- Email: [email protected]
In vivo evaluation of a novel gastric retentive formulation based on ion exchange resins
journal of
ELSEVIER
Journal of Controlled Release 42 (1996) 105-113
controlled release
In vivo evaluation of a novel gastric retentive formulation based on ion exchange resins F. A t y a b l
•a S
" , H.L. Sharma
a
, H.A.H.
Mohammad
b, J.T. F e l l b
aDepartment of Medical Biophysics, University of Manchester, Manchester M13 9PL, UK bDepartment of Pharmacy, University of Manchester, Manchester M13 9PL, UK
Received 11 May 1995; accepted 8 January 1996
Abstract Systems that exhibit gastric retention are of value in several areas of therapy. A novel floating system based on ion exchange resins has been investigated and evaluated in vivo. The method relies on ion exchange resins loaded with bicarbonate, which, on contact with media containing hydrochloric acid, release carbon dioxide causing the resin to float. Extension of the floating time is achieved by coating the bicarbonate loaded resin particles with a semipermeable membrane. Two resins were investigated and both exhibited in vitro floating times of over 24 h using a standardised procedure. Studies in human volunteers were carried out using gamma scintigraphy. The coated resins were compared to an uncoated control in subjects receiving a light breakfast. The coated resin based on Dowex 2X 10 showed significantly prolonged residence times (P < 0.002) over the non-coated control when compared at 60 and 150 min using a modified gastric emptying index. Keywords: Gastric emptying; Floating system; Ion exchange resins; Coating
1. Introduction Studies on the gastric emptying of solid pharmaceuticals have revealed the highly variable nature o f the process [1]. Although delays in gastric emptying can occur, particularly after food, or if the dosage form is administered immediately after Phase III of the Migrating Motor Complex [2], in many cases gastric emptying can be rapid. This latter case has led workers to investigate the possibility o f designing dosage forms with gastric retentive behaviour. Such a dosage form is attractive in that it theoretically permits control over the time and site of drug release. This would be particularly valuable for drugs :g
Corresponding author.
exhibiting an absorption window in the small intestine or drugs such as weak bases which dissolve better in the acid environment of the stomach. In addition the devices may be useful for local treatment of the stomach or, if formulated in a particular manner, prevention or damage limitation of gastrooesophageal reflux. The systems investigated range from complex devices which remain in the stomach due to their size [3] to relatively simpler systems such as bioadhesive agents [4], t h e use of passage delaying food excipients [5] and floating devices [6,7]. The system reported here is prepared from ion exchange resin beads. The beads are loaded with bicarbonate, which, on contact with hydrochloric acid, release carbon dioxide which is trapped within
0168-3659/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PII S01 68-3659(96)01344-2
106
F. Atyabi et al. / Journal of Controlled Release 42 (1996)105-113
a semipermeable membrane surrounding the beads. This causes them to float. This paper reports the results of a gamma scintigraphic investigation into the in vivo behaviour of the resin beads.
2. Materials and methods
2.1. Materials Two types of ion exchange were used in this study. The method of preparation was similar for both. Amberlite IRA-400 (BDH Ltd., UK) (14-50 mesh) resin beads were fractionated by sieving and the fraction 355-500 /xm was retained. Dowex 2X 10 resin beads (Fluka, UK) (50-100 mesh) were passed through a 250 /xm sieve and the fraction retained on the sieve collected. The mean particle size of these fractions was determined by optical microscopy to be 4 0 0 / z m for IRA-400 and 279/zm for Dowex 2×10. This range of particle size is judged to be comparable with sustained release drug beads found in many formulations. The ion exchange resins were loaded with bicarbonate by mixing the resin beads with 1 M NaHCO 3 solution for 15 min, decanting, and then mixing for a further 15 min with a fresh solution. The beads were then filtered, washed with deionised water, and dried overnight at 40°C.
2.2. Uptake of sodium pertechnetate the ion exchange resins
(99mTc)by
A sample of 0.5 g ion exchange resin loaded with bicarbonate was soaked in deionized water for 15 min. An aliquot of sodium pertechnetate in saline (40 MBq) was then added. The suspension was stirred at room temperature and, at predetermined time intervals, samples were withdrawn using a pipette with a glass filter tip. The samples were counted in an autogamma counter to determine the remaining unbound pertechnetate.
