Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
W~94/1~113C 2 1 3 9 7 4 7 1'C1`/1)K93/00227
drug delivery device and a method of making such device
The present invention relates to drug delivery devices ;
for delivering drugs to the colon and comprising a
polymer matrix and a drug contained in or surrounded by ;~
the matrix.
A large number of drugs are very sensitive to proteolytic
enzymes contained in the digestive juices of the stomach
and the small intestine. Drugs, such as peptides and
proteins, are degraded by the proteolytic enzymes, thus
reducing the absorption substantially.
Though oral administration is much more convenient and
acceptable to the patient, the most common mode of
deliveriny drugs, such as peptides and proteins, is by ~ ~
parental administration. ~ ;
Investigations have shown that the concentration of pro~
teolytic enzymes in the colon juices is much lower than
the concentration in the juices of the stomach and the
small intestine.
It would thereore be very advantageous to ~find a suit-
able technique for delivering drugs selectively to the
colon by administration through the alimentary canal.
Polymeric materials such as hydrogels have been widely
used in drug carrier systems for controlled release or
used as stimuli sensitive devices. Such devices are for ~'
instance described in "1-lydrogels in Medicine and Pharm-
acy", N.A. Peppas (Ed.), CRC Press, 1987. The formula- ~ ;
tions described therein are generally not biodegradable.
The release of pharmacologically active agents "loaded"
into such gels is typically controlled by simple diffu-
sion in the device which depends on the water content in
~V~94/~1l3( 2 1 3 9 7 4 7 I c~ /DK93tO0227 ~
' ',~':.'' ,',
t:he gel. Th~se gels are therefore not: suitable for drug
delivery to specific regions of the intestines after oral
administrat:io
EP Patent Application 357 401 discloses a biodegradable
hydrogel matrix comprising a protein, a polysaccharide,
and a cross-linking agent. However, this composition is !
not used for oral administration.
US Patent 4 024 073 discloses a hydrogel composition
comprising a water-soluble polymer containing a chelating
agent bound to the polymer chain, and a polyvalent metal
ion cross-lin)cing the polymer molecules through the
chelating agent. The hydrogel is useful as a carrier for
timed release of drugs and medicaments and is not ,;'~
targeted to the colon. ,;
.:, ~, ~: . .,:
JP Patents 1 156 912, JP 62 010 012, JP 5 721 315, DE
Publication 3 400 106 and US Patent 4 496 553 describe
20 the preparation of compressed tablets for slow-release of ~ ; "
drugs using soluble polymers or polysaccharides. These
are all conventional tablets disintegrating in a time-
dependent fashion and are not specifically targeted to
the colon. ~ ;
Patent Application GB 2 066 070 describes a pharmaceuti-
cal formulation of a tablet for release. of an active sub-
stance in the colon. This tablet contains the active com-
ponent in the centre covered by a coating consisting of -
30 cellulose and derivatives thereof. The coating is degrad-
able by bacteria present in the colon. A drawback of this '
system is, however, that the coating can dissolve in the
stomach or the upper gastro-intestinal tract. Therefore,
the patent describes a system which is vulnerable to
35 inter-individual variations in intestinal transit time ~;-
and which does not specifically release the active
substance in the colon.
':''~, ','
W 0 ')4/01136 213 9 7 4 7 rCl`/DK93/00227
3 . ;
Osmotic drug devices for delivering a drug to the colon
is described in GB Patent Applications 2 166 051 and
2 166 052. These devices comprise a laminated membrane ~`~
surrounding a compartment containing a drug. The membrane
results in a time delay in the commencement of
substantial release of the drug. Such osmotic drug de~
vices have the same disadvantages as the device described
in GB Patent Application 2 066 070. ;
A publication relating to the field of the present inven-
tion is "Chemically-modified polysaccharides for enzyma-
tically-controlled oral dr~g delivery" (Kost et al., Bio- ~;
materials, 11, 695-698, 1990). This paper describes a
system of ionically cross-linked starch used for con-
trolled release of macromolecules to the intestines. The
system takes advantage of the presence of amylases in the
small intestine and does therefore not target the release ~,~G
to the large intestine or the colon.
