Biodegradable Micro Particles

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E L S E V I E R International Journal o f Pharmaceutics 116 (1995) 1-9

i n t e m a t i o n a lj o u r n a l o fp h a r m a c e u t i c s

Invi t ed Review

R e c e n t a d v a n c e s o n t h e u s e o f b i o d e g r a d a b l e m i c ro p a r t ic l es a n d

n a n o p a r t i c l e s i n c o n t r o l l e d d r u g d el iv e r y

Lisa Brannon-Peppas

Biogel Technology, Inc. , 952 1 Valparaiso Court, Indianapolis , I N 46268, USA

Received 16 June 1994; modified version received 3 October 1994; accepted 5 O ctober 1994

A b s t r a c t

The poss ib i l i ty of us ing b iodegradable polymers as drug ca r r i e rs was brought to the a t t en t ion of many sc ient i s t s

w he n b i o r e s o r ba b l e s u t u r e s e n t e r e d t he m a r ke t t w o de c a de s a go . S i nce t ha t t i m e , r e s e a r c he r s i n pha r m a c y , c he m i c a l

e ng i ne e r ing , a nd o t he r d i sc i p li ne s ha ve s t ri ve n t o de s i gn b i ode g r a da b l e po l ym e r s w i th de s i r ed de g r a da t i on m e c ha -

n i s m s a nd m e c ha n i c a l p r ope r t i e s . B i ode g r a da b l e po l ym e r s ha ve a dva n t a ge s ove r o t he r c a r r i e r s y s t e m s i n t ha t t he y

ne e d no t be s u r g ic a ll y re m o ve d w he n d r ug de l i ve ry is c om pl e t e d a nd t ha t t he y c a n p r ov i de d i r e c t d r ug de l i ver y to t he

s ys t e m i c c i r c u l a t i on . T he d r ug a nd po l ym e r m a y be c om bi ne d i n a num be r o f d i f f e r e n t w a ys de pe nd i ng upon t he

appl ica t ion of in te res t . Micropar t i cu la te formula t ions have the wides t appl i cabi l i ty to the wides t va r i e ty of formula -

t ion needs : ora l de l ive ry , in t ramuscula r in jec t ion , subcutaneous in jec t ion , and t a rge ted de l ive ry . Thi s rev iew

addres ses recent work u t i l i z ing b iodegradable polymers for cont ro l l ed drug de l ive ry , focus ing on mic ro- and

nan opar t i cu la te de l ive ry sys tems conta in ing p oly( lac ti c acid), poly(glycol ic ac id) or th e i r cop olymers .

K e y w o r d s : C on t r o l l e d r e l e a se ; B i ode g r a da b l e po l ym e r ; M i c r opa r ti c le ; N a nopa r t i c l e

I . I n t r o d u c t i o n

T h e m o s t w i d e l y u s e d a n d s t u d i e d c l as s o f

b i o d e g r a d a b l e p o l y m e r s is t h e p o l y e s t e r s , in c l u d -

i n g p o l y ( l a c t i c a c id ) , p o l y ( g l y c o l i c a c i d ) , a n d t h e i r

c o p o l y m e r s . P o l y (g l y c o li c a c i d ) ( h e n c e f o r t h r e -

f e r r e d t o a s P G A ) w a s f i r s t m a r k e t e d i n 1 9 7 0 a s a

b i o d e g r a d a b l e s u t u r e a n d p o l y ( la c t i c a c i d )

( h e n c e f o r t h r e f e r r e d t o a s P L A ) w a s i n v e s ti g a t ed

a s a d r u g d e l i v e r y m a t e r i a l a s e a r l y a s 1 97 1 . B y

v a r y in g t h e m o n o m e r r a t i o s in t h e p o l y m e r p r o -

c e s s in g a n d b y v a r y i n g t h e p r o c e s s i n g c o n d i t io n s ,

t h e r e s u l t i n g p o l y m e r c a n e x h i b it d r u g r e l e a s e

c a p a b i l i ti e s f o r m o n t h s o r e v e n y e a r s ( L e w i s ,

1 9 9 0 ). T h e d e g r e e o f c r y s ta l l i n i ty h a s a s i g n i f i c a n t

e f f e c t o n t h e r a t e o f d e g r a d a t i o n . T h e s e p o l y -

m e r s , w h ic h h a v e b e e n p r e p a r e d a s f il m s, m i -

c r o p a r t i c l e s , r o d s , a n d o t h e r f o r m s , d i s p l a y a b u l ke r o s i o n h y d r o l y s i s .

