Acta Pharm.

52 (2002) 171–179 Original research paper

Bioadhesive controlled release metronidazole

vaginal tablets*

AMAL HASSAN EL-KAMEL1** Metronidazole vaginal tablets were prepared by direct

MAGDA SAMIR SOKAR2
VIVIANE FAHIM NAGGAR2
SAFAA SALAH AL GAMAL2
1 Department of Pharmaceutics
Faculty of Pharmacy, King Saud
University, Kingdom of Saudi Arabia
2Department of Pharmaceutics
Faculty of Pharmacy, Alexandria
University, Egypt
Received February 15, 2002
Accepted July 12, 2002
compression using four single bioadhesive polymers na-
mely: sodium carboxymethylcellulose (NaCMC), methyl-
cellulose (MC), hydroxypropylmethylcellulose (HPMC)
and Carbopol 934, and HPMC/NaCMC mixture in dif-
ferent ratios. The drug-polymer ratio was 1:4. The drug
dissolution rate at pH 4.8 from single polymer tablets
followed the sequence: MC > Carbopol > NaCMC >
HPMC, while in water it was: MC > NaCMC > Carbo-
pol > HPMC. Drug dissolution rate from tablets contain-
ing NaCMC : HPMC (2:1) was an intermediate between
that from either NaCMC or HPMC tablets.
Swelling studies indicated an increase in swelling indi-
ces with time at 37 °C for both blank and medicated tab-
lets. Measurement of mucoadhesion gave the same rank
order for both medicated and blank tablets namely:
NaCMC > Carbopol > HPMC > MC. Adhesion behaviour
of tablets prepared from NaCMC : HPMC (2:1) was in-
termediate between that of NaCMC and HPMC tablets.
Generally, the presence of drug increased the adhesive-
ness of the formulation while that of the mucolytic agent
decreased it.
Keywords: bioadhesion, cellulosic polymers, Carbopol,
swelling, release study, mucolytic agent

Hydrophilic polymers that bind to mucin or epithelial surfaces are becoming valu-
able in drug delivery as they can reduce bioavailability problems resulting from a too
short residence time of the dosage form at the action or absorption site (1). These poly-
mers, by localizing the dosage form at a specific site where mucus is present, like buccal
or nasal cavity, stomach and intestine, bladder or vagina and by decreasing the release
rate of the drug, will also ensure patient compliance by reducing dose, frequency of ad-
ministration and ultimately drug-side effects (1). In this respect, monolithic matrix for-

* This paper has been presented at Alexandria Second International Conference of Pharmaceutical Sciences and
Technology, October 25–27, 2000.
** Correspondence, e-mail: amalelkamel@yahoo.com

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A. H. El-Kamel et al.: Bioadhesive controlled release metronidazole vaginal tablets, Acta Pharm. 52 (2002) 171–179.

mulations are of particular interest, since if rigid enough, their structural integrity will
not be disrupted by the swelling and hydration that normally occurs to the mucus adhe-
sive component (2).
Metronidazole is an important active substance that has been widely and success-
fully used for over 37 years in the treatment of some protozoal and anaerobic bacterial
infections. For cases that persist after oral treatment and where resistant trichomonads
are suspected, a combination of oral and topical therapy may be effective. Moreover, in
clinical circumstances where low systemic levels would be desirable, e.g. in pregnancy,
topical treatment might be indicated. On the other hand, mucoadhesive vaginal tablets
are easily used and may stay day and night, compared to other conventional forms like
vaginal creams (3). A mucoadhesive tablet of metronidazole intended for local applica-
tion in the vagina has been previously developed using Carbopol 934 and HPMC K4M
mixture (4). Bouckaert et al. (5) reported that there was no significant difference in clini-
cal efficacy after application of a single vaginal metronidazole bioadhesive tablet com-
pared to a standardized oral treatment. The bioadhesive matrix consisted of modified
starch/polyacrylic acid mixture.
In a continuing investigation, this work aims to formulate metronidazole tablets to
adhere to the vagina for an adequate time and to maintain sustained drug release by an
easy, simple, nonexpensive method.

EXPERIMENTAL

Materials
Metronidazole powder (Pharco Pharm. Ind., Egypt), sodium caboxymethylcellulose
(NaCMC), hydroxypropylmethylcellulose (HPMC) and methylcellulose (MC) (BDH
Chemicals Ltd, UK), Carbopol 934 (The BF Goodrich Company, USA) and N-acetyl-L-
cysteine (AC) (Duncan, UK) were used. All other chemicals are of analytical or pharma-
ceutical grade.