Recently, Rubinstein et al. (Pharm. Res., 9, 276-278,
1992) have described colonic drug delivery by use of a
chondroitin matrix. The system consists of a drug em- ~;~
bedded in a compressed matrix of chondroitin. This matrix
may disintegrate at any time during the transit of the
small intestine. Thus, this system is not suitable for
site-specific drug delivery to the colon.
W~ Publication 92/00732 describes a composition for oral
de]ivery of therapeutically active substances to the
co~on. The composition comprises a matrix core having the
actiVe substance or substances dispersed therein, and an
o~ter cover Layer without any active substance. Both the
matrix core and the outer cover layer are based upon
polysaccharides such as pectin and/or dextran for~ing
coacervate through polyvalent cation cross-linking where
the cation is bi- or trivalent.
~VO 94/011.~() 2 1 3 9 ~ ~ ~ 1'CI`/I)K93/00227
.~ .,,,....
In the stomach of a patier-t having a normal gastric acid
function, hydrogen ions will penetrate into both the
outer layer and the core of the composition and by ion- ;~
exchange substitute hydrogen ions for the polyvalent
cations, leaving the polysaccharide chains non-complexed
to a great extent and more or less holding the compo~
sition together by sterical effects rather than by cation
connections.
This means that the composition is more or less
disintegrated during passage through the stomach and the ,~
small intestine, and that the disintegration during this j~
passage is extremely dependent on the presence of other
cations, residence time of the composition and
particularly on the gastric acid function of the very ,
patient. In other words, a composition of the above type ,~ -
may be able to deliver active substances to the colon of
a patient, if the composition is specifically composed ;
for the patient. Such composition is therefore not
commercially suitable.
The use of hydrogels containing biodegradable bonds has ;- ,
previously been described by Br0ndsted and Kopecek in
Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18, ~-~
345-346, 1991. The hydrogels exhibit pH-dependent swel- ,~
ling due to incorporated acidic groups in the polymer
backbone and biodegradability due to enzymatically labile
cross-links. The system utilizes the presence of
microbial azoreductases in the colon. The hydrogels
disintegrate after the degradation of cross-links and the
release of polymer backbone.
By using these acidic hydrogels it is possible to avoid
any substantial degradation and release of drug in the
stomach. However, the degradation of the hydrogel and :`''~ .'.~4`'~
thus the release of drug to the colon appears to be very
slow, and when passing the colon only a part of the drug
' ,:~,'.~-.'"'
WO~4/0113-~ 213 9 7 4 7 l~cr/l)K93/oo227
. . '
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may be released.
Drug delivery to the colon has been obtained by using ~ -
dextran prodrugs (Larsen et al., Pharm. Res., 6, 995-999, ;~
1989) which release the active substance after cleavage ;~
by microbial enzymes being present only in the colon. The
drug was covalently bound to the dextran. As the prodrug
reached the colon, bacterial dextranases were able to
break down the dextran releasing the drug after
hydrolysis of the covalent bond. A disadvantage of this
system consists in a severe drug loading problem. -~
Furthermore, the drug must possess a suitable functional -~
group for modification and be able to withstand
experimental conditions for coupling to the dextran ~;
carrier. ~s
It is therefore evident that there is a need for an oral
drug delivery device with improved selectivity to the
colon.
The object of the present invention is to provide such
oral drug delivery device for delivering drug to the
colon by use of which device it is possible to deliver
one or more drugs to the colon without substantial loss ,~
of drug in the stomach, the small intestine, and faeces.
' :'
The drug delivery device according to the invention com-
prises a polymer matrix and a drug contained in or
surrounded by the matrix and is characterized in that the
polymer matrix is a covalent cross-linked hydrogel matrix
comprising dextranase degradable polymer and a cross- ;-
linking agent providing network linkage between the
polymer chains.
.,
As mentioned before, dextranases are only present in the ~-
colon. In the drug delivery device according to the in-
vention the drug is protected by the cross-linked dextra-
, ~,, :, . .
