Download Document

Impact of Film Properties and Drug Physicochemical Properties on Diffusion
TM
through a Poly (Vinyl Alcohol) Film for the Development of GIRES
Caroline Blackshields, PhD1, Catherine McHugh, MSc2, Thomas Leonard, PhD3, Alan Cullen, MSc2 , Kieran Madigan, BSc2, Patricia
Duffy, MSc2 and Abina Crean, PhD1
1Pharmaceutics,
School of Pharmacy, University College Cork, Cork, Republic of Ireland
2Merrion Pharmaceuticals, 3rd Floor, Biotechnology Building, Trinity College Dublin, Dublin 2, Republic of Ireland
3Merrion Pharmaceuticals, LLC, 219 Racine Drive, Suite D, Wilmington, NC 28403-8702, United States of America
[email protected]
RESULTS AND DISCUSSION
INTRODUCTION
1. A tablet which generates CO2 in a controlled manner in
the stomach medium, Figure 1.
2. The CO2 gas is trapped within
the pouch causing it to expand
in volume and decrease in
density.
% CO2 Produced
Figure 1
Tailored for fast gas generation
Tailored for slow gas generation
100
90
80
70
60
50
40
30
20
10
0
Diffusion media was 0.1 N HCl.
A concentration of 0.5 mg/ml
drug was used in each case.
The results illustrated that the
diffusion of drugs through the
film could be reduced by
increasing the film thickness,
Figure 4. The results also
illustrated
the
impact
of
molecular weight on diffusion.
1. The acidic gastric media which
ingresses into the pouch
interacts with the bicarbonate
tablet to generate gaseous
CO2.
The GIRES™ drug delivery system consists of the following
elements:
10
20
30
40
50
60
Time (minutes)
70
80
90
100
2. A semi-permeable polymeric pouch swells as gas is
generated (Figure 2, Figure 3).
Figure 4
0.16
Film A
Film B
Film C
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
Benzoic Acid
Caffeine
Baclofen
Model Drug
Acylcovir
Quinine
2. Impact of Concentration Gradient on Diffusion
3. The pouch floats and is too
large to be expelled through
the pylorus.
0
1. Impact of Film Properties on Diffusion
The concentration gradient is
the driving force for diffusion of
a
compound
across
a
membrane.
The
rate
of
transport of a model compound
(caffeine) across the film
increases with respect to donor
vessel concentration, Figure 5.
4. The gas present in the pouch
gradually dissolves into the
liquid medium causing the
pouch to deflate and reduce in
size until it is eventually
eliminated.
Figure 5
0.7
Diffusion Rate ( m mol/min)
The GIRES™ system is a novel gastroretentive drug
delivery technology. Gastroretentive drug delivery is
particularly attractive for drug molecules that act locally in
the stomach or with a narrow absorption window in the
upper GI tract.
Diffusion Rate ( m mol/min)
Schematic of GIRESTM in-vivo
y = 0.0394x + 0.0311
R2 = 0.9877
0.6
0.5
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
Concentration (mg/ml)
Figure 2
Figure 3
Both the size and density of the swollen pouch enable it to be
retained in the stomach for prolonged periods of time. The
GIRESTM technology has demonstrated a gastric retention time
of 16 to 24 hours in-vivo [1] as illustrated in Figure 2. A
swollen GIRESTM pouch is illustrated in Figure 3.
3. Impact of Molecular Weight on Diffusion
The drug incorporated into the GIRES™ pouch is released from the formulation by diffusion through the film. In order to gain a
better understanding of the impact of drug physicochemical properties on its release from the GIRESTM system a number of
compounds with diverse physicochemical properties were screened for diffusion through PVA film. The pouch in the GIRES™
system is commonly composed of PVA.
Figure 6
0.2
0.18
Diffusion Rate ( m mol/min)
OBJECTIVES
All model compounds were
present in the donor cell at an
available concentration of 2
mg/ml in deionised water.
There was no direct correlation
observed,
implying
that
diffusion is affected by other
physicochemical properties of
the compounds, such as
aqueous solubility, molecular
volume and ionisation state,
Figure 6.
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
0
100
200
300
400
500
600
700
800
Molecular Weight (g/mol)
Physicochemical properties investigated included molecular weight, aqueous solubility and ionisation state. The impact of film
thickness on model compound diffusion was also studied.