2.3. Labelling and coating The bicarbonate loaded ion exchange resin beads were labelled as follows. Resin beads (1.5 g) were placed in a test tube and soaked in deionised water
for 15 min. A small amount of sodium pertechnetate solution in a sterile vial obtained from a technetium generator was added to the tube. The amount was calculated to give 4 MBq of activity at the time of administration. The resin suspension was mixed intermittently for -~5 min using a vortex mixer. The suspension was then left to settle. The supernatant was removed and the labelled resin beads were recovered by filtration on a filter paper followed by washing thoroughly with deionised water. The resin beads were allowed to dry in air for 20 min. The slightly damp resin beads were coated with Eudragit RS using a coacervation phase separation technique to give a final weight increase of 9%. Eudragit RS (0.1 g) was dissolved in 10 g of a 3% w/v solution of polyisobutylene in methylene chloride/n-hexane (60/40 v/v). One g of damp resin beads were added to this and 15 ml of n-hexane was dropped in at 1 ml/min with continuous stirring to form the coating. Fifty ml of n-hexane was then added to harden the coating, the beads were removed, washed 3 times with nhexane, dried at 40°C for 12 h and stored in a desiccator until required. The final procedures removed remaining polyisobutylene and solvents.
2.4. Stability of 99mTClabelled resins Stability tests were carried out to confirm that the radiolabel remained bound to the resin for the duration of the study. Tests were carried out using appropriate standard buffer solutions at pH 1.2, 5.8 and 7.5. One g 99mTclabelled resin beads were placed in test tubes with 5 ml of the buffer in a water bath maintained at 37°C. Three tubes were used for each measurement and the data obtained from the average of the 3 samples. The mixtures were stirred and 0.2 ml samples were taken at predetermined time intervals using a pipette with a glass wool filter tip. The radioactivity in the samples was counted in an autogamma. The activity counted was corrected for decay and the data was expressed as a percentage of the original activity. At the end of the experiment the supernatant was removed and the resins were washed, dried and measured for activity. The activity remaining associated with the resin beads corrected
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
110 100
9O 80 70 60 o
=~
50 40 3O 20 10
0
T 0
'
I 1
,
I
,
2
I 3
,
I 4
,
I 5
,
I 6
Time (h)
Fig. 1. Uptake of pertechnetate ions by the ion exchange resins.
for decay, was expressed as a percentage of the initial activity. 2.5. G a m m a s c i n t i g r a p h y
The in vivo behaviour of the coated and uncoated resin beads was monitored using a single channel analysing study in 12 healthy volunteers of mean age 34 years (range 22-49). None of them had symptoms or a past history of GI disease, or were taking any medication. All had given their informed consent to participate in the study. The study was approved by the University of Manchester Committee on the Ethical Research on Human Beings and the administration of radioisotopes to human volunteers was subject to an A R S A C licence from the Department of Health. Coadministration of a radiolabelled meal with the formulation enabled delineation of the GI anatomy and the subsequent position of the formulation to be identified. The test meal was a light breakfast
107
consisting of 200 ml milk, 40 g cornflakes and 6 g sugar. A small amount of 99mTc-DTPAsolution was added to the test meal to give an activity of 1.5 MBq at the time of administration. To standardise conditions of GI motility, the subjects were required to fast for 12 h prior to the commencement of each experiment. Each of the two forms (one coated and one uncoated as a control) was administered in 1 g quantities in size 0 hard gelatin capsules to each subject on two separate occasions and in a randomised fashion. Adequate time (at least 1 week) was allowed to elapse between experiments. After an overnight fast, on the morning of the study, the subjects were allowed to eat the radiolabelled breakfast. Subsequently, the capsules were swallowed together with 200 ml water. This volume was considered sufficient to prevent sticking in the oesophagus and together with the breakfast, to allow floating to occur. The position of the formulation in the stomach was followed by asking the subject to stand in front of a gamma camera (Ohio Nuclear Sigma, 410 camera). The gamma camera had a 40 cm field of view and was fitted with a medium energy parallel hole collimator. The 140 keV gamma rays emitted by 99mTC were imaged. The images were recorded on a magnetic disk. Three external marks containing less than 1 MBq 99mTc sodium pertechnetate were attached to the skin (with lead shielding facing the body), one overlying the liver to the right of the stomach and two on either side of the lower abdomen. These markers were used as reference points during the image analysis. Anterior images of 120 s duration were recorded. The subjects were imaged for the first 60 min continuously. For the rest of the experiment, 10 min images were taken at 30 min intervals. Between the images, the subjects were permitted to walk and carry out normal activities but they were not allowed to take any food or drink until the formulation had left the stomach completely. The images were recorded using an on line computer system (Maps 2000, Link System, UK), and stored on magnetic disc for analysis. Each image displayed on the monitor screen was analyzed for radioactivity remaining in the stomach by creating two regions of interest, one around the upper half of the stomach and the second around the
108
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
lower half. An additional region of interest was created around the whole stomach from the images t a k e n before administration of the formulation, to assess background activity. The counts from the regions of interest were corrected for background and decay. The values subsequently calculated represented the percentage of the total radioactivity administered and these were plotted against time for each individual and for each preparation.
