Degradation of Surfactants and Polymers in Drug Delivery

10
Degradation of Surfactants
and Polymers in Drug Delivery
Biodegradable systems are interesting in drug delivery for a number of reasons.

In particular, the degradation can be used in order to control the release rate of
a drug, but it may also be valuable in order to decrease the risk for accumulationrelated diseases, and to control the biological response to the active drug. By the
use of biodegradable chemical links, it is possible to make particles, gels, surface
coatings, and self-assembled structures, which degrade with orders of magnitude
different half-lifes.
10.1
BIODEGRADATION OF POLYMERS
A number of polymers used in pharmaceutical applications are biodegradable,

either by chemical or enzymatic action, or both (Figure 10.1). Different polymers
are characterized by different stability toward degradation. While some, e.g., polyanhydrides, are very labile and degrading over a time scale of minutes, others
are much more stable (Table 10.1).
For polymers to be relevant for pharmaceutical applications for their biodegradation, they should typically degrade, at physiological conditions, over a
time scale from minutes to weeks, depending on the application. If the polymers
are less stable than this, their controlled preparation and storage may be difcult,
while more stable polymers are effectively not biodegradable in the context of
Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.
294
FIGURE 10.1 Chemical structure of some biodegradable polymers.
Chapter 10
Degradation of Surfactants and Polymers in Drug Delivery
295
TABLE 10.1 Typical Hydrolysis Rates

for Some Different Types of Polymers
Class
Hydrolysis rate*
Polyanhydride
Polyketal
Polyorthoester
Polyacetal
Polyester
Polyurea
Polycarbonate
Polyurethane
Polyamide
0.1 hours
3 hours
4 hours
0.8 years
3.3 years
33 years
42,000 years
42,000 years
83,000 years
* Time required for 50% hydrolysis at pH 7 and

25C.
Source: From Pierre et al., J. Bioact. Compatible
Polym. 1986, 1, 467.
drug delivery. In particular, polyesters have received considerable attention as

biodegradable polymers for drug delivery. Such polymer undergo hydrolysis in
aqueous environment. The rate of the degradation can be controlled straightforwardly, e.g., by controlling the monomer structure or monomer mixture composition. As an illustration, Figure 10.2 shows the effect of composition on the degra-
FIGURE 10.2 Effect of the composition on the hydrolytic degradation rate of poly
(lactide)-poly(glycolide) copolymers. (Redrawn from Asano et al., J. Controlled Release 1989, 9, 111.)
296
Chapter 10
FIGURE 10.3 Chemical composition of a poly(lactide)-poly(glycolide) (75/25) block

copolymer during degradation. (Data from Li et al., J. Mater. Sci. Mater. Med. 1990,
1, 131.)
dation rate of poly(lactide)-poly(glycolide) copolymers (Figure 10.1). Since

