DATA AND REVIEW
High Molecular Weight
Poly(ethylene oxide)–Based
Drug Delivery Systems
Part I: Hydrogels and Hydrophilic Matrix Systems
S. Dhawan,* M. Varma, and V.R. Sinha
Polyethylene oxide resins are non-
ionic, high molecular weight, water-
soluble polymers with good
hydrophilicity. Their use in
controlled-release delivery systems
has gained recent interest, and
several oral drug delivery systems
based on hydrophilic matrix and
hydrogels have
been successfully
commercialized.
The authors
review the
properties and
use of PEO in
hydrogels and
hydrophilic
Figure 1: Structure of polyethylene oxide.
matrix systems.
S. Dhawan, PhD, is a
lecturer in pharmaceutics at
the University Institute of
Pharmaceutical Sciences
(UIPS), Panjab University,
Chandigarh 160014, India,
tel. 191 172 2541142,
fax 191 172 2541142,
sanjudhawan@rediffmail.com
and kdd@glide.net.in.
K. Dhawan, PhD, is a drugs
inspector with the Department
of Drugs Control and Regulatory
Affairs, Haryana Health
Department (India). M. Varma
is a research associate at Dabur
Pharmaceuticals (India), and
V.R. Sinha, PhD, is a
professor of pharmaceutics at
UIPS, Panjab University.
*To whom all correspondence should
be addressed.
72 Pharmaceutical Technology MAY 2005
P
olyethyl ene oxide (PEO) resins are made com m erc i a lly
by the catalytic polymerization of ethylene oxide in the
presence of metallic catalyst systems. They are available
with average molecular weights from 200 to 7 3 106.
Produ cts with a molecular weight less than ;25,000 are vis-
cous liquids or waxy solids commonly referred to as poly(eth-
yl ene glycols) (1). The PEO resins descri bed in this revi ew have
a molecular range from ;1 3 105 to 7 3 106. They are repre-
s en ted by the formula (OCH2CH2)n in wh i ch n repre s ents the
avera ge nu m ber of ox yethyl ene groups (;2000 to more than
100,000). As shown in Figure 1, the molecule bet ween the brack-
ets corresponds to the repeat unit of po ly ( ethyl ene oxide). Th e
brackets indicate that this unit is repeated n-times to form the
polymer.
Various grades of PEO are ava i l a ble that differ from one an-
o t h er depending on their molecular weight. All these grade s
find official status in USP 23–NF 18 (see Table I).
Physical properties of PEO
All the grades of PEO are wh i te to of f - wh i te powder or gra n-
ules with a mild ammonical odor. They have crystalline melt-
ing point ra n ge of 62–67 8C, with autoign i ti on tem pera tu res of
280–330 8C and thermal decom position temperatu res of
423–425 8C. They form association complexes through hydro-
gen bonding with a nu m ber of m on om eric and po lym eric el ec-
tron acceptors as well as certain inor ganic el ectro lytes. E l ectro-
chemically, t h ey are classified as non - i onic polymers. The
decompositi on produ cts of PEO are carbon monoxide and car-
bon dioxide. Th ey have a bulk den s i ty of ;500 kg/m3 and con-
tain less than 3% of silicon dioxide and 1% of volatiles. PEOs
a re tough, crystalline po lym ers at room tem peratu re , and their
glass transition temperature decreases slightly with increasing
molecular wei ght from 245 to 253 8C . Th ey are nontoxic, non-
i rritant, and do not generate residue, sediment, or va porous el-
ements (2). All these properties indicate that these polym er
grades are stable to work with.
Solution propert i e s. PEOs are com p l etely solu ble in water at
tem pera tu res as high as 98 8C and com p l etely solu ble in certain
organic solvents su ch as ch l ori n a ted hydroc a rbons. Limited sol-
u bi l i ty exists in a wide va ri ety of other or ganic solvents (e . g . ,
acetone, anisole, but a n o l , butyl acet a te , ethanol, i s opropanol,
w w w. p h a rm t e ch . c o m

Table I: PEO water-soluble resins (Union Carbide literature
377).
Approximate Viscosity range
molecular (cP) at 258 C
2% solution 1% solution
weight 5% solution
100,000 30–50
200,000 55–90
300,00 600–1200
900,000 8800–17,600
2,000,000 2000–4000
4,000,000 1650–5500
5,000,000 5500–7500
7,000,000 7500–10,000
tolu en e , and xyl en e ) , but the resin in these solvents is solu bl e
on ly at el eva ted tem pera tu re s , and the resin may prec i p i t a te
f rom the soluti on at room tem pera tu re. Al t h o u gh PEOs are
completely soluble in cold or warm water, they undergo an in-
verse solu bi l i tyrel a ti onship near the boiling point of w a ter (3).
Thus at ;98 8C, the resin becomes insoluble in water and pre-
cipitates. In solution, PEOs give a pH from ;6.5 to 7.5.
Viscosity. The visco s i ty of the aqu eous soluti ons of PEO resins
depends on the molecular weight, con cen tra ti on , tem perature,
and, because of their pseudoplastic character, the rate of shear
a pp l i ed du ring the vi s co s i ty measu rement. The viscosity in-
creases direct ly as ei t h er the molecular wei ght of the resin or its
concen trati on in aqu eous soluti on incre a s e s . The viscosity of
5% solution of PEOs with molecular weight 100,000, 200,000,
300,000 and 900,000 is 30–50, 55–90, 600–1200, and
8800–17,600 cP, re s pectively. The viscosity of 2% soluti on of
PEO with molecular weight 2 3 106 has been reported to be
2000–4000 cP. High molecular weight PEOs have high viscos-
ity. For example, 1% solution of PEO with molecular weight 4
3 106, 5 3 106, and 7 3 106 has vi s co s i ty of 1650–3500,
5500–7500, and 7500–10,000 cP, respectively.