3. Results and discussion
3.1. Uptake o f sodium pertechnetate by ion exchange resins
Fig. 1 shows the uptake of pertechnetate anions by Amberlite ion exchange resin (IRA-410) and Dowex 2×10 resins at different times. Almost complete uptake (99%) was achieved and over 80%
of the free pertechnetate anions were bound to the resin in 2 min.
3.2. Stability o f
99mTClabelled
resins
The stability of 99mTC labelled IRA-410 and Dowex 2X10 resins was tested in simulated gastric and intestinal fluids. Fig. 2 and Fig. 3 show the 99mTC release from IRA-410 and Dowex 2X10 at different pH values respectively. No significant release of 99mTCoccurred at any pH after 3 h. 99mTC IRA-410 lost less than 1% of its activity in simulated gastric fluid in 3 h, about 2.5% in pH 5.8 and 2% in simulated intestinal fluid (Fig. 2). 99mTC labelled Dowex 2×10 lost less than 1% of its activity in solutions of different pH.
3_
~-pH1.5 mpH5.8 -~pH7.5
1.20 1.10
-~-pH1.5 -t-pH5.8
1.00
/
/
-o-pH7.5 2H
0.90
/
-g
/
e/J ¢¢1
0.80
m ¢D
"~ 0.70 ¢o ®
/
0.60 ¢3
~
o.so
<
0,40 0.30 0.20 0.10 I --~ I
0.00
'
I
1
'
I
2
'
I
3
'
I
0
1
4
Time (h) Fig. 2. Release of 99mTC from IRA-410 at different pH values.
I
I
2
I----~
3
Time (h) Fig. 3. Release of values.
99mTC
from Dowex 2X10 at different pH
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
3.3. In vivo studies
109
110
The percentage radioactivity remaining in the upper stomach with time is compared for the coated and uncoated resins in Fig. 4 and Fig. 5. Gamma camera images of the coated resin beads are shown in Fig. 6 and Fig. 7. The in vivo floating times for the coated and uncoated resin beads are given in Table 1. Coating the preparation traps the carbon dioxide generated and significantly prolongs the floating time. The gastric emptying of material from the stomach can be interpreted by a gastric emptying index introduced by Grimes and Goddard [8]. Gastric Emptying Index = 1 - f(t)/A
- ~ - Costed -B-Uncoated
100 90 -
~
80
-
2
03
.-= 70
.~
-
~ 6o E o
-
~> so ~ 40
where f(t) is the fraction of the initial activity remaining in the stomach at time, t and A is the area
11o
20
10
100
- ~ - Coated coated
9O
I
100
200
Fig. 5. Residence o f coated a n d u n c o a t e d I R A - 4 1 0 in the u p p e r stomach.
70 60 50 4O
<
I
Time (min)
8O --
30
30 2O I0
o
' 0
l
I
100
200
Time (min) Fig. 4. R e s i d e n c e o f coated a n d u n c o a t e d D o w e x 2 × 10 in the u p p e r stomach.
under the curve. The index has certain advantages in that all of the data is used and it is independent of the emptying pattern. In a similar way, a floating index can be calculated based on emptying from the upper delineated stomach region to the lower. Values of zero are achieved when the material remains in the upper stomach throughout the study and a value of 1 indicates that all the material has emptied from the upper stomach at the time of the first observation. Values of the floating index after 60 and 150 min are shown in Table 2 and Table 3. The data was compared using a Wilcoxon matched pair signed ranks test. For the Dowex 2 × 10, the indices for the coated and uncoated preparations are significantly different (P < 0.005 (60 min); P < 0.002 (150 min)). There was also a significant difference in the indices for the coated and uncoated IRA-410 preparations (P < 0.01 at 60 and 150 min).
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
110
?
C
c~
Fig, 6. Gamma camera images of the radiolabelled uncoated IRA-410 in the stomach of volunteer 5; A, 60 min; b, 120 min; c, 180 min and d, 210 min.
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
111
Fig. 7. Gamma camera images of the radiolabelled coated IRA-410 in the stomach of volunteer 5; a, 60 min; b, 120 min; c, 180 min; d, 210 min.
