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A review of biodegradable polymeric systems for oral insulin delivery

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DOI: 10.3109/10717544.2015.1052863 · Source: PubMed

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A review of biodegradable polymeric systems for oral

insulin delivery
a a b a a a
Yue Yuan Luo , Xiang Yuan Xiong , Yuan Tian , Zi Ling Li , Yan Chun Gong & Yu Ping Li
a
School of Life Science, Jiangxi Science & Technology Normal University, Nanchang, China
and
b
China National Pharmaceutical Industry Co., Ltd., Beijing, China
Published online: 24 Jun 2015.

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To cite this article: Yue Yuan Luo, Xiang Yuan Xiong, Yuan Tian, Zi Ling Li, Yan Chun Gong & Yu Ping Li (2015): A review of
biodegradable polymeric systems for oral insulin delivery, Drug Delivery

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REVIEW ARTICLE

A review of biodegradable polymeric systems for oral insulin delivery

Yue Yuan Luo1, Xiang Yuan Xiong1, Yuan Tian2, Zi Ling Li1, Yan Chun Gong1, and Yu Ping Li1
1
School of Life Science, Jiangxi Science & Technology Normal University, Nanchang, China and 2China National Pharmaceutical Industry Co., Ltd.,
Beijing, China

Abstract Keywords
Currently, repeated routine subcutaneous injections of insulin are the standard treatment for Bioavailability, biodegradable, insulin,
insulin-dependent diabetic patients. However, patients’ poor compliance for injections often oral delivery, polymer
fails to achieve the stable concentration of blood glucose. As a protein drug, the oral
bioavailability of insulin is low due to many physiological reasons. Several carriers, such as History
Downloaded by [Xiang Yuan Xiong] at 02:11 07 August 2015

macromolecules and liposomes have been used to deliver drugs in vivo. In this review article,
the gastrointestinal barriers of oral insulin administration are described. Strategies for Received 7 April 2015
increasing the bioavailability of oral insulin, such absorption enhancers, enzyme inhibitors, Revised 15 May 2015
enteric coatings are also introduced. The potential absorption mechanisms of insulin-loaded Accepted 15 May 2015
nanoparticles across the intestinal epithelium, including intestinal lymphatic route, transcellular
route and paracellular route are discussed in this review. Natural polymers, such as chitosan and
its derivates, alginate derivatives, g-PGA-based materials and starch-based nanoparticles have
been exploited for oral insulin delivery; synthetic polymers, such as PLGA, PLA, PCL and PEA
have also been developed for oral administration of insulin. This review focuses on recent
advances in using biodegradable natural and synthetic polymers for oral insulin delivery along
with their future prospects.

