COLON SPECIFIC DRUG DELIVERY FOR MEBEVERINE HYDROCHLORIDE

1
COLON SPECIFIC DRUG DELIVERY FOR MEBEVERINE
HYDROCHLORIDE
Samia Omar 1 , Basmah Al Dossary 2, Hanan Refai 3
, Omaimah Al Gohary 2 1. Department of
Pharmaceutics, Faculty of Pharmacy, Helwan
University, Cairo, Egypt
2. Department of Pharmaceutics, College of
Pharmacy, King Saud University, Riyadh, KSA 3.
Department of Pharmaceutics, Faculty of Pharmacy,
Cairo University, Cairo, Egypt
Mebeverine Hydrochloride (MB-HCl) as
an effective spasmolytic drug was formulated as a
CODESTM . The core tablet containing lactulose
and the drug in free form formula 1 (F1), or as
microspheres with 2 different polymer drug
lactulose ratios (110.5 and 210.5) formula
2 (F2) and formula (F3) respectively. The core
was coated by Eudragit? E100 which was then
coated by Eudragit? L100. The release profiles of
the coated CODESTM systems were compared with
uncoated compressed tablets. The uncoated tablet
showed a drug release of 93 after 1 hour in
simulated gastric condition (pH 1.2). The release
characteristics of the coated systems revealed
that the enteric coating prevented any drug
release in simulated gastric or duodenal
conditions in the first 3 hours (pH 1.2 - 6.1),
drug was slightly liberated in simulated
intestinal fluid (pH 7.4) phase 1 (P1). After 4
hours pH was adjusted at 7 and ß-glucose-oxidase
was added, which is an enzyme produced by
enterobacteria present in the colon. The drug
release suddenly increased to reach 95, 72 and
60.4 for F1, F2 and F3, respectively. This
result was confirmed with the I.R. spectrum
study. Where, a covalent bond with a double bond
of the polymer was formed probably with the drug
resulting in the sustained drug release from the
microspheres with a significant difference (pgt
0.01) for MB-HCl released from CODESTM and
CODESTM prepared from microspheres. This
colon-specific drug delivery technology was
confirmed by the in vivo investigation, using
X-ray images for guinea pigs, where the tablet
began to disintegrate after 10 hrs of tablet
swollen. The results of our study show that
Mebeverine Hydrochloride CODESTM colon-specific
drug delivery can act as a successful trigger for
drug release in the colon from specially coated
tablets containing microspheres.
1. Tabletting and Coating

• Tableting was performed using Tablet Press
  under a compression force of 250 kgf/cm2 using
  10 mm (diameter), round and concave punches.
• Coating was performed by a coating pan technique.
  First, the tablet cores were coated with
  acid-soluble coating material, Eudragit E100.
  followed by an enteric coating material Eudragit
  L100 with HPMC barrier in between. The film
  thickness is expressed in terms of the
  percentage total weight gain (TWG), and products
  with a TWG of 3, 6 and 10 were obtained.

2. Preparation and Characterization of
Microspheres

• Microspheres with 2 different Eudragit E100
  drug lactulose ratios ( 1 1 0.5 and ratio
  2 2 1 0.5) were prepared. Drug
  microspheres were prepared by O/W dispersion
  method using solvent evaporation technique.
• Prepared microspheres were characterized for
  average particle sizes and shape using image
  analyzer.
• The drug content was determined by an organic
  solvent extraction procedure. The amount of
  MB-HCl in the alcoholic solution was determined
  spectrophotometrically at 264 nm.
• The interaction between the drug and the polymer
  was investigated using IR spectrometry.