Powder propert i e s. To prep a re a solid do s a ge form containing
one or more active ingred i ents (su ch as drugs), the material
being com pre s s ed into the do s a ge form must possess certain
physical ch a racteri s tics that lend itsel f to processing in su ch a
m a n n er. Am ong other things , the material to be com pre s s ed
must be free flowing, lu bri c a ted, and, most important, must
possess su f f i c i ent co h e s iveness to en su re that the solid do s a ge
form remains intact after compression. Granular grades of PEO
can be com pressed because gra nules impart good flow proper-
ties. Yang et al. determined the powder properties, mechanical
properti e s , rh eological properties, and rel a ted para m eters su ch
as surface morphology, particle size, glass transition tempera-
ture, and degree of crystallinity of bulk PEO samples (4). The
angle of repose was found to be ;35 for all the grades of PEO.
The aerated bulk density of PEO varies from 0.39 to 0.53 and
the packed density va ries from 0.42 to 0.59. The true density
values of PEOs are similar, and the degree of crystallinity does
not seem to decrease as molecular weight increases (4).
Hi gh crystallinity and smooth sym m etric chains make PEOs
mech a n i c a lly strong, although their glass tra n s i ti on tempera-
tu res are well below 0 8C . The degree of crys t a ll i n i ty is likely to
va ry du ring material processing su ch as shearing and tabl eting.
Yang et al. also reported that bulk WSR N-80H (molecular
wei ght 0.2 3 106) as received had a crystallinity of 85% (4). Th e
crys t a llinity was redu ced to 61.2%, however, wh en the materi a l
was compressed at 2000 lb, and its crystallinity was reduced to
50.6% wh en ground for 5 min with a pestle and mortar. This
is prob a bly a re sult of the stru ctu ral irreg u l a ri ties in the crys-
tal latti ce by sheari n g, slip planes, and stressing. It also has been
reported that because of the vi s coel a s tic beh avi or and large axial
ex p a n s i on of PE O, tablets of rel a tively low tensile strength were
produ ced. Hen ce , PEOs should be bl en ded with high ly com-
pre s s i ble excipients to produce tabl ets on a high - s peed produ c-
tion press.
Applications
Hydrogels. The hydrogel drug delivery systems represent a sig-
nificant interest to ph a rm aceutical practi ce because of their po-
tentiality for drug release within large limits (5). These mono-
lithic systems, under certain conditions, can release drugs at a
constant rate, approximating a zero-order reaction kinetics as
a re sult of case II tra n s port. Graham stu d i ed the diffusion of
u n i form ly dispers ed caffeine in water-swo ll en PEO hyd rogel s
by qu a n ti t a ting the release of solute from thin slabs into a fi-
nite volume of s o lution at 37 8C (6). Fracti onal release fo llowed
a time (t0.5) rel a ti on for thicknesses bet ween 1 and 5 mm and
various polymer compositions with equilibrium water uptake
of 118–530 parts per 100 dry polymer. Values of the diffusion
coef f i c i ent were calculated from the ex peri m ental re sults by as-
suming the hyd rogel to be an infinite sheet and a rectangular
para ll el ep i ped. Both bound and free water were iden ti f i ed in
differen tial calori m etry scans of the hydrogel . The diffusion co-
efficient for the various water contents obeyed the Davis rela-
ti on , and this equation appe a red to represent the diffusion ch a r-
acteristics of these PEO hydrogels quite accurately.
McNei ll and Graham investi ga ted the release of water-soluble
solutes from PEO hydrogels (7). The hydrogels—which owe their
hydrophilicityas a result of PEO conten t — s well ed and absorbed
as mu ch as three times their dry wei ght in water. Th ey had a glass
tra n s i ti on tem pera tu re bel ow body tem pera tu re. A ra n ge of d i f-
fusates was studied ranging from low water-soluble prostaglandin
E2 to high ly water-soluble lithium chlori de. Devi ce geometry was
restri cted to approximations to infinite slabs with more than 85%
total surface area over the top and bo t tom su rf aces so that release
was predominantly one-dimensional and the contro lling va ri-
a ble was thickness. The increase in surface area with time, drug-
solu bi l i ty in the water-swelling matri x , and the presence of c rys-
tallinity were important factors governing the profile and level
of release ra te with time. The diffusional ex ponent, n, ra n ged
from 0.79 to 1; that is, good anomalous to zero-order release.
This is a high ly de s i ra ble ra n ge of va lues for contro ll ed - release
devi ces.
Transforming growth factor-beta 1 (TGF-beta 1) has bene-
ficial effects on wound healing. However, the ideal method for
its ad m i n i s trati on to the wound site remains unknown. Puo-
lakkainen et al. incorpora ted TGF- beta 1 into a po l ox a m er gel ,
Du oderm hydroactive paste, and PEO hydrogel (8). The release
Pharmaceutical Technology MAY 2005 73
DATA AND REVIEW
of 125I-label ed TG F- beta 1 from the carri ers was measu red in
full - t h i ckness wounds in rats. The healing of the wounds was
analyzed by histology and wound area measurements. Wound
size measurements and the analysis on the amount of cellular
influx, fibroplasia, and granulation tissue showed that a single
dose (1 mg/wound) of locally administered TGF-beta 1 signif-
icantly (p , 0.01) enhanced the wound healing. Kofinas et al.
also ob s erved that hydrogels form ed from po ly ( ethyl ene oxide)
are of i n terest for bi om edical app l i c a ti on s , su ch as the trans-
portation of growth factors (9).
Mc Neill and Graham inve s ti gated the diffusive release of
proxyphylline from urethane cro s s - l i n ked PEO hyd rogels in
w a ter- s wo llen slabs, s ph ere s , and cyl i n ders (10). Con trary to
gen eral conventi onal wi s dom, they found that cyl i n ders and
sph ere s , wh i ch have considera ble po ten tial advantages for ora l
delivery, could provi de good anomalous ra tes for wh i ch the
ex pon ent of release into water from the dry xerogels was 0.8,
com p a red with 1.0 for zero - order. An expon ent of 0.94 was
found for release into water from larger xerogel flat slabs,
t h ereby confirming that these con f i g u rati ons can provi de es-
s en tially constant del ivery formu l a tions from wh i ch the ac-
tive agent cannot be dumped. The experimental release of
prox yphylline was sustained from swollen sph eres of these
po lym ers.