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: W~94/011~6 2 13 9 7 4 7 I'CI/D~93/00227
nase degradable polymer when the device passes through `
the stomach and the small intestine. When reaching the
colon, the polymer matrix is degraded by dextranase and ;
the drug is released. I -~
The rate of degradation of the polymer matrix and thereby
the release of drug depends on several factors such as
the choice of dextranase degradable polymer, the cross~
linking agent, the degree of cross-linking, the water
content of the hydrogel matrix and the configuration and
size of the finished device. The device according to the
invention can be constructed so that practically all of
the drug is released in the colon. ;
The dextranase degradable polymer in the device according ~;
to the invention must be essentially resistent to the
digestive juices of the stomach and the small intestine.
Preferably, the dextranase degradable polymer is dextran
or a modified dextran. Several methods for modifying dex-
tran is known. See for instance W.M. Meckernan and C.R. ;;,~s
Ricketts, Biochem J., 76, 117-120, 1960 regarding prepa-
ration of diethylaminoethyldextran, and K.Nagasawa et
al., Carbohydr. Res., 21, 420-426, 1972 regarding
synthesis of dextran sulphate.
By using modified dextran instead of ordinary dextran it
is possible to obtain a hydrogel matrix with a more
hydrophobic or a more hydrophilic as well as charged
character. This can be used to control the swelling pro-
perties of the hydrogel matrix. The dextranase degradable
polymer is also chosen depending on which drug is to be -~
loaded into the hydrogel matrix, so that the dextranase ~ ~ .
degradable p~lymer will not react with the drug in a
manner which irreversibly inactivates the drug. -~
',' ':" ' ':' ~.,.~',..':
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W~94/0113G 21 3 9 7 ~ 7 l~C-I~/DK93/00227
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.';'~' ' '~`' '
Particularly preferred is sulfated, alcoxylated, oxydated
or esterificated dextran.
The dextranase degradable polymer may have a molecular
weight between 10,000 and 2,000,000 g/mol, preferably ~ r~
between 40,000 and 2,000,000 g/mol.
If the dextranase degradable polymer is dextran, a mole-
cular weight between 70,000 and S00,000 is optimal.
.. '
The cross-linking agent can be any non-toxic agent which
is able to provide a network linkage of the polymer
structure. The polymer may be held together by covalent
bonds, such as urethane, ester, ether, amide, carbonate,
or carbamate bonds. Diisocyanate that provides urthane
bonds, such as hexamethylenediisocyanate and 1,4-
phenylenediisocyanate, are preferred as cross-linking
agent.
,, ; :~.
The degree of cross-linking in the hydrogel, like the
composition of the hydrogel itself, affects the degrada-
tion kinetics, loading, and the overall release profile
of the matrix. That is, a higher degree of cross-linking
will generally result in slower degradation and release,
while a lower degree of cross-linking will result in
faster degradation and release.
Of course, the influence which the degree of cross-
linking has on the release of the drug depends upon the
molecular size of the drug and the way the drug is loaded
into the device. Preferably, the cross-linking agent
constitutes 0.05-25 mol-% of monomeric units in the
hydrogel.
,: . .' ::, ~ ;'
The drug can in principle be any type of drug. The device
according to the invention is especially advantageous for ~ -~
use when administering drugs for treatment of diseases in
:.:- - ~
........
2139747 : `
W()')4/011~(, 1'CI`/I)K93/00227
tt-e colon, e.g. steroids, 5-aminosalicylic acid, anti- ;~
inflammatory agents, anti-cancer agents, enzymatic agent,
and bacterial cultures, or for administration of drugs
which are unstable in the stomach and/or the small intes-
tine, e.g. peptides such as insulin, vasopressin, or
growth hormones, proteins, enzymes, and vaccines.
The device according to the invention is also advanta~
geous for use in time-delayed administration of drugs. ~ -
1 () , ': ` ': ` ' ~ .
By use of tlle device according to the invention drugs,
such as agents for treatment of rheumatism and other
analgesic agents, can be administered to the patient at , `~
bedtime and be effective in the morning, as the time it
takes the device to reach the colon is about 8 hours. ;
The drug can be loaded into the hydrogel matrix in seve-
ral ways. For instance the drug, or a gelatine capsule
containing the drug, can be coated by the hydrogel ma-
trix, or the drug can be contained in the lumen of the
hydrogel device, i.e. the drug is surrounded by a thicker `~
layer of hydrogel matrix. ~;
Methods of incorporating drug in hydrogels are common
knowledge to a person skilled in the art and are forexample described in S.W. Kim et al., Pharm. Res., 9,
283-290, 1992.