Table 1 Floating times of resin beads in 0.1 M HCI Resin
IRA-410 Dowex-2 X 10
Floating time (h) Uncoated beads
Coated beads
3 1
>24 >24
The volunteers taking part in this study fasted overnight and were given a light, predominantly liquid meal prior to the administration of the capsule. Under these conditions, the meal would be expected to leave the stomach rapidly and material dispersed in the meal, for example the contents of a capsule, would be emptied along with the meal [9]. The
112
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
Table 2 Floating indices obtained from coated and uncoated preparations (Dowex 2 X 10) Subjects
1 2 3 4 5 6
M e a n ± S.D.
Coated
Uncoated
60min
150 min
60min
150min
0.006 0.001 0.008 0.005 0.010 0.020 0.010 ± 0.007
0.018 0.017 0.018 0.004 0.021 0.017 0.016 ± 0.006
0.025 0.020 0.024 0.020 0.031 0.026 0.024± 0.004
0.030 0.024 0.033 0.026 0.040 0.035 0.031 ± 0.006
Table 3 Floating indices obtained from coated and uncoated preparations (IRA-410) Subjects
1 2 3 4 5 6
M e a n ± SD
Coated
Uncoated
6 0 m in
150min
6 0 m in
150min
0.0007 0.0020 0.0004 0.0010 0.0030 0.0002 0.0012 ± 0.0010
0,020 0.016 0.004 0.015 0.010 0.010 0.013 ± 0.005
0.0002 0.0170 0.0190 0.0240 0.0220 0.0110 0,0160 ± 0.0085
0.030 0.031 0.039 0.059 0.031 0.028 0.036 ± 0.012
results obtained in this study show that a significant delay in gastric emptying can be achieved. A limited period of floating occurs with the uncoated resin beads (Table 1). This will be due to the carbon dioxide released being attached to the surface of the beads. Both resins have densities of - 1 . 2 g/cm 3 which would cause them to sink in 0.1 M HC1. The density of the stomach contents will vary but measurements on samples from fasting subjects all gave values of around 1.0 g / c m 3 [10]. This implies that both coated and uncoated formulations will float, but the uncoated one will only remain floating while any carbon dioxide bubbles remain attached. The coated preparation remains in the upper stomach for over 3 h which is superior to the non-coated system and would be a marked increase in retention over a conventional formulation.
4. Conclusions A coated ion exchange resin bead formulation load with bicarbonate has been shown to have gastric
retentive properties. The fact that the beads can accommodate both bicarbonate and technetium ions implies that anionic drugs could also be accommodated by the system. This has been achieved in practice, using theophylline as a model drug, and will be the subject of a subsequent publication. Whether the system is compatible with a wider range of drugs has not yet been investigated. The system therefore has potential as a gastric retentive device for the sustained release of drugs as well as a combined antacid and anti-reflux agent.
References [1] S.S. Davis, J.G. Hardy and J.W. Fara, Transit of pharmaceutical dosage forms through the small intestine. Gut 27 (1986) 886-892. [2] L.C. Kaus, J.T. Fell, H.L. Sharma and D.C. Taylor, On the intestinal transit of a single non-disintegrating object. Int. J. Pharm. 20 (1984) 315-323. [3] K. Park and H. Park, Enzyme digestible balloon hydrogels
for long term oral delivery: synthesis and characterization. Proc. Int. Symp. Control. Release Bioact. Mater. 14 (1987) 41-42.
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113 [4] D. Harris, J.T. Fell, H.L. Sharma and D.C. Taylor, Gastrointestinal transit of potential bioadhesive systems in the rat. J. Control. Release 12 (1990) 55-65. [5] R. Gr6ning and G. Heun, Oral dosage forms with controlled gastro-intestinal transit. Drug Dev. Ind. Pharm. 10 (1984) 527-539. [6] P.R. Sheth and J. Tossounian, The hydrodynamically balanced system (HBS): a novel drug delivery system for oral use. Drug Dev. Pharm. Ind. 10 (1984) 313-339. [7] H.M. Ingani, J. Timmermans and A.J. Mo~s, Conception and investigation of peroral sustained release dosage forms with enhanced gastro-intestinal transit. Int. J. Pharm. 35 (1987) 157-164.
113
[8] D.S. Grimes and J. Goddard, Gastric emptying of wholemeal and white bread. Gut 18 (1977) 725-729. [9] E. Hunter, J.T. Fell, R.T. Calvert and H.L. Sharma, In vivo disintegration of hard gelatin capsules in fasting and nonfasting subjects. Int. J. Pharm. 4 (1980) 175-183. [10] H. Mohammad, Studies on the wettability of pharmaceutical powders, Ph.D. thesis, University of Manchester, 1983.