poly(glycolide) undergoes hydrolytic degradation faster than poly(lactide), increasing the copolymer poly(lactide) content results in a prolonged degradation
process (Figure 10.2).
As a result of the faster degradation of one of its components, the composition of biodegradable copolymers generally changes during the degradation process. Thus, due to the preferential degradation of poly(glycolide) blocks, poly(lactide)-poly(glycolide) block copolymers become enriched in poly(lactide) during
the degradation process (Figure 10.3).
If the two copolymer components have different tendency for crystallization, degradation may result in a change also in the state of polymer crystallinity.
For poly(lactide)-poly(glycolide) copolymers, the preferential degradation of
poly(glycolide) has been found to result in a degradation-induced crystallization
(Figure 10.4).
In analogy to the protective effect toward hydrolytic degradation of drugs
through incorporation in micelles or other drug carriers, the hydrolytic degradation of polymers may be controlled by the accessibility of water to the labile
bonds. In particular, by incorporating hydrophobic groups a water-soluble polymer can be made to collapse (Chapter 8), thereby reducing the contact between
the hydrolytically labile groups and the aqueous environment, hence also reducing the hydrolysis rate (Figure 10.5).
The hydrolytic degradation rate depends not only on the polymer composition but also on other factors, such as:
297
FIGURE 10.4 Crystallinity evolution during degradation of poly(lactide)-poly(glycolide) (75/25) block copolymer. (Data from Li et al., J. Mater. Sci. Mater. Med. 1990,
1, 131.)
FIGURE 10.5 Effect of polymer substituent (size of ester group in half esters) on
the hydrolytic degradation rate. (Redrawn from Heller et al., J. Appl. Polym. Sci.
1978, 22, 1991.)
298
Chapter 10
1. Polymer architecture and crystallinity. (Generally, the degradation increases with decreasing crystallinity.)
2. Polymer architecture and structure formation. (Structures and architectures precluding contact between the labile group and water generally
display slower hydrolysis.)
3. Temperature. (Generally, the degradation increases with increasing
temperature.)
4. pH. (Generally, the hydrolysis rate increases at low and at high pH.)
5. Presence of a drug. (May both promote and preclude polymer hydrolysis.)
The issue of the effects of polymer self-assembly on the hydrolytic degradation rate is relevant in relation to the use of surface active polymers for drug
delivery. An example of this is given by PEO-poly(lactide) (E m L n ) block copolymers, which form micelles with the poly(lactide) residues constituting the hydrophobic micellar core if the poly(lactide) chains are sufciently long. If the
latter are short, on the other hand, they are unable to induce micelle formation
(in analogy to other hydrophobic groups). When in the micellar core, the ester
groups in the poly(lactide) residues are shielded from contact with water, and
hence at least partly protected from hydrolysis. One would therefore expect PEOpoly(lactide) copolymers forming micelles to be characterized by a slower hydrolytic degradation of the poly(lactide) residue than that of block copolymers
not forming micelles. Indeed, Figure 10.6 shows that the hydrolysis of E 39 L 5
(which does not form micelles) is considerably faster than that of E 39 L 20 (which
form micelles). Thus, for E 39 L 5 , the ester bonds are constantly exposed to the
aqueous environment, and hydrolysis proceeds relatively rapidly. For E 39 L 20 , on
the other hand, the labile bonds are partially protected from hydrolysis and the
degradation is slower.
Apart from the polymer structure and composition, the most interesting
parameter for varying the hydrolysis of biodegradable polyesters in drug delivery
is probably pH. This is due to pH gradients in the gastrointestinal tract (Figure
10.7 and Table 10.2), which may be used together with biodegradable polymers
for a directed delivery to a specic region in the gastrointestinal tract.
As with low molecular weight esters, polyester hydrolysis is catalyzed by
both acid and base, which means that degradation and degradation-induced drug
release is enhanced at high and at low pH, whereas the hydrolytic degradation
at neutral pH is generally limited (Figure 10.8). This pH-dependent degradation
may allow efcient encapsulation of a drug at storage conditions (often dry or
at close to neutral pH), partial or complete acid-catalyzed polymer degradation
in the stomach or the small intestine, and drug release either in the stomach or
in the intestine, depending on the polymer degradation stability and the drug
physicochemical properties.
299
FIGURE 10.6 Hydrolytic degradation of E 39 L 5 (open symbols) and E 39 L 20 (lled

symbols) at 37C and unadjusted pH. (Redrawn from Muller et al., J. Colloid Interface Sci. 2001, 236, 116.)
FIGURE 10.7 Schematic illustration of the different regions of the gastrointestinal

tract. (Redrawn from Hwang et al., Crit. Rev. Ther. Drug Carrier Syst. 1998, 15,
243.)
300
Chapter 10
TABLE 10.2 Average pH in Healthy Humans in

the Fasted and Fed State at Various Sites in the
Gastrointestinal Tract
Location
Stomach
Duodenum (mid-distal)
Jujenum
Ileum
pH (fasted)
pH (fed)
1.3
6.5
6.6
7.4
4.9
5.4
5.26.0
7.5
Source: From Horter et al., Adv. Drug Del. Syst. 1997,