B i o d e g r a d a b l e p o l y m e r s h a v e lo n g b e e n o f in -

t e r e s t in c o n t r o l le d r e l e a s e t e c h n o l o g y b e c a u s e o f

t h e a b i l it y o f t h e s e p o l y m e r s to b e r e a b s o r b e d b y

t h e b o d y . T h i s a l l e v i a t e s t h e n e e d f o r r e m o v a l ,

o f t e n s u r g ic a ll y , o f a d r u g r e l e a s e d e v i c e . K n o w l -

e d g e a n d s k il l i n t h e f i e ld o f b i o d e g r a d a b l e p o l y -

m e r t e c h n o l o g y is p r o g re s s in g r a p i d l y e n o u g h t h a t

0378-5173/95/$09.50 © 1995 Elsevier Science B.V. All rights reservedS S D I 0 3 7 8 - 5 1 7 3 ( 9 4 ) 0 0 3 2 4 - 6



2 L. Bran non- Pepp as/Inter nation al Journal of Pharmaceutics 116 (1995) 1- 9

researchers have at their disposal a substantial

number of degradable polymers with a range of

degradation rates. Not only may researchers use

a single polymer, copolymer, or blend, but they

may also use a combination of polymers.

2. Drug de l ivery systems using biodegradable mi-

cropartic les and n ano part ic les o f poly(lactic ac id)

and poly(lactic-co-glycolic acid )

There are a large number of research groups,

worldwide, examining poly(lactic-co-glycolic) acids

(PL A/P GA) , especially in the form of micropar-

ticles and nanoparticles, for use in controlled

drug delivery systems. Most researchers utilize a

solvent evaporation technique, or modificationthereof, to prepare microparticles or nanoparti-

cles of PL A/ PG A (Grandfils et al., 1992; Ike et

al., 1992; Yamakawa et al., 1992; Alonso et al.,

1993; Fawaz et al., 1993; Iwata and McGinity,

1993; Niwa et al., 1993; Scholas et al., 1993;

Verrecchia et al., 1993; Yamaguchi and Ander-

son, 1993; Zhifang et al., 1993). Other particles

are prepared by grinding of larger slabs (Mauduit

et al., 1993a,b,c) or by a salting-out process (AI-

lemann et al., 1993).

2.1 . Micropar t icu la te sys tems

In order to analyze the in vivo biocompatibility

of microspheres of Medisorb 65/35 PLA/PGA,

Yamaguchi and Anderson (1993) injected mi-

croparticles into the back of the side of rats and

monitored their response for 150 days. They ob-

served only mild inflammation and unimpaired

wound heal ing throughout the study. At 150 days,

the microparticles completely degraded with min-

imal inflammatory response. The conclusion was

that PLA/PGA polymers were good biocompati-ble materials from implantation through com-

plete degradation. The injection vehicles used

were aqueous dextran solutions at 262 mg mi-

croparticles/2 ml or 87 mg microparticles/ml. It

was also observed that microspheres of a size

1-20 ~m were phagocytosed, as determined by

their being surrounded by macrophages and with-

out foreign body giant cell attachment. In vitro

work has also shown that microparticles less than

12 ~m in diameter are phagocytosable by

macrophages.

In a series of papers, Mauduit et al. (1993a,b,c)

studied the release a local antibiotic, gentamicin

sulfate, from both microparticles and films of

amorphous and semicrystalline poly(lactic acid)s.

Microparticles prepared from amorphous materi-

als showed a burst of drug release, followed by 2

months of sustained release. Microparticles pre-

pared from semicrystalline PLA, in contrast, re-

leased all of the drug within 6 h, a result only of

morphological differences between the micropar-

ticles, not differences in biodegradation rates. In

this case, the microparticles from amorphous PLA

were formed by mixing gentamicin sulfate with a

polymer/acetone solution and allowing the ace-tone to evaporate, then grinding the remaining

polymer/antibiotic mixture. Chloroform was used

as the solvent for preparation of microparticles

from semi-crystalline PLA. The semi-crystalline

polymer preparation technique produced porous

microparticles, probably due to variations in the

solvent evaporation rate. It is therefore important

to control the solvent evaporation rate in all

microparticle prepara tion techniques so as to have

reproducible particle morphology.