ELSEVIER
Journal of Controlled Release 42 (1996) 105-113
controlled release
In vivo evaluation of a novel gastric retentive formulation based on ion exchange resins F. A t y a b l
•a S
" , H.L. Sharma
a
, H.A.H.
Mohammad
b, J.T. F e l l b
aDepartment of Medical Biophysics, University of Manchester, Manchester M13 9PL, UK bDepartment of Pharmacy, University of Manchester, Manchester M13 9PL, UK
Received 11 May 1995; accepted 8 January 1996
Abstract Systems that exhibit gastric retention are of value in several areas of therapy. A novel floating system based on ion exchange resins has been investigated and evaluated in vivo. The method relies on ion exchange resins loaded with bicarbonate, which, on contact with media containing hydrochloric acid, release carbon dioxide causing the resin to float. Extension of the floating time is achieved by coating the bicarbonate loaded resin particles with a semipermeable membrane. Two resins were investigated and both exhibited in vitro floating times of over 24 h using a standardised procedure. Studies in human volunteers were carried out using gamma scintigraphy. The coated resins were compared to an uncoated control in subjects receiving a light breakfast. The coated resin based on Dowex 2X 10 showed significantly prolonged residence times (P < 0.002) over the non-coated control when compared at 60 and 150 min using a modified gastric emptying index. Keywords: Gastric emptying; Floating system; Ion exchange resins; Coating
1. Introduction Studies on the gastric emptying of solid pharmaceuticals have revealed the highly variable nature o f the process [1]. Although delays in gastric emptying can occur, particularly after food, or if the dosage form is administered immediately after Phase III of the Migrating Motor Complex [2], in many cases gastric emptying can be rapid. This latter case has led workers to investigate the possibility o f designing dosage forms with gastric retentive behaviour. Such a dosage form is attractive in that it theoretically permits control over the time and site of drug release. This would be particularly valuable for drugs :g
Corresponding author.
exhibiting an absorption window in the small intestine or drugs such as weak bases which dissolve better in the acid environment of the stomach. In addition the devices may be useful for local treatment of the stomach or, if formulated in a particular manner, prevention or damage limitation of gastrooesophageal reflux. The systems investigated range from complex devices which remain in the stomach due to their size [3] to relatively simpler systems such as bioadhesive agents [4], t h e use of passage delaying food excipients [5] and floating devices [6,7]. The system reported here is prepared from ion exchange resin beads. The beads are loaded with bicarbonate, which, on contact with hydrochloric acid, release carbon dioxide which is trapped within
0168-3659/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PII S01 68-3659(96)01344-2
106
F. Atyabi et al. / Journal of Controlled Release 42 (1996)105-113
a semipermeable membrane surrounding the beads. This causes them to float. This paper reports the results of a gamma scintigraphic investigation into the in vivo behaviour of the resin beads.
2. Materials and methods
2.1. Materials Two types of ion exchange were used in this study. The method of preparation was similar for both. Amberlite IRA-400 (BDH Ltd., UK) (14-50 mesh) resin beads were fractionated by sieving and the fraction 355-500 /xm was retained. Dowex 2X 10 resin beads (Fluka, UK) (50-100 mesh) were passed through a 250 /xm sieve and the fraction retained on the sieve collected. The mean particle size of these fractions was determined by optical microscopy to be 4 0 0 / z m for IRA-400 and 279/zm for Dowex 2×10. This range of particle size is judged to be comparable with sustained release drug beads found in many formulations. The ion exchange resins were loaded with bicarbonate by mixing the resin beads with 1 M NaHCO 3 solution for 15 min, decanting, and then mixing for a further 15 min with a fresh solution. The beads were then filtered, washed with deionised water, and dried overnight at 40°C.
2.2. Uptake of sodium pertechnetate the ion exchange resins
(99mTc)by
A sample of 0.5 g ion exchange resin loaded with bicarbonate was soaked in deionized water for 15 min. An aliquot of sodium pertechnetate in saline (40 MBq) was then added. The suspension was stirred at room temperature and, at predetermined time intervals, samples were withdrawn using a pipette with a glass filter tip. The samples were counted in an autogamma counter to determine the remaining unbound pertechnetate.
