journal o f

controlled
release
ELSEVIER Journal of Controlled Release 38 (1996) 11-20

Design and evaluation of sustained-release and buccal adhesive

propranolol hydrochloride tablets
Buket Taylan a, Yilmaz (~apan a,., Olgun Gtiven b, Sirri Kes c, A. Atilla Hincal a
aDepartment of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
b Department of Chemistry, Hacettepe University, Beytepe, 06532 Ankara, Turkey
c Department of Cardiology, Faculty of Medicine, Hacettepe University, 06100 Ankara, Turkey
Received 2 December 1994; revised 3 May 1995; accepted 21 June 1995

Abstract

The release of propranolol hydrochloride incorporated into sustained-release and buccal adhesive tablets was studied in vitro.
The formulation containing 20% hydroxypropyl methylcellulose (HPMC) yielded good sustained-release matrix tablets. B uccal
adhesive controlled-release tablets were prepared by compression of HPMC with polycarbophil (PAA), which served as the
bioactive adhesive compound. The release behaviour of buccal adhesive tablets was found to be non-Fickian. The adhesion force
was significantly affected by the mixing ratio of HPMC and PAA in the tablet and the weakest adhesion force was observed at
the ratio of 1:1 (HPMC:PAA). Interpolymer complex formation was confirmed between HPMC and PAA in acidic medium by
turbidity, viscosity and FT-IR measurements. The kinetics of sustained-release and buccal adhesive tablets of propranolol were
examined in nine healthy volunteers. Conventional propranolol (Dideral®) was also studied for comparison purposes. As
compared to conventional propranolol (40 mg), a single dose of 20% HPMC ( 160 mg) produced a smoother plasma level
profile, with lower and delayed peak times. Dose corrected AUC0_8 values were greater after Dideral® than after 20% HPMC
( 168.7 _ 80.3 vs 97.3 _ 36.1 ng h m l - 1p < 0.05). The buccal delivery of propranolol caused ulceration and serious irritation
that took weeks to heal. There was no significant difference (p > 0.05) in the AUCw4 values between 20% HPMC and buccal
adhesive tablets.

Keywords: Propranolol; Buccal adhesive; Sustained-releasetablet; Interpolymer complex; Human clinical study

I. Introduction 1 and 2 h) can vary up to 7-fold after oral administration

Propranolol, a non-selective beta-adrenergic block-
ing agent, has been widely used in the treatment of
hypertension, angina pectoris, and many other cardio-
vascular disorders. Propranolol is subjected to an exten-
sive and highly variable hepatic first-pass metabolism
following oral administration, with a reported systemic
bioavailability of between 15 and 23% [ 1,2]. In addi-
tion, initial plasma levels of propranolol ( Cmaxbetween
* Corresponding author. Tel. (90) -312-310-15-24.
due to individual variations in hepatic metabolic activ-
ity [ 3 ]. Because of its relatively short plasma half-life,
patients are routinely asked to take propranolol in
divided daily doses every 6 to 8 h. Such frequent drug
administration may reduce patient compliance and thus
therapeutic efficacy [4]. In recent years slow or sus-
tained-release formulations of propranolol has become
available with claims that these formulations maintain
beta-adrenoceptor blockade throughout a 24 h period
and enable the drugs to be given once daily. Previous