Further studies (Mauduit et al., 1993c) evalu-

ated the differences between the release of gen-

tamicin base and gentamicin sulfate, with the

findings that not only were there differences in

physical appearance between the two types of

formulations (those with gentamicin sulfate were

waxy whereas those with gentamicin base were

more solid) but also differences in release behav-

ior. The microparticles containing gentamicin

base released nearly 50% of their drug in a burst

at the beginning of the experiment, and essen-

tially no additional drug for the remaining 24

days of the study. Those microparticles preparedwith gentamicin sulfate released at a high but

steady rate for the first 4 days, then at a substan-

tially lower rate for the remaining 21 days of the

study. To further elucidate these behaviors, a

third study involved preparation of films of gen-

tamicin sulfate with PLAs of various types. It was

noted that the degradation rate of the PLA de-

pended upon the presence of gentamicin. Inter-



L. Brannon-Peppas / International Journal of Pharmaceutics 116 (1995) 1-9 3

actions between the carboxylic end groups and

the antibiotics were thought to be the cause.

Other drug delivery studies with various

PLA/PGA and PLA microspheres included re-

lease of norethisterone (Zhifang et al., 1993)

which showed drug release over 96 h in vitro and

from intramuscular injections in rats for 45 days

in vivo. Release of a neurotensin analogue

(Yamakawa et al., 1992) in vitro showed a 20%

burst of release, followed by release for 1 month

with PLA of molecular weight (Mol. Wt) 2000.

However, with PLAs of Mol. Wt 4000 and 6000,

the in vitro release demonstrated a smaller burst,

followed by a lag time of 2-3 weeks with no

significant release, then release for at least 5

more weeks. Studies with the anti-cancer drug

cisplatin (Ike et al., 1992) showed in vitro releasefor 30-57 days, and in vivo for 21-42 days from

microparticles prepared from PLA of Mol. Wt

12 000.

A recent study compared the immune re-

sponse due to intraperitoneal or subcutaneous

administration of microparticles of PLA/PGA

containing ovalbumin, which is a poor immuno-

gen (O'Hagan et al., 1991) The microparticles

elicited a significantly greate r response than un-

encapsulated ovalbumin. The microparticles were

prepared by solvent evaporation technique and

had an average particle size of approx. 5 ~m. It

was found that particles of less than 6-7 ~m

diameter are effectively phagocytosed by various

macrophage populations which can allow delivery

of entrapped drugs intracellularly to the cells

responsible for immune response initiation. The

preliminary results from this study showed that

PLA/PGA microparticles are an effective anti-

gen delivery system that can induce potent pri-

mary and secondary immune responses.

Biodegradable microspheres have also been

studied as an embolic material (Grandfils et al.,1992). Microparticles of PLA, again prepared by

a solvent evaporation procedure, were injected

intravenously and were designed to stop blood

flow in areas surrounding tumors before surgery

to reduce hemorrhagic complications during

surgery. Particles of 100-160 p~m diameter, in-

jected at a concentration of 5 mg/m l, were found

to be successful in this endeavor because their

size is appropriate to reach the precapillary arte-

rioles.

2.2. Hybrid microparticulate systems: microparti-

cles in implants and films

While biodegradable microparticles have

proven to be useful in a wide range of controlled

drug delivery applications, our research group

has investigated opportunities for utilizing

biodegradable microparticles in composite or hy-

brid systems with other biodegradable or non-

degradable systems (Brannon-Peppas, 1992, 1994;

Brannon-Peppas et al., 1994). The release rates

and profiles of both hydrophilic drugs (gentami-

cin sulfate) and hydrophobic drugs (/3-estradiol)

have been shown to be significantly changed whenthe biodegradable microparticles containing these

drugs are incorporated into silicone (nondegrada-

ble) or gelatin (degradable) films. These studies

utilized low molecular weight PLA/PGA poly-

mers of ratios 50:50, 65:35 and 75:25.

The drug release from the microparticles

within the silicone films does not exhibit the

initial high burst of release in vitro from free

microparticles. However, except for systems with

high drug loadings (> 40%) and high microparti-

cle loadings (> 30%), the majority of the gentam-

icin sulfate was not released from these formula-

tions. These microparticle-silicone composite sys-

tems are currently under investigation for deliv-

ery of proteins and peptides which would not

otherwise be able to be released from traditional

solid silicone implants. Incorporation of mi-

croparticles into gelatin films only slightly de-

creased the initial burst of drug release, but

greatly increased the length of time of the drug

release.