Introduction enhancers (Degim et al., 2004; Zhang et al., 2011a,b) to

enhance the absorption of insulin. But most of the recent
To be effective, an orally administered protein drug must
literatures concentrate on the novel drug delivery systems
transit along the gastrointestinal (GI) tract, pass through the
made of biodegradable macromolecular materials, which
mucus layer, traverse across the intestinal epithelium, enter
could be used to carry insulin. In this review, the attention has
into the portal vein and finally reach the systemic circulation
been focused on the use of biodegradable natural and
(Chen et al., 2011).
synthetic polymers (Alonso, 2004).
However, oral administration of pure insulin showed less
effect due to the following factors. Firstly, insulin can be
easily degraded by the acidic conditions in stomach and the The absorption of oral insulin
proteases existing in the GI tract. Secondly, insulin is a kind
After the oral administration of insulin preparations, the drugs
of hydrophilic protein with a molecular weight of about 6000
should firstly transport along the GI tract. However, the pH
Da, and thus it is difficult for insulin to be encapsulated in
of stomach environment is 1.2–3.0 and the pH in intestine is
hydrophobic carriers and the permeation of insulin through
6.5–8.0. Such variations make it difficult for protein drugs,
the intestinal epithelium is limited. Thirdly, because of the
such as insulin to remain activity in GI tract (Wang & Zhang,
liver first-pass effect, the bioavailability of untreated insulin is
2012). Some pH-sensitive materials, including hydroxypropyl
extremely low (Sonaje et al., 2010a,b,c).
methylcellulose phthalate (HPMCP) (Maroni et al., 2009;
In order to solve these problems, a lot of work has been
Wang & Zhang, 2012; Wu et al., 2012a,b,c), polycarboxylates,
carried out to develop new oral insulin delivery systems. The
polyaminomethacrylates (EudragitÕ ) (Wu et al., 2012a,b,c;
loading efficiency of insulin on hydrophobic carriers could be
Marais et al., 2013; Viehof et al., 2013) were used as enteric
improved by the addition of distearyldimethylammonium
coatings. A previous study showed that HP55 (one kind of
bromide or soybean phospholipid (Cui et al., 2006; Li et al.,
HPMCP) modifications were capable of protecting insulin
2013). Other studies used enteric coatings (Zhao et al., 2013),
against acidic gastrointestinal conditions and then dissolving in
enzyme inhibitors (Werle et al., 2007) and permeation
the small intestinal environment. This modification reduced
the cumulative release rate of insulin in simulated gastric fluid
Address for correspondence: Dr Xiang Yuan Xiong, School of Life from 33.24 to 15.87%, while cumulative release rates of insulin
Science, Jiangxi Science & Technology Normal University, Nanchang
330013, China. Tel: 86-791-8539361. Fax: 86-791-3815794. Email: in simulated intestinal fluid increased from 15 to 58.06% after
xyxiong@gmail.com this modification (Zhao et al., 2013).
 2 Y. Y. Luo et al.
In addition to the acidic environment, insulin could also be
hydrolyzed by the pepsins and other proteases in the GI tract.
In a previous study, trypsin/chymotrypsin inhibitor aprotinin
was used to protect insulin from degradation. Eight hours
after oral administration of insulin-loaded chitosan–aprotinin
conjugate, the mean blood glucose level decreased to
84 ± 6%, while the mean blood glucose level in the control
group (rats received no treatment) increased to 121 ± 8% of
the initial blood glucose level (Werle et al., 2007). However,
using enzyme inhibitors may lead to serious side effects, such
as pancreatic hypertrophy, impairs dietary protein digestion
and some potentially harmful changes in body functions
(Rekha & Sharma, 2013).
Before traveling across the intestinal epithelium, the drugs
should firstly pass through the intestinal mucus layer. As a
selective barrier which enables the exchange of nutrients,
water, and small molecules while being impermeable to
pathogens, mucus layer is negatively charged and renewed
continuously (Cone, 2009). Generally speaking, molecules
with neutral surfaces could cross the mucus layer easily, while
Downloaded by [Xiang Yuan Xiong] at 02:11 07 August 2015
positively charged molecules have a stronger attraction with
mucus (des Rieux et al., 2013). Some bioadhesive materials
were used to increase the intestinal retention time. Chitosan, a
cationic polymer, was the most widely used due to its
electrostatic interaction with negatively charged mucins (Sung
et al., 2012). Some weakly anionic carboxyl-containing
polymers, including poly(acrylic acid), poly(methacrylic
acid), carboxymethylcellulose, sodium alginate were capable
of forming hydrogen-bonds with mucins by binding their
carboxylic segments to the oligosaccharide branches of
mucins, which contribute to their mucoadhesiveness
(Khutoryanskiy, 2011).
Three possible uptake routes in the small intestine
Mostly, there are three possible routes for the absorption of
nanoparticles-based oral insulin delivery system (Figure 1):
the first, via the densely clustered M cells located on the
surface of Peyer’s patches (Lopes et al., 2014); the second, via
transcellular route, which mainly absorbs lipophilic particles
through the cell membrane of enterocytes; and the last, via
paracellular avenues, through the tight junctions (TJs)
between two adjacent enterocytes (Shahbazi & Santos, 2013).
Intestinal lymphatic route
As an alternative way for oral insulin delivery, the intestinal
lymphatic pathway transports drugs directly to the vena cava,
Figure 1. Three possible routes through the
intestinal epithelium.
Drug Deliv, Early Online: 1–10
thus bypassing the first-pass effects and improving the
bioavailability (Yun et al., 2013). Peyer’s patches act as an
entrance for drug to the lymphatic vessels, via the M cell
transportation of peptides from the intestinal lumen to the
underlying lymphoid cells. Lymphatic pathway has been
shown to function in the absorption of highly lipophilic
compounds. According to a previous study, the liposomal
formulation could facilitate the uptake of cefotaxime (a
hydrophilic drug) through lymphatic absorption. The drug
concentration in the lymph was higher than that in the plasma
when administered via liposomal formulation. The bioavail-
ability of oral cefotaxime-loaded liposomes increased about
2.7 and 2.3 times compared with its oral administration via
aqueous solution and the physical mixture, respectively (Ling
et al., 2006).
Transcellular route
Uptake of NPs via the transcellular pathway depends on their
particle size and hydrophobicity. It is known that particles
smaller than 300 nm could be uptaken by enterocytes (He et al.,
2012), while particles larger than 500 nm were more likely to
be absorbed in jejuna Peyer’s patches (Bakhru et al., 2013).
Han et al. (2012) used insulin-loaded hyaluronic acid (HA)
nanoparticles for insulin delivery through transcellular route.
The plasma glucose levels of diabetic rats receiving oral
administration of insulin-loaded HA nanoparticles (50 IU/kg)
reduced by 24% in 2 h and 32–39% in during 3–8 h, while the
group treated with the same dose of insulin solution showed no
change in blood glucose (Han et al., 2012).
In general, bioadhesive materials showed non-specific
interactions with mucus layers. Receptor-mediated transport
via receptor-specific ligands modifications of insulin delivery
carriers were used to enhance the absorption of oral insulin.
Promising targets, such as enterocytes, mucus layers and M
cells have been studied (des Rieux et al., 2013). Biotin
(vitamin B7) (Zhang et al., 2014) and lectins, such as wheat
germ agglutinin (WGA) (capable for binding to N-acetylglu-
cosamine and sialic acid), tomato lectin, Ulex europaeus
agglutinin1 have been exploited to modify the protein drug
carriers (Kim et al., 2005; Zhang et al., 2005). Vitamin B12-
coated nanospheres could also be used as target delivery
carrier through VB12-IF-IF receptor mediated endocytosis of
villous epithelium. Insulin-loaded dextran nanoparticles
conjugated with VB12 derivatives showed profound (70–
75% blood glucose reductions) and prolonged (54 h) anti-
diabetic effects in STZ-diabetic rats (Chalasani et al.,
 DOI: 10.3109/10717544.2015.1052863 Review of biodegradable polymeric systems for oral insulin delivery 3