EXPERIMENTAL METHODS
PVA film was manufactured to a specified thickness,
Table 1.
Table 1
Film
Thickness (mm)
A
84
B
106
C
122
The rate of transport was determined from the slope of
the best fit linear regression line. The model drugs and
their respective physicochemical properties investigated
in this study are shown in Table 2.
Diffusion studies were carried out at 37oC using side
by side jacketed diffusion vessels (Prism Research
Glass, North Carolina), with an internal volume of
250 ml, Figure 3. Diffusion media were deionised
water or 0.1 N HCl, where specified. A known
concentration of drug was added to the donor vessel.
Samples were periodically removed from the
receiving vessel and assayed for drug concentration.
Figure 3
Table 2
Model Drug
MW
(g/mol)
Aqueous Solubility
(mg/ml)
Benzoic Acid (C7H6O2)
122.1
3.4 [2]
Theophylline (C20H24N2O2)
180.2
8.3 [2]
Caffeine (C8H10N4O2)
194.2
22 [2]
Baclofen (C10H12ClNO2)
213.6
4.3 [2]
Acyclovir (C5H11N5O3)
225.21
2.5 [3]
Levobupivacaine Base (C18H22N2O)
288
pH Dependant [4,5]
Quinine (C20H24N2O2)
324.4
0.5 [2]
Quinidine (C20H24N2O2)
324.4
0.5 [2]
Furosemide (C12H11ClN2O5S)
330
0.018 [6]
Hydroflumethiazide (C8H8F3N3O4S2)
331.3
0.300 [2]
Trihydroxyethyl Rutin (C33H42O19)
742.68
Soluble*
DONATING
CHAMBER
RECEIVING
CHAMBER
4. Impact of Solubility on Diffusion
To investigate a molecule with
constant molecular weight and
variable solubility, the diffusion
of Levobupivacaine base, a
weakly basic (pKa = 8.03)
compound [4, 5] was studied in
different pH media, Table 3.
The
ionised
form
of
levobupivacaine
showed
enhanced diffusion due to
increased solubility at pH 1.2
and pH 4.0. The rate of
diffusion at these pHs were not
significantly different (P > 0.05).
No diffusion was observed at
pH 7.4 where solubility is at a
minimum. However if the film
and the diffusant are ionised,
interactions may occur that
may hinder or assist in the
diffusion which may influence
these results .
Table 3
pH
Amount in Solution (DC)
(mg/ml)
Diffusion Rate
(mmol/min)
1.2
2.0
0.041± 0.0032
4.0
2.0
0.027 ± 0.05
7.4
n/d
n/a
5. Statistical Analysis
Analysis of the data with a general regression
model indicated that both the molecular weight and
the solubility of the model compounds had a
statistically significant (P < 0.05) impact on the rate
of diffusion through the films. The thickness, in the
range studied, was not seen to be significant.
However, diffusion rates of individual molecules
between thin and thick films studied were
significant.
CONCLUSION
It is apparent that the diffusion of a compound through the PVA membrane is not dependant
on any one factor but on a combination of factors. The influence of molecular weight,
concentration gradient, aqueous solubility and film thickness on drug transport across the
PVA films has been demonstrated in this study. These results highlight the potential to modify
the rate of drug release from the GIRESTM system by altering these parameters and the
ability to tailor the system to achieve the desired release profile for individual drugs.
REFERENCES
1. Wilson, A.M., Ramtoola, Z., O. Conaghey, O., McGoldrick, C. A., Hou, S.Y., Cumming, K.I. (2002)
AAPS PharmSci, 4, S1, 1045
2. Rytting, E, Lentz, K.A., Chen, X-Q, Qian F., Venkatesh, S. (2005) The AAPS Journal, 7, (1), Article 10
3. http://us.gsk.com/products/assets/us_zovirax.pdf
4. Wilson, T.D. (1990) Analytical Profiles of Drug Substances, 19, 59 - 94
5. Shah, J.C. and Maniar, M. (1993) Journal of Controlled Release, 23, 261- 270
6. Shin, S-C. and Kim, J.(2003) International Journal of Pharmaceutics, 251, 79-84
* Technical Information.
The authors wish to acknowledge Enterprise Ireland for their funding of this project as part of the Innovative Partnership Initiative