Material Paper - 1
Material Paper - 1
Material Paper - 1
An in vitro model for the evaluation of the adhesion of solid oral dosage forms to
the oesophagus
John D. Smart a, , Sian Dunkley b , John Tsibouklis b , Simon Young c
a
b
c
School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, BN2 4GJ, United Kingdom
School of Pharmacy and Biomedical University Sciences, University of Portsmouth, Portsmouth, United Kingdom
School of Medical Sciences, RMIT University, PO Box 71, Bundoora, Victoria 3083, Australia
a r t i c l e
i n f o
Article history:
Received 15 October 2012
Received in revised form 5 February 2013
Accepted 6 February 2013
Available online 1 March 2013
Keywords:
Oesophageal adhesion
Bioadhesion
Mucoadhesion
Non-adhesive coatings
a b s t r a c t
Adhesion of solid oral dosage forms to the oesophagus can be a disadvantage when delivering drugs that
may cause oesophageal damage, or can be an advantage when developing localised therapies for this
region. In this study, apparatus to investigate coatings that may inuence oesophageal retention was
developed and evaluated. The apparatus incorporated a section of porcine oesophageal mucosa held at
by the application of a gentle vacuum and kept moist by the application of a simulated saliva solution. The
resistance to the application of more physiologically relevant shear stresses was evaluated. Using a range
of materials it was found that differences in oesophageal adhesion could be identied. Materials like
sodium alginate were highly adhesive and had a tendency to re-adhere while parafn waxes showed no
adhesion. The rapid loss of the polymer coat from the surface for water swellable materials was identied
as an issue.
2013 Elsevier B.V. All rights reserved.
1. Introduction
The adhesion of solid formulations to the oesophagus during
swallowing has been widely implicated in medication-induced
injury to this organ. Adherence during swallowing results in a high
local drug concentration within the oesophagus, which may lead to
oesophageal damage when the drug is irritant. Formulations containing emeporonium bromide, apple cider vinegar, alendronate
sodium, tetracycline and potassium chloride are implicated in such
damage (Hill et al., 2005; Jaspersen, 2000; Ueda et al., 2011). Moreover, formulation adhesion within the oesophagus usually leads to
a delay in the onset of action of the drug, which may profoundly
affect both bioavailability and pharmacokinetics. Formulation size,
shape and surface characteristics (coating) have been identied as
factors that affect dosage-form adhesion in the oesophagus during
swallowing (Channer and Virjee, 1985; Marvola et al., 1982; Perkins
et al., 2001). However, adhesion to the oesophagus could also be
advantageous, for example in locating a formulation for the treatment of gastrooesphageal reux disease (Batchelor et al., 2002),
pain and inammation (Mako et al., 2009) or for delivering diagnostic agents (Collaud et al., 2007). The overall aim of this study is to
develop an in vitro apparatus to investigate both putative adhesive
Corresponding author. Tel.: +44 1273 642091; fax: +44 1273 6420.
E-mail addresses: [email protected], the smart [email protected]
(J.D. Smart).
0378-5173/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.02.017
200
work adhesive performance has been shown to vary between tensile and shear testing (Mortazavi and Smart, 1995). The apparatus
described will therefore use shear stresses to measure adhesive
interactions in terms of the force needed to pull a disc coated with
the test material over a attened section of oesophageal mucosa.
In this paper the development and evaluation of such a test system will be described, along with some initial studies investigating
some materials with contrasting adhesive properties.
Fresh porcine oeosophagi were obtained within 30 min of sacrice from P.C. Turner abattoir, Farnborough, Hants. A normal saline
solution was added to the tissues to prevent dehydration during
transit. On return to the laboratory the luminal mucosae were
individually dissected free from the outer musculature using the
following procedure. A longitudinal cut was made through both
layers of the musculature down one side of the oesophagus (using
round-ended dissection scissors), taking great care not to disrupt
the delicate epithelium. At the pharyngeal end of the oesophagus the epithelium was separated from the closely bound layers
of musculature using sharp-tipped dissection scissors. The musculature was subsequently discarded after being peeled away from
the underlying submucosa, in a single motion, using minimum
force. Tissue was then ash frozen in liquid nitrogen, and stored
in polythene bags frozen at 20 C until use.
Prior to each experiment, the epithelial tissues were thawed
by immersion in normal saline at an ambient temperature, for a
minimum period of 2 h. The epithelium was then cut open longitudinally down one side, unfolded and subsequently mounted into
the test apparatus exposing the luminal test surface. Once clamped
into position a vacuum (ca. 10 Torr) was applied to the tissue maintaining it in position throughout the testing procedure.