2007a,b). Goblet cell-targeting ligands, such as CSKSSDYQC
peptide, which identified from a random phage-peptide
library was found to have affinity with the goblet cells.
After oral administration in diabetic rats, the CSKSSDYQC
peptide modified insulin-loaded nanoparticles showed a better
hypoglycemic effect with a 1.5-fold higher relative bioavail-
ability compared with unmodified ones (Jin et al., 2012).
Paracellular route
As to hydrophilic molecules, the paracellular pathway is the
only way for their uptake. However, the tight junctions are
difficult for large molecules to pass through. Drugs are
generally excluded from this pathway without the use of
permeation enhancer (Chuang et al., 2013). As the decreasing
of calcium ion concentration leads to the opening of the tight
junctions, Ca2+ chelating agents, such as ethylene glycol
tetraacetic acid (EGTA) (Chuang et al., 2013), diethylene
triamine pentaacetic acid (DTPA) (Su et al., 2012), could
enhance the paracellular permeability by reversible opening
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Other biocompatible polymers, including poly(acrylic
acid) and chitosan, are capable of opening the tight junctions
reversibly (Woitiski et al., 2011; Gao et al., 2013a,b).
Poly(acrylic acid) and its derivatives have shown ability in
binding Ca2+ (Gao et al., 2013a,b). Oral administration of
insulin-loaded carboxymethyl cellulose/poly(acrylic acid)
hydrogels (60 IU/kg) to diabetic rats reduced fasting plasma
glucose levels to 72.4% within 6 h post-administration. The
relative bioavailability of oral administration of the insulin-
loaded poly(acrylic acid) hydrogels (6.59%) was 10 times
higher than oral administration of free insulin solution (less
than 0.5%) (Gao et al., 2013a,b). However, the opening of the
tight junctions might cause the absorption of bacterial toxins,
leading to some safety problems (Chen et al., 2011). The
approaches to improve the bioavailability of insulin are
summarized in Table 1.
Natural polymers
Chitosan