2.3. Systems prepared by modification of tradi-tional soluent evaporation techniques

In order to evaluate the possibility of using

serum albumin instead of poly(vinyl alcohol) as a

stabilizer during the preparation of biodegrad-

able microparticles of poly(lactic acid), Verrec-

chia et al. (1993) measured both the bound and

free serum albumin present on the surface of



4 L. Brannon-Peppas/International Journal of Pharmaceutics 116 (1995) 1- 9

PLA nanoparticles prepared by a solvent evapo-

ration process. It was found that the amount of

adsorption is directly related to the surface area

of the particles. A part of the serum albumin was

irreversibly bound, and a portion was reversibly

bound. The researchers do not suggest that any

portion of the serum albumin is physically en-

trapped within the nanoparticles, but 35-45% of

the albumin is permanently bound to the parti-

cles.

Tetanus vaccines, prepared with both 50:50

PLA/PGA and PLA, were prepared as mi-

croparticles using modified solvent evaporation

and solvent extraction procedures (Alonso et al.,

1993). Depending upon whether the tetanus tox-

oid was incorporated into the microparticles as a

solid or as an aqueous solution, the release be-havior differed slightly. Lower molecular weight

polymers showed bursts of 25-35% release in the

first day, then slower release. Higher molecular

weight polymers (50:50 PLA/PGA, Mol. Wt

100 000) released less than 10% of the drug in the

first day, but also had only released 25% of the

total loaded amount after 27 days. The advantage

of a solvent extraction method described is that

microspheres are formed within 30 min as op-

posed to several hours with traditional solvent

evaporation techniques.

A multiple-emulsion solvent evaporation tech-

nique was used to prepare conventional and

multi-phase PLA/PGA microspheres containing

water-soluble compounds (Iwata and McGinity,

1993). Because of the high water solubility of

some drugs, traditional solvent evaporation meth-

ods to prepare microparticles with these drugs

yield very low drug loading efficiencies because of

drug partitioning into the aqueous phase from

the polymer phase. This new method yielded

particles with many distinct zones of drug within

a main polymer matrix. The conventional methodyielded a more homogeneous mixture of polymer

and drug throughout the microparticle. For re-

lease of brilliant blue and chlorpheniramine

maleate, this study did not show any burst o f drug

release for either type of formulation, yet the

multi-phase microspheres consistently showed a

larger amount of drug released that did the cor-

responding conventional microlaarticles.

2 .4 . N a n o p a r t i c u l a t e s y s t e m s

While microparticles have been prepared us-

ing PLA and PLA/PGA for many years,

nanoparticles of these materials are fairly new

and are the result of modifications of existing

preparation techniques and the realization that

sub-micron particles could find utility in particu-

lar drug targeting applications. It has been found

that PLA nanoparticles injected intravenously are

taken up by cells of the mononuclear phagocyte

system, mainly the Kuppfer cells (Fawaz et al.,

1993). This may naturally concentra te these parti-

cles close to liver parenchymal ceils and facilitate

biliary clearance and enterohepatic circulation. In

general, such nanoparticles are rapidly cleared

from the blood and are concentrated in the liver,spleen and blood marrow.

PLA nanoparticles containing savoxepine, a

new neuroleptic drug, were prepared by a re-

versible salting-out process (Allemann et al.,

1993). A cross-flow filtration technique utilizing

magnesium chloride hexahydrate and magnesium

acetate tetrahydrate as salting-out agents resulted

in a 90% entrapment of the drug, in a process

which takes only 3 h to prepare one batch of

nanoparticles.

Nanospheres of PLA/PGA (75:25) of diame-

ters less than 200 nm have also been prepared

especially for site-specific delivery (Scholas et al.,

1993). Biodistribution of injected colloidal carri-

ers is highly dependent upon their size and their

surface properties. For example, for targeted ad-

ministration to the lung, particles should be sev-

eral microns in diameter. If particles are larger

than 250-300 nm they will be captured by filtra-

tion in the spleen.