0168-3659/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved

SSD10168-3659(95)00094- 1
12 B. Taylan et al. / Journal of Controlled Release 38 (1996) 11-20
studies have shown that the systemic bioavailability of
sustained-release propranolol is significantly lower
(40-70%) than that of the conventional propranolol
tablet [ 5 ]. Hence sustained-release propranolol tablets
with a high patient compliance have found wide accep-
tance, avoiding fail to take correct dosage.
Alternative routes of administration including intra-
venous, rectal, transdermal and nasal routes have been
attempted to improve the systemic bioavailability of
propranolol, as these routes can allow the drug to reach
the systemic circulation, bypassing the liver and escap-
ing first-pass metabolism [6--8].
Bioadhesive polymers such as sodium carboxyme-
thylcellulose, Carbopol 934, polycarbophil (PAA,
polyacrylic acid loosely crosslinked with divinyl gly-
col) and hydroxypropylcellulose or hydroxypropyl
methylcellulose (HPMC) are suitable for use in buccal
adhesive preparations because when hydrated with
water, they can adhere to the oral mucosa and withstand
salivation, tongue movements and swallowing for a
significant period of time. HPMC and PAA have been
used as principal excipients to achieve adhesion to the
oral mucous membrane and to control the drug release
from the tablet.
The objectives of this study were: (a) to examine
the in vitro release characteristics of propranolol hydro-
chloride from different sustained-release matrix tab-
lets; (b) to elucidate factors affecting the bioadhesion
property of compressed tablets consisting of HPMC
and PAA. In this connection the interpolymer complex
formation between HPMC and PAA seems to be par-
ticularly noteworthy; (c) to evaluate the bioavailability
and pharmacokinetics of the formulated buccal adhe-
sive and sustained-release propranolol hydrochloride
tablets, a commercially available conventional tablet
was used for comparison.
2. Experimental
2.1. Materials
Propranolol hydrochloride (Sanofi-Do~u Ilaq, Tur-
key), HPMC (Metolose 90 SH 15000, Shinetsu Chem-
ical Co., Japan), lactose (Fast Flo, Foremost Food Co.,
USA), PAA (Noveon AA1, BF Goodrich, Belgium),
HPMC (Methocel K4M, Colorcon, UK), magnesium
stearate (E. Merck, Germany), 40-rag conventional
release tablets (Dideral ® B1 0593, Sanofi-Do~u Ilaq,
Turkey), and polymethylmethacrylate (Eudragit
RSPM, R6hm Pharma, Germany) were used.
2.2. Preparation of sustained-release tablets
HPMC was used as matrix material in this investi-
gation. The powders were mixed and directly com-
pressed with 1% of magnesium stearate incorporated
prior to compression. Tablets were compressed on a
single punch-tablet machine Korsch EK/0 at a tablet
weight of 400 mg using a flat, nonbeveled punch of 12
mm diameter.
Sustained-release matrix tablets were formulated to
contain 160 mg or 40% propranolol hydrochloride, 20,
30 and 40% matrix material (Metolose 90 SH 15000)
of total tablet weight. In order to obtain constant tablet
weight, different percentages of lactose were added as
filler excipient.
2.3. Preparation of buccal adhesive tablets
Tablets were prepared by direct compression of 80
mg propranolol hydrochloride with a mixture of HPMC
( Methocel K4M) and PAA in mixing ratios of 9:1, 8:2,
7:3, 6:4, 5:5, 4:6, 3:7, 2:8 or 1:9 at a tablet weight of
160 mg. 1% magnesium stearate was used as a lubricant
and the same compression equipment was utilized as
for sustained-release tablets.
2.4. Release test
For in vitro release of propranolol hydrochloride
from sustained-release tablets, a Prolabo-Paris type dis-
solution tester (USP XXII) was used at 100 rpm paddle
speed in 1000 ml of the dissolution medium at 37°C.
Buffer solutions pH 1.5 for the first 2 h and pH 6.8 for
the next 6 h were employed as the dissolution media.
The manufactured buccal adhesive tablets were
tested for dissolution in 500 ml of Mcllvaine buffer
(pH 6.6) using the USP XXII Apparatus II, Prolabo