of the tight junctions. Caco-2 cell monolayers treated with

EGTA or g PGA–EGTA nanoparticles produced a signifi-
cantly larger reduction in TEER compared to the control cells
(Chuang et al., 2013). Since calcium ions are also very crucial
to sustain the activity of many intestinal proteases, Ca2+
chelating agents could also be used as an enzyme inhibitor to
protect insulin against intestinal proteases.
Bile salts, such as sodium glycocholate (Niu et al., 2011),
sodium taurocholate (Degim et al., 2004) and sodium
deoxycholate (Niu et al., 2012) were most widely used to
modify insulin-loaded liposomes as a penetration enhancer.
These might be attributed to the good deformability of
liposomes containing bile salts (Hu et al., 2013). Niu et al.
(2012) compared the differences between liposomes contain-
ing sodium glycocholate, sodium taurocholate and sodium
deoxycholate, and the highest oral bioavailability was observed
in rats administrated with insulin-loaded sodium glycocholate
(8.5 and 11.0% in non-diabetic and diabetic rats, respectively).
Chitosan (CS) is a natural polysaccharide derived from
the partial deacetylation of chitin, a biopolymer generally
found in crustacean shells and insects. The primary building
blocks of CS are glucosamine and N-acetyl-glucosamine. It is
biocompatible, biodegradable and protective (Mukhopadhyay
et al., 2013). The utilization of chitosan for oral insulin
delivery is based on the mucoadhesive property and the
ability to mediate the opening of the tight junctions reversibly
(Jose et al., 2012, 2013) (Figure 2).
A recently published report studied an iron oxide–CS
nanocomposite loaded with insulin. The iron oxide nanopar-
ticles were obtained in chitosan solution by eco-friendly laser
ablation technique. The insulin-loaded iron oxide-chitosan
nanoparticles were found to effectively reduce the blood
glucose level when administered orally in diabetic rats. About
51% blood glucose level reductions were achieved in severely
diabetic rats (Kebede et al., 2013). This approach is

Table 1. Approaches to improve the bioavailability of insulin.

Approaches Systems Mechanisms Shortcomings References

Insulin modifications Distearyldimethylammoni-
um bromide, soybean
phospholipid
Permeation enhancers Chelators (EGTA, DTPA)
Bile salts
Enteric coatings HPMCP, EudragitÕ
Enzyme inhibitors Trypsin/chymotrypsin
inhibitor
Bioadhesive materials Chitosan, PAA, PMAA
Improve the hydrophobicity (Cui et al., 2006; Li et al.,
of insulin 2013)
Chelating Ca2+, thus Cause the absorption of (Su et al., 2012; Chuang
opening the tight bacterial toxins in GI et al., 2013)
junctions tract
Open the tight junctions (Degim et al., 2004;
and improve deformabil- Niu et al., 2011, 2012;
ity and permeation Hu et al., 2013)
pH-sensitive Rapid release in intestinal (Cui et al., 2007; Maroni
et al., 2009; Wang &
Zhang, 2012; Wu et al.
2012a,b,c; Marais et al.,
2013; Viehof et al.,
2013; Zhao et al., 2013)
Protect insulin from deg- Introducing side effects or (Werle et al., 2007)
radation by proteases in do harm to body
GI tract functions
Adhere to mucus layer and Limited by the turnover of (Khutoryanskiy, 2011;
prolong the retention the mucus layer Sung et al., 2012)
time
 4 Y. Y. Luo et al.
Figure 2. Schematic illustrations of the opening of chitosan-mediated reversible tight junction (TJ) (Sung et al., 2012).
Downloaded by [Xiang Yuan Xiong] at 02:11 07 August 2015
promising, since the nanoparticles can be used in site-directed
drug delivery due to its magnetic properties.
CS derivatives
The pKa of CS is approximately 6.5. CS is insoluble in
neutral environment, where CS starts to lose charge, and this
leads to the loss of its mucoadhesive properties and TJ
opening activities (Qian et al., 2006). To overcome these
drawbacks, several CS derivatives, including quaternized
chitosan, thiolated chitosan, carboxylated chitosan and
amphiphilic chitosan have been synthesized and evaluated
for their potential in oral insulin delivery (Chen et al., 2013).
Quaternized chitosan can reserve its positive charge in
neutral condition, which leads to a residence time increase
and enhanced bioavailability (Sun & Wan, 2007). Sonia et al.
(2011) explored N-(2-hydroxyl) propyl-3-trimethyl ammo-
nium chitosan chloride (HTCC) for oral insulin delivery. The
results showed that quaternized chitosan had a stronger
electrostatic interaction with mucus, and the percentage of
adhesion was 95% for HTCC (the percentage of free amino
groups was 36%) as compared to 72% for naive chitosan (the
percentage of free amino groups was 78%). However, the high
positive charge of quaternized CS derivatives may cause
toxicity to cell membranes. Poly(ethylene glycol) (PEG) was
used to modify N-Trimethyl chitosan chloride (TMC) in order
to reduce the cytotoxicity. The hemolysis assay showed that
TMC modified with PEG has a better biocompatibility than
TMC without PEG modification (Prego et al., 2006;
Zhu et al., 2007).
Thiolated chitosan have been proved to be more
mucoadhesive compared with unmodified CS (Chen et al.,
2013). The thiolated TMC, trimethyl chitosan-cysteine
(TMC-Cys) was prepared to combine the mucoadhesion of
TMC and the permeation enhancing abilities of thiolated
polymers for oral insulin delivery. Compared to TMC
nanoparticles, TMC-Cys nanoparticles significantly increased
insulin absorption through rat intestine by 1.7 to 2.6-fold,
and mucoadhesion and permeation enhancing effects of
TMC-Cys nanoparticles were improved significantly
Drug Deliv, Early Online: 1–10
(Yin et al., 2009). When comparing the mucoadhesion of
different thiolated chitosans, it was found that Chitosan–
thiobutylamidine exhibited the highest mucoadhesion, fol-
lowed by Chitosan–4-mercaptobenzoic acid, Chitosan–gluta-
thione, Chitosan–6-mercaptonicotinic acid, Chitosan–N-
acetyl cysteine, Chitosan–thioglycolic acid and Unmodified
chitosan (Mueller et al., 2011).
Previous research studied carboxylated chitosan by mod-
ifying chitosan with negatively charged carboxyl groups, in
order to increase the water solubility of chitosan (Cui et al.,
2007; Liu et al., 2013). In a previous study, carboxylated
chitosan-grafted poly(methyl methacrylate) nanoparticles
(CCGN) were prepared. The pharmacological bioavailability
after oral administration of insulin-loaded CCGN at 25 IU/kg
was 9.7%, while a long-lasting hypoglycemic effect could be
observed after oral administration of insulin-loaded CCGN
(Cui et al., 2009).
Amphiphilic CS derivatives, such as lauroyl sulphated
chitosan (LSCS) were used for oral insulin delivery. It was
showed that LSCS were non-toxic and lauroyl sulfated
modification on chitosan improves mucoadhesion of CS
greatly. Moreover, LSCS could also protect insulin from
enzymatic degradation and reversely open the tight junctions
(Shelma & Sharma, 2011).
Alginate derivatives
Alginate, an anionic mucoadhesive polysaccharide consist-
ing of various ratios of b-D-mannuronopyranosyl and
a-L-guluronopyranosyl units linked by (1!4)-O-glycosidic
bonds, has always been used for preparing microparticles
(Chan & Neufeld, 2010). It shows a property of mild gel-
formation by ionically cross-linked with multivalent cations,
such as calcium ions, thus enabling drug retention within the
gel matrix (Sarmento et al., 2007a,b). The large porosity of
alginate beads often leads to low encapsulation efficiency and
rapid release of the drug. Low drug encapsulation efficiency
of alginates can be improved by the addition of chitosan and
dextran sulfate (Martins et al., 2007; Reis et al., 2007; Sonia
& Sharma, 2012).
 DOI: 10.3109/10717544.2015.1052863 Review of biodegradable polymeric systems for oral insulin delivery 5