Nanospheres containing indomethacin or 5-

fluorouracil (as model water-insoluble and

water-soluble drugs) were prepared using a modi-fied solvent evaporation technique with a high-

speed homogenizer. The resulting particles were

found to be 400-600 nm in diamete r (Niwa et al.,

1993) This study found that the release of in-

domethacin into phosphate-buffered saline was

highly dependent upon the polymer molecular

weight, with faster release from the nanoparticles

prepared from the polymer with the lowest



L. Brannon-Peppas / International Journal of Pharmaceutics 116 (1995) 1- 9 5

molecular weight (Mol. Wt 12279 vs 66671 vs

127598).

3. Protein and pept ide del ivery from PLA/PGA

particulate systems

Efforts are also continuing on delivery of pro-

teins and peptides from biodegradable micropar-

ticles (Sanders et al., 1985; Hor a et al., 1990;

Heya et al., 1991). Controlled release of inter-

leukin-2 and variations from 50:50 PLA/PGA

microspheres, on the order of 50-200 /zm in

diameter, showed a burst of release, followed by

a period of extremely low release for days 6-15,

ending with nearly constant release through 30

days (Hora et al., 1990). Thyrotropin-releasing

hormone (TRH) release was studied from mi-

croparticles prepared from 75:25 PLA/PGA and

100% PLA (Heya et al., 1991). The microparticles

were prepared using a modified solvent evapora-

tion system based upon a wate r/o il/ wat er emul-

sion system and were approx. 50 ~m in diameter.

The injection vehicle used was an aqueous solu-

tion containing 1% sodium carboxymethylcellu-

lose and 0.5% Tween 80. Lower molecular weight

polymers gave larger bursts of release of TRH

and faster overall release (Mol. Wt 5000, 6000,

8000 and 11000). Drug release was faster thanthe polymer weight loss, indicating that the drug

diffused through the channels formed in the poly-

mer at advanced stages of degradation. Release

of nafarelin (LHRH analogue) was found to fol-

low a triphasic pattern with an initial burst, then

a low rate of release, followed by a higher rate of

release in some early work carried out on this

system (Sanders et al., 1985) Microparticles of

50:50 PLA/PGA with 10-50 /xm diameters

showed in vitro release for up to 40 days and in

vivo activity for even up to 70 days. A similar

system is now marketed worldwide and is known

as the Lupron depot.

4. Delivery of ant i -cancer agents from P L A /P G A

particulate systems

Some studies have addressed the encapsula-

tion of anti-cancer agents into PLA and

PLA/PGA microparticles (Wada et al., 1988a,b).

Aclacinomycin (or aclarubicin hydrochloride) is

an anti-cancer agent which has many undesirable

side effects such as nausea, vomiting, anorexia,

leukocytopenia and thrombocytopenic toxicities.

It would be desirable to target delivery of this

drug to only cancerous tissues. Microspheres were

prepared by traditional solvent evaporation meth-

ods using PLA in a variety of molecular weights

(3600, 4000, 4800, 7200 and 10 000) (Wada et al.,

1988a) The drug release rate was found to be

strongly dependent upon both molecular weight

and drug loading rate. Microparticles of higher

molecular weight polymers showed release in vitro

for more than 35 days. Adriamycin and cisplatin,

other anti-cancer drugs, have also been encapsu-

lated into PLA and PLA/PGA by traditionalsolvent evaporation methods (Wada et aI., 1988b)

These formulations were prepared with quite high

drug loadings of 50-70 wt%, with in vitro release

only lasting for up to 17 days.

5. Delivery of vaccines from P L A /P G A particu-

late systems

Another advantage of biodegradable drug de-

livery systems is that they can be designed to

deliver vaccines in a number of pulses from a

single injection of microencapsulated drug. A sig-

nificant effort, in concert with th e World Health

Organization, is in place in a number of institu-

tions to develop vaccine delivery systems for de-

veloping countries. For example, biodegradable

microspheres of PLA/PGA 50:50 with only 1%

of the toxoid vaccine of staphylococcal entero-

toxin B (SEB) dramatically increased the circulat-

ing IgG anti-toxin toxoid when compared to free

toxoid (Eldridge et al., 1991). This study used a

mixture of microspheres of 1-10 /zm and 20-50/zm. This mixture gave an initial release from the

smaller microspheres and a later release from the

population of microspheres with the larger size.

