REVIEW ARTICLE Clin Pharmacokinet 1999; 37 Suppl.

1: 1-6
0312-5963/99/0001-0001/$03.00/0

© Adis International Limited. All rights reserved.

Current Status of Sustained Release

Formulations in the Treatment
of Hypertension
An Overview
Ernst Mutschler1 and Heinrich Knauf 2
1 Pharmakologisches Institut für Naturwissenschaftler, Johann Wolfgang Goethe-Universität,
Frankfurt/Main, Germany
2 Medizinische Klinik I, St. Bernward-Krankenhaus, Hildesheim, Germany

Abstract The principal advantages to be gained from controlling the variables of drug
release in sustained release formulations are as follows: (i) a more uniform plasma
drug profile with fewer occasions when super- or subtherapeutic concentrations
of the drug, or its active metabolite(s), occur; and (ii) a smoother therapeutic
response over the dosage interval (provided the time-course of drug effects re-
flects the plasma concentration-time profile). Clinically, this offers the potential
to optimise drug therapy and decrease the occurrence of concentration-related
adverse effects. In addition, sustained release formulations may increase the like-
lihood of patient acceptance of therapy, and a once-daily sustained release for-
mulation of a shorter-acting drug that provides a ‘residual’ therapeutic response
at the end of the dosage interval can provide additional ‘cover’ in comparison
with a once-daily conventional (immediate release) formulation.
In the treatment of hypertension, there are potential advantages to be gained
from continuous 24-hour control of blood pressure (BP), particularly in view of
epidemiological evidence linking the apparent underperformance of antihyper-
tensive therapy in some major intervention trials in reducing the occurrence of
coronary heart disease to predicted levels with a relative failure to control diurnal
BP fluctuations. In this regard, the concept of the trough : peak ratio as a measure
of antihypertensive efficacy has gained increasing acceptance during recent
years. A sustained release antihypertensive formulation offering an improved
plasma concentration-time profile and an adequately high trough : peak ratio may
therefore provide more consistent 24-hour BP-lowering activity, with attenuation
of early morning BP surges and maximal target organ protection. This, coupled
with the fact that sustained release formulations can also provide economic ad-
vantages in cardiovascular therapeutics by lowering overall health expenditure
(which more than offsets their usually higher acquisition costs in comparison with
immediate release formulations), suggests that they may have an increasingly
important role to play in the future.
2 Mutschler & Knauf
Numerous pharmacological intervention trials
in hypertension have demonstrated benefits from
reducing cardiovascular morbidity and mortality.
In particular, the risk of stroke, and to a lesser ex-
tent, coronary heart disease (CHD), is reduced by
strategies that effectively lower elevated blood
pressure (BP) to ‘normal’ levels.[1,2] However, the
reduction in CHD events in the various interven-
tion trials has not been as large as predicted, and
this has generated concern in view of the high in-
cidence of CHD in industrialised societies. The
complex reasons for this phenomenon are not to-
tally understood: it may be due, among other rea-
sons, to (i) the extent of CHD at the onset of anti-
hypertensive treatment; (ii) the different duration
of treatment necessary to reduce coronary events
compared with cerebrovascular events;[3] (iii) un-
derestimation of the true therapeutic benefit in clin-
ical trials;[4] and (iv) a relative failure of drug treat-
ment to achieve optimal levels of BP ‘control’
and/or to maintain them over a 24-hour dosage in-
terval.[5,6]
Consequently, the achievement of continuous
BP control with antihypertensive therapy is viewed
as a key aspect in maximising the benefits of treat-
ment. Recent developments in this area have fo-
cused on improving dosage formulations of antihy-
pertensive drugs to provide consistent BP control
over a full 24-hour period. By controlling the pa-
rameters of drug release, sustained release formu-
lations offer the potential to optimise treatment
and, at the same time, decrease the occurrence of
certain adverse effects.[7-10] This review discusses
the pharmacokinetic basis for sustained release for-
mulations and their current status in the manage-
ment of hypertension.
1. Pharmacokinetic Basis for Sustained
Release Oral Drug Formulations
A number of different technologies designed to
achieve sustained/controlled drug release1 from
oral formulations have been developed during the
1 In this review, no distinction will be drawn between the
terms sustained release and controlled release for rate-control
oral drug delivery systems.
© Adis International Limited. All rights reserved.
past 2 decades, and include slowly disintegrating
matrix tablets, hydrophilic gel tablets/capsules,
capsules containing slowly eroding polymer-
coated pellets, and pellets or tablets coated with
diffusion-controlling (‘osmotic pump’) mem-
branes.[7,9,11] The objectives are to render drug ab-
sorption and distribution predictable by controlling
the rate and duration of release and to thereby
achieve zero-order kinetics, i.e. a constant release
of the drug with time.[9,10] Consequently, the main
pharmacokinetic advantage expected from a sus-
tained release oral formulation is a more uniform
plasma drug profile,[12] with fewer occasions when
either super- or subtherapeutic concentrations of
the drug, or its active metabolite(s), occur (fig. 1).
Sustained release formulations allow drugs with
relatively short elimination half-lives that are nor-
mally administered several times daily to be given
once or twice daily with effectiveness comparable
to that with conventional (immediate release) for-
mulations and fewer adverse effects.[9] For drugs
with intrinsically long elimination half-lives that
are normally administered once daily, sustained re-
lease formulations minimise fluctuations in drug
concentrations, which can reduce the amount of
drug necessary for a clinical response. This is the
case, for example, with the diuretic indapamide,
the reformulation of which in a sustained release
tablet is the subject of other articles appearing in
this supplement.[13-16] For other drugs, e.g. those
with low therapeutic concentration ratios (i.e. the
ratio of the highest tolerable to the lowest effective
plasma concentration), the reductions in peak con-
centrations achieved with a sustained release formu-
lation may make such agents more clinically accep-
table. Moreover, drugs that cause gastrointestinal
irritation may be rendered more tolerable by con-
trolling their release rate in the gut.[7]
1.1 Specific Pharmacokinetic
Characteristics of Sustained Release
Formulations
The design of delivery systems for which ab-
sorption rates are independent of rate-limiting fac-
tors such as pH variations in the gastrointestinal
Clin Pharmacokinet 1999; 37 Suppl. 1
Current Status of SR Formulations in Hypertension 3