25, 3.
Besides chemical degradation, polymers may undergo enzyme-catalyzed

degradation. While naturally occuring polymers such as polypeptides and polysaccharides are most susceptible to this also numerous synthetic polymers undergo enzymatic degradation (Table 10.3). Indeed, also seemingly inert polymers,
such as nylon, poly(ether urethane), poly(terephthalate), poly(hydroxybutyrate),
poly(ester-urea), poly(-caprolactone), and poly(glycolic acid), are degraded by
enzymes.
The enzymatic degradation of polymers depends on a number of factors
apart from those related to the polymer chemical structure, including the following and many other, frequently system-specic, parameters.
1.
2.
3.
4.
5.
Temperature
pH
Electrolyte concentration
Presence of enzyme inhibitors
Presence of surfactants, other organic compounds (e.g., urea), cations
(certain systems), and other cosolutes
6. Presence of hydrophobic interfaces (lipases)
As a rule of thumb, enzymes are most efcient at or close to the conditions
(e.g., salt concentration, pH, and cation concentration) where they perform their
biological function. Departing from these conditions, on the other hand, often
results in a decreased enzymatic activity, and therefore also in a decreased enzymatic degradation rate of polymers.
In particular, biodegradable polymer systems are used in drug delivery
since they allow a way to control the drug release rate. In many cases, there is
a close correlation between the polymer matrix degradation on the one hand, and
the drug release rate, on the other (Figure 10.9). Since the degradation rate may
be controlled over orders of magnitude through the choice of copolymer composi-
301
FIGURE 10.8 (a) Effect of pH on the hydrolysis rate constant k obs for ethyl acetate.
(b) Inuence of pH on the degradation rate, as monitored by a relative viscosity
/ 0 decrease, of a random multiblock polyester-amide. (Redrawn from Bamford
et al., eds., Chemical Kinetics, vol. 10, Elsevier, 1972 (a), and de Simone et al.,
J. Appl. Polym. Sci. 1992, 46, 1813 (b).)
tion and structure and through a number of external parameters, the drug release
rate may be widely controlled with some accuracy. Furthermore, a drug release
sustained over extremely long times may be reached using this approach. The
latter is interesting, e.g., in relation to sustained release of drugs from drug-loaded
implants.
302
Chapter 10
TABLE 10.3 Examples of Enzymatic Degradation

of Polymers
Poly(-caprolactone)
Poly(dioxane)
Poly(ester-urea)
Poly(ether urethane)
Poly(ethylene terephthalate)
Poly(glycolic acid)
Poly(hydroxybutyrate)
Poly(lactic acid)
Poly(lysine)
Chymotrypsin
Trypsin
Papain
Esterase
Chymotrypsin
Elastase
Subtilisin
Cathepsin
Leucine aminopeptidase
Papain
Urease
Trypsin
Esterase
Papain
Esterase
Ficin
Carboxypeptidase A
Clostridiopeptidase A
Bromleain
Esterase
Esterase
Pronase
Proteinase K
Bromelain
Lipase
Trypsine
Chymotrypsin
Carboxypeptidase B
Elastase
Papain
Ficin
Source: From Park et al., Biodegradable Hydrogels for Drug Delivery, Technomic, 1993.
However, the drug release from biodegradable polymer systems may be