Abraham et al. ob s erved that hydrogels made from PEO pro-
vided an aqueous environ m ent for unhindered diffusion of
small polar molecules (11). These hyd rogels also provi ded a
suitable matrix for a large protein such as glucose oxidase and
retain the enzyme in the active form. Although electron-beam
irrad i a ti on can be detrimental to pro tein stabi l i ty, it is po s s i bl e
to incorpora te pro tein in su ch hydrogel matri ces by keeping the
irradiation to ultra-low doses. These hydrogels can be suitable
platforms for drug delivery across the skin.
Lambov et al. studied the factors that can even tu a lly influ-
en ce the release of d ru gs from PEO hydrogels (12). Th ey deter-
mined a differen ce in the swelling of wet and dri ed matrices.
G en era lly, the release takes place as an anomalous diffusion (re-
lease ex pon ent n = 0.53 to 0.86). The ra te and kinetics of re-
lease (t1/2 or zero - order prevailing) depen ded mostly on the dru g
content in the matrices and the irradiation dose.
Si lverman et al. dem on s trated that ph o topo lym erizable PE O
hydrogels can be used as a tissue adhesive and that such an ad-
hesive sign i f i c a n t lyredu ces seroma formation in the rat mas-
tectomy model (13).
Savas and Guven synthesized PEO hyd rogels by irrad i a tion
and then characteri zed them for their network structure, swelling
properties in water, and the number average molecular weight
between crosslinks (14). Sa l i c ylic ac i d , phthalic ac i d , and resor-
cinol were used as model su b s t a n ces for their contro ll ed release
from hydrogels. The active su b s t a n ceupt a ke capac i ty of hydro-
gels was lowest for phthalic acid and highest for re s orcinol in
the gel system. The release was lowest both in rate and in total
amounts in hyd rogels containing phthalic ac i d . The release was
greater in samples with salicylic acid and highest in those with
resorcinol.
PEO hydrogels were synthesized and used to produce coated
wires and con duits for baboon blood com p a tibi l i ty stu d i e s .
74 Pharmaceutical Technology MAY 2005
Bl ood material interactions were studied both by SEM and 111In-
labeled platelet deposition. The formulations containing PEO
had low levels of platelet deposition (15).
Ma suda and Nakanishi inve s ti ga ted the swelling beh avi or of
PEO gel in soluti ons of va rious salts (16). The gel de - s well ed in
s o lutions of s od ium salts and swelled in solutions containing
s tron gly hydrated cati on s . The degree of swelling of the gel was
in the following order: CsCl , KCl , NaCl , LiCl and BaCl2
, Sr Cl2 , Ca Cl2 , MgCl2. These re sults were interpreted in
terms of i n teracti ons bet ween the po lym er and the ions thro u gh
the hydration layers of the cations.
The swelling behavior of rad i och em i c a lly cro s s l i n ked PEO
gels in aqu eous sod ium dodec yl su l f a te (SDS) with and with-
o ut Na Cl was investi ga ted (17). In the absen ce of NaCl, PE O
gels with various degrees of crosslinking began to swell from a
concentration lower than the critical micelle concentration of
SDS, and then showed sigmoidal enhancements of swelling in
a high er SDS con cen trati on regi on until the degrees of s well i n g
re ach ed maximum va lues. When Na Cl was pre s ent, the swelling
beh avi or of PEO gel was different from that wh en Na Cl was ab-
sent. The concentration where the swelling appears decreased
with an increase in NaCl concentration.
Alexandre et al. prep a red PEO mac romon om er-based hy-
drogels for artificial or gans (18). Th ey ob s erved that implanted
PEO hyd rogels are well tolerated by the host immune sys tem .
A biocompatibility test of the hydrogel showed that only a few
f i broblasts were ad s orbed on the hydrogel su rf ace . Di f f u s i onof
glucose through PEO hydrogels was possible.
Hyung and Bae prep a red various hyd rogels, com po s ed of
short hydrophilic PEO and hydroph obic bl ock , by po lycon den-
sati on re acti on (19). Po ly ( tetra m et hyl ene oxide) (PTMO) or
po ly ( d i m et hyl siloxane) (PDMS) was ch o s en as a hyd roph obi c
bl ock because of t h eir wi de use as a bi omaterial. Most hyd ro-
gels showed a comparable value of macrophage density to Pel-
l ethane (Dow), control po lymer, whereas they did significantly
lower forei gn body giant cell den s i ty and covera ge because of
the presence of PE O. The more significant degrad a ti on was ob-
s erved in the hyd rogels with lon ger PEO bl ock and PTMO as a
hydrophobic block instead of PDMS.
In an other stu dy, t wo kinds of chitosan-based hyd rogels, a
crosslinked chitosan referen ce gel and a ch i to s a n – PEO semi-
interpenetrating network (semi-IPN), with potential pH-sen-
sitive swelling and drug delivery properties were characterized
(20). Swelling studies were performed on the two kinds of hy-
d rogels by differen tial scanning calori m etry at pH 1.2 and by
the gravi m etric met h od at pH 1.2 and pH 7.2. The pH-depen d-
ent swelling properties were ob s erved with both hydrogel s , t h ey
were however improved for the semi-IPN. The re sults obt a i n ed
by both tech n i ques were in good agreem ent and indicated that
the semi-IPN contained more bound water than the reference
gel, prob a bly because of the pre s en ce of the hyd rophilic PEO
chains. The semi-IPN displayed improved mechanical proper-
ties compared with those of the reference gel.
Hydrophilic matrix sys te m . Hyd rophilic matrix tablets are a
common and commerc i a lly successful means for prolonged ora l
d rug del ivery. Th ere are nu m erous app l i c a ti ons of PEO in ma-
trix systems. Sako et al. (21) investigated the effect of gelation
w w w. p h a rm t e ch . c o m
DATA AND REVIEW
of t wo types of PEO matri ce s — s l owgelling (SG) tabl et and
rapid gelling (RG) tablet containing PEG 6000—on the
colonic release of acetaminophen in dogs. Slow gelling and
rapid gelling showed similar drug-release behavior in vitro.
