Polyacrylamide hydrogels as sustained release drug delivery dressing materials

Radiat. Phys. Chem. Vol. 22 No 3-5 pp, 907-915 1983

/83/0990%09505.00/0 © 1985 Pergamon Press Lid

Printed in Great Britain

POLYACRYLAMIDE HYDROGELS AS S U S T A I N E D R E L E A S E D R U G DELIVERY D R E S S I N G M A T E R I A L S

J. Rosiak~

K. B u r o z a k a n d W. P~kala

I N S T I T U T E OF A P P L I E D R A D I A T I O N CHEMISTRY T e c h n i c a l U n i v e r s i t y / Politeohnika / 93-590 L6d/, W r 6 b l e w s k i e ~ o

15, Poland

ABSTRACT The p o s s i b i l i t y

of the polyaer~lamide

h y d ~ o ~ e l s a p p l i c a t i o n as s u s t a i n e d re-

lease d r u g delivery systems is discussed. This I m p e r reports r i e d out in order to o b t a i n a new type of dressings

ne foil coated on one-side w i t h the d r u g a n d on opposite a c r y l m n i d e hydro~el

one w i t h the poly-

layer.

The doses of 60Co ~ - i r r a d i a t i o n

n e c e s s a r y %o prepare p o l y a c r y l a m i d e

tions w i t h desirable v i s c o s i t i e s were determined. dressin~ materials

some w o r k car-

c o n s i s t i n g of p o l y u r e t h a -

solu-

Release rate of d r u g from

through the col layer versus quality a n d q u a n t i t y of the

a d d - o n h y d r o ~ e l w e r e investigated.

The release rate increases f o r h i g h amount

of the ooatin6 gel as w e l l as w i t h the increase The tentative b i o l o g i c a l

of the polyaorylamide

tests have s h o w n f u l l b i o o o m p a t i b i l i t y

content.

a n d useful-

ness of this type of dressings f o r the clinical purposes.

INTRODUCTION Since

the d e v e l o p m e n t

of 2 - h y d r o x y e t h 7 1 m o t h a o r y l a t e / H E M A / gels in the

early 1960's L-I_7, h y d r o g e l s

as a class of m a t e r i a l s have f r e q u e n t l y b e e n

o o n s i d e m e d f o r use as b i o o o m p a t i b l e L-27.

The soft s n o n - a b r ~ s l v e

meabili~y

t O l o w m o l e c u l a r weight

dru~s~ baoterioides~

interfaces

of hydro~ls

release

of previously

through

the

RPC22 :3/5-NN

swelled

their w e t t a b i l i t 7 a n d per-

b i o l o g i c a l l y active substances

such as

a n t i b o d i e s a n d emmymes make it possible to prepare m a -

terlale w i t h ~ o o d or e v e n excellent b i o m e d i c a l The ability

in a v a r i e t y of a p p l i c a t i o n s

quality of the ~elsj

%o swell i n w a t e r physically

in water

entrapped

hydrool

p~operties.

gives

the

drugs

or

membranes. 907

possibility their

~dual

The intention

of gx~dual diffusion of our

inves--

908

J. ROSIAK, K. BURCZAK AND W. PEKALA

ti~ations Was

to elaborate

the new kind of dressin6 materials

aotlvity

of dru~ due to u t i l i z a t i o n

swellin~

in the aqueous medium.

of the m e n t i o n e d

The poor moohanloal

properties

riety of teohniques

f o r ooatin~ hydro6els

stren6~h L'~_7.

The prooess

prompted

of hydrogel

the development to improve

of a va-

their

of hydro~el / by the radiation

polymerio

base needs speoial

oxygen f r o m the system or introduoin~

oondi-

not always w a n t e d oata-

L'4,5_7.

lysts

We f o u n d rial

resistant

property

on surfaoes

of stable 6~aftin6

m e t h o d / on the meohanioally tlons., r e m o v l n ~

o£ hydro6els

w i t h prolon6n~d

in

our investigations

that

for

it is enough to ooat m e o h a n i o a l l y

a layer of hydro6~el° The polymerio te meohanioal

properties

the

Proper

work of

the

dressing

one side of the polymerio

oarrier apart from a s s u r i n g

is also the souroo

of therapeutio

mate-

oaxTier w i t h

the appropria-

a6~ent / Fi~.