Methods
Preparation of tablets. – All powders were sieved and fractions corresponding to par-
ticle size range 100–315 mm were used for tablets preparation. Tablets containing 20%
metronidazole were prepared by direct compression of powder mixture using flat face 9
or 12 mm punch (Erweka single punch tablet machine, Germany).
In vitro release studies. – The drug release rate was determined using USP dissolu-
tion apparatus II (6) (Hanson Research Corp., USA). A tablet was glued in the center of 9
cm diameter glass disc. Dissolution medium was 650 mL of either distilled water or ci-
trate buffer pH 4.8 maintained at 37 ± 0.1 °C and stirred at 25 rpm. Sample (5 mL) was
withdrawn at suitable time intervals, compensated with fresh dissolution medium and
assayed spectrometrically (Ultrospec III, Pharmacia LKB Biochrom, UK) at 319 nm. No
interference occurred due to tablet excipients or to cyanoacrylate glue at this wave-
length. Samples were assayed in triplicate.

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 A. H. El-Kamel et al.: Bioadhesive controlled release metronidazole vaginal tablets, Acta Pharm. 52 (2002) 171–179.

Swelling study. – The swelling index for placebo and medicated tablets was deter-
mined in buffer pH 4.8 at 37 ± 0.1 °C after 0.25, 0.5, 1, 2 and 4 hours (7).
Swelling index of MC tablets could not be measured due to complete dissolution of
the tablets. Each experiment was performed in triplicate.
Bioadhesion study. – The balance method (7) was adopted to measure bioadhesion
properties with some modifications. A rabbit intestine was dissected and placed in nor-
mal saline after being washed from all food debris. The intestine was cut into 5 cm
length parts and adhered to a moving platform with cyanoacrylic glue; placebo and me-
dicated tablets were glued to different weights (1, 2, 5 and 10 g). This was followed by
taring the balance. A volume (0.1 mL) of either buffer pH 4.8 or 0.1 mol L–1 N-acetyl-
cysteine in water was slowly added by means of plastic syringe over the mucus mem-
brane. The platform was slowly raised till the tablet touched the mucosa and left in con-
tact for 15 minutes, after which the balance was retared and corresponding weights were
added on the pan. The addition stopped upon the detachment of the tablet from mu-
cosa. The equivalent adhesion force was then calculated in g cm–2. Each adhesion experi-
ment was repeated six times.

RESULTS AND DISCUSSION

Dissolution rate
Results of the release study of metronidazole in water and in buffer pH 4.8, from the
various polymeric matrices containing a single polymer, are shown in Fig. 1.
In general, the release rate was higher in water than in buffer pH 4.8, except for tab-
lets containing MC. Based on dissolution efficiency calculated for all formulations after
7 h (DE, %), the release rank order in water was as follows: MC (63.5%) > NaCMC
(45.4%) > Carbopol (37.8%) > HPMC (18.6%), while in buffer pH 4.8 it was: MC (78.8%)
> Carbopol (34.1%) > NaCMC (27.8%) > HPMC (19.7%). Concerning the nonionic poly-

a) b)
100 100

80 80
Drug released (%)

Drug released (%)

60 60

40 40

20 20

0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (h) Time (h)
Fig. 1. Metronidazole release profile from different tablet formulations containing single polymer
in: a) distilled water b) buffer pH 4.8. HPMC (D), NaCMC (£), MC (×) and Carbopol (¯). Error
bars represent SD (n = 3).

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A. H. El-Kamel et al.: Bioadhesive controlled release metronidazole vaginal tablets, Acta Pharm. 52 (2002) 171–179.