.'"
In a preferred embodiment of the device according to the ;;~
invention, the drug is homogeneously dispersed in the
cross-linked hydrogel matrix.
:"": ` ' ,.,','~
Depending on how the drug is loaded, the hydrogel
matrices can be formed into capsules, tablets, films,
microspheres, or the like. The compositions formulated
using the hydrogel matrices can include conventional `~ ;-
pharmaceutical carriers or excipients, adjuvants, etc. ~;
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- W0 94tO113fi ~13 9 7 4 7 1'Cr/DK93tO0227 ~,
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The device according to the invention can contain more
than one drug, e.g. the device can contain one drug of
high molecular weight in the lumen of the hydrogel matrix
and another drug of lower molecular weight dispersed ,~
homogeneously in the matrix.
It will be obvious to a skilled person that other combi~
nations also comprising drugs which are released in,the
stomach or the small intestine are possible.
' .'~' .~ "'`'
Another object of the invention is to provide a method of '~
making a drug delivery device according to the invention. '~
. ~ ",
The method according to the invention comprises
, ''
a) dissolving a dextranase degradable polymer in a
solvent, ,''
b) adding a cross-linking agent capable of cross-linking~,~,,;"',,
the polymer with covalent bonds to the solution,
c) allowing the cross-linking agent to react with the
dextranase degradable polymer to provide a cross-~,- '-
linked hydrogel matrix. ~ ~ ,
25 , ';~
The drug can be loaded into the device before the cross- ';~;, ,
linking reaction has finished by use of several methods. ~,
These methods are also common knowledge to persons, ','
skilled in the art and are for instance described in S.Z. '~
Song et al., J. Pharm. Sci., 70, 216-219, 1981.',,,~,'~',''
, ~
In a preferred embodiment the drug is loaded into the
device after the cross-linking reaction has finished by ~' ''-';,
means of the following steps: ';',;',~''',''~-~
"~ ','''
a) the hydrogel matrix is predried, preferably to a- '''',
water content lower than 30 weight-% and particularly ,~
,. ::.'.'.'
'..',.' '~: ', ' . .
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~ ~.~ 94//!1136 213 9 7 4 7 , crlDK93/oo227
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lower t~lan 10 weight~
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b) the dried hydrogel matrix is brought into contact
with a liquid drug or a drug solution and is allowed
to swell,
c) lf desired, the hydrogel is dried.
This last method provides a very simple and easy method t~
of making a device according to the invention by which
the drug is homogeneously dispersed. ~ `
To describe the invention further a series of examples
are given. , ~ir~:
~
Fig. 1 is a graph showing the equilibrium degree of swel- -,
ling of a device according to the invention
depending on the contents of DMSO. ~ !~
Fig. 2 is a graph showing the equilibrium degree of swel-
ling of a device according to the invention
depending on the contents of cross-linking agents.
Fig. 3 is a graph showing the equilibrium degree of swel- ~ ç
ling of a device according to the invention
depending on the molecular weight of dextran.
Fig. 4 is a graph showing the degradation in the cecum ~;
and in the stomach, respectively, of a device ~-~
according to the invention depending on time. ~/;,
Fig. 5 shows the release profiles of hydrocortisone from i- ,?
a device according to the invention.
. . . - ., .