2.3. Labelling and coating The bicarbonate loaded ion exchange resin beads were labelled as follows. Resin beads (1.5 g) were placed in a test tube and soaked in deionised water
for 15 min. A small amount of sodium pertechnetate solution in a sterile vial obtained from a technetium generator was added to the tube. The amount was calculated to give 4 MBq of activity at the time of administration. The resin suspension was mixed intermittently for -~5 min using a vortex mixer. The suspension was then left to settle. The supernatant was removed and the labelled resin beads were recovered by filtration on a filter paper followed by washing thoroughly with deionised water. The resin beads were allowed to dry in air for 20 min. The slightly damp resin beads were coated with Eudragit RS using a coacervation phase separation technique to give a final weight increase of 9%. Eudragit RS (0.1 g) was dissolved in 10 g of a 3% w/v solution of polyisobutylene in methylene chloride/n-hexane (60/40 v/v). One g of damp resin beads were added to this and 15 ml of n-hexane was dropped in at 1 ml/min with continuous stirring to form the coating. Fifty ml of n-hexane was then added to harden the coating, the beads were removed, washed 3 times with nhexane, dried at 40°C for 12 h and stored in a desiccator until required. The final procedures removed remaining polyisobutylene and solvents.
2.4. Stability of 99mTClabelled resins Stability tests were carried out to confirm that the radiolabel remained bound to the resin for the duration of the study. Tests were carried out using appropriate standard buffer solutions at pH 1.2, 5.8 and 7.5. One g 99mTclabelled resin beads were placed in test tubes with 5 ml of the buffer in a water bath maintained at 37°C. Three tubes were used for each measurement and the data obtained from the average of the 3 samples. The mixtures were stirred and 0.2 ml samples were taken at predetermined time intervals using a pipette with a glass wool filter tip. The radioactivity in the samples was counted in an autogamma. The activity counted was corrected for decay and the data was expressed as a percentage of the original activity. At the end of the experiment the supernatant was removed and the resins were washed, dried and measured for activity. The activity remaining associated with the resin beads corrected
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
110 100
9O 80 70 60 o
=~
50 40 3O 20 10
0
T 0
'
I 1
,
I
,
2
I 3
,
I 4
,
I 5
,
I 6
Time (h)
Fig. 1. Uptake of pertechnetate ions by the ion exchange resins.
for decay, was expressed as a percentage of the initial activity. 2.5. G a m m a s c i n t i g r a p h y
The in vivo behaviour of the coated and uncoated resin beads was monitored using a single channel analysing study in 12 healthy volunteers of mean age 34 years (range 22-49). None of them had symptoms or a past history of GI disease, or were taking any medication. All had given their informed consent to participate in the study. The study was approved by the University of Manchester Committee on the Ethical Research on Human Beings and the administration of radioisotopes to human volunteers was subject to an A R S A C licence from the Department of Health. Coadministration of a radiolabelled meal with the formulation enabled delineation of the GI anatomy and the subsequent position of the formulation to be identified. The test meal was a light breakfast
107
consisting of 200 ml milk, 40 g cornflakes and 6 g sugar. A small amount of 99mTc-DTPAsolution was added to the test meal to give an activity of 1.5 MBq at the time of administration. To standardise conditions of GI motility, the subjects were required to fast for 12 h prior to the commencement of each experiment. Each of the two forms (one coated and one uncoated as a control) was administered in 1 g quantities in size 0 hard gelatin capsules to each subject on two separate occasions and in a randomised fashion. Adequate time (at least 1 week) was allowed to elapse between experiments. After an overnight fast, on the morning of the study, the subjects were allowed to eat the radiolabelled breakfast. Subsequently, the capsules were swallowed together with 200 ml water. This volume was considered sufficient to prevent sticking in the oesophagus and together with the breakfast, to allow floating to occur. The position of the formulation in the stomach was followed by asking the subject to stand in front of a gamma camera (Ohio Nuclear Sigma, 410 camera). The gamma camera had a 40 cm field of view and was fitted with a medium energy parallel hole collimator. The 140 keV gamma rays emitted by 99mTC were imaged. The images were recorded on a magnetic disk. Three external marks containing less than 1 MBq 99mTc sodium pertechnetate were attached to the skin (with lead shielding facing the body), one overlying the liver to the right of the stomach and two on either side of the lower abdomen. These markers were used as reference points during the image analysis. Anterior images of 120 s duration were recorded. The subjects were imaged for the first 60 min continuously. For the rest of the experiment, 10 min images were taken at 30 min intervals. Between the images, the subjects were permitted to walk and carry out normal activities but they were not allowed to take any food or drink until the formulation had left the stomach completely. The images were recorded using an on line computer system (Maps 2000, Link System, UK), and stored on magnetic disc for analysis. Each image displayed on the monitor screen was analyzed for radioactivity remaining in the stomach by creating two regions of interest, one around the upper half of the stomach and the second around the
108
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
lower half. An additional region of interest was created around the whole stomach from the images t a k e n before administration of the formulation, to assess background activity. The counts from the regions of interest were corrected for background and decay. The values subsequently calculated represented the percentage of the total radioactivity administered and these were plotted against time for each individual and for each preparation.