mer, methylcellulose, the release pattern in both media studied was high. This may be
due to the inability of the polymer to surround the drug particles under the compression
conditions used. In water, nearly 40% release of the drug was observed in the first 2
hours (Fig. 1a). Methylcellulose hydrates on contact with water forming a gel layer at
the surface of the tablet, causing the tablet to expand. It has been observed that the gel-
lified layer formed after hydration of this polymer does not adhere well to the tablet but
is detached rapidly even with a moderate agitation (8). This is followed by the formation
of fresh surface and subsequent removal of gel barrier. On the other hand, in acidic me-
dium, owing to some protonation of ether linkages, a decrease in tortuosity of the hy-
drated film leads to a more rapid drug release than in water (9).
The lowest drug release rate was obtained with HPMC in both media. HPMC
builds up, after its dissolution, an excessively viscous gel around the tablet. This is more
resistant to water penetration and erosion. Dissolved drug is released by diffusion
through the viscous gel. Since the erosion rate of the swollen gel is slow compared with
the rate of advance of the swelling front into the glassy tablet core, the diffusional path-
length for the drug might increase with time, thus causing the release rate to decrease
(10).
Being a polyelectrolyte, NaCMC is very sensitive to the presence of ions. It has been
reported that NaCMC network structure is looser in distilled water than in presence of
salts. Also, at pH 4.8 ionization of carboxylic group of NaCMC decreases – pKa @ 3 (8).
This affects polymer chain conformation and polymer network structure becomes tight-
er. Therefore, the release rate in buffer pH 4.8 is expected to be slower than in water.
Since the aim of the work is to obtain adequate release of the drug, it is thought to
prepare formulae containing mixture of NaCMC (fast drug release) and HPMC (slow
drug release) in different ratios. Taking DE % as a parameter, the following sequence
was observed in water for NaCMC to HPMC ratios: 4:1 (38.1%) ³ 2:1 (38.2%) > 1:1 (23.4%),
whereas in buffer pH 4.8, the sequence was: 1:1 (29.4%) > 2:1 (27.5%) > 4:1 (20.3%).
It has been reported that there is interaction between NaCMC and HPMC due to
formation of hydrogen bond that will hinder the swelling of CMC (11). Also, the relax-
ation of NaCMC chain will be restricted in presence of another polymer (HPMC). This
will decrease erosion of NaCMC and at the same time prevent the increase in the dif-
fusional pathlength of HPMC. Intermediate drug release between either HPMC or
NaCMC-metronidazole tablets, was observed from the matrix containing 2:1 NaCMC
and HPMC in both media.
Drug release from Carbopol 934 was higher at pH 4.8 than that from NaCMC ma-
trix (Fig. 1b). At pH 4.8 Carbopol will be less ionized than NaCMC. So, the opportunity
of formation of hydrogen bond with the drug will be less than in case of NaCMC, lead-
ing to higher release of the former. Conversely, in water drug release from Carbopol was
lower than that from NaCMC (Fig. 1a). It was reported for Carbopol that there are acid
weakening inductive effects of ionized carboxylate residues that affect the ionization po-
tential of neighbouring groups (12). This may lead to high coiling and proximity of
carboxylic groups leading to intramolecular hydrogen bonding. The cross linking of
Carbopol affects also elasticity of the chains as water penetrates inside the polymer net-
work and this leads to entrapment of the drug inside the cross linked network of the
polymer (12).

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A. H. El-Kamel et al.: Bioadhesive controlled release metronidazole vaginal tablets, Acta Pharm. 52 (2002) 171–179.

The mode of drug release from the prepared tablets was calculated using the fol-
lowing equation: Mt/M¥ = k tn (13), where Mt/M¥ is the fraction of the solute release
into dissolution medium, k is a constant which is related to the properties of the polymer
and drug, n is the diffusional exponent. The values of n for all the formulations tested in
both dissolution media were calculated (Table I). In general, the release behavior was
non-Fickian with values of n varying from 0.633 to 0.984 for buffer pH 4.8, while they
ranged from 0.665 to 0.868 in case of water. Values of 0.5 < n < 1.0 indicate an anomalous
(non-Fickian or coupled diffusion-relaxation) drug release (13). Correlation coefficients
calculated according to zero-order or Higuchi square root of time equation, indicated
that the in general release approximated more probably the zero-order than the Higuchi
model.

Table I. Estimated values of k and n obtained by regression of log Mt/M¥ vs. log ta,b

n k
Formula
Buffer pH 4.8 Water Buffer pH 4.8 Water
CP934 0.702 ± 0.017 0.810 ± 0.020 0.733 ± 0.005 0.365 ± 0.030
NaCMC 0.714 ± 0.015 0.840 ± 0.008 0.530 ± 0.040 0.270 ± 0.008
HPMC 0.633 ± 0.015 0.665 ± 0.010 0.783 ±0.015 0.590 ± 0.090
MC 0.984 ± 0.030 0.832 ± 0.020 0.935 ± 0.080 0.609 ± 0.039
NaCMC : HPMC (1:1) 0.738 ± 0.020 0.792 ± 0.015 0.494 ± 0.020 0.251 ± 0.010
NaCMC : HPMC (2:1) 0.707 ± 0.018 0.868 ± 0.025 0.550 ± 0.010 0.267 ± 0.010
NaCMC : HPMC (4:1) 0.725 ± 0.015 0.846 ± 0.030 0.352 ± 0.008 0.208 ± 0.010
a From the relation: Mt/M¥ = k tn
(ref. 13).
b Results are expressed as mean ± SD (n = 3).