dissolution tester, at 50 rpm and 37 +__0.2°C. Each tablet
was inserted in a metal die having a central hole 12 mm
in a diameter which was sealed at the lower end with
paraffin wax so that the drug could be released only
from the upper face of the device.
 B. Taylan et al. / Journal of Controlled Release 38 (1996) 11-20
Samples were withdrawn at appropriate time inter-
vals, filtered and assayed for propranolol using a UV-
160 A Shimadzu spectrophotometer at 289 nm.
2.5. Turbidity measurement
HPMC solution (2.5 ml, 0-0.02%) was mixed with
PAA solution (2.5 ml, 0-0.02%) at 37°C for 1 h to
prepare the sample solution. Buffer solutions (pH 3.0,
4.5 and 6.0) were used to dissolve samples. The total
polymer concentration was fixed at 0.02% in all sam-
ples. The turbidity of each sample solution was deter-
mined at 600 nm, where there was no absorption due
to polymers in solution, using a UV-160A Shimadzu
spectrophotometer.
2.6. Viscosity measurement
This method was originally described by Satoh et al.
[9]. HPMC solution ( 10 ml, 0-1%) mixed with PAA
solution (10 ml, 0-1%) was incubated at 30°C for 7
days. Total polymer concentration was fixed by dilution
with buffer solution at 0.5% in all samples. After cen-
trifugation for 20 rain at 15,000 rpm in a Sorvall Super-
speed Centrifuge SS-3, the viscosity of the
dispersion-free supernatant solution was determined at
37°C by the use of an Ubbelohde viscometer (Schott-
Gen Mainz, K:0.004765). Buffer solution, pH 3, was
used to prepare the sample solution.
2.7. Preparation of the interpolymer complex
HPMC solution at pH 3 (20 ml, 0-0.1%) was mixed
with PAA solution at pH 3 (20ml, 0-0.1%). The sam-
ple solution was then-incubated at 37°C for 10 days.
The total polymer concentration was fixed by dilution
with buffer solution, pH 3, at 0.05% in all samples.
After the removal of water in the sample solution by
the use of a lyophilizator (Virtis, Model Freeze Mobile
6), the interpolymer Complex formed that remained
was dried in a vacuum for 3 days at room temperature.
2.8. IR absorption spectroscopy
FT-IR spectroscopy of HPMC-PAA complexes used
a Nicolet 520 FT-IR spectrometer.
13
2.9. Preparation of the propranolol:PAA binding
interaction
Propranolol hydrochloride (4 g) was dissolved in
20 ml distilled water. PAA ( 1 g) was dissolved in 20
ml distilled water by adjusting the pH to 7.4 by stoi-
chiometric addition of 1.0 M NaOH. The PAA solution
was slowly added to the propranolol hydrochloride
solution with constant stirring at 37°C for 2 h. The
precipitate formed in the reaction was filtered off and
washed with distilled water. The product was dried at
40°C for 3 days.
2.10. Bioadhesion experiments
For this purpose, the tensile experiment reported in
the literature [10] was adapted using the Instron
(Model 4301, Instron Ltd., UK) apparatus. Cyanoac-
rylate adhesive was used to fix the tablet and the bovine
sublingual mucosa to the upper and lower metallic sup-
ports, respectively.
Bovine tongue along with tissue was collected
immediately after killing the animal, frozen at - 20°C
until use. Just before use, it was thawed to 4°C in normal
saline solution, and ~ 2 mrn thick mucosa was cut
carefully and placed on the lower support of the Instron
apparatus. During the experiment, 20 /xl of distilled
water was placed on the tablet surface and the two
surfaces (tablet and mucus) were brought in contact
with a force of 0.5 N and kept in this condition for 10
min. Then the tensile experiment was performed at a
constant extension rate of 5 mm/min.
2.11. In vivo studies
Nine healthy volunteers, five females and four males,
after the explanation of the experimental protocol,
agreed to participate in the study and written informed
consent was obtained from each patient. The age of the
subjects ranged between l 9 and 27 years ( 23 _+2 years)
and their weights between 50 and 85 kg (63 ___12 kg).
All subjects were determined to be in good health on
the basis of medical history, complete physical exam-
ination, laboratory tests, electrocardiogram and chest