determined also by other factors than the polymer degradation rate. An example
of this is the drug hydrophobicity, where frequently a slower release is observed
for the same polymer system with increasing drug hydrophobicity. Furthermore,
basic drugs may behave as catalysts, which may enhance the degradation rate
303
FIGURE 10.9 In vitro release of p-nitroaniline (circles) from a poly(carbophenoxyvaleric acid) matrix, as well as the fractional degradation of the matrix (triangles).
(Redrawn from Dombs et al., Makromol. Chem. Macromol. Symp. 1988, 19, 189.)
and hence also the release rate. On the other hand, basic drugs may also neutralize
the polymer terminal carboxyl residues of polyesters, thereby reducing the autocatalysis due to the acidic end groups, and therefore also the degradation rate
and the release rate.
The degradation of polymers may have also a range of other effects, e.g.,
relating to gel strength, bioadhesion, responsiveness, etc. For example, when biodegradable polymers are used as steric stabilizers for colloidal drug carriers, such
as liposomes, emulsions, or polymer particles, the colloidal stability of such systems at physiological conditions may depend on the state of degradation. As an
illustration of this, Figure 10.10 shows the stability toward salt-induced occulation of polystyrene particles coated by PEO-poly(lactide) copolymers. In an aqueous solution, these copolymers adsorb at the hydrophobic polystyrene particles
with the hydrophobic poly(lactide) block as the anchor. At sufciently high copolymer concentration, saturation adsorption is achieved, and an efcient steric
stabilization of the polystyrene dispersion is obtained also at high salt concentration (Chapter 9).
As degradation of the anchoring poly(lactide) block progresses, the anchoring of the copolymer at the polystyrene particle surface deteriorates. This, in turn,
results in a weaker adsorption, and in a decreased amount copolymer adsorbed,
which causes the steric protective capacity by the copolymer layer to decrease,
304
Chapter 10
FIGURE 10.10 The aggregate size in polystyrene dispersions stabilized by block

copolymers in 10 mM sodium sulfate as a function of degradation of the anchoring
poly(lactide) block for E 39 L 20 (a) and E 39 L 5 (b). (Redrawn from Muller et al., J. Colloid Interface Sci. 2001, 236, 116.)
and eventually the polystyrene particles to occulate. The longer the anchoring
poly(lactide) block, the more extensive degradation is required in order to weaken
and reduce the copolymer adsorption sufciently to induce occulation.
In some cases, such a degradation-induced destabilization of colloidal drug
carriers may be advantageous. For example, when a good storage stability of a
colloidal drug carrier system is required and release to either the stomach or the
intestine desired, degradation-induced occulation through acid-catalyzed hydrolysis (stomach) or enzymatic action (intestine) may be used to localize the colloidal drug carriers at the site of action, thereby improving the drug bioavailability.
On the other hand, if colloidal drug carriers stabilized by such polymers are
administered intravenously, the degradation-induced occulation may cause seri-
305
ous side effects relating to emboli formation. In the latter case, therefore, care
must be taken to avoid such effects.
As discussed in relation to liposomes (Chapter 4), sterically stabilized and
particularly PEO-modied colloidal drug carriers are quite interesting due to prolonged bloodstream circulation time, a comparably even tissue distribution, reduced toxicity effects, etc. The origin of the advantageous effects of PEO-containing coatings of colloidal drug carriers in intravenous drug delivery is the low
serum protein adsorption caused by the PEO chains. On biodegradation of the
anchoring block of a PEO-containing copolymer, on the other hand, the PEO
chains are released and the serum proteins can adsorb. For the PEO-poly(lactide)
block copolymers discussed above, the polymer is strongly anchored at hydrophobic particle surfaces when the poly(lactide) moiety is intact, which efciently
prevents serum proteins from adsorbing. On degradation of the poly(lactide)
block, however, the polymer does no longer adsorb as extensively and strongly
at the surface, and hence is not capable of reducing the protein adsorption (Figure
10.11). Hence, opsonization and RES uptake of colloidal drug carriers stabilized
by such polymers will result from this degradation.
Since the circulation time of intravenously administered colloidal drug carriers is rather critically dependent on PEO-chains present on the surface, triggering colloidal drug carriers with such detachable polymer coatings may be
FIGURE 10.11 Adsorption of brinogen at a hydrophobic surface from phosphate

buffer at 25C without copolymer (open diamonds), and with adsorbed intact (triangles) or extensively degraded (lled diamonds) E 39 L 5 . (Redrawn from Muller et al.,
J. Colloid Interface Sci. 2000, 228, 326.)
306
Chapter 10
obtained also by other methods, e.g., through incorporation of a disulde-linked