They were administered by intraperitoneal injec-

tion in mice. Higher antibody levels were seen for

at least 90 days upon a single injection of the

mixed population of microspheres. The response

of the microparticles of size less than 10/zm after



6 L . B r a n n o n - P e p p a s / I n t e r n a t i o n a l Jo u r n a l o f P h a r m a ceu t i c s 1 1 6 ( 19 9 5) 1 - 9

injection appears to be both a depot effect as well

as because of the rapid phagocytosis of the micro-

spheres by antigen-presenting accessory cells such

as T cells. Other efforts include delevopment of

oral delivery systems based upon biodegradable

microparticles (Eldridge et al., 1989). Orally ad-

ministered microspheres, containing SEB toxoid,

of 1-10 /zm are taken up by Peyer's patch lym-

phoid tissue of the gut, and those of size 5-10

/.~m can remain there for up to 35 days, providing

controlled release.

Some studies have also been conducted using

the diphtheria toxoid delivered with PLA mi-

croparticles of Mol. Wt 49 000 (Singh et al., 1991).

These formulations have shown release up to 75

days in vivo, comparable to traditional treatment

requiring three injections as opposed to a singleeffective injection with microparticle formulation.

The microparticles prepared by a variation of the

solvent evaporation method, were implanted sub-

cutaneously and were of the size 30-100/~m.

6 . O t h e r f o r m s o f P L A / P G A u s e d fo r d r u g de li v-

ery

Recent work has been reported with tablets or

slabs of PLA/PGA (Omelczuk and McGinity,

1992; Asano et al., 1993; Fischel-Ghodsian and

Newton, 1993; Pistner et al., 1993; Zhang et al.,

1993) including analysis of drug release kinetics

from slabs with and without surrounding rate-

limiting membranes (Fischel-Ghodsian and New-

ton, 1993) and the effect of the polymer glass

transition and molecular weight of the drug re-

lease behavior of theophylline (Omelczuk and

McGinity, 1992). Release of albumin from rods

prepared from PLA/acetone suspensions which

were then coated with pure PLA was found to be

most strongly dependent upon the geometry ofthe system (rod length compared to cross-sec-

tional area) and drug loading (Zhang et al., 1993)

Melt-pressed formulations of calcitonin with PLA

showed an initial burst of drug release and com-

plete release within 3 days for polymers of Mol.

Wt 1400, and 24 days for Mol. Wt 4400 (Asano et

al., 1993). A long-term degradation study of PLA

in vivo was conducted using rods and blocks of

high molecular weight PLA (120 000, 200 000 and

429000) (rods 25 x 3 x 2 mm, blocks 3 x 3 x 2

mm) which were implanted into the dorsal muscle

of rats (Pistner et al., 1993). The lower specimens

were totally degraded with 1 year and the moder-

ate molecular weight specimens nearly degraded

in 2 years. All polylactides were incorporated

well, forming a collagenous fibrous layer without

tissue irritation.

Vert et al. (1992) have evaluated the biocom-

patibility of biodegradable polymers and the

mechanism of drug release from them (Shah et

al., 1992). It has been found that the initial degra-

dation of the polyesters is hydrolytic, and that

during the latter stages, enzymatic degradation

may also take place (Vert et al., 1992). The re-

lease of drug from these degrading polymers is acombination of diffusion and degradation, which

each mechanism predominating at a specific time

in the degradation of the polymer (Shah et al.,

1992). Initial drug release may be in large part

due to diffusion, depending upon the drug that is

releasing. The increase in release rate often seen

with drug release from biodegradable microparti-

cles is due to the kinetics of the polymer weight

loss after bulk hydrolysis has progressed to a

point where there is measurable weight loss from

the polymer instead of simply a decrease in the

average molecular weight as occurs early in the

biodegradation process.

7 . P L A / P E G a n d P L A / P E O b lo c k c o po ly m e rs

f o r d r u g d e l i v e r y

Some work has also been performed to com-

bine poly(ethylene glycol) and poly(lactide-co-gly-

colide)s in the same drug delivery formulation.

The research groups that have addressed this

opportunity have usually taken the route ofpreparing block copolymers of PLA and PEG or

PEO (Cohn and Younes, 1988; Zhu et al., 1990).

Much of this work has been spurred by the fact

that PEG is non-toxic and has been cleared by

the US Food and Drug Administration for inter-

nal use in the human body (Zhu et al., 1990).

Release in vitro of norethisterone (30 wt% drug)

from copolymers of PLA and PEG showed no



L. Brannon-Peppas / International Journal of Pharmaceutics 116 (1995) 1-9 7

greater a burst of release than from PLA alone

and a significantly higher rate of release, when

compared to PLA alone, from that point on.