roentgenogram.
14 B. Taylan et al. / Journal of Controlled Release 38 (1996) 11-20
Study design
The subjects were given each of the following infor-
mation as a single dose on three separate occasions in
an open-label three-way crossover treatment:
1. One 40-mg commercially available conventional
tablet;
2. One 160-mg formulated sustained-release tablet
containing 20% HPMC;
3. One 80-mg formulated buccal adhesive tablet was
initially coated manually on all sides except one
with the water impermeable polymer Eudragit
RSPM. The coating solution used was prepared as
follows: 12,5% dry Eudragit RSPM was dissolved
in a mixture of 60% ( w / w ) isopropyl alcohol and
40% ( w / w) acetone. The coating was dried at room
temperature. When the permeabilty of the drug from
the coating was tested it was found to be imperme-
able. These coated tablets were then placed in the
buccal sulcus, below or above the canine tooth of
each of the nine volunteers.
The administration sequence was assigned ran-
domly. Drug administration was separated by a period
of one week during which subjects did not take any
medication. Subjects were fasted for 10 h before each
drug administration and 4 h thereafter. Conventional
and sustained-release propranolol hydrochloride tab-
lets were administered with 100 ml of water.
Collection of samples
Blood samples were obtained (5 ml via an indwell-
ing heparinized scalp-vein needle) at 0, 0.25, 0.50,
0.75, 1, 2, 3, 4, 6 and 8 h and placed in citrated tubes.
Following centrifugation, the plasma were stored in the
deep-freeze until analyzed.
Plasma assay of propranolol
Propranolol concentrations in the plasma was deter-
:mined using a modified method proposed by Koshakji
and Wood [ 11 ]. Plasma samples (2 ml) obtained after
oral or buccal administration of propranolol were added
to 0.1 ml 2M NaOH, extracted with 5 ml ether. The
organic layer was separated and extracted with 3 ml
0.01 M HC1. Finally aliquots of the aqueous layer were
injected into the HPLC.
The modular HPLC consisted of Water Assoc.
Model 510 constant flow pump, a Waters Assoc. 717
autosampler and IBM Model (pc/2, 80/386) chro-
matography workstation. Samples were analyzed on a
Waters Assoc./xBondapak phenyl column (4 mm × 30
cm, 10/.~m average particle size) and propranolol was
quantitated in a Waters Assoc. Model 470 fluorescence
detector, with excitation wavelength set at 238 nm and
emission wavelength at 360 nm. The mobile phase, pH
3.5, consisted of acetonitrile:water:acetic acid:meth-
anol:triethylamine (350:700:10:400:0.05, v / v ) and
was run through the HPLC system at a rate of 2 ml/
min at room temperature. The variation coefficient of
the method varies from 5% (for plasma propranolol
level of about 4 ng m1-1) to 2.5% (for plasma pro-
pranolol level of about 20 ng m l - ~). The lower limit
of the detection is 2 ng m l -
Data analysis
Area under the plasma concentration time curve
(AUC) was calculated for zero to 8 h using the trape-
zoidal rule. The maximum plasma concentration
achieved (Cmax) and time to maximum plasma con-
centration (tin,x) were observed from the measured
plasma concentrations following drug administration.
Statistics, using ANOVA in conjuction with Duncan's
multiple range test, were performed in order to dem-
onstrate differences in the bioavailability of proprano-
lol from the various routes of administration used.
Differences were considered to be significant at a level
of p < 0.05.
3. Results and discussion
3.1. Conformation of interpolymer complex
formation
Interpolymer complex formation was confirmed
employing turbidity and viscosity measurements in
media of various pH values (pH 3.0, 4.5 and 6.0).
Fig. 1 shows the turbidity of the HPMC/PAA mixture
solution as a function of the weight ratio of HPMC and
PAA. Maximum turbidity was observed at a weight
ratio of 1:1 in the acidic medium (pH 3.0). This result
suggested that the interpolymer complex of HPMC and
 B. Taylan et aL / Journal of Controlled Release 38 (1996) 11-20 15