PEO-phospholipid conjugate in liposomes. Such systems offer advantages compared to degradable polymer coatings in that the triggering from stability/circulation to destabilization can be tailored rather straightforwardly by different stability of the linker group between the PEO chain and the hydrophobic domain. In
particular, this is interesting from the perspective of a pH-dependent coating,
which will allow long circulation in the bloodstream, but which will come off,
e.g., on passage through a cancer tissue, where the pH is frequently slightly lower,
thereby offering a targeting mechanism. Similarly, pH-dependent detachment of
stabilizing PEO chains may offer a mechanism for pH-dependent DNA release
in gene therapy (cf. Chapter 4).
As discussed in Chapter 2, block copolymer micelles offer opportunities
in intravenous drug delivery, e.g., in the treatment of tumors, or in targeting to
selected tissues or cell types. Also here, biodegradable polymers may be used in
order to obtain a degradation-induced transition, e.g., from long-circulating micelles containing solubilized drugs to a disintegrated system, thereby resulting
in a localized burst release of the drug at low pH, or some other suitable condition.
Note, however, that also for such systems, emboli formation may be a real risk.
As an illustration of this, Figure 10.12 shows the particle size for a micellar
solution of E 39 L 20 as a function of the state of degradation of the poly(lactide)
FIGURE 10.12 Particle size (squares) and scattering intensity (circles) of solutions
of E 39 L 5 (open) and E 39 L 20 (lled) as a function of the degree of degradation of the
poly(lactide) block. (Redrawn from Muller et al., J. Colloid Interface Sci. 2001, 236,
116.)
307
block. For the intact copolymer, small micelles are formed, while for extensively
degraded copolymers, only the PEO homopolymer and lactic acid residues are
present. At intermediate degradation of the poly(lactide) block, on the other hand,
large particles are formed by long blocks of poorly soluble poly(lactide). In comparison, the E 39 L 5 copolymer does not generate as long insoluble poly(lactide)
blocks on degradation, and hence less such particle formation occurs. Again, care
should be employed when using biodegradable polymers in intravenous drug
delivery.
Biodegradable polymer gels are useful, e.g., for oral, buccal, topical, ocular,
nasal, and vaginal drug delivery. Gel systems are frequently preferred in these
applications due to suitable rheological properties and bioadhesion. Biodegradation of such systems, in turn, offers advantages related to ease of removal or
lack of need of removal, and sustained release. Considering the advantageous
properties of PEO and PEO-containing copolymers in many drug delivery applications, as well as the general advantages with biodegradable systems, biodegradable gels from functional PEOs offer particularly interesting possibilities (Figure
10.13).
By varying both the nature of the labile link and the architecture of the
PEO, different gel dissolution times may be obtained (Table 10.4).
An area where biodegradable gels, and notably biodegradable polysaccharide gels, are useful is colon drug delivery. The main reason for this is that the
fermentation of polysaccharide carriers caused by microbial enzymes in the large
intestine may be used to obtain efcient controlled release formulations. Examples where such formulations are of interest include, e.g., the treatment of Crohns
FIGURE 10.13 Schematic illustration of degradation of a gel containing physically

entrapped (a) and covalently bound (b) drugs D.
308
Chapter 10
TABLE 10.4 Degradation of PEO-Ester-Based Gels at pH 7 and 37C