In oral ad m i n i s trati on to dogs , the two formu l a tions showed
similar gastroi n te s tinal transit, re aching the co l on within
2–4 h after oral do s i n g. In contra s t , however, the two tabl et s
produced different plasma levels from 2 h postdosing, with
plasma levels of RG tabl ets high er than those of SG tabl et s
and with smaller individual vari a ti on. Di rectly ob s erved
co l onic dru g - release behavi or of RG tabl ets was similar to
in vitro drug release, whereas that from SG tablets was sup-
pressed. The research ers conclu ded that co l onic drug release
was closely rel a ted to the gel a ti on of hydrophilic matrix, and
rapid gelation provided continuous in vivo drug release. Figure 2: Effect of polyethylene oxide concentration on release t50–t90
Di m i trov and Lambov inve s ti ga ted the release of vera- values of glipizide from hydrophilic matrices. Upon wetting of the tablet,
pamil hydrochlori de from high molecular wei ght PEO tabl et s the polymer on the tablet surface hydrates to form a gel layer, which
(22). The drug release proceeded as a contro ll ed diffusion expands with time into the interior of the tablet, allowing diffusion of the
with the va lue of n ranging from 0.44 to 0.47. Zhang and drug from the tablet core. It is expected that the release kinetics are
Mc G i n i ty investigated the release of chlorpheniramine governed by the erosion–drug diffusion process after the swelling front
m a l e a tefrom matrix tabl ets prep a red by hot-melt ex tru s i on meets at the core of the tablet.
(23). Du ring the hot-melt ex tru s i on proce s s , a dry powder
bl end of d ru g, po lym er, and other ad juvants was fed into the
extruder and melted inside the barrel of the machine. The order. This novel approach in formu l a ti on developm ent co u l d
molten mass was extruded through a rod-shaped die and then po ten ti a lly be used for con s t a n t - ra te delivery of high ly solu bl e
c ut manu a lly into 400-mg tabl et s . Ch l orph eniramine maleate bi oactive agents over an exten ded peri od for specific bi oph a r-
and PEO were stable under the processing conditions. The mo- m aceutical need s .
lecular wei ght of the PE O, the drug loading percen t a ge , and the Pillay and Fassihi also worked to probe the mechanism as-
i n clu s i onof po ly(ethyl ene glycol) as a processing aid influ enced s oc i a ted with indu ced matrix sti f fening via tex tu ral analysis as
the processing conditions and the drug release properties of the a consequ ence of in situ el ectro lyte interacti ons within hydrox-
ex truded tabl ets. Release of ch l orph en i ramine maleate from the ypropyl met hyl cellulose (HPMC) and PEO matrices in rela-
matrix tabl ets was faster in acidic med ium than in purified water ti on to their role in con tro lling the release of highly solu bl e
and ph o s ph a te bu f fer (pH 7.4). D rug release from the matrix dru gs su ch as dilti a zem hyd roch l ori de (25). The dynamics of
tablet was contro ll ed by ero s i on of the PEO matrix and the dif- HPMC and PEO matrix swelling du ring hydration in the pre s-
fusion of the drug through the swollen gel layer at the surface en ce of a ppropri a te electro lytes inten ded to indu ce con s t a n t
of the tablets. Chlorpheniramine maleate was dispersed at the drug-release ra tes from simple monolithic sys tems were influ-
m o l ecular level in the PEO matrix at low dru g - l oading level s , en ced by con ti nu o u s ly shifting peri ph eral matrix sti f fening to-
and the re s e a rchers observed rec rystall i z a ti on of ch l orph en i- w a rd the matrix core in a manner dependent on electro lyte
ramine maleate at high dru g - l oading level s . Ho t - m elt ex tru s i on con tent and hydration time. Ma trix ero s i on for HPMC and
was shown to be a vi a ble novel met h od to prepare su s t a i n ed - PEO con trols (i . e . , wi t h o ut el ectro lyte) fo ll ow linear dissolu-
release tabl et s . PEO was a stable and su i t a ble po lym eric carri er ti on kineti c s , and formu l a ti ons with el ectro lyte ch a racteri s ti-
for the hot-melt extrusion process. cally undergo a squ a re - roo t - of - time decline in weight. The
Pillay and Fassihi de s c ri bed a novel monolithic drug deliv- s welling po ten tial of the electro lyte - containing matri ce s , in-
ery sys tem for metoprolol tartara te (24). This sys tem fo llowed f lu en ced by the boundary infiltrati on proce s s , reflected con-
p H - i n depen dent zero-order kinetics over an ex ten ded peri od . s i derable su ppre s s i on du ring the first 2 h of ex po su re to the
PEO was used as a hyd rophilic gel–based swell a ble po lym eric m ed ium, wh ereas su b s equent events differed in both po lym ers.
material for this novel approach. The sys tem used va rious el ec- Yi et al. used PEO as a sustained-release matrix sys tem of ce-
trolytes, namely, sodium carbonate and/or pentasodium f a trizine propyl ene glycol, which is a new sem i s y n t h etic broad -
tri po lyph o s phate. E l ectro lytic con du ctivity measu rements per- spectrum and orally active cephalosporin (26). F ive kinds of
formed with the simultaneous analysis of matrix swelling sustained-release matrix tablets were formulated with various
s h owed that sod ium carbon a te formed a high ly re active ma- content of PEO and other ingredients. On increasing the PEO
trix within the first 3 h of med ium pen etrati on . On the other con tent, the dru g - release ra te from matrix tablets dec re a s ed .
hand, l a r ger molecules su ch as pen t a s od ium tri po lyph o s ph a te Af ter oral administra ti on, Cefa-PG PEO matrix tablets were
m a i n t a i n eda constant con du ctivi ty level , wh i ch may be rel a ted more bi oavailable than gen eral Cefa-PG capsules in be a gle dogs .
to its lower solubi l i ty and diffusion in comparison with sodium The area under the curve for the sustained-release PEO matri x
carbon a te . On the basis of m odel fitting and stati s tical analy- tablet was higher than that of the general dosage form.