Sustained release formulation

Conventional formulation

Adverse effects
Plasma drug concentration

Maximum safe concentration

Desired
therapeutic
range
Minimum effective concentration

Subtherapeutic effect

0 6 12 18 24
Time (hours)

Fig. 1. Theoretical plasma concentration-time profiles for a relatively short-acting drug normally administered 4 times daily (conven-
tional formulation) and for the same drug given via a sustained release formulation once daily. The plateau concentration achieved
with the sustained release formulation avoids the occurrence of concentrations above the maximum safe level and below the
minimum effective level with the conventional formulation (after Kellaway,[7] with permission).

tract, gastric emptying, binding to food, etc. should
result in less variability in plasma drug concentra-
tions.[12] Although some sustained release formu-
lations have an initial rapid-release component that
provides an initial loading dose, most exhibit a
constant rate of release and a slow absorption pro-
file, which minimise fluctuations between peak
(Cmax) and trough (Cmin) plasma drug concentra-
tions.[8] There are strict requirements for these for-
mulations so that predictable and reproducible
drug release can be ensured, and disadvantages
such as reduced bioavailability, adverse effects of
food on absorption, dose dumping, plasma level
variability, etc. avoided.[10] During the develop-
ment of a sustained release formulation, both the
single dose and steady-state pharmacokinetic pro-
file need to be characterised and compared with
conventional (immediate release) formulations of
the drug.[17] The steady-state profile should be re-
producible both with and without food, from day
to day and at various dose levels. Some of the phar-
macokinetic parameters that should ideally be as-
sessed in such studies are shown in table I.
Among these parameters, the plateau time [e.g.
the time the plasma concentration exceeds 75% of
Cmax (t75)] and the residual concentration at the end
of the dosage interval (expressed as a percentage
of Cmax or the average plasma concentration) char-
acterise the ‘strength’ of the sustained release for-
mulation, while the various peak-trough charac-
teristics (e.g. % peak-trough fluctuation, % swing,
% AUC fluctuation) characterise the rate of ab-
sorption.[17] The ability of a sustained release for-
mulation to reduce the rate of absorption and pro-
duce a more uniform plasma concentration curve
of the type illustrated in figure 1 will be indicated,
for example, by an increase in tmax and t75 and a
decrease in Cmax and peak-trough fluctuation rela-
tive to an immediate release formulation, while
similar values for AUC over the dosage interval
(AUCτ) and t1⁄2 will indicate equivalent absorption
and elimination.
1.2 Relationship to the Time-Course of
Drug Effects
The pharmacokinetic profile of a sustained re-
lease formulation needs to be related to the time-
course of drug effect, which should be measured
throughout a dosage interval to gain an insight into
the ability of the formulation to maintain a thera-
peutic response over this period. This is because
the concentration-effect relationship may be com-
plex and the plasma concentrations achieved may
actually exceed those producing the maximum

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999; 37 Suppl. 1
4 Mutschler & Knauf

Table I. Some of the parameters that should ideally be determined in single and multiple dose pharmacokinetic studies of sustained release
oral formulations (after Steinijans,[17] with permission)
Pharmacokinetic parameters Single dose studies Multiple dose studies (steady state)
Conventional parameters
AUC, tmax, Cmax, kabs, λz, t1⁄2 AUC or Cav, tmax, Cmax, Cmin, kabs, λz, t1⁄2
Residual concentration at end of the proposed Residual concentration at the end of the
dosage interval (as % of Cmax) proposed dosage interval (as % of Cssmax or Cav)
Plateau time (t75, half-value duration) Peak-trough characteristics (% peak-trough
fluctuation, % swing, % AUC fluctuation)
Alternative parameters
Mean residence time Plateau time (t75, half-value duration)
Mean absorption time
Approximation of plasma concentration
AUC = area under the plasma concentration-time curve; % AUC fluctuation = 100 [AUC (above Cav) + AUC (below Cav)] / AUC; Cav = average
plasma concentration (AUCτ, where τ = dosage interval); Cmax = peak plasma concentration; Css max = Cmax at steady state; Cmin = minimum
plasma concentration; kabs = absorption rate constant; λz = terminal rate constant; % peak-trough fluctuation = 100 (Cmax=− Cmin)/Cav; %
swing = 100 (Cmax − Cmin)/Cmin; t1⁄2 = apparent elimination half-life; t75 = time the plasma concentration exceeds 75% of Cmax; tmax = time to
peak plasma concentration.