ABSORBANCE
The complexation between PAA and HPMC was
0'16 I
also investigated by FT-IR spectroscopy. A single peak
O.141- at 1728 c m - ~was recorded for pure PAA correspond-
ing to streching vibration of carbonyl (C = O) band.
O.12
When HPMC was mixed with PAA in 40-80% ratios
the single peak was observed to shift to lower wave-
O.1
lengths ( 1700 c m - 1) and split into two distinct peaks
0.08 ( 1676 c m - 1). This is generally explained to be due to
the presence of free and hydrogen-bonded carbonyl
0.06 groups in the system.This can be considered as a spec-
troscopic evidence of interpolymer complexation
0.04 between PAA and HPMC.
0.02_,
3.2. Characterization of propranolol/PAA complex

0 20 40 60 80 100 120 The complex was characterized by the FT-IR spec-

WEIGHT FRACTION OF HPMC (%)
pH 3 ---I-- pH 4.6 + pH 6
Fig. 1. Turbidity of the HPMC/PAA system as a function of polymer
mixing ratio in media of various pH values at 37°C (total polymer
concentration 0.02%).
PAA could be formed in the acidic medium at a weight
ratio of 1:1. No interpolymer complex formation was
observed in the higher pH region (pH 4.5 and 6.0)
since the pKa value of acrylic acid the main monomer
of PAA, was reported to be 4.25 at 25°C [12]. The
dissociation of carboxyl groups of PAA might be
important for the balance of complexation and decom-
plexation. Although the interpolymer complex could
tra. The IR spectrum of the complex in comparison
with the physical mixture (1:1) are shown in Fig. 3
which shows the appearance of a new absorption band
at 1555 c m - 1. This is considered to be the result of salt
formation: when ionization occurs, with formation of
the C O O - group, rezonance is possible between the
two C-O bonds. As a consequence, the characteristic
carbonyl absorption is replaced by the band in the 1550
c m - J region. This band corresponds to autosymmetr-
SPECIFIC VISCOSITY
10
8

be formed in the tablet owing to the acidity of PAA

independent of the pH value of the dissolution medium
in the initial dissolution stage, the acidity in the tablet 8
is expected to decrease with the penetration of the dis-
solution medium. Fig. 2 shows the viscosity of the
supernatant in the HPMC/PAA mixture solution as a 4
function of the weight ratio of HPMC and PAA in the
acidic medium (pH 3.0). When the weight fraction of
HPMC in samples was from 10 to 50%, the viscosity
2
of the supernatant in the HPMC/PAA solution was
observed to be almost the same as that of the medium.
In the case of HPMC alone, the viscosity of this solution
increased continously with increase in polymer con-
o 20 40 8o 80 lOO
centration. Therefore, the decrease in viscosity
WEIGHT FRACTION OF HPMC (%)
observed in the HPMC/PAA mixture system showed
Fig. 2. Viscosityof supernatantsolutionin the HPMC/PAAsystems
that the interpolymer complex was formed in the acidic as a functionof polymermixingratioat pH 3 and 37°C (totalpolymer
medium and was removed by centrifugation. concentration, 0.5%).
16 B. Taylan et a l. /Journal of Controlled Release 38 (1996) 11-20

fore, the adhesion force of propranolol hydrochloride

buccal adhesive tablets may be affected by the pro-
pranolol/PAA binding ratio. But the influence of
HPMC percentage, was not significant among drug
3 containing systems (p > 0.05). However, the use of
different percentages of HPMC appeared to affect the
bioadhesion force on the drug free systems. No signif-
icant differences were observed among replicate meas-
urements (p > 0.05). The results were in agreement
with several reports given in the literature [ 10,14]