sis, the research ers showed that drug-release kinetics were zero Ma ggi et al. eva lu a ted the ef fect of UV light on the release
76 Pharmaceutical Technology MAY 2005 w w w. p h a rm t e ch . c o m
ch a racteri s tics of ex ten ded - release matri x tions containing a soluble drug (diltiazem) f rom the swelling and dissolving sys tems,
tablets containing HPMC or PEO as re- and, alternatively, PEO or HPMC of two Apicella et al. examined the solvent pen-
tarding polym ers (27). Two dru gs, n i fedip- different vi s co s i ty grades (30). These for- etrati on , po lym er swelling, and dissolu-
ine (insoluble and photolabile drug) and mulations had the same composition ex- ti on behavi or of etophyll i n e - containing
diltiazem (soluble and photostable drug) cept for the po lym er used . Results showed PEO tablets (31). The authors reported
were used in the stu dy. P h o todecom po s i- that slower release ra tes can be obt a i n ed the pen etra ti on depth evo luti on kineti c s
tion of nifedipine was evaluated, and the from the plain matri ces containing HPMC of t a bl ets made of p u re PEOs with aver-
formation of the photoproducts was fol- compared with those containing PEO. age molecular wei ghts of 600,000 and 4 3
lowed du ring the dissoluti on process. Re- Swelling pro p e rties of PEO hyd rophilic mat r i c e s. 106 containing 10% etophylline. The PE O
garding the dissolution stability, the ma- To characterize properly the drug release tablets of molecular weight of 600,000
trix tabl ets containing HPMC ex po s ed to
UV light did not show significant differ-
ences in dru g - release profiles com p a red
with the same non - i rradiated formu l a-
tion. The matrix tablets that con t a i n ed
PEO were ex po s ed to the same conditions
of UV light showed a rem a rk a ble increase
of drug-release rate within the first min-
utes of the dissolution test (burst effect),
which is particularly important because
it can cause the loss of the desired thera-
peutic control.
Luber and Bunick described an inven-
ti on rel a ted to an immed i a te-release tabl et
capable of being chewed or disintegrated
in the oral cavi ty, which comprised a phar-
maceutically active ingredient and a ma-
trix com posed of po ly ( et hylene ox i de )
having average molecular weight from
;500,000 to ;10,000,000 (28). The tabl et
possessed exceptionally good mouth feel
and stability.
Bern er and Louie de s c ri bed con troll ed -
release oral dosage forms for the con ti nu-
ous, su s t a i n ed administration of
c i proflox acin to the upper ga s trointestinal
tract of a pati ent in wh om the fed mode
was indu ced (29). The majority of the
a gent was delivered on an ex ten ded-release
basis to the stom ach, duodenu m , and
u pper regi ons of the small intestine, with
d rug del ivery in the lower gastrointestinal
tract and colon substantially restri cted. Th e
do s a ge form com prised a matrix of a bi o-
compatible, hydrophilic, erodible po lymer
PE O. The drug release ra te was pri m a ri ly
contro ll ed by ero s i on ra te .
G e o m atrix system. The Geom a trix tech n o l-
ogy is a vers a ti l e , well - k n own met h od to
ach i eve ex ten ded release of d ru gs at a con-
stant ra te (see Figure 2). It consists of a
hyd rophilic matrix core , wh i ch con t a i n s
the active ingredient, and one or two im-
perm e a ble or sem i perm e a ble polym eric
coa ti n gs (films or com pressed barriers)
applied on one or both bases of the core.
Maggi et al. prepared four core formula-
Ci rcle/eINFO 53 Pharmaceutical Technology MAY 2005 77
DATA AND REVIEW
showed an almost linear shape in the penetration depth curve
as a functi on of ti m e , which indicated that after a very short
i n i tial tra n s i en t , the pen etra ti on front moved into the po lym er
at a constant ra te. The tabl et containing the PE O of h i gh er mo-
lecular weight was characterized by an initial rapid water pen-
etra ti on ra te. It was ob s erved that a sharp front moved at a con-
stant ra te thro u gh the unpen etra ted tabl et core after a swelling
time sign i f i c a n t ly larger than the time elapse detected for the
PEO of lower molecular weight.
Kim observed the swollen gel thickness and outer diameter
of a dru g - f ree PEO tabl et (32). It was observed that the con-
stant gel thickness was obtainable with the PEO tablets of mo-
l ecular weight 900,000 and 2 3 10 6, whereas the swo ll en gel
thickness from the PEO tablet of 4 3 106 kept increasing with
time. E a rly in the swell i n g – ero s i on proce s s , the overa ll size of
the tablet along with the gel layer increased rapidly as a result
of the immediate swelling of the PEO tablet. The swelling rate
of the polymer equals the dissolution rate of the swollen poly-
mer gel, re su l ting in the synch ron i z a ti on of the gel-layer thick-
ness. With the low molecular wei ght PE O, the synch ron i z a ti on
of the gel-layer thickness took place earlier compared with the
PEO of high molecular weight. The constant gel-layer thick-
ness occ u rred short ly after the outer diameter began to dec rease.
The higher the molecular wei gh t , the later the synch ron i z a ti on
took place . However, for a high er molecular weight (43 106)
t a bl et , a synch ron i zed gel layer was not obt a i n ed and the gel-
layer thickness con ti nu ed to increase. The re s e a rchers also con-
clu ded that with high molecular weight PEO and HPMC, the
s welling of the po lym er was the dominant step in con tro ll i n g
release kinetics over the ero s i on of the swo ll en polymer. With
PEO of l ow molecular wei gh t , the ero s i onwas the ra te - deter-
mining step for the release kineti c s . However, the degree of
swelling of PEO was high er than HPMC, t h erefore drug release
from PEO matrices provided more favorable kinetics with n =
0.8 as compared with n = 0.66 for HPMC (32).
Ma ggi et al. eva lu a ted the rel a tive influ ence of d rug diffusion
and polymer erosion mechanisms of PEO in the drug delivery
process (33). They stu d i ed the hyd rati on behavior of matrix
t a bl ets containing a water- s o lu ble drug and PEOs of t wo dif-
ferent molecular wei gh t s : Po lyox WSRN 1105 (molecular wei gh t
0.9 3 106) and Polyox WSRN 301 (molecular weight 4 3 106).
Re sults showed that the PE O with the high er molecular wei gh t
swelled to a greater extent and formed, upon hyd ration, a
s tron ger gel, wh i ch is therefore less liable to ero s i on than the
PEO of lower molecular weight.