The apparatus consisted of the porcine oesophageal mucoadhesion test system described previously mounted on a platform
that could be lowered at a rate of 1 mL min1 constructed at the
University of Portsmouth (Fig. 1). The nylon cord passed through
a small wheel and attached to the base of a top-pan balance (GEC
Avery), linked to a PC computer to collect the data, and this was analysed using a standard spreadsheet programme (except program
in computers).
Epithelial tissues were mounted in the in vitro test celI and
allowed to equilibrate for ca. 30 min at a 10 angle (an angle the
was near to horizontal but did not allow saliva to pool on the tissue), with a ow of simulated saliva of 1 mL min1 . Initially, the
coated glass disc was attached to the cord descending from the
balance; the lid of the test cell chamber was lifted. Preliminary
studies revealed that the application of a 2 g weight to the uncoated
surface of the disc gave better more reproducible data. These circular weights were created using solder and ling to the appropriate
size, and tted to the coated glass discs just before the experiment
commenced.
The coated glass disc was placed on to the surface of the PTFE
launch using tweezers (roughened or coated surface downwards)
such that it would be pulled up the 10 incline. The lid of the test cell
chamber was replaced immediately. Shear force was then applied
by lowering the mobile platform at a rate of ca. 0.2 mm s1 and
simultaneously, the balance output was collected, recording the
force applied at intervals of 1 s for a period of 290 s. Once the cord
attached to the balance was fully taut, the PTFE launch was carefully
removed allowing the test disc and tissue to come into contact. The
201
Fig. 2. Force distance curve for a typical sodium alginate coated disc.
3. Results
202
Table 1
Average work done (WD) and maximum detachment force (MDF) values for all the materials and rouqhened qlass controls evaluated in the in vitro test system (n = 6).
Material
WD (J)
s.d.
MDF (mN)
s.d.
Sodium alginate
Glass control
PVA
Glass control
HPMC
Glass control
F127
Glass control
Gelatin
Glass control
PEG
Glass control
Parafn wax
Glass control
1.96 (0.09)
4154.03
666.35
625.23
628.94
1209.28
665.01
1121.57
526.20
575.25
605.51
591.50
585.49
416.44
532.32
1379.01
72.71
57.00
73.54
339.70
118.83
361.05
59.86
76.02
70.79
98.85
54.69
54.84
57.52
263.42
13.72
29.11
13.44
95.14
14.52
81.85
11.56
19.83
12.58
12.70
12.86
8.61
10.60
111.39
1 .11
8.36
2.99
43.68
2.52
37.57
1.92
7.61
2.03
1.84
2.05
1.35
1.42
1.92 (0.10)
1.73 (0.18)
1.82 (0.17)
1.89 (0.20)
1.83 (0.16)
3.5 (0.20)
dye was retained on the disc with F127, whereas none was evident for PEG, indicating that all the coating had been removed.
This observation was conrmed by drying the discs and reweighing, demonstrating that 97% of the weight of the coat was removed
for PEG, whereas for F127 82.7% (SD 24.16) was removed.
4. Discussion
The aim of this study was to develop a test system to evaluate
adhesion of solid oral dosage form coatings to oesophageal mucosa
using shear stresses. Two materials were investigated in the initial
experiments; these were the high molecular weight sodium alginate, with established bioadhesive properties (Smart, 2005), and
PEG, a relatively low molecular weight non-adhesive material. In
a typical graph, there would be an initial increase from zero in the
force measured as the tension is applied to the cord and joint. If
no adhesion occurs then the force measured will correspond to
the frictional force of pulling the disc across the mucosa as seen
in the controls. If adhesion occurs then there would be a signicant
increase in the force measured relative to the control. In the case
of sodium alginate, such adhesion of the lm-coated disc to the
mucosal surface was evident, and once broken the adhesive joint
reformed when moved down the tissue until rebroken (Fig. 2). This
is the pattern one might expect of an adhesive material, if dislodged
it will simply re-adhere at the next contact point. PEG was expected
to hydrate rapidly and form a lubricating lm between disc and
mucosa; but the graph obtained with this showed little change to
that of the disc alone (Fig. 3). This coating is being rapidly removed
in an aqueous environment and therefore the forces generate are
similar to the glass disc alone.
Fig. 4. Relative work done and maximum detachment force for a range of test
coatings (n = 6, SD bars).
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