Swelling and adhesion

The rank order of swelling index of medicated tablets at 37 °C in buffer pH 4.8 was
as follows: Carbopol 934 > NaCMC > HPMC. Generally, the swelling index of placebo
tablets was higher than that of the medicated ones except in case of Carbopol. It has
been reported that the presence of drug affects the property of the matrix (14). The incor-
porated drug decreased the swelling index of HPMC and NaCMC tablets at 37 °C. Me-
tronidazole has slight solubility at pH 4.8 (15) and it replaced part of the hydrophilic
polymer matrix and decreased the wettability of the surface and hence water penetra-
tion within the matrix (14). Conversely, the swelling index of Carbopol matrix increased
in presence of drug. Since the space available for the drug is restricted due to cross link-
ing network, the presence of the drug along the polymer chains will cause their relax-
ation with subsequent allowance of water entrance. Water causes ionization of carbo-
xylic groups of NaCMC and Carbopol with subsequent repulsion and relaxation of the
polymer chains that result in increase in water penetration and hence increase in swell-
ing index by time.
The rate of water uptake at 37 °C in the case of placebo and medicated HPMC tab-
lets decreased with time. This could be due to the development of viscous gel layer

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 A. H. El-Kamel et al.: Bioadhesive controlled release metronidazole vaginal tablets, Acta Pharm. 52 (2002) 171–179.

which was formed soon as the polymer swelled and opposed the fluid entrance via blo-
cking the existing pores (16). In the case of tablets prepared from mixtures of NaCMC
and HPMC there was no significant difference in swelling index neither between the
prepared mixture formulations nor between the mixture formulations and each polymer
alone.
Modified balance method was used to measure the bioadhesion of the prepared for-
mulae (7). The obtained rank order for the bioadhesive force measured at room tempera-
ture was as follows: NaCMC > Carbopol > HPMC > MC for both medicated and placebo
tablets. Generally, the adhesion force was directly proportional to the applied weight
(Fig. 2). This could be due to establishment of an intimate contact between the muco-
adhesive polymer and the mucus gel (17). Sodium carboxymethylcellulose can increase
surface charge density of the tablet. Moreover, the carboxylic group can form hydrogen
bonds with tissue. In addition, NaCMC tablet has initial faster hydration rate that pro-
motes interpenetration of the polymer chain with the tissue (18). All these factors have
no doubt contributed to higher bioadhesive strength of NaCMC tablets. Carbopol being
mostly unionized at pH 4.8 and containing numerous proton-donating carboxylic groups,
can form hydrogen bonds with the negatively charged mucus gel following the forma-
tion of physical entanglements (19). Mortazavi and Smart (20) have reported the forma-
tion of intermolecular complexes between the glycoprotein and Carbopol 934 molecules.
It has been reported that even the ionized part of Carbopol has bioadhesion force. Ion-
ization of Carbopol results in diminishing the intramolecular hydrogen bonds and gen-
erates a stretched cylindrical shape, which is then more able to penetrate a mucin net-
work than the coil form of unionized Carbopol (21). The adhesion force of HPMC was
found to be less than that of NaCMC and Carbopol. This could be due to formation of
thick and viscous-swollen gel. This gel is not continuous, forming localized pockets of
polymer (22).

100

80
Adhesion force (g cm–2)

60

40

20
Fig. 2. Adhesion force measured for
medicated tablets containing single
0 polymer: HPMC (¯), NaCMC (£),
0 2 4 6 8 10 12 MC (D) and Carbopol (×). Error bars
Applied mass (g) rapresent SD (n = 6).

Methylcellulose tablets exhibited the least adhesion force. This may be due to dis-
ruption of structural integrity of the matrix (2). The results of measurement of adhesion
force are in agreement with those of Ch’ng et al. (23) and Rao and Buri (24), who re-

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A. H. El-Kamel et al.: Bioadhesive controlled release metronidazole vaginal tablets, Acta Pharm. 52 (2002) 171–179.

ported that the polyanions like Carbopol 934 and NaCMC adhere strongly to the mucus
compared to the nonionic polymers like MC and HPMC. Generally, the adhesion force
of medicated tablets was higher than that of placebo ones. This may be due to possible
formation of hydrogen bond between drug and mucus. Fig. 3 showed the adhesion force
measured for tablets prepared from HPMC and NaCMC either alone or in mixture of
different ratios and at applied weight of one gram. The adhesion force increased with in-
crease of NaCMC content. The formulation which contains NaCMC : HPMC 2:1 showed
reasonable adhesion properties relative to that of NaCMC tablets while it is much supe-
rior to that of HPMC tablets.

