Hydroxypropylmethylcellulose (HPMC) 0.61
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Polyethyleneoxide (PEO) 0.76

PEG6000 used as filler in matrix tablet.

The data shown in Table III indicate that tablets made fiom PEO were the only
ones tested that exhibited erosion dominated drug release (n > 0.66). The other three
polymers tablets (HPC, HEC, and HPMC) exhibited diffusion dominated drug release
(n < 0.66). The actual release profiles (shown in Figure 5 for PEO and H P M C ) also
demonstrated these differences in that a pseudo-zero order release profile was
achieved only with PEO while the other polymers resulted in tablets exhibiting more
non-linear release profiles.

Time (hr) Ti m e (hr)

Figure 5: In vitro acetaminophen release profile from PEO and HPMC matrix
tablets. The arrow shows the time of initiation (1 hour) of mechanical stress as
described in the text.

The data shown in Figure 5 also demonstrate an additional important

characteristic of the O C A S formulation. The arrows indicate the initiation of
mechanical stress on the formulations. The mechanical stress involved shaking the
formulations in dissolution medium at 320 strokes/min in the presence of 50 g of

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glass beads. Only a very minimal increase in drug release was observed utilizing
PEO whereas an abrupt and dramatic increase in drug release was seen when H P M C
was used as the gel-forming polymer. These data indicate that the gel formed with
PEO possesses significant structural rigidity that is important in maintaining both
physical integrity and consistent drug release during contractile activity present in the
gastrointestinal tract.

While in vitro release data are important in developing and characterizing

sustained release dosage forms, the in vivo performance is the critical test of
functionality. A comparison of in vitro and in vivo performance can be utilized to
demonstrate that the dosage forms performs independent of gastrointestinal variables.
Conventional PEO matrix tablets (gelation index = 21%) and O C A S PEO/PEG tablets
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(gelation index = 76%) were prepared and evaluated in both in vitro and in vivo
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models. Both formulations demonstrated reasonably pH-independent in vitro drug

release between p H 1.2 and p H 6.8 over a 12 hour dissolution time. The release
profile for O C A S was somewhat more linear than that observed with the conventional
gel matrix tablet, especially between 8 and 12 hours, but both formulations achieved
greater than 85% drug release within 10 hours. Two different in vivo experiments
were conducted in dog models. In one study, both conventional and O C A S tablets
were dosed at various times prior to necropsy and the tablets then retrieved and
analyzed for in vivo drug release. In another experimental model, dogs received
either conventional or OCAS tablets containing acetaminophen and plasma drug
profiles determined. The pharmacokinetic parameters from this study are
summarized in Table IV and a graphic summarization of all results is shown in Figure
6.
The data presented in Table IV and Figure 6 clearly indicate that this
conventional gel matrix tablet exhibits decreased in vivo drug release in the colon. In
contrast, drug release from OCAS appears to remain consistent even when the dosage
form enters the colonic region. It is proposed that the reason for the consistent O C A S
performance is the fully hydrated state of the dosage form prior to its arrival in the
"water-deficient" colon region.
As mentioned in the introduction, the gastrointestinal variables that can impact
the performance sustained-release once-a-day dosage forms are generally influenced
by the presence of food. Enzyme activity, motility, pH, fluid content, and bile salts
are all modified in the fed state versus the fasted state. In order to determine whether
OCAS would perform independent of the effects of food, a dog study was conducted
comparing nicardipine hydrochloride absorption from O C A S and conventional gel
tablets. The resultant pharmacokinetic parameters are summarized in Table V .
The data presented in Table V indicate that significantly greater absorption
(AUC) is achieved with O C A S compared to the conventional gel and that the O C A S
system is relatively free of food effects (547 vs 681 ng.hr./ml A U C for fasted vs fed,
respectively). B y contrast, an approximate 2-fold food effect was observed with the
conventional gel formulation. Again, it is likely that the very rapid hydration of the
O C A S formulation is an underlying cause for the relative food effect independence.

In Controlled Drug Delivery; Park, K., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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Table I V : Pharmacokinetic Parameters

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Formulation AUCo-24hr Cmax Tmax MET

(ng.hr./ml) (ng/ml) (hr) (hr)

OCAS 2702+ 151 350 + 36.1 1.5 + 0.3 7.0 + 0.3

Conventional 1470 + 537 344 + 21.7 1.3 + 0.3 4.0+1.2

Mean + S.E.

0 2 * β β 10 12 14 0 2 4 β β 10 12 14
Time (hr) Time (hr)

Figure 6: In vitro and in vivo release performance of OCAS and conventional gel
tablets.

In Controlled Drug Delivery; Park, K., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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Table V : Pharmacokinetic Parameters of O C A S and Conventional G e l

Nicardipine Hydrochloride Tablets in Fed and Fasted Dogs

Formulation Food AUCo-24hr Cmax Tmax

(ng.hr./ml) (ng/ml) (hr)

OCAS Fasted 547 + 180 82 + 14.8 3.9 + 1.1

Fed 681 + 108 87 + 17.8 4.7 + 1.5
Conventional Fasted 125 + 32 54 + 12.5 1.3 + 0.2
Fed 239 + 62 47 + 12.6 4.3 + 1.2

Ν = 6, mean + S.E.
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In summary, O C A S is a rapidly hydrating gel matrix tablet that performs

relatively independent of the effects of pH, mechanical stress, and location in the
gastrointestinal tract. In addition, at least with the model compound employed, food
effects appear minimal. As such, the technology represents an advance in sustained
release formulations that might have applications in once-a-day drug therapy.

Future Challenges and Opportunities

Sustained-release formulations for once-a-day therapy have been a target of

pharmaceutical research and development for several decades with a limited variety
available as marketed products. Advances as those described with O C A S represent
attempts to further refine and develop new applications. Significant challenges and
opportunities, however, still remain in this field and are summarized in Table VI.
Although significant advances have been made in developing and
commercializing once-a-day dosage forms, the field is still amenable to continued
improvement and applications. Probably the two most critical fields for investigation
are technologies for improving colonic absorption and applications of once-a-day
technologies for biomolecules.
Technologies such as O C A S can effective achieve drug release in the colon.
However, until pharmaceutical approaches are available to improve colonic
absorption, once-a-day products will be limited to those few drugs that exhibit high
colonic permeability. In normal gastrointestinal transit, it can be expected that
dosage forms will have approximately 4-6 hours available for drug release prior to
arrival at the colon. This time window will continue to limit development of once-a-
day dosage forms unless colonic absorption improvement is adequately addressed.
Finally, little progress has been achieved in oral delivery systems for
biotechnology products, even with immediate release or targeted delivery systems.
As more progress is achieved with this class of compounds, their in vivo behavior
will be more fully understood. One can then anticipate extending that knowledge to
once-a-day dosage forms in a manner similar to what has been done with traditional
organic drug candidates.

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ACS Symposium Series; American Chemical Society: Washington, DC, 2000.
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Table V I : Future Challenges and Opportunities for Once-a-Day O r a l Delivery

Systems

Formulation design to optimize 24 hour absorption

Biopharmaceutical techniques for improved colonic absorption
Gastric retention techniques to minimize large intestine residence time
Chronopharmaceutics
Matching release/absorption profiles with therapeutic needs
Technology improvements to minimize effects of gastrointestinal variables
Applications to biotechnology products (i.e. peptides, proteins, genes, etc)
Formulation strategies
Stability
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Local therapy or systemic absorption

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In Controlled Drug Delivery; Park, K., et al.;

ACS Symposium Series; American Chemical Society: Washington, DC, 2000.