drug effect (Emax) at certain times; alternatively, the
drug effect may be delayed in relation to changes
in plasma concentration, with the result that the
shape of the therapeutic response profile may be
independent of the shape of the plasma concentra-
tion curve. In the case of an antihypertensive drug,
for example, it is important to measure the time-
course of the BP-lowering activity over a 24-hour
period to determine whether the smoother plasma
concentration-time curve achieved with a sus-
tained release formulation is reflected in a
smoother diurnal BP profile and that circadian
changes in BP are accounted for.
Such investigations are necessary for estimation
of the trough : peak ratio, i.e. the ratio of residual
fall in BP measured just prior to the next dose to
the maximum fall during the dosage interval (mea-
sured at steady state and corrected for placebo ef-
fects).[18,19] This ratio has been advocated by the
US Food and Drug Administration as a useful index
of not only the drug’s duration of action over the
dosage interval, but also its safety in terms of
avoiding exaggerated peak effects that may lead to
impaired cerebral perfusion and a risk of symp-
tomatic hypotension, particularly in the elderly.An
antihypertensive drug should have a trough : peak
ratio of at least 50% and, ideally, the ratio should
consistently exceed 60%.[5]
In studies of the 24-hour BP-lowering efficacy
of the sustained release formulation of indapam-
ide, the pharmacokinetic characteristics of which
are discussed in more detail in another article in
this supplement,[14] the group placebo-adjusted
trough : peak ratios calculated after 2 months’
treatment were 85% for diastolic BP and 89% for
systolic BP.[20] The 24-hour BP profile in 57 pa-
tients who received indapamide sustained release
1.5mg daily for 3 months is shown in figure 2.
2. Advantages of Sustained Release
Formulations in Antihypertensive
Therapy
The availability of various classes of antihyper-
tensive drugs (e.g. calcium antagonists, β-blockers
and, more recently, diuretics) in sustained release
formulations has greatly influenced the application
of these drugs in clinical practice.[9] Because plasma
drug concentrations remain reasonably consistent
throughout the dosage interval, without the major
fluctuations at peak and trough seen with conven-
tional formulations, they may produce better 24-
hour BP control and an improved efficacy : safety
ratio, with fewer adverse effects caused by concen-
tration peaks.
As pointed out above, the lack of consistent BP
control over a full 24-hour period may be an im-