I /°

[//////potymer,c supporf + d r u g / / / ~

r//////~//////////////////~

I Fig.

I.

Soheme

MATERIALS Samples

hydroge.[ l.ayer

material

grade

aoxylamide

/ PAA / h y d r o g e l s

mido aqueous

aox71amide /

solutions

Aoxylamide

room temperature

in

solutions

in isotopio

visoometer,

The oonversion

degree

p~esented

F~LrKA AG / w a s u s e d were obtained

the

0,187 Gy/s. Visoo-flexlble ultrazonio

L-6_7.

of the size 5 x ~ om were l~ePared for invee-

i n a w a y W h i o h is sohematioally

A~lytioal

weight.

oonstruotion

A N D PROCEDURE

of the d r e s s i ~

ti~atlons

of dressin~

I

oonoentmtion were imdiated devioe

tO ~ r e ~ r e

2. hydrogel.

b y 60Co ~ - i A ~ . ~ a d i a t i o n mn~e in

f r o m 16 t o

the presenee

BK 10 0 0 0 w i t h

properties

in Fig.

the

of P A A hydro6~la

Poly-

of aox~la-

30 p o r o e n t a ~ e of o~en

oonstant

at

dose rate

were examined usln~

UNIPAN Type - 508. of

t h e monomer was i n v e s t i ~ a t o d

speotrophotometrioally

by

Polyacrylamide hydrogels

909

PREP(~FRATIONI

I

_1

r

t COATING WITH HYDROGEL

-

I INTRODUCTION OF [ANTIBIOTIC

_ CONFECTION-[ NINO i I I I

STERILIZATION

tFig. 2.

Soheme

b a s i n ~ on the faot,

of d r e s s i n g preparation°

that aqueous

of a b s o r p t i o n in u l t r a v i o l e t

the struoture merio

of a o r y l a m i d e

exhibit

the m a x i m u m

at wave length equal to 199 nm.

The therapeutlo a~ent, a n t i b i o t i o p r o d u o e d by P h a r m a o e u t i o

solutions

oalled o h l o r o t e t r a o y o l i n e

F i r m ,, POLFA " - T a r o h o m i n ,

hydroohloride

series number I01108Oj

of w h i o h is p r e s e n t e d in Fi 6. 3: was i n t r o d u o e d into the poly-

support / p o l y u r e t h a n e

sponge / as s a t u r a t e d m e t h a n o l s o l u t i o n L-7_7°

The studies of the rate of d r u g release as a f u n c t i o n of time through P A A h y dro~el later into w a t e r were o a r r i e d out w i t h the a i d of B e o ~ - m n Ao~a M I V speotrophotometer

f o r w a v e length 275 nm. B i o l o g i o a l aotivity of ohlorotetra-

oyoline h y d r o o h l o r i d e was also d e t e r m i n e d s p e o t r o p h o t o m e t r i o a l l y

in the U V

r ~ g i o n a o o o r d l n ~ to m e t h o d o l o g y L-8_7. The toxloity of the S l ~ e a d PAA h y d r o ~ e l s was tested on p r o t o z o a n S p i r o s t o e ~ m a m b i g u u m o b s e r v l n 6 its b e h a v i o u r a n d sux~ival a f t e r i n t r o d u o i n ~ it into I aqueous extraots

of the p r e p a r e d PAA ~els.

RESULTS Chlorotetraoyoline tlon

hydrool~oride

on mioroorKantsms

latively

high

radiation

/

is

obaz~oterimed

Staphylooooous resistanoe

aureus,

durin~

by a wide speotrum Esoheriohia

irradiation

in a solid

It dissolves w e l l b o t h in m e t h a n o l a n d in water. Aqueous tetraoyoline hydroohloride

exibit f o u r oharaoteristio

ooli

/

state

solutions

of ao-

and a ~eL-9_7.

of ohloro-

bands of a b s o r p t i o n

in

910

J. ROSIAK, K. BURCZAK AND W. PEKALA

c¢

CH3 OH ""

H

H

H

H, ~(CH=) H

%

"

CONI~ OH

Fig. 3.

0

OH

0

Structural formula of chlorotetraoycline hydroohlorids.

the UV region / 199, 230, 275 and 365 nm /, what enables qulok, quantitative analysis. This antibiotio dissolved in water loses its biologioal aotivity 8s a result o f

hydrolysis. The deorease of biologioal aotivity to 50 ~ ooours

al~eady after four days of storing the solution at room temperature / Fig° 4 /°

100

8C

Z60 -~

°411 o

N 2o

en

o

I

2

I

4

I

6

I

8

l J0

Dose [kOy]

Fig. 4.

The dose dependenoe of biologioal aotivity of ohloro%et~aoyoline hydroohlorlde°

Rapid deorease o f biologioal aotivity o f olLlorotetraoyoline hydroohloride is the result of ixTadiation of aqueous solutions. 10 kGy dose of 60Co ~--ixTa-dlation souses almost 90 ~ lose of its biologloal aotivity / Fig. ~ /.

In the prooess of obtaining dressing materials the physiooohemioal properties and the behaviou~ of ol~orotetraoyoline h y d r o o h l o r i d e d u r i n g 60Co ~ - i r r a d i a -

Polyacrylamide hydrogels

tion

as well

der

as

the

the influence

data

given

w h i o h are l~obebly effioient the prooess

of aor~lamide

to aooount / Fig. T h e dependenee irTadlatlon

in

of i ~ d i a t l o n

91l

C9,1o_7 o n

litereture

of a considerable

/

soavengers

the

amount

of e~ a n d H, a o t i ~

polymerization

in aqueous

formation

/

un-

of free r a d i o a l s , as i~hlbltors

solutions,

were

of

taken in-

2 /.

of v i s c o s i t y

of aorylamide

dose is shown in Fig.

300

solutions versus

600o

~-

5.

c~

250

o

f.

x 200 ' ~..

aqueous

150

s

too 5o 0,1 0,2 0,3 0,4 0,5 06 Do. [kC~] l~g.

5.

The dose lutlonsz kg/m~ / k ~ m 3 /o

AS i t

can be seen,

ty

the

of

level

irrespective

izTadiated

ohax~aoteristic

caxTied

out

in

dependenoe of viscosity of aoz~/imnlde so•20 % a o r y l m n l d e solution /i~ = 1.047 ! O30 ~ a o r - / l a m i d e s o l u t i o n / ~ : 1,057 Dose rate I = 0,187 Gy/s. J

for

l~ralel

should plot

be

different

of

90 ~ .

the in

the

de~ee

for vs.

1 ~ aqueous

of

contrast

with

ous extracts

m a d e o f PAA h y d ~ o ~ e l s or

was

decay

of motions,

observed.

was

extracts

sponge.

protozoan

for

/

as

the

Fig.

6 /,

hydrogela non-toxic

deformation

in Fig.

the

estimation, 5 /,

The above

conversion

by biolo6~ioal of protozoan prepared for

or destruction

from

the

is

almost

testa

oon-

Spirostomum

for

ooatin~

solutions,

these

the

which

dressing.

aqueous

a fixed

determine

may b e c o n c l u d e d

confirmed

acrylamide

were

to

preparing it

viscosi-

and reaches

0rganoleptio allowed line

and beha~-lour

polyurethane No w e a k n e s s

In

used

dose

of survival

dashed

which,

of conversion

observation

ambi~uum in

doses

/

constant

rapidly

measurements,

15 ~ m PAA g e l s

monomer conversion

Such high

sistin~

for

for

initially

increases

concentrations.

8 ~

characteristic

was r e a c h e d

concentration,

solution

to viscosity

rar~Ee o f d y n a m i c v i s c o s i t y

range

of

aorylamide

the

the

aque-

mioroor~anisms. of

the

tested

912

J. ROSIAK, K. BURCZAK AND W. PEKALA

[

I I

I _l ./ o'.3 FiG. 6.

o'.s o'.6 12°

Dose [kGy]

The dose d e p e n d e n o e of v l s o o s i t y and o o n v e r s i o n de6Tee of 20 ~ a o r y l a m i d e solution.

S t u d i e s of the d o 6 T e e of dru G release as the f u n o t i o n of time were o a r r i e d out i n o o n d i t i o n s olose to these in w h i c h the ready dressings are to be utilized. D r e s s i n ~ samples w e r e f r e e l y p l a o e d w i t h ~el o o a t e d side on the v e s s e l for w e i G h i n 6 s w h i o h was ~ om h i g h a n d its surface was oa 5 om 2- The v e s s e l was f i l l e d w i t h d i s t i l l e d w a t e r of temperature 298 K u p to the point of o b t a i n i n g the menlsous. T h i s a l l o w e d the ~ d u a l

s w e l l i n g of Gel in oontaot w i t h w a t e r

a n d the d1~u~ d i f f u s i o n tb_rou~h the s w e l l i n ~ ~el l a y e r into the w a t e r oontain e d in the vessel. The a m o u n t of the dru G was m e a s u r e d s p e o t r o p h o t o m o t r i o a l l y . The k i n e t i o of a n t i b i o t i o release is s h o w n in Fi~. 7 .

It oan b e

s e e n that the

p r e s o n o e of ~el oauses 8Tadual d i f f u s i o n of a n t i b i o t i c f r o m the oarTier layer t h r o u g h the h y d r o g e l m e m b r a n e into water. The amount of d1~u~ r e l e a s e d d u r i n ~

14,8 h f r o m

the dressings,

n o n - o o a t e d w i t h ~el~ is about I/5 o£ the r e s p e o t i v e

a m o u n t f r o m the dressir~s o o a t s d w i t h h y d r o 6 e l layer. A p p l i o a t i o n of d i f f e rent kinds of h y d r o G e l s o b t a i n e d b y i r r a d i a t i o n of aox-ylamide solutions of d i f f e r e n t m o n o m e r o o n o e n t r a t i o n s makes it possible / see Fi~. 7 / to control the z~ate of dl-ug r e l e a s e f r o m the d~essin~. Fi~ux~

8 shows

the

dependenoe

of

the

de~ee

of

antibiotic

release

from

the

d ~ e s s i n g m a t e r i a l on the stz~uoture of ~el put on a l a y e r of p o l y u r e t h a n e 8ponce. B a s i n ~ o n FilE. 8 it oan be n o t i o e d that w i t h the same gel o o a t i n ~ the b e s t d e ~ r ~ e of d r u ~ r~lease durirqE one day was r e a o h e d for the ~el obtain e d b y i z T a d i a t i o n of ao1~ylamide s o l u t i o n of 25 ~ oonoentration. As experiments h a v e proved~

not only the k i n d of col is deoisive about the

Polyacrylamide hydrogels

913

°°t

2

0

7.

.

,o

o

Fig.

~

.

.

.

I

;o

I

;o

3o

m

Time [ h ]

T h e t i m e c l e p e n d e n o e of t h e r e l e a s e rotetraoyoline hydroohloride from

d e g r e e o£ o h l o the dresein~s.

70

6O so

s

~ 30

-~20 10 I

Concentrationof acrytamidesotution[%] Fig.

amount

that

a deoreaee period

Relatio~hip tetx~oyoline oonoentx~tton Coatin~ with

of dx~g release.

of entihiotio shows

8.

of

release for

Figure in

eaoh kind

of value

the

9,

whioh

funotton

of ~1

of a degree

t ~ n e was aot~%evsd.

between the z~lease dense of ohlorohydmoohloride after 24 h o u r s a n d t h e of aox-/lamtde solution. hydro~le :~ 0,02 k~/m 2.

there

presents

the

of surfaoed exists

of drug

dependenoe

densit~ in

the

the

de@roe

o f PAA h y d r o s @ e l ,

an optimum ooatt~,

release

of

source

above whioh of a defined

9]4

J. ROSIAK, K. BURCZAK AND W. PEKALA

80

6O 0

S

~4o

I

i

Get coating [kg/m 2]

Fi6.

R e l a t i o n s h i p b e t w e e n the z~lease de6Tee of ohlorotetz~oyollne h y d r o o h l o r l d e after 24 h o u r s a n d the ~el ooatin6

9.

• ~

Aooordind~

to

materials

have

-

- without ~el - 16 ~ aozTlamlds 25 ~ aozTlamide 30 ~ aoz~lamlde

preliminary

pharm~cologioal

estimation

the

examined

dressing

the f o l l o w i n g advantages:

they ~ive the possibility ty of z ~ u l a t i n G si~

solution solution solution.

material

of a controlled

the release

by ohoosin~

dz~

release

rate of the therapeutic

the w a y of p r e p a r i ~

rect contact w i t h the wound / hyd~oGel

and the possibili-

agent from the d~es-

the layer Which is in di-

/~

- they do not stick to the wound} - they have a wide range materials

of applioation~

they can be u s e d both as d r e s s i ~

in case of burns and dressings

dermatolocioal - the hydro~el

on z~nnin~ wounds

i~ness |

layer of the dressin~ which is in direct

w o u n d stiokin~

in case of

closely

teotion a ~ i n s t

to the in~ured skin~

infection

uomi~

nin~ the w a t e r f r o m the plasmap this is v e r ~ important

because

~ives not only mechanical

from the outslde~

of the ctvessing}

the lY~ocess of ~eproduotion

of

bacteria. Tn the which

I~esent were

state

passed

to

of the

studies clinic

we prepared to

be

tested

a series

pro-

but also due to retai-

~ives thermostability it stops

contact w i t h the

of

on animals

dressin~ and

materials,

people.

Polyacrylamide hydrogels

915

REFERENCES t.

Wiohterle Nettle,

2. Hoffnmn,

t O.p a n d D. L 4m 18~,

/1960/.

Hyd~ophilio

Gels for

Biolo6ioal

Use.

117.

A.S./1981/.

A Review of

Bioohemioal Prooessln~ Troatments

t h e Use o f R a d i a t i o n

plus

Chemioal and

to Prepare Novel Biomaterlals.

Radlat.

rhea. Chem., 18, 323-3~2. 3- Rather, B.D., and A.S. Hoffman /1976/. Synthetio Hyd~o~els for Biomedioal Applioations. In , Hydrogels for Medioal and Related Applioations "~ J.D. Andrade /Ed./. ACS Symposium Series ~1, 1-36.

~. Rather, B.D. t and A.S. Hoffman /197~/. The E~feot of Cup~io Ion on the Radiation Grsftln~ of N-VinTI-2-P~Trolldone

and Other H T ~ o p h i l i o

mers to Silloone Rubber, J. AppI. Pol~mer Soi.p

Mono-

18, ~183-3204.

5. Br~tkowsEa, W., M. Martynolis t and H. Hflbner /1978/. Spirostomum amblRuum as the Test 0b~eot in the T n v e a t i ~ t l o n s on the Environmental Proteotion. Bull. WAM t I~ ~6. 6. Rosiak, J . , K. Burozak, and W. P~Eala /1982/. Manufaotuz~ of Drossln~ M&te~iale in Composition with Dru6s. Polish Patent No. 236365. 7. Polish Pharmaoopoeia /1970/, IV Ed. j Vol. I ~

PZWL, ~ Warsaw.

8° Eohnp I~.W./1961/. D e t e r m i ~ t i o n of Tet~aoTolinee by Ext~aotion of Fluoresoent Complexes. Applioation ~o Biolo6~ioal Materials. Anal. Chem., /7/, 862-866. 9° Holland,

J. and oo-workers /1967/. E~feot of Gamma Irradiation / 60Co /

on Che Tetl-aQyolines° In , RadiosterilImation of Medloal Produots / Proo. Syrup. Budapest, 1967 /, IAEA, Vienna° pp. 69-81°

N

10. Dzi@~ielewski, J°0./1977/. Gamma Radiolysis of Tetraoyolines in Solutions. II Deoomposition Yields of Funotional Groups and Baeio Chemioal Prooesses Resultin~ from Ga~m~a Irradiation in Me~hanolio Solutions of 0xytetraoyoline Hyd~oohloride° Bull. Aoad. Polon. Sol.! Set. Sol. Chlm., 25, ~91-~99.