~ WO94/01136 213 9 7 4 7 rCT/DK93/00227
EXAMPLE l
Preparation of biodegradable dextran hydrogels
1.5 grams (9.25 mmol glucose units) of dextran 70 (MW
70,000, commercially available from Pharmacia) was dis-
solved in 8.5 ml (85 vol-%) anhydrous dimethylsulphoxide
(DMS0). Immediately upon dissolution of the dextran to a
clear slightly viscous solution 86 ~l (0.46 mmol ~5 mol-
%) of hexamethylenediisocyanate (HDI, cross-linking
agent) was added. This was done in a thoroughly dried
glass bowel, as the cross-linking reaction is obstructed
by traces of water. The solution was transferred to the
reaction mould for fabrication of films by means of a
needle and syringe. The mould consists of two water-
~acketed teflon-coated aluminum blocks, between which
blocks the solution was placed. By controlling the
distance between the blocks using a spacer ring, it is -~
possible to control the thickness of the resulting hydro- ;
gel film. The temperature was set to 70 C. The cross-
linking reaction took place at this temperature for 24
hours. -
In a similar manner four other hydrogels containing dex-
tran 70 and various amounts of HDI and DMSQ were synthe-
sized. Two gels had 2.5 and lO mol-% of HDI and two had
80 and 90 vol-% of DMS0. ; `
,.,, ,,~..,.,.~,,
Also the molecular weight of dextran was varied. Hydro- ~
gels were made with dextran lO, 500 and 2000 (MW lO,000, ~ i500,000 and 2,000,000, respectively). ~i
; ' ', '. '
Table l shows a scheme of the synthesized hydrogels.
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;~ WO94/01136 213 9 7 4 7 1~CI/DK93/00227
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TAsLE l
Sample Dextran DMSO HDI
(Molecular (Vol-%) (Mol-%)
weight) -
A70 OOO 85 2.5
B70 OO0 85 5
C 70 OO0 85 lO
D 70 OO0 80 lO ;~
E 70 000 90 lO
F 500 O00 85 5 ;i~i
G 2 OOO O00 85 5 ~ ,
The vol-% is calculated in relation to the volume of the ' ;!
! . .~; . -,~, ~ j'/
resulting reaction mixture. The mol-% is calculated on ~
the basis of the molar content of glucose in the amount `~"'."'`''~4,'
of dextran used.
~,: . ' ~,
EXAMPLE 2
Determination of equilibrium degree of swelling of' ~`'
biodegradable dextran hydrogels ,
~.,., .. :.s,.~.. ;,,
The equilibrium degree of swelling of hydrogels prepared ~ ';,',,
as in example l, samples A-G, was studied. Three discs
were cut from each hydrogel and the weight of the swollen '~
gel in water and DMSO was measured. The gels were washed
with water and dried at room temperature for 2 days and ~,,''',',~.. :~.,'~1,~'t,
in vacuum at 40-50 C for 2 days. The equilibrium degree
of swelling was evaluated as the ratio of the mass of -,
swollen gel to that of the dry gel. ;
Figure l illustrates the dependence of equilibrium degree
of swelling of hydrogels containing various amounts of
''"'`'."`- ''''
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~ WO94tO11~6 213 9 7 ~ 7 l~CT/DK93/00227
13 ~
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DMS0 in the reaction mixture. An increasing amount of -
DMS0 in the reaction mixture results in an increase of
the equilibrium degree of swelling of the resulting
hydrogel. This is more distinct in DMS0 than in water.
Figure 2 shows that the equilibrium degree of swelling
decreases as the cross-linking density of the hydrogel
increases.
From Figure 3 it can be seen that if the molecular weight
of the dextran is varied, it does not have any sub~
stantial influence on the equilibrium degree of swelling.
The equilibrium degree of swelling is greater in DMS0 ;;
than in water. Thus, DMS0 appears to be a good example of ~ ~
a possible medium f OI drug loading into the hydrogels. ,~ ;
EXAMPLE 3 :~:
...,, .-
Evaluation of degradability of hydrogels in-vitro
The in-vitro degradability of hydrogels was investigated ~';
using dextranase (50 kilo Dextranase Units/g). Discs, 5
mm in diameter and 1.6 mm in thickness, of hydrogel films
prepared as described in example 1, were cut and swollen '; `
to equilibrium in 0.1 M acetate buffer pH 5.4. After
swelling equilibrium was reached, the discs were trans- -
ferred to the enzyme mixture consisting of 1 ml 0.1 M -
acetate buffer pH 5.4 and 0.5, 3 or 12 ul dextranase. The
mixture was incubated in a water bath at 37 C, and the ~-
time required for complete dissolution of the discs, ~, '.''''''',''',',~f.':',''.'
was recorded. Degradation of the gels was followed by a ~-
decrease in thickness. - ~
.. ~ :: .