Alginate/chitosan capsules were widely used for controlled

release of oral protein drugs (Sarmento et al., 2007a,b; Čalija
et al., 2011; Zhang et al., 2011a,b). Zhang et al. (2011a,b)
encapsulated insulin in alginate–chitosan microspheres via
different loading methods, and it was shown that the highest
loading efficiency (56.7%) and remarkable activity mainten-
ance (99.4%) were achieved when the insulin was loaded
during the chitosan solidification process, while the network
formation between chitosan and alginate-Ca microspheres
greatly reduced the porosity and decreased the leakage of
insulin.

g-PGA-based materials
Poly-g-glutamic acid (g-PGA) is a water-soluble, biodegrad-
able and non-toxic polymer. Many studies used nanoparticles
composed of poly-g-glutamic acid (g-PGA) and CS for oral
insulin delivery. With a smaller size and a higher loading
efficiency compared with purely CS nanoparticles (Lin et al.,
2007), the pH-sensitive CS/g-PGA nanoparticles could resist
Downloaded by [Xiang Yuan Xiong] at 02:11 07 August 2015

gastric acid while released rapidly in certain area of the small

intestine (Sonaje et al., 2010a,b,c). g-PGA conjugated cova-
lently by diethylene triamine pentaacetic acid (DTPA) could
further prevent enzymolysis and prolong the residence time
of the CS/g-PGA-DTPA system for oral insulin delivery
(Su et al., 2012).
Tripolyphosphate (TPP) and MgSO4 were added