3.4. In vitro release studies

Buccal adhesive tablets

Release phenomena of propranolol hydrochloride
I I I I from the tablets consisting of various mixing ratios of
207E3. 7 1828. 7 1578. 7 1328.7
W~vemumloer ( c m - - :t) HPMC and PAA were investigated considering the
Fig. 3. FT-IR spectra of the p r o p r a n o l o l / P A A complex. effect of interpolymer complex formation. To investi-
PAA:propranolol hydrochloride ratio; l, physical mixture of PAA gate more precisely the effect of interpolymer complex
and propranolol hydrochloride; 2, 1:3; 3, 1:1. formation on the release of propranolol hydrochloride
results were analysed according to the following equa-
ical vibrations of the C O 0 - structure and is used as a tion [ 15 ].
diagnosis of the C O 0 - group [ 13 ].
M,/M= = kt" ( 1)
3.3. Bioadhesion properties of HPMC-PAA tablets
where Mt/M~ is the amount of propranolol hydrochlo-
ride (%) released at time t (h), n is a diffusional expo-
Table 1 shows the adhesion force of HPMC-PAA nent and k is the apparent release rate ( % / h ) . In all
tablets to the bovine sublingual mucus at various mix- cases, the n value was between 0.47 and 0.71
ing ratios of HPMC/PAA. The results of this study (Table 2).
clearly demonstrate that the adhesion force observed at In the case of an insoluble and nonswellable polymer
a mixing ratio of 1:1 (HPMC:PAA) was less than in matrix, drug release has generally been expressed by a
tablets of other mixing ratios. Table 1 also shows that Fickian diffusion mechanism, i.e., the time dependence
the interpolymer complex formation between HPMC of the square root of time (n = 0.5). Therefore, the non-
and PAA inhibited the adhesion force of the tablet as
observed in bovine sublingual mucus. It is clear that Table 1
very thin and strong gel layer formation at the boundary Bioadhesion force (N) for buccal adhesive tablets in contact with
bovine sublingual mucus (n = 8)
might be necessary for adhesion. In this connection,
the interpolymer complex formed in the gel layer acts % HPMC Without drug (N) With drug (N)
as an inhibitor of the adhesion due to its hydrophobic- ( mean ± SD) ( mean ± SD )
ity. The results of our bioadhesive analysis with the
propranolol hydrochloride-containing tablets indicate 0 14.2±1.1
l0 8.1±0.9 4.7±0.5
that the presence of drug had a great effect on the
20 8.4±1.8 3.4±0.4
bioadhesive strength formed. According to ANOVA 30 8.5±1.1 4.4±0.7
results, there was a significant difference between the 40 6.0±0.4 3.8±0.8
mean adhesion force values of the drug free and drug 50 5.6±1.4 4.4±0.6
containing systems (p < 0.05); the decrease of ~ 20- 60 6.0±0.3 3.9±0.7
70 5.8±0.9 3.9±0.8
60% in the force of adhesion due to the presence of the
80 5.7±0.8 5.0±1.1
drug containing systems is shown in Table 1. There-
 B. Taylan et al. / Journal of Controlled Release 38 (1996) 11-20 17

Table 2 When Eq. 1 is applied during early stages of release

Kinetic constants (k), release exponents (n) and determination coef-
(fraction released, < 0.7) to the geometries other than
ficients ( r 2) following linear regression of dissolution data of buccal
adhesive and sustained release propranolol hydrochloride tablets
slabs (i.e., tablets), the value of the diffusional expo-
(n=6) nent, n, depends on the geometry of the system. In the
case of a cylinder, Fickian diffusion is defined by
Formulation n (mean + S D ) k r2 n=0.45 and Case II by n = 0 . 8 9 [ 15]. These results
showed that for formulations containing HPMC, non-
Buccal adhesive
tablets (PAA:HPMC)
Fickian diffusion mechanism predominates (n > 0.45 ),
9:1 0.60+0.03 5.10 0.904 and the release rates were not reduced by increasing
8:2 0.69 ___0.05 4.65 0.962 the polymer concentration (Table 2). Owing to slow
7:3 0.47 + 0.05 5.62 0.896 erosion of the outer gel layer of HPMC matrices, the
6:4 0.64 + 0.04 4.70 0.964
diffusional path length for the drug increased with time
5:5 0.54-t-0.06 5.62 0.984
4:6 0.59 + 0.05 5.69 0.992
and hence the release rate decreased with time.
3:7 0.48 + 0.02 7.82 0.957 The main objective was to have a release in the range
2:8 0.71 +0.08 5.55 0.999 of 35-60% by 2 h, 55-80% by 4 h and 70-95% by 8 h
1:9 0.58+0.03 9.05 0.981 for the 12-h sustained-release preparations according
Sustained-release
to USP XXII. The 20% HPMC matrix tablets gave the
tablets
20% HPMC 0.53 + 0.03 26.9 0.996
desired release and were evaluated further in vivo.
30% HPMC 0.53 + 0.04 25.1 0.985 Drugs released from conventional propranolol hydro-
40% HPMC 0.47 ___0.02 24.3 0.992 chloride tablets conforms with the requirements of USP
XXII.
Fickian release behaviour obtained here may suggest
that release of propranolol hydrochloride was con- 3.5. In vivo studies
trolled by a combination of diffusion of propranolol
hydrochloride from the matrix and three dimensional The mean plasma propranolol concentrations and a
network structure which was produced by the complex summary of kinetic parameters produced by the con-
formation following water penetration into the tablet. ventional, sustained-release and buccal adhesive tab-
Similar phenomena have been reported in the release lets, to 9 normal subjects, are presented in Table 3. The
behaviour of metronidazole from tablets consisting of AUC, Cmaxand tmaxvalues obtained for 40 mg conven-
Methocel K4M and Carbopol 934 [ 10]. tional tablets were similar in terms of extent and vari-
The buccal adhesive propranolol hydrochloride tab- ability to those reported previously [16,17]. The
lets containing PAA:HPMC ratio of 2:8 showed suit- formulated sustained-release tablets resulted in Cmax
able release and adhesive properties to the buccal values lower than those produced by the conventional
mucous membrane. The release characteristics of the tablets (p < 0.05). The AUCo_8 values for the conven-
buccal adhesive tablet reveals the possibility of sus- tional and formulated sustained-release tablets were
tained delivery of propranolol hydrochloride. In addi- 168.7+80.3 and 97.3+36.1 ng h ml -~ ( n = 9 ) ,
tion, this selected percentage of HPMC-PAA was free respectively. According to the results of the ANOVA,
of complexation between two polymers could act inde- the AUCo_8 values were significantly different
pendently and the in vivo experiments were carried out (p < 0.05 ). Estimated bioavailability value (relative to
with this formula. conventional propranolol) was 57% for formulated
sustained-release tablet. These studies have shown that
Sustained-release tablets sustained-release tablet fulfill the criteria required for
For HPMC incorporated matrix tablets, the released a sustained-release preparation, i.e., smooth plasma
amount of propranolol hydrochloride decreased as the level profile and long duration of effect. After acute
matrix concentration was increased. When 20, 30 and dosing sustained-release tablet produced peak plasma
40% of HPMC were incorporated into the formulation level which was drastically reduced and considerably
the amount of propranolol hydrochloride released, delayed as compared to conventional propranolol. The
decreased from 78 to 66 to 59%, respectively. bioavailability of the sustained-release tablet is much
18 B. Taylan et al. / Journal of Controlled Release 38 (1996) 11-20