Table 2 shows ~ for different gels when the enzyme mix- -
ture consisted of 12 ul dextranase/ml buffer. As cross~
linking density increases, increases, and thus the ; -
. ~ .,.
, WO94/0113G 21397~7 BCT/DK93/00227
: ,. . :
14
degradability decreases. This also relates to the
equilibrium degree of swelling; the higher the degree of
swelling, the higher the degradability of the hydrogel. ~;
However, the results also indicate that structural
factors, too, influence on the degradability of the
hydrogels.
Table 3 shows that as the amount of dextranase increases,
the rate of degradation increases.
1 0 .. ,. . ,.~
i , . .: . . .
TABLE 2
Sample ~ (min) ;~ -
A 18 i 1.5
B 36 + 4.6 ` ' ~
C 60 + 4.9 ' ~'
D 255 il5 ,~
E 46 i 1 -:
F 46 i 2 ~ , " ~,,
G 33 i 0.6
,''~' '~.~
TABLE 3
^
SampleAmount of dextranase (~(min) ."r.. ,~
:" ~ ~ ".., ;,
B 0.5 157 i 5.3
B 3 131 il4.8 ~ ~`
B 12 36 + 4.6
. . ~
WO94/01136 213 9 7 4 7 PCT/DK93/00227
EXAMPLE 4
Evaluation of degradability of hydrogels in-vivo
The dry weight of 6 samples B hydrogel discs 5 mm in dia-
meter was recorded and the discs pre-swollen in isotonic
potassium phosphate buffer pH 7.4. Each disc was placed
in a gauze bag. The gauze bags were implanted in the
stomach and the cecum o male SD rats (200-300 g) and
secured to the intestinal wall to prevent excretion of
the gels. The rats were then allowed water and food ad
libitum. At various times (1, 2 and 3 days) the rats were
sacrificed and the gels recovered. The gels were washed ~;
in DMS0 and water and then dried. The dry weight was re-
corded and the degradation of the gels was evaluated as ~
degradation (loss in dry weight in percent of initial dry -
weight). The initial dry weight was between 42 and 45 mg. ` -~
Figure 4 shows that after 3 days the gels implanted in
cecum were degraded, whereas gels implanted in the
stomach did not degrade. This shows that degradation of ' i;
the gels takes place in~vivo and that this takes place in ;
the cecum and not in the stomach.
.; ;. . .: :.,: ~.
EXAMPLE 5 ;
Loading and in-vitro release of hYdrocortisone
Hydrogel discs, prepared as described in example 1, 5 mm
in diameter and 1.6 mm in thickness (sample B), were
washed in water and dried. After drying, the discs were
immersed in a drug solution of hydrocortisone in DMS0
(72.5 mg/ml). After 24 hours the gels were dried in
vacuum af 50 C for 2 days. Release of hydrocortisone -~
from the discs was studied in 0.1 M acetate buffer pH 5.4 ~ `~
with (24 ul dextranase/ml buffer) and without dextranase
present. A gel was immersed in 5 ml release medium and ~
.::
WO94/0l136 2 1 3 9 7 4 7 I'CI'tl)K93/00227 ` ~
16 -
kept in a water bath at 37 C. At time intervals of eight
minutes when enzymes were present and thirty minutes when
no enzymes were present, samples of 2.5 ml were taken and '~;
replaced by fresh medium. The amount of released hydro~
cortisone was determined by reverse phase HPLC on a C-18
column with methanol:water 60:40 as mobile phase, UV de-
tection at 242 nm and an injection volume of 20
After 30 min 0.72 mg of hydrocortisone was released from ,~
the gel immersed in enzyme-containing buffer as compared ~ ,',~;
with 0.11 mg from the gel in pure buffer. This shows that ,~
the release is drastically increased in the presence of ~,;',",~'
dextranases. ",~
Figure 5 shows the release profiles of hydrocortisone
from the hydrogels. A much quicker release of hydrocor- "''''~'"
tisone is obtained when dextranase is present in the ;~
release medium. i~`
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