X-ray images of the ingested MB-HCl CODESTM to
guinea pig are illustrated in Figure 5. from the
figure, the tablet shows no disintegration in
the first (2-3 hrs). A result which correlates
with the in vitro drug release studies in
simulated gastric and duodenal fluids (fig. 5-A).
Tracer on the surface of the tablet are present
in the small intestine (7-8 hrs), indicating the
leaching of few amounts of drug as illustrated in
X-ray images (B). This results is in conformation
with conducting the in vitro drug release studies
in simulated intestinal fluids. The tablets were
found to disintegrate almost completely after
10-12 hrs, (fig. 5-C), owing to the effect of
enzymatic action of micro flora in the colon
which act on lactulose that might leach through
the acid-soluble coating layer and produce
organic acids with pH sufficient to dissolve the
Eudragit E100 coat.
Fig ( 2 ) A- (MB-HCl) Microspheres (ratio
110.5) B- (MB-HCl) Microspheres
(ratio 210.5)
IR spectroscopy was done to investigate the
interaction between drug and polymer interaction
(Fig 3). the principal IR spectral assignments of
Mebeverine hydrochloride were observed at the
same frequencies (1266, 1715 cm-1) for both
types of microspheres D, E. However,Observing the
functional group region of the IR spectrum of the
drug, polymer and microsphere, it is to be
noticed that a peak at about 2500 cm-1 in the
drug spectrum which is thought to be a (N-H)
formed probably a covalent bond with a double
bond of the polymer resulting in a disappearance
of that peak in the spectrum of the microsphere.
This would explain the sustained drug release
from the microspheres.
Figure 2 illustrates that the O/W dispersion
method for the preparation of microspheres using
solvent evaporation technique as well as the type
of solvents used yields microspheres with
spherical and uniform shape (Herrmann et al.
1998). Using image analyzer, the figure revealed
that, the size of microspheres increases from ?
4-7um to 10-12 um for microspheres with formula
FII and FIII, respectively.
3. In vitro Release Studies
Drug release studies were performed using the
rotating basket method according to USP 24 with a
rotation speed of 100 rpm. The dissolution of
drug was conducted in pH gradient dissolution
medium maintained at 37 C. A tablet was first
placed in 0.1 N HCl pH 1.2 for 2 h. (average
gastric empting time). Then, the pH was raised to
6.1 for 1 h (average duodenum transit time). The
pH was further increased to 7.4 by adding the
appropriate amount of trisodium phosphate for 2 h
(average intestinal transit time). Finally, the
pH was adjusted at 7 and ß-glucosidase was added
at a concentration of 0.1 in the last 2 hrs.
Aliquots were withdrawn and assayed
spectrophotometrically for mebeverine HCl at
264 nm.
Colon-specific drug delivery systems have
attracted a great deal of interest recently for
the local treatment of colonic disorders. The
study provide that CODESTM is one of the very
promising techniques which based on a
combination of pH and microflora michanisms for
the colon targeting of mebeverine hydrochrloride
(MB-HCl) an effective spasmolytic drug that acts
on gastrointestinal smooth muscle with selective
effect on colon. In-vitro release indicates that
the drug began to release only at pH 7 and in
presence of ß-glucosidase (simulated colonic
condition). Furthermore, microspheres containing
formulations result in a more sustained effect
with prolonged action of MB-HCl in the colon. A
condition that is more promising for drugs that
are selectively act on colon.
Figure 4 reveals that, the release of MB-HCl
from uncoated tablet was very fast, about 94 of
the drug was liberated in one hour. This
indicates that, the drug is completely released
in the stomach. For (MB-HCl) CODESTM , the tablet
didn't disintegrate or release the drug 3 h
after immersion into simulated gastric and
duodenal conditions (pH 1.2 - 6.1), owing to the
protection effect of the enteric coating. In
simulated intestinal fluid (pH 7.4) a slight
liberation of the drug was observed phase 1
(P1). At that pH the enteric coat completely
dissolve and the drug might leach through the
acid-soluble coat (Eudragit E100) which become
slightly permeable and swellable (Yang et al
2002). After 2 hours pH was adjusted at 7 and
ß-glucosidase was added. From Figure 2 it is to
be noticed that, drug was released rapidly from
CODES after a 5-h lag time to reach 95, 72 and
60.4 for FI F II and F III, respectively Phase
2. This finding is explained by the fact that,
the polysaccharide inside the core tablet
(lactulose) dissolved and diffused through the
coating and degraded by ß-glucosidase into
organic acid. This lowered the pH surrounding the
system below 5 which is sufficient to dissolve
the acid-soluble coat (Yang et al 2002).
Subsequently, the drug is target in the colon.
The significantly lower drug release percentage
of F II and F III compared to F I is due to
microencapsulation of the drug in the prepared
two formulae (Wu et al., 2003). As expected the
higher concentration of the polymer in FIII
resulted in a slower drug release as compared
with FII, this result was confirmed with the I.R.
spectrum study. where, a covalent bond with a
double bond of the polymer was formed probably
with the drug resulting in the sustained drug
release from the microspheres.
4. X-ray Animal Studies
In order to find out the in vivo performance of
the prepared MB-HCl CODESTM, Tablet containing
barium sulphate was ingested to guinea pig. An
x-ray image for the GIT was taken every 2 hrs, to
visualise the passage of the coated tablet in the
GIT of guinea pig and the location at which the
tablet begin to disintegrate and release the drug.