Table 3
Mean plasma propranololconcentrationsand kinetic parameters followingthe administrationof 160-mgformulated sustainedrelease, 40-mg
commerciallyavailableconventional(Dideral®) and 80-mgbuccaladhesivetabletsof propranololhydrochloride(n = 9) ( ± standarddeviation)

Time (h) Commerciallyavailableconventional Formulatedsustained-release Buccal adhesive tablet (PAA:HPMC

tablet (Dideral~) tablet(20% HPMC) ratio 2:8)

0.25 13.0 + 0.2 - -

0.50 17.8 ___11.2 8.5 ± 2.6 -
0.75 23.8 + 18.9 12.9 + 5.5 -
1 27.7 + 19.7 23.9 + 12.4 8.3 + 2.3
1.5 30.1 + 19.9 37.4+ 18.2 10.4_+5.6
2 30.8 ___16.9 50.8 _+23.9 18.6 _+16.1
3 27.8_+ 10.2 67.2+21.1 34.4-+24.7
4 24.6 -+ 11.2 61.7 _+21.7 51.7 _+23.5
6 18.5 _+10.8 55.9 _+27.9
8 11.7_+5.6 42.7_+ 19.9
Cmax(ng/ml) 38.9--+16.1 72.2_+20.2
(18.0:1:5.1)a
tmax (h) 2.2 _+1.1 4.1 + 1.1
AUC,~8 (ng h ml -I ) 168.7+80.3 389.5_+144.3
(97.3+36.1 a
AUCo_4(ng h m1-1) 97.5_+45.2 (41.4+15.5) a (41.75:25.8) a