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999; 37 Suppl. 1
Current Status of SR Formulations in Hypertension
portant factor in the relative failure of major phar-
macological intervention trials in hypertension to
achieve predicted reductions in CHD incidence.
Epidemiological evidence supporting this conclu-
sion includes the following:
• Casual or ‘clinic’ BP measurement does not pre-
dict target organ damage from hypertension as
accurately as 24-hour BP measurement.[21]
• BP variability is an additional and independent
determinant of target organ damage.[22] The in-
cidence of cardiovascular complications in hy-
pertensive patients appears to be higher when
night-time BP remains elevated.
• The highest incidence of cardiovascular events
occurs in the morning, which probably equates
with the period when the BP-lowering efficacy
of conventional once-daily antihypertensive re-
gimens is minimal.[5,22,23]
Although there is, as yet, no direct evidence that
continuous 24-hour BP control provides a better
long term outcome in protecting against cardiovas-
cular events, intuitively, these findings point to the
importance of attempting to achieve this.[5,22,23] In
this regard, sustained release formulations with ap-
propriate pharmacokinetic profiles and high
trough : peak ratios may provide a number of im-
portant advantages in optimising antihypertensive
therapy, including the following:
SBP at baseline
DBP at baseline
180
Blood pressure (mm Hg)
160
140
120
100
80
60
1 2 3 4 5 6 7 8 9 10 1112 1314 15 16 17 18 19 20 21 22 23 24
Time after administration (hours)
Fig. 2. Mean 24-hour ambulatory blood pressure responses in
57 patients with mild to moderate essential hypertension who
received indapamide sustained release 1.5mg daily for a period
of 3 months (after Mallion et al.,[20] with permission). DBP =
diastolic blood pressure; SBP = systolic blood pressure.
© Adis International Limited. All rights reserved.
5
• other antihypertensive activity with reduced di-
urnal BP variability
• attenuation of early morning BP surges, and
• maximal target organ protection.
In addition, a further advantage offered by sus-
tained release formulations may be the ability to
achieve an equivalent clinical response with a
lower daily dosage in comparison with conven-
tional (immediate release) formulations. For exam-
ple, in the case of indapamide, pharmacokinetic
studies have shown that the minimum plasma con-
centration (Cmin) with the sustained release formu-
lation at a dosage of 1.5mg daily is similar to that
with the 2.5mg immediate release formulation,[24]
and clinical studies in patients with mild to mod-
erate hypertension have documented similar 24-
hour blood pressure control with the 2 formula-
tions.[20] This has important implications in terms
of safety, particularly in view of the suggestion that
the adverse metabolic effects of the drugs used in
the major clinical trials in hypertension (princi-
pally conventional thiazide diuretics and β-block-
ers) could have partially attenuated their benefits
with regard to BP control, and that this could be
another potential reason for the lower than ex-
pected reduction in CHD in these trials.[23] Reduc-
ing the effective dosage is also in agreement with
the current recommendations of national and inter-
national guidelines for hypertension management,
SBP after 3 months which emphasise the importance of using the low-