Dissolution time
Proprionic acid ester

Carboxymethylated ester
t 1/2 (days)
4-arm PEO
8-arm PEO
43
4
2030
23
6070
57
Source: Data from Zao et al., in Harris et al., eds., Poly(ethylene glycol)Chemistry
and Biological Applications, ACS Symp. Ser. 680, 1998.
disease, ulcerative colitis, spastic colon, constipation, and colon cancer. Moreover, colon administration is also promising for systemic absorption of, e.g., peptides and proteins, which are extensively degraded in the gastrointestinal tract
(Table 10.5).
A number of polymer systems are relevant in this context, e.g., coatings
by amylose, cyclodextrins, galactomannan or pectin, as well as matrices formed
by, e.g., chondroitin sulfate, dextran, pectin, or galactomannan. Just to provide
one example, Figure 10.14 shows results on degradation of dextran and degradation-induced drug release for this system.
Another way to control the enzymatic degradation rate and drug release
rate is addition of an enzyme inhibitor to the drug formulation. In particular, an
approach here is to chemically modify the polymer with an inhibitor, and to
control the degradation rate by the concentration and type of inhibitor on the
polymer chain (Figure 10.15).
TABLE 10.5 Drugs of Interest in Colon-Specic

Drug Delivery
Indication
Colonic diseases
Crohns
Ulcerative colitis
Spastic colon
Colorectal diseases
Constipation
Cancer
Systemic absorption
Immunization
Drug
Anti-inammatory agents
Anti-inammatory agents
Anticholinergics
Laxatives
Chemotherapeutic agents
Peptides, proteins, oligonucleotides
Vaccines
Source: From Hovgaard et al., Crit. Rev. Ther. Drug Carrier Syst. 1996,
13, 185.
309
FIGURE 10.14 (a) Degradation, as indicated by loss in dry weight, of dextran hydrogels in a human colonic fermentation model. Results are shown in the form of
remaining dry weight (open symbols) and the production of short chain fatty acids
(SCFA) (lled symbols) at a dextran gel cross-linking concentration of 4.0% (triangles) and 5.9% (circles). (b) Enzyme-triggered release of hydrocortisone from
swollen dextran hydrogels at pH 5.4 and 37C after addition of enzyme at 80 min
(lled symbols) compared with the release in the presence of enzyme at 0 min
(open symbols). (Redrawn from Simonsen et al., Eur. J. Pharm. Sci. 1995, 3, 329
(a), and Brnsted et al., STP Pharma Sci. 1995, 5, 65 (b).)
310
Chapter 10
FIGURE 10.15 (a) Comparison of the inhibitory effect of carboxypeptidase A for

EDTA-modied chitosan (circles), DTPA-modied chitosan (lled squares), and in
the absence of inhibitor-modied chitosan (open squares). (b) Structure of the chitosan-inhibitor conjugate. (Redrawn from Bernkop-Schnurch, Int. J. Pharm. 2000,
194, 1.)
As discussed in Chapter 8, analogous effects were obtained on the release of

indomethacin from a calcium pectate gel in the absence and presence pectinolytic
enzyme known to be present in the colonic region (Figure 8.42). Together, these
examples illustrate that drug release to the colon may be controlled by the stability
of the matrix to enzymatic degradation, and that a specic targeting to the colon
or large intestine can be obtained by this approach.
311
As discussed in Chapter 9, biodegradable particles have been found to be