12

10
Adhesion force (g cm )
–2

Fig. 3. Adhesion force measured

2
for medicated tablets containing
HPMC or NaCMC separately or
0
in a mixture. Error bars represent HPMC NaCMC NaCMC:HPMC NaCMC:HPMC NaCMC:HPMC
SD (n = 6). (1:1) (2:1) (4:1)

N-acetyl-L-cysteine (AC) is a mucolytic agent known to alter the conformation of

mucoproteins by exchanging its sulfhydryl group with disulphide bonds of mucus (25).
Due to this, generally, all the polymer tablets (single or mixed polymers) adhered to mu-
cus to much less extent in presence of AC. However, at low applied weight (1 or 2 g)
HPMC adhered better in the presence of AC (Table II). This may be due to high affinity
of HPMC to epithelial cell surface compared to that of the mucus (24).

Table II. Adhesion force of medicated HPMC tablets in the presence and in the absence of
N-acetylcysteine (AC)

Adhesion force (g cm–2)a

Applied mass (g)
without AC with AC
1 7.2 ± 0 .9 9.6 ± 0.6
2 6.4 ± 0.7 10.8 ± 0.8
5 16.0 ± 1.2 11.2 ± 1.0
10 34.8 ± 2.8 19.2 ± 1.5
a Results are expressed as mean ± SD (n = 6).

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A. H. El-Kamel et al.: Bioadhesive controlled release metronidazole vaginal tablets, Acta Pharm. 52 (2002) 171–179.

CONCLUSIONS

In conclusion, metronidazole vaginal tablets formed of Carbopol 934 or of mixture

of NaCMC with HPMC in a ratio of 2:1 gave a suitable release rate that was more or less
constant all over the period of the study. These polymers are safe and inexpensive and
can be compressed directly without the need of any additional excipients. Moreover, the
formed matrices have reasonable swelling and good bioadhesive property thus enhanc-
ing patients’ compliance.

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S A @ E TA K

Bioadhezivne vaginalne tablete metronidazola s kontroliranim osloba|anjem

AMAL HASSAN EL-KAMEL, MAGDA SAMIR SOKAR, VIVIANE FAHIM NAGGAR i SAFAA SALAH AL-GAMAL

Vaginalne tablete metronidazola pripravljene su metodom kompresije pomo}u slje-

de}ih bioadhezivnih polimera: natrijeve karboksimetilceluloze (NaCMC), metilceluloze
(MC), hidroksipropilmetilceluloze (HPMC) i Carbopola 934. Pripravljene su i tablete
metronidazola sa razli~itim omjerima HPMC i NaCMC, uz omjer lijeka i polimera 1:4.
Osloba|anje lijeka iz tableta pra}eno je u puferskoj otopini pH 4,8 i destiliranoj vodi. Pri
pH 4,8 osloba|anje je slijedilo niz: MC > Carbopol > NaCMC > HPMC, a u vodi: MC >
NaCMC > Carbopol > HPMC. Brzina osloba|anja iz tableta s omjerom NaCMC : HPMC
2:1 bilo je izme|u vrijednosti dobivenih iz tableta sa samim NaCMC ili HPMC polime-
rom. Bubrenje tableta sa ili bez ljekovite tvari (pri 37 °C) pove}avalo se s vremenom.
Mukoadhezivnost tableta sa ili bez ljekovite tvari opadala je na sljede}i na~in: NaCMC >
Carbopol > HPMC > MC. Adhezivnost tableta metronidazola pripravljenih iz NaCMC :
HPMC 2:1 bila je izme|u adhezivnosti NaCMC i HPMC tableta. Op}enito, prisutnost
ljekovite tvari pove}ala je, a prisutnost mukolitika smanjivala je adhezivnost pripravka.

Klju~ne rije~i: bioadhezija, celulozni polimeri, Carbopol, bubrenje, osloba|anje, mukolitik

Department of Pharmaceutics, Faculty of Pharmacy, King Saud University

Kingdom of Saudi Arabia

Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt

179