Drug release from a hyd rophilic matrix sys te m . A hyd rophilic matrix
t a bl et is a simple-to - formu l a te, yet effective , sustained - rel e a s e
d rug del ivery system, in wh i ch a bi oactive is uniform ly distri b-
uted within a po lym er matrix. Because PEO is non - i onic, no
interaction between the drug and polymer is expected. Mensi-
tieri et al. observed that the low-molecular weight PEO shows
a zero-order release kinetic over the entire duration of the test
(34). To increase mucoadhesion, however, it could be blended
with higher-molecular weight fractions to increase gel elastic-
ity and adhesion.
Kim et al. investigated the release of theophylline from PEO
tablets and observed that the release of the drug was not influ-
78 Pharmaceutical Technology MAY 2005
en ced by the pH va ri a ti on of the dissoluti on med ium (35). Th i s
result su ggested that PEO may be a good candidate for oral dru g
del ivery sys tems because oral do s a geforms travel along the ga s-
trointestinal tract in which the pH changes from an acidic en-
vironment in the stomach to a weak base.
Wu et al. devel oped a com preh en s ive mathem a tical model
to de s c ri be the tra n s port ph en om ena in contro ll ed - release of a
small-molecule drug from PEO cyl i n d rical tabl ets (36). Severa l
aspects in release kinetics were taken into acco u n t , i n cluding
the swelling of the hyd rophilic matrix and water pen etra ti on ,
t h ree - d i m en s i onal and con cen tra ti on - depen dent diffusion of
drug and water, and po lym er dissoluti on . At low and moder-
ate initial load i n gs , drug-release profiles using this model were
predicted with an extremely good agreement with experimen-
tal data. At very high loadings, the model showed ra t h er accept-
a ble agreem ent bet ween theoretical and ex peri m ental re sults.
The overa ll release process was high ly depen dent on the matri x
swelling, diffusion, and polymer dissolution.
Ef fe ct of drug solubility on the release of drug from a matrix system. Ki m
investigated the effects of drug solubility on zero-order release
kinetics and elucidated the release mechanism of a drug from
d i rect ly com pre s s ed tabl ets of PEO (35). Di rect ly compre s s ed
t a bl ets con s i s ting of PEO (molecular wei ght 0.9, 2.0, and 4.0 3
106) and dru gs (solu bi l i ty ranging from 290 to 25,000 mg/L)
were formu l a ted with or wi t h o ut a water-soluble exc i p i ent (lac-
tose). The re s e a rch ers observed that as the solu bi l i ty of the dru g
decreased, the du ra ti on of drug release increased. The release
of d i cl ofen ac sod ium (2.5% solubility in water) was ch a racter-
ized as non - F i ckian kinetics. In this case, drug diffusion thro u gh
the swollen gel matrix was the governing step for the drug re-
lease. As drug solu bility dec re a s edbel ow 1% (theophylline and
salicylic acid), drug release slowed as a result of the longer dis-
soluti on time of the drug ion in the matrix. As the drug solu-
bi l i tydec re a s ed further bel ow 1000 mg/L, the dissoluti on of the
d rug became a dominant process in con tro lling the drug re-
lease from PEO tabl ets. This acco u n ted for a constant release
with n = 0.96 and n = 1.10 for su l f a t h i a zole and sufapyridine
to as high as 85–90% release, respectively.
Ef fe ct of polymer molecular weight and concentration on drug release. Ap i-
cella et al. stu d i edthe release of b-hyd rox yet hyl theophylline
from va rious molecular bl ends of PEO (31). Th ey ob s erved that
the drug release from the high molecular wei ght PEO was stri ctly
rel a ted to po lym er swelling ra t h er than dissoluti on, and dru g
release from the low molecular wei ght PEO was stri ct ly depen d-
ent upon the polymer dissolution mechanism.
Kim inve s ti ga ted the effect of PEO molecular weight and
d rug loading on the release of dru gs of va rying solu bi l i ty from
direct ly compre s s ed tabl ets (35). The drug release was contro ll ed
at a zero - order ra te by the dissoluti on of the drug at high load-
ing (39%) from tabl ets containing PEO of m o l ecular wei ght 4.0
3 106. The release of w a ter insolu ble drugs from high molec-
ular wei ght (0.9 3 106) tabl ets was swelling–erosion con tro ll ed,
resulting in zero-order release kinetics. At low loading (20%),
d rug diffusion thro u gh the swollen gel layer was the governing
release mechanism. For a high ly water-solu ble drug (e.g., di-
cl ofen ac sod ium), drug diffusion was the contro lling mech a-
nism regardless of the molecular weight of the PEO.
w w w. p h a rm t e ch . c o m
 Mi glani prep a red hyd rophilic matri ces containing glipizide,
PEO, dicalcium phosphate, and lubricants (37–39). At ex trem ely
low po lym er conten t , the hydroph obic ef fect of d i c a l c iumph o s-
ph a te resulted in low - s welling tabl ets and the sys tem beh aved
l i ke an ero s i on sys tem. Because of the hyd roph obic natu re of
d i c a l c ium ph o s phate, the en try of the pen etrant into the ma-
trix was rel a tively slower, t h ereby re sulting in a low degree of
swell i n g.However, at a particular concen trati on , the hydrophilic
effect of the polymer was high enough to form a gel that acted
as a diffusion barri er. Af ter that con cen trati on , the release of
the drug dec re a s ed with an increase in polym er con tent (see
F i g u re 3). But wh en lactose was used as a dilu en t , the release
ra te dec re a s ed with an increase in po lym er con tent owing to
the formation of an effective gel layer.
Conclusion
Various grades of h i gh molecular wei ght PEO are available that
can be sel ected depending upon the natu re of active ph a rm a-
ceutical agent and del ivery sys tem requ i red. PEO resins form
a s s oc i a ti on com p l exes with a wide va ri ety of m on om eric and
po lym eric or ganic com po u n d s . The form a ti on of an associa-
ti on com p l ex with one of these com pounds gen era lly produ ces
a produ ct with properties and uti l i ty qu i te different from those
of either com ponent. PEO hyd rogels have attracted interest for
bi om a terials app l i c a ti ons because of t h eir gen era lly favora bl e
bi ocompatibility. Va rious therapeutic agents su ch as tra n s form-
ing growth factor beta 1, proxyphyll i n e , and caffeine have been
incorpora ted in the hydrogel s . Ch i tosan-PEO semi-IPN showed
pH-dependent swelling. Factors that influ en ce the release of
d ru gs from hyd rogels also have been investiga ted. G en erally,
the release takes place as anamolous diffusion. Various hy-
d rophilic as well as hyd roph obic block po lym ers have been
u s ed with PEO for hydrogel s . PEO has been used for contro ll ed -
release matrix sys tems of w a ter- i n s o lu ble as well as water- s o l-
u ble dru gs . The dru g - release mechanism is contro ll ed by sev-
eral va ri a bles in a dynamic proce s s . Du ring the release of d ru gs
from hyd rophilic matri ces of PE O, t wo mechanistic ph en om-
ena take place : the swelling and the ero s i on of the po lymer.