aValues in parentheses are corrected for the differencein dosage,

lower than that of conventional propranoloh our esti-
mated value of 57% is similar to the 50% calculated
from the data of Serlin et al. [4] and the previous
single-dose data of McAinsh et al. [ 18]. It has been
suggested that the low bioavailability of sustained-
release tablet results from a continous delivery to the
liver of smaller amounts of propranolol (from sus-
tained-release formulation), therefore cannot provide
an AUC which is similar to that produced by the inter-
mittent dumping of large boluses of propranolol from
conventional formulations. Results reported here also
demonstrate that, with the sustained-release tablet
interpatient differences in bioavailability, estimated as
coefficient of variation of AUCo_8 values, was lower
than with conventional tablet after acute administration
(37% vs 47%).
Buccal adhesive propranolol tablets produced seri-
ous irritation and caused lesions of unique severity and
duration. At the site of application propranolol caused
human buccal ulceration that took up to weeks to heal.
These mucosal irritation results observed in our inves-
tigation are in agreement with several reports given in
the literature [ 19,20]. These buccal adhesive tablets
have to be withdrawn at the end of 4 h due to the serious
irritation which followed even after the removal of the
tablets. Since blood samples were not collected after 4
h, Cmax and/max could not obtained for the buccal adhe-
sive tablets.
To our knowledge, no information has thus far been
published concerning the in vivo bioavailabilityof buc-
cal adhesive propranolol preparations in healthy sub-
jects. Measurable plasma levels of drug following
buccal administration were not obtained until 1 h after
application. The mean AUC calculated from 0 to 4 h
( A U C o ~ ) for the conventional and buccal adhesive
tablets were 97.5 + 4 5 . 2 ng h m l - ' and 41.7 + 25.8 ng
h m l - ' (n = 9), respectively (Table 3). These values
were significantly different (p < 0 . 0 5 ) . The AUCw4
values for buccal adhesive and sustained-release tablets
did not differ from one another (p > 0.05). In particular
we observed that the bioavailability of the buccal adhe-
sive tablet is much lower (our estimated value of
~ 43% calculated as the ratio between AUCo_4) than
that of conventinal propranolol. It has been suggested
that the low bioavailability of buccal adhesive tablet
results from a propranolol/PAA binding interaction.
The variability of buccal absorption was reflected by a
coefficient of variation of the AUCw4 of 61.8%. A fresh
dry, tablet placed in the buccal sulcus is associated with
a variable period of instability in location until it
becomes sufficiently dampened to stick firmly to the
mucosa. The surface area of contact between tablet and
 B. Taylan et al. / Journal of Controlled Release 38 (1996) 11-20
m u c o s a at this stage is d e p e n d e n t upon the topography
of the mucosal surface i m m e d i a t e l y adjacent to the
tablet. For these reasons, propranolol buccal absorption
s h o w e d great intersubject variation ( T a b l e 3).
4. Conclusion
A new buccal adhesive system for the release o f
propranolol h y d r o c h l o r i d e was d e v e l o p e d using
H P M C and P A A in various amounts. T h e release rate
o f propranolol hydrochloride f r o m H P M C / P A A tab-
lets was greatly affected by changes in the p o l y m e r
m i x i n g ratio, suggesting a possible interaction b e t w e e n
H P M C / P A A and p r o p r a n o l o l / P A A f o l l o w i n g water
penetration into the tablet. The n o n - F i c k i a n release
b e h a v i o u r obtained, suggest that the release o f pro-
pranolol h y d r o c h l o r i d e is controlled by a c o m b i n a t i o n
o f diffusion o f propranolol hydrochloride in the matrix
and s w e l l i n g o f the matrix f o l l o w e d by water penetra-
tion into the tablet. This n e w system s h o w e d significant
b i o a d h e s i v e characteristics in contact with b o v i n e sub-
lingual mucus, as a function o f P A A content, interpo-
l y m e r c o m p l e x f o r m a t i o n ( H P M C / P A A ) and binding
interaction b e t w e e n p r o p r a n o l o l / P A A . It is n o t e w o r t h y
that b l o o d propranolol concentrations after buccal
a d h e s i v e propranolol tablets were sufficient to induce
significant/3-adrenoceptor blockade. Administration of
buccal a d h e s i v e propranolol tablets has no significant
advantage o v e r sustained-release propranolol tablets.
M e a n w h i l e we are o f the opinion that buccal propran-
olol does not exhibit the reliable absorption character-
istics p r e v i o u s l y suggested [ 21,22 ].
Acknowledgements
The authors wish to thank Sanofi-Do~u Ilaq (Tur-
k e y ) , Seppic ( F r a n c e ) , C o l o r c o n ( U K ) , B.F. G o o d -
rich ( B e l g i u m ) and R 0 h m P h a r m a ( G e r m a n y ) .
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