DBP after 3 months
est possible dosage to achieve ‘target’ BP levels.
Finally, sustained release formulations may also
offer advantages in terms of patient compliance.
Prolongation of the dosage interval for a drug nor-
mally administered several times daily has obvious
advantages for compliance. However, even for
drugs that are normally administered once daily,
sustained release formulations may offer the ad-
vantage of providing better ‘cover’ for poorly com-
pliant individuals who may periodically miss one
of their daily doses. This is because the antihyper-
tensive efficacy can be expected to diminish more
slowly with a formulation that has a relatively high
trough : peak ratio in comparison with one that has
a lower trough : peak ratio.[25]
Clin Pharmacokinet 1999; 37 Suppl. 1
6 Mutschler & Knauf
3. Conclusions: Current Status of
Sustained Release Formulations in the
Treatment of Hypertension
The overall impact of sustained release formu-
lations lies in their potential to improve the thera-
peutic response and reduce adverse effects, as well
as enhancing the likelihood of patient acceptance
of the treatment. In view of epidemiological evi-
dence suggesting that antihypertensive therapy
should be based on achieving consistent BP control
over a full 24-hour period, a good case can be made
for selecting a sustained release formulation of a
drug with proven clinical efficacy in treating hy-
pertension, provided the formulation has been
shown to have an appropriately high trough : peak
ratio and its duration of action over the recom-
mended dosage interval has been established.
Differences between various sustained release
formulations that affect their selection and use cen-
tre around practical issues such as cost, patient
compliance and tolerability. In terms of costs, re-
cent analyses have shown that the use of sustained
release formulations can provide important eco-
nomic advantages by lowering overall healthcare
expenditures (e.g. physician, hospital and labora-
tory costs of diagnosing and treating adverse ef-
fects, re-evaluating and adjusting dosages, etc.).
For a number of drugs used in cardiovascular med-
icine, the use of sustained release formulations has
been reported to more than offset their higher ac-
quisition costs in comparison with conventional
(immediate release) formulations.[26] Such find-
ings serve to confirm the increasing status of sus-
tained release formulations in the overall therapeu-
tic armamentarium against hypertension.
References
1. Hansson L. The benefits of lowering elevated blood pressure: a
critical review of studies of cardiovascular morbidity and
mortality in hypertension. J Hypertens 1996; 14: 537-44
2. Hansson L. Success in the treatment of hypertension: a status
report. J Hypertens 1997; 15 Suppl. 2: S11-15
3. Moser M. Effect of diuretics on morbidity and mortality in the
treatment of hypertension. Cardiology 1994; Suppl. 2: 27-35
4. Linjer E, Hansson L. Underestimation of the true benefits of
antihypertensive treatment: assessment of some important
sources of error. J Hypertens 1997; 15: 221-5
5. Meredith PA. Role of trough to peak efficacy in the evaluation
of antihypertensive efficacy. J Hypertens 1998; 16 Suppl. 1:
S59-64
© Adis International Limited. All rights reserved.
6. Mancia G, Sega R, Milesi C, et al. Blood-pressure control in the
hypertensive population. Lancet 1997; 349: 454-7