3. Results and discussion
3.1. Uptake o f sodium pertechnetate by ion exchange resins
Fig. 1 shows the uptake of pertechnetate anions by Amberlite ion exchange resin (IRA-410) and Dowex 2×10 resins at different times. Almost complete uptake (99%) was achieved and over 80%
of the free pertechnetate anions were bound to the resin in 2 min.
3.2. Stability o f
99mTClabelled
resins
The stability of 99mTC labelled IRA-410 and Dowex 2X10 resins was tested in simulated gastric and intestinal fluids. Fig. 2 and Fig. 3 show the 99mTC release from IRA-410 and Dowex 2X10 at different pH values respectively. No significant release of 99mTCoccurred at any pH after 3 h. 99mTC IRA-410 lost less than 1% of its activity in simulated gastric fluid in 3 h, about 2.5% in pH 5.8 and 2% in simulated intestinal fluid (Fig. 2). 99mTC labelled Dowex 2×10 lost less than 1% of its activity in solutions of different pH.
3_
~-pH1.5 mpH5.8 -~pH7.5
1.20 1.10
-~-pH1.5 -t-pH5.8
1.00
/
/
-o-pH7.5 2H
0.90
/
-g
/
e/J ¢¢1
0.80
m ¢D
"~ 0.70 ¢o ®
/
0.60 ¢3
~
o.so
<
0,40 0.30 0.20 0.10 I --~ I
0.00
'
I
1
'
I
2
'
I
3
'
I
0
1
4
Time (h) Fig. 2. Release of 99mTC from IRA-410 at different pH values.
I
I
2
I----~
3
Time (h) Fig. 3. Release of values.
99mTC
from Dowex 2X10 at different pH
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
3.3. In vivo studies
109
110
The percentage radioactivity remaining in the upper stomach with time is compared for the coated and uncoated resins in Fig. 4 and Fig. 5. Gamma camera images of the coated resin beads are shown in Fig. 6 and Fig. 7. The in vivo floating times for the coated and uncoated resin beads are given in Table 1. Coating the preparation traps the carbon dioxide generated and significantly prolongs the floating time. The gastric emptying of material from the stomach can be interpreted by a gastric emptying index introduced by Grimes and Goddard [8]. Gastric Emptying Index = 1 - f(t)/A
- ~ - Costed -B-Uncoated
100 90 -
~
80
-
2
03
.-= 70
.~
-
~ 6o E o
-
~> so ~ 40
where f(t) is the fraction of the initial activity remaining in the stomach at time, t and A is the area
11o
20
10
100
- ~ - Coated coated
9O
I
100
200
Fig. 5. Residence o f coated a n d u n c o a t e d I R A - 4 1 0 in the u p p e r stomach.
70 60 50 4O
<
I
Time (min)
8O --
30
30 2O I0
o
' 0
l
I
100
200
Time (min) Fig. 4. R e s i d e n c e o f coated a n d u n c o a t e d D o w e x 2 × 10 in the u p p e r stomach.
under the curve. The index has certain advantages in that all of the data is used and it is independent of the emptying pattern. In a similar way, a floating index can be calculated based on emptying from the upper delineated stomach region to the lower. Values of zero are achieved when the material remains in the upper stomach throughout the study and a value of 1 indicates that all the material has emptied from the upper stomach at the time of the first observation. Values of the floating index after 60 and 150 min are shown in Table 2 and Table 3. The data was compared using a Wilcoxon matched pair signed ranks test. For the Dowex 2 × 10, the indices for the coated and uncoated preparations are significantly different (P < 0.005 (60 min); P < 0.002 (150 min)). There was also a significant difference in the indices for the coated and uncoated IRA-410 preparations (P < 0.01 at 60 and 150 min).
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
110
?
C
c~
Fig, 6. Gamma camera images of the radiolabelled uncoated IRA-410 in the stomach of volunteer 5; A, 60 min; b, 120 min; c, 180 min and d, 210 min.
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
111
Fig. 7. Gamma camera images of the radiolabelled coated IRA-410 in the stomach of volunteer 5; a, 60 min; b, 120 min; c, 180 min; d, 210 min.