promising as drug delivery vehicles, not the least in relation to oral drug delivery.
Particular focus in this context has been paid to oral vaccines. From a delivery
point of view, particle encapsulation facilitates a successful vaccination through
the oral route, since it allows a way to circumvent exposure of the material used
for immunization, e.g., peptides, proteins, cells, and viruses, to the harsh conditions in the stomach, thereby reducing their degradation. The polymer particles
may also be benecial for immunization by acting as adjuvants, and by being
taken up by Peyers patches, thereby obtaining a benecial localization effect.
Although a number of different particle systems may be used for oral vaccination, particularly biodegradable poly(lactide), poly(glycolide) or their copolymers are interesting in this context since they are taken up sufciently efcient
by Peyers patches, since they are readily biodegradable, and since the resulting
degradation products are essentially nontoxic and readily resorbable. Analogous
to other forms of biodegradable polymers, the degradation of polymer particles
depends on a range of parameters. In particular, the polymer structure and composition are prime parameters for controlling the degradation rate and drug release.
However, the particle size and size distribution also affect the degradation rate.
In particular, the degradation rate, and consequent drug release, has been found
to increase with a decreasing particle size. This is expected, since smaller particles
is equivalent to a larger surface area, which favours hydrolytic degradation (Figure 10.16).
FIGURE 10.16 Release of naltrexone from biodegradable polymer particles of different size. (Redrawn from Yolles et al., in Juliano, ed., Drug Delivery Systems
Characteristics and Biomedical Applications, Oxford University Press, 1980.)
312
Chapter 10
Biodegradable polymers for drug delivery are generally chosen such that
the degradation products are essentially harmless, and ideally naturally occuring
in the human metabolism. Sometimes, however, biodegradation may result also
in negative effects. One such example is the oxidative cleavage which may occur
for PEO in the presence of light and oxygen. Although carboxyl groups tend to
be the end product after oxidative cleavage, sometimes aldehydes are generated,
which may have irritating or even toxic side effects. In pharmaceutical development work, this must be considered by following the metabolic fate of both the
drug and the drug carrier.
10.2
BIODEGRADATION OF PHOSPHOLIPIDS
From the perspective of drug delivery, biodegradation of lipids, either chemically

or enzymatically, is important since this affects the structure and stability of emulsions, microemulsions, liquid crystalline phases, and dispersed lipid particles.
This, in turn, may have implications for the drug release rate and other drug
delivery aspects for such systems. Of particular importance in this context is the
enzymatic degradation of glycerides or phospholipids through the action of lipases and phospholipases.
The enzymatic degradation rate in lipid and phospholipid systems depends
on a range of factors, including the nature of the lipid, the nature of the enzyme,
the enzyme concentration, but also on temperature, pH, salt concentration, and
many other factors. Here, only a few of these aspects will be discussed in brief.
The effect of lipase addition on the leakage of an encapsulated substance
from phosphatidylcholine liposomes is illustrated in Figure 10.17. In these experiments, carboxyuorescein was incorporated in the aqueous compartment of the
liposomes, and its release followed by monitoring the release-related decrease in
self-quenching (Chapter 4). As can be seen, addition of lipoprotein lipase causes
the encapsulated substance to be released to an extent which depends on the
enzyme concentration. The higher the lipoprotein lipase concentration, the faster
the phospholipid degradation, and the faster the occurrence of packing defects
resulting from the degradation. Therefore, the higher the enzyme concentration,
the faster the release of the encapsulated substance.
A central parameter for the rate of enzymatic degradation of phospholipids
and glycerides in relation to drug delivery is the length and saturation of the
hydrocarbon chains. In general, the degradation rate increases with a decreasing
length and an increasing degree of unsaturation of the hydrocarbon chains (Figure
10.18). This is probably due to a combination of packing effects, phospholipid
layer cohesion and uidity. Since the longer and saturated lipids pack more effectively, display larger cohesion, and a decreased uidity compared to the shorter
and unsaturated ones, the lipase action is precluded, hence resulting in a decreased
degradation rate.
313
FIGURE 10.17 Effect of lipoprotein lipase (LpL) concentration on the uorescence

from 6-carboxyuorescein due to its release from phosphatidylcholine liposomes.
The lipoprotein lipase concentrations used (g/ml) are indicated. (Redrawn from
Fugman et al., Biochim. Biophys. Acta 1984, 795, 191.)
FIGURE 10.18 Relative rate of hydrolysis of sonicated diacyl phosphatidylcholine