7. Kellaway IW. Scientific rationale and clinical implications of
sustained-release formulations. Br J Clin Pract 1988; 42
Suppl. 60: 9-13
8. Goldberg Arnold RJ, Kaniecki DJ. Selection of oral controlled-
release drugs: a critical decision for the physician. South Med
J 1993; 86: 208-14
9. Katz B, Rosenberg A, Frishman WH. Controlled-release drug
delivery systems in cardiovascular medicine. Am Heart J
1995; 129: 359-68
10. Colombo P, Bettini R, Peracchia MT, et al. Controlled release
dosage forms: from ground to space. Eur J Drug Metab Phar-
macokinet 1996; 21: 87-91
11. Chien YW. Rate-control drug delivery systems: controlled re-
lease vs. sustained release. Med Prog Technol 1989; 15: 21-46
12. Read NW, Sugden K. Gastrointestinal dynamics and pharma-
cology for the optimum design of controlled-release oral dos-
age forms. Crit Rev Ther Drug Carrier Syst 1988; 4: 221-63
13. Bataillard A, Schiavi P, Sassard J. Pharmacological properties
of indapamide: rationale for use in hypertension. Clin Phar-
macokinet 1999; 37 Suppl. 1: 7-12
14. Damien G, Huet de Barochez B, Schiavi P. Galenic develop-
ment and pharmacokinetic profile of indapamide sustained
release 1.5mg. Clin Pharmacokinet 1999; 37 Suppl. 1: 13-19
15. Donnelly R. Clinical implications of indapamide sustained re-
lease 1.5mg in hypertension. Clin Pharmacokinet 1999; 37
Suppl. 1: 21-32
16. Hansson L. Pursuit of the optimal outcome in hypertension.
Clin Pharmacokinet 1999; 37 Suppl. 1: 33-38
17. Steinijans VW. Pharmacokinetic characterization of controlled-
release formulations. Eur J Drug Metab Pharmacokinet 1990;
15: 173-81
18. Omboni S, Parati G, Zanchetti A, et al. Calculation of trough-
to-peak ratio of antihypertensive treatment from ambulatory
blood pressure: methodological aspects. J Hypertens 1995;
13: 1105-12
19. Myers MG. Suggested guidelines for determining the trough-
to-peak ratio of antihypertensive drugs. Am J Hypertens 1996;
9: 76S-82S
20. Mallion J-M, Asmar R, Boutelant S, et al. Twenty-four hour
antihypertensive efficacy of indapamide, 1.5-mg sustained re-
lease: results of two randomized double-blind controlled stud-
ies. J Cardiovasc Pharmacol 1998; 32: 673-8
21. Parati G, Pomidosssi G, Albini F, et al. Relationship of 24-hour
blood pressure mean and variability to severity of target-organ
damage in hyertension. J Hypertens 1987; 5: 93-8
22. Meredith PA, Perloff D, Mancia G, et al. Blood pressure vari-
ability and its implications for antihypertensive therapy.
Blood Press 1995; 4: 5-11
23. Myers MG. Twenty-four-hour blood pressure control: a brief
review of aspects of target-organ protection. J Hypertens
1996; 14 Suppl. 6: S7-10
24. Schiavi P, Jochemsen R, Hiley M, et al. Pharmacokinetics of
slow and immediate release formulations of indapamide after
repeated administration, in healthy volunteers. Eur J Drug
Metab Pharmacokinet 1996; Special Issue: 41
25. Elliott HL, Meredith PA. Trough : peak ratio: clinically useful
or practically irrelevant? J Hypertens 1995; 13: 279-83
26. Powers Cramer M, Saks SR. Translating safety, efficacy and
compliance into economic value for controlled release dosage
forms. Pharmacoeconomics 1994; 5: 482-504
Correspondence and reprints: Prof. Dr Dr Ernst Mutschler,
Pharmakologisches Institut für Naturwissenschaftler, Jo-
hann Wolfgang Goethe-Universität, Biocentre Niederursel,
Marie-Curie-Straβe 9, Frankfurt/Main, Germany.
Clin Pharmacokinet 1999; 37 Suppl. 1