The release kinetics of the drug from the tabl et are depen dent
upon the relative magn i tu de of the ra te of po lym er swelling at
the moving ru bbery – glassy front and the ra te of po lym er ero-
sion at the swo ll en po lymer–dissoluti on med ium front. It is
prefera ble to attain the synch ron i z a ti on of the vel oc i ties of the
s welling front and the ero s i on front to ach i eve zero - order re-
lease kinetics from PEO matrices. Wa ter- s o lu ble dru gs are re-
l e a s ed by diffusion of the drug through swo ll en gel layer, and
insoluble drugs are released by ero s i on of the polym er layer.
The molecular weight of PEO, con cen tra ti on of po lym er, sol-
ubility of the dru g, and the amount of the drug affect the re-
lease of the drug from the matri ce s .
Acknowledgments
The authors ex press their heartfelt gra ti tu de to Mr. Ri c a rdo
Du a rtrej of Union Ca rbi de Inc. for providing the litera tu re and
samples of PEO.
References
1. D.B.Braun, “Poly(et hyl ene oxide)” in Ha n d b ook of Water Sol u ble Gums
and Resins, R.L. D avidson, Ed. (Mc Graw – Hi ll Book Com p a ny, New
York, NY, 1980), pp.19.1–19.33.
2. Sentry Polyox Wa ter Sol u ble Resins in Su s t a i n ed - Release Oral Pharm a-
ceutical Applications (Literature 377, Union Carbide, Danbury, CT).
3. F.W. S tone and J.J. S tratta, “ Et hyl ene Oxide Po lym ers ,” in En c ycl ope-
dia of Polym er Sci en ce and Technology, Vol. 6 (John Wi l ey & Son s , Inc.,
New York, NY, 1967), pp. 103–145.
4. L. Ya n g, G. Venkatesh, and R. Fassihi, “Ch a racterization of Com pre s s-
ibi l i tyand Com p acti bi l i ty of Po ly ( et hyl ene ox i de) Po lym ers for Mod-
i f i edRelease Application by Com p acti on Si mu l a tor,” J. Ph a rm. S ci . 85
(10), 1085–1090 (1996).
5. N.B. Gra h a m , “Hyd rogels for Useful Therapy,” s pecial publ i c a tion,
Royal Society of Chemistry, 87(High Value Polymers), 79–97 (1991).
6. N.B. Graham et al., “Caffeine Release from Fully Swollen Poly(ethyl-
ene oxide) Hydrogels,” J. Controlled Release 5 (3), 243–252 (1988).
7. M.E. Mc Nei ll and N.B. Gra h a m , “ Properties Con tro lling the Di f f u-
sion and Release of Water-Soluble Solutes from Poly(ethylene oxide)
Hyd rogels, II: Di s pers i on in an In i ti a lly Dry Sl a b,” J. B i o m a ter. Sci.
Polym. Ed. 5 (1–2), 111–130 (1993).
8. P.A. Pu o l a k k a i n en et al., “The Enhancem ent in Wound Healing by
Tra n s forming Growth Factor- beta 1 (TG F- beta 1) Depends on the
Topical Delivery System,” J. Surg. Res. 58 (3), 321–329 (1995).
9. P. Kofinas, V. Athanassiou, and E.W. Merrill, “Hydrogels Prepared by
E l ectron Irrad i a ti on of Poly ( et hyl ene ox i de) in Wa ter So luti on : Un-
ex pected Depen den ce of Cross-link Den s i ty and Pro tein Di f f u s i on
Coefficients on Initial PEO Molecular Weight,” Biomaterials 17 (15),
1547–1550 (1996).
10. M.E. Mc Nei ll and N.B. Gra h a m , “ Properties Con tro lling the Di f f u-
sion and Release of Water-Soluble Solutes from Poly(ethylene oxide)
III: Devi ce Geom etry,” J. Biomater. Sci. Polym. Ed. 7 (11), 937–951
(1996).
11. W. Abraham et al., “Hyd rogels for Ion toph oretic Ex tracti on of G lu-
cose through Skin,” Polym. Mat. Sci. Eng. 76, 570 (1997).
12. N. Lambov, M. Dimitrov, and S. Tsankov, “Biopharmaceutical Study
of Cro s s - l i n ked Po ly ( et hyl ene oxide) Hyd rogels.” Pharmazie 52,
790–793 (1997).
13. R.P. Si lverman et al., “Tra n s dermal Photopo lym eri zed Adhesive for
Seroma Prevention,” Plast. Reconstr. Surg. 104, 2331 (1999).
14. H. Savas and O. Guven , “ Inve s ti ga tion of Active Su b s t a n ce Rel e a s e
from Poly(ethyl ene ox i de) Hydrogels,” Int. J. Ph a rm. 224 (1–2), 151–158
(2001).
15. S.L. Verdon et al., “Scanning Electron Microscopy Analysis of Poly(et h-
ylene ox i de) Hyd rogels for Blood Contact ,” Scan. Microsc. 4 (2),
341–349; discussion 349–350 (1990).
16. Y. Ma suda and T. Na k a n i s h i , “ Ion-Specific Swelling Beh avior of
Poly(ethylene oxide) Gel and the Correlation to the Intrinsic Viscos-
i ty of the Po lym er in Salt So lutions,” Colloid Polym . Sci. 280 (6), 547–553
(2002).
17. Y. Masuda et al., “ Swelling of Po ly ( ethyl ene oxide) Gel in Aqu eous
Solutions of Sodium Dodecyl Sulfate with Added Sodium Chloride,”
Colloid Polym. Sci. 280 (5), 490–494 (2002).