of different chain length and saturation by phospholipase A 2 . (Redrawn from LeKim et al., Adv. Prostagland. Thromb. Res. 1978, 3, 31.)
314
Chapter 10
The presence of cholesterol in phospholipid layers reduces the enzymecatalyzed hydrolysis of gel phase phospholipids. With an increasing concentration of cholesterol, the degradation rate is successively reduced, and at high cholesterol concentrations it is virtually absent (Figure 10.19). The origin of this
effect is unclear at present, but may be related to a reduced adsorption capacity
of the lipase at the lipid surface in analogy to the decreased adsorption observed
for serum lipoproteins (Figure 4.8).
The effects of pH on the enzymatic degradation of lipids and phospholipids
is a somewhat complicated issue, notably depending rather strongly on the nature
of the enzyme system. All enzymes display a pH-dependent activity, however,
and at very high and very low pH, the activity is generally low due to destruction
of the protein native conformation and other factors. As an illustration of this,
Figure 10.20 shows the pH-dependent hydrolysis of phosphatidylcholine vesicles
by phospholipase D.
Phospholipids also display a pH-dependent chemical hydrolysis. In particular, phospholipids display a similar pH-dependent hydrolysis as many esters, i.e.,
increased degradation at low and high pH due to acid-and base-catalyzed hydrolysis (Figure 10.21). Also, hydrolysis is enhanced at elevated temperature.
Although the examples on the effects of hydrolysis of lipids and phospholipids in the present discussion have been taken from liposome systems, analogous effects occur also in liquid crystalline phases, lipid nanoparticles, and
other lipid/phospholipid structures, causing system-dependent effects, e.g., re-
FIGURE 10.19 Effect of cholesterol on the hydrolysis of DPPC-cholesterol mixtures

by phospholipase A 2 . The mol% of cholesterol is indicated in each curve. (Redrawn
from Tinker et al., Can. J. Biochem. 1978, 56, 552.)
315
FIGURE 10.20 Effect of pH on the activity of phospholipase D on phosphatidylcholine large unilamellar vesicles. (Redrawn from Kim et al., Bull. Korean Chem. Soc.
1992, 13, 381.)
FIGURE 10.21 Effect of pH on the hydrolysis rate K obs of phosphatidylcholine liposomes at 40C (open symbols) and 70C (lled symbols). (Redrawn from Grit et
al., J. Pharm. Sci. 1993, 82, 362.)
316
Chapter 10
TABLE 10.6 Effect of Degradation Time on the Liquid

Crystalline Phases Formed by the Monoolein/Water/
Sodium Oleate System (50.7/42.2/7.1 wt%) After
Lipase Addition
Time (h)
0
1
4
13
16
20
54
Space group
Ia3d (bicontinuous cubic)
Ia3d (bicontinuous cubic)
Reversed-hexagonal
Reversed-hexagonal
Reversed-hexagonal
Hexagonal Fd3m (reversed micellar cubic)
Fd3m (reversed micellar cubic)
Source: From Caboi et al., Langmuir, in press.
lating to structure, stability, and drug release. As an illustration of the latter,

Table 10.6 shows results on the effect of lipase action on a liquid crystalline
phase formed by monoolein/sodium oleate/water. As can be seen, lipase-mediated hydrolysis of monoolein results in a progression of the liquid crystalline
phases formed in the order bicontinuous cubic reversed hexagonal reversed micellar cubic. This could be expected from simple packing considerations, since an increased degradation results in an increasing amount of sodium
oleate (and glycerol), and a decreasing amount of monoolein. An analogous
progression can be observed simply by increasing the sodium oleate concentration in monoolein samples.
BIBLIOGRAPHY
Bruch, S. D., Controlled Drug Delivery, CRC Press, Boca Raton, 1983.
Eldridge, J. H., R. M. Gilley, J. K. Staas, Z. Moldoveanu, J. A. Meulbroek, T. R. Tice,
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Degradation of Surfactants and Polymers in Drug Delivery

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10

Biodegradable systems are interesting in drug delivery for a number of reasons.

A number of polymers used in pharmaceutical applications are biodegradable,

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

FIGURE 10.1 Chemical structure of some biodegradable polymers.

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.