Block copolymers of PLA and PEO have been

investigated with the aim of developing a new

family of biodegradable polymers (Cohn and

Younes, 1988). These new polymers ranged from

20 to 84% PLA and the PEO chains were of Mol.

Wt 600-6000 (which in reality qualify them as

PL A/ PE G copolymers). The incorporation of the

PEO into the polymer yielded a highly hy-

drophilic material, with equilibrium water con-

tents higher than 60%. For hydrolytically sensi-

tive drugs such as proteins, this type of material is

usually not desirable because the stability of the

drug may often be compromised when in such a

water-filled environment. PLA/PGA polymersare excellent for protein and peptide release be-

cause of their hydrophobic nature which serves to

protect the drugs from the fluid in the in vivo

environment and thus increase their stability as

well as control their release. These new copoly-

mers were successful, however, in combining the

material strength and hydrophobicity of the PLA

with the elasticity and hydrophilicity of the PEO

but no drug delivery data was presented.

Studies have shown that subcutaneously ad-

ministered nanoparticles are taken up by the

lymph nodes (Trubetskoy et al., 1993). PEG at-

tached to individual drug molecules has been

shown to significantly increase the drug circula-

tion time because of the masking effect of the

PEG and its resulting lack of uptake into the

reticulo-endothelial system (Katre, 1993). PEG is

the most extensively studied method for extend-

ing circulating half-life of proteins (Davis et al.,

1991) PEG is a linear, uncharged, hydrophilic,

nonimmunogenic molecule that has been used to

modify a large number of compounds, including

trypsin, superoxide dismutase, catalase, adeno-sine deaminase, bovine serum albumin, asparagi-

nase, uricase, lipase, hemoglobin, interleukin-2

and arginase. At least six PEG-enzyme conju-

gates have reached clinical trials: PEG-adenosine

deaminase (for severe combined immunodefi-

ciency disease, SCID); PEG-antigen E (for rag-

weed hay fever); PEG-asparaginase (for acute

lymphoblastic, lymphocytic and undifferentiated

leukemias and for lymphomas); PEG-honeybee

venom (for reperfusion injury associated with or-

gan transplantation); and PEG-uricase (for hype-

ruricema associated with chemotherapy or gout).

For use in magnetic resonance imaging con-

trasting agents, liposomes were studied which

were unmodified as well as surface modified with

dextran or PEG. PEG-modif ied liposomes showed

an imaging efficiency of more than twice that of

the other liposomes. PEG-coated 'stealth'

nanospheres have been prepared by using diblock

copolymers of PLA/PGA and PEG (Mol. Wt

350-20000) (Gref et al., 1993). During prepara-

tion of the nanoparticles, using solvent evapora-

tion techniques, the PEG segment migrates to the

surface of the particles, leaving it 'covered' with a

PEG layer. Particles thus prepared were on theorder of 200 nm in diameter. After injection of

plain or modified nanospheres (using Indium ra-

dioactivity tracking) 5 rain afte r injection 40% of

the unmodified nanoparticles were found in liver

and 15% in blood. Modified nanoparticles, how-

ever, showed 15% in the liver and 60% in the

blood with a significantly improved circulating

time. Plain nanospheres completely disappeared

from blood in 4 h, but at that same time approx.

30% of modified nanospheres were still circulat-

ing. Delivery of antisense oligonucleotides using

an injectable polymer composed of PEG chains

with a degradable oligo-lactide segment and reac-

tive acrylate segment on each en d has also been

studied recently (Hill-West and Hubbell, 1993).

8 . C o n c l u s i o n s

Biodegradable microparticles have one of the

greatest ranges of utility in controlled release of

any formulation yet studied. They can be utilized

in injectable formulations, oral formulations,bioadhesive systems, and as the principal

release-controlling component of degradable and

non-degradable implants and films. The future

opportunities for the in vivo use of PLA/PGA

polymers as biodegradable microparticles are be-

ing well examined by researchers worldwide, with

advances in the field being made continuously.

While the potential for PLA/PGA formulations



8 L . Brannon-P eppas / In terna t iona l Journa l o f Pharmaceu tics 116 (1995) 1 -9

is evident, researchers must also remember the

possibilities for combining the desirable charac-

teristics of these delivery systems with other ma-

terials, natural and synthetic, to yield controlled

drug delivery formulations for an even wider

range of applications.

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