Table 1 Floating times of resin beads in 0.1 M HCI Resin
IRA-410 Dowex-2 X 10
Floating time (h) Uncoated beads
Coated beads
3 1
>24 >24
The volunteers taking part in this study fasted overnight and were given a light, predominantly liquid meal prior to the administration of the capsule. Under these conditions, the meal would be expected to leave the stomach rapidly and material dispersed in the meal, for example the contents of a capsule, would be emptied along with the meal [9]. The
112
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113
Table 2 Floating indices obtained from coated and uncoated preparations (Dowex 2 X 10) Subjects
1 2 3 4 5 6
M e a n ± S.D.
Coated
Uncoated
60min
150 min
60min
150min
0.006 0.001 0.008 0.005 0.010 0.020 0.010 ± 0.007
0.018 0.017 0.018 0.004 0.021 0.017 0.016 ± 0.006
0.025 0.020 0.024 0.020 0.031 0.026 0.024± 0.004
0.030 0.024 0.033 0.026 0.040 0.035 0.031 ± 0.006
Table 3 Floating indices obtained from coated and uncoated preparations (IRA-410) Subjects
1 2 3 4 5 6
M e a n ± SD
Coated
Uncoated
6 0 m in
150min
6 0 m in
150min
0.0007 0.0020 0.0004 0.0010 0.0030 0.0002 0.0012 ± 0.0010
0,020 0.016 0.004 0.015 0.010 0.010 0.013 ± 0.005
0.0002 0.0170 0.0190 0.0240 0.0220 0.0110 0,0160 ± 0.0085
0.030 0.031 0.039 0.059 0.031 0.028 0.036 ± 0.012
results obtained in this study show that a significant delay in gastric emptying can be achieved. A limited period of floating occurs with the uncoated resin beads (Table 1). This will be due to the carbon dioxide released being attached to the surface of the beads. Both resins have densities of - 1 . 2 g/cm 3 which would cause them to sink in 0.1 M HC1. The density of the stomach contents will vary but measurements on samples from fasting subjects all gave values of around 1.0 g / c m 3 [10]. This implies that both coated and uncoated formulations will float, but the uncoated one will only remain floating while any carbon dioxide bubbles remain attached. The coated preparation remains in the upper stomach for over 3 h which is superior to the non-coated system and would be a marked increase in retention over a conventional formulation.
4. Conclusions A coated ion exchange resin bead formulation load with bicarbonate has been shown to have gastric
retentive properties. The fact that the beads can accommodate both bicarbonate and technetium ions implies that anionic drugs could also be accommodated by the system. This has been achieved in practice, using theophylline as a model drug, and will be the subject of a subsequent publication. Whether the system is compatible with a wider range of drugs has not yet been investigated. The system therefore has potential as a gastric retentive device for the sustained release of drugs as well as a combined antacid and anti-reflux agent.
References [1] S.S. Davis, J.G. Hardy and J.W. Fara, Transit of pharmaceutical dosage forms through the small intestine. Gut 27 (1986) 886-892. [2] L.C. Kaus, J.T. Fell, H.L. Sharma and D.C. Taylor, On the intestinal transit of a single non-disintegrating object. Int. J. Pharm. 20 (1984) 315-323. [3] K. Park and H. Park, Enzyme digestible balloon hydrogels
for long term oral delivery: synthesis and characterization. Proc. Int. Symp. Control. Release Bioact. Mater. 14 (1987) 41-42.
F. Atyabi et al. / Journal of Controlled Release 42 (1996) 105-113 [4] D. Harris, J.T. Fell, H.L. Sharma and D.C. Taylor, Gastrointestinal transit of potential bioadhesive systems in the rat. J. Control. Release 12 (1990) 55-65. [5] R. Gr6ning and G. Heun, Oral dosage forms with controlled gastro-intestinal transit. Drug Dev. Ind. Pharm. 10 (1984) 527-539. [6] P.R. Sheth and J. Tossounian, The hydrodynamically balanced system (HBS): a novel drug delivery system for oral use. Drug Dev. Pharm. Ind. 10 (1984) 313-339. [7] H.M. Ingani, J. Timmermans and A.J. Mo~s, Conception and investigation of peroral sustained release dosage forms with enhanced gastro-intestinal transit. Int. J. Pharm. 35 (1987) 157-164.
113
[8] D.S. Grimes and J. Goddard, Gastric emptying of wholemeal and white bread. Gut 18 (1977) 725-729. [9] E. Hunter, J.T. Fell, R.T. Calvert and H.L. Sharma, In vivo disintegration of hard gelatin capsules in fasting and nonfasting subjects. Int. J. Pharm. 4 (1980) 175-183. [10] H. Mohammad, Studies on the wettability of pharmaceutical powders, Ph.D. thesis, University of Manchester, 1983.