18. E. Alexandre et al., “Poly(ethylene oxide)–Based Hydrogels Designed
for Artificial Organs,” Polym. Mat. Sci. Eng. 89, 240–241 (2003).
19. P. J. Hyung and Y. H. Bae, “Hydrogels Based on Poly(ethylene oxide)
and Poly ( tetra m et hyl ene oxide) or Poly(dimethyl siloxane) III: In Vivo
Biocom p a ti bi l i ty and Bi o s t a bi l i ty,” J. Biomed. Mater. Res. 64A, 309–319
(2003).
20. M.N. Khalid et al., “Water State Characterization, Swelling Behavior,
Th erm a l , and Mechanical Properties of Ch i tosan-Ba s ed Net work s ,”
Eur. J. Pharm. Sci. 15 (5), 425–432 (2002).
21. K. Sa ko et al., “Relati onship between Gelati on Ra te of Con tro lled-
Release Acet a m i n ophen Tabl ets Containing Po ly ( et hyl ene oxide) and
Colonic Drug Release in Dogs,” Pharm. Res. 13 (4), 594–598 (1996).
22. M. Di m i trov and N. L a m bov,“S tu dy of Verapamil Hydroch l ori de Re-
lease from Com pre s s edHydrophilic Po lyox-WSR Tablets,” Int. J. Ph a rm.
189 (1), 105–111 (1999).
Pharmaceutical Technology MAY 2005 79
DATA AND REVIEW
23. F. Zhang and J.W. McGinity, “Properties of Sustained-Release Tablets
Prep a red by Hot-Melt Ex tru s i on ,” Pharm. Dev. Technol. 4( 2 ) , 241–250
(1999).
24. V. Pillay and R. Fassihi, “A Novel Approach for Constant-Rate Deliv-
ery of Hi gh ly So lu ble Bi oactives from a Simple Monolithic Sys tem,”
J. Controlled Release 67 (1), 67–78 (2000).
25. V. Pillay and R. Fassihi, “Probing the Dynamics of Matrix Hydration
in the Presence of Electrolytes,” Drug Delivery 8 (2), 87–92 (2001).
26. E.H. Yi et al., “Pharmaceutical Formulation and Evaluation of a Sus-
tained - Release Hyd rophilic Ma trix Ta bl et of Cef a trizine Propyl en e
G lycol using Poly ( et hyl ene oxide),” Ya k che Ha k h oe chi 31 (1), 37–41
(2001).
27. L. Maggi et al., “Photostability of Extended-Release Matrix Formula-
tions,” Eur. J. Pharm. Biopharm. 55 (1), 99–105 (2003).
28. J. Luber and F. J. Bu n i ck, “Soft Tablets Containing Hi gh Molecular
Weight Poly(ethylene oxide),” US Patent appl. publ. 2003175336 (2003).
29. B. Berner and J. Louie-Helm, “Polymer-Based Gastric Retentive Oral
Dosage Form with Restri cted Drug Release in the Lower Gastroi n-
testinal Tract,” US Patent appl. publ. 20030104052 (2003).
30. L. Maggi, R. Bruni, and U. Con te ,“ Hi gh Mo l ecular Wei ght Po lyet hyl-
ene oxides (PEOs) as an Alternative to HPMC in Controlled Release
Dosage Forms,” Int. J. Pharm. 195 (1–2), 229–238 (2000).
31. A. Ap i cella et al., “Po ly ( ethyl ene oxide) (PEO) and Di f ferent Mo l ec u-
lar Weight PEO Bl ends Monolithic Devi ces for Drug Release,” B i o m a-
terials 14 (2), 83–90 (1993).
32. C.J. Kim, “Drug Release from Compressed Hydrophilic Polyox-WSR
Tablets,” J. Pharm. Sci. 84 (3), 303–306 (1995).
33. L. Maggi et al., “ Di s s o luti on Beh avi or of Hyd rophilic Matrix Tabl et s
Containing Two Di f ferent Polyet hyl ene ox i des (PEOs) for the Con-
trolled Release of a Water-Soluble Drug: Dimensionality Study,” Bio-
materials 23 (4), 1113–1119 (2002).
80 Pharmaceutical Technology MAY 2005
34. G. Mensitieri et al., “Polyoxyethylene (PEO)-Based Delivery Systems:
In f lu en ce of Po lym er Mo l ecular Wei ght and Gel Viscoel a s tic Beh av-
i or on Drug Release Mechanism,” Polymer Prepri n t s ( Am erican Ch em-
ical Society, Division of Polymer Chemistry) 33 (2), 88–89 (1992).
35. C.J. Kim, “Effects of D rug So lu bility, D rug Load i n g,and Polym er Mo l-
ecular Wei ght on Drug Release from Po lyox Ta bl et s ,” Drug Dev. Ind.
Pharm. 24 (7), 645–651(1998).
36. N. Wu et al., A Co m preh en s ive Mathem a tical Mod el for Co n troll ed Dru g
Rel e a se from a Hi gh ly Swellable and Di s soluble Polym er Ma trix: Poly(eth-
ylene oxide) (PEO) (American Institute of Chemical Engineers, New
York, NY), pp. 2133–2157 (2003).
37. S. Mi glani (Dhaw a n ) , “ Prep a ra ti on and Eva lu a ti on of Con tro ll ed Re-
lease Oral Do s a ge Forms of Glipizide and Ni fedipine,” PhD thesis,
Un ivers i ty In s ti tute of Pharmaceutical Scien ce s , Panjab Un ivers i ty,
Chandigarh (2002).
38. S. Dhawan, and A . K . Singla, “Com po s i ti on and a Met h od of Ma i n-
taining Blood Glu cose Level by Employing the Hydroph i l i c
Ma tri x – Based Oral Con tro ll ed - Release An ti d i a betic Com po s i ti on ,”
US Patent 6,703,045 (2004).
39. S. D h awan and A.K. Si n gl a , “Com po s i ti onand a Met h od of Maintain-
ing Bl ood Glu cose Level by Employing the Hyd rophilic Ma trix-Ba s ed
Oral Con tro ll ed Release An ti d i a betic Compositi on ,” Indian Pa ten t
965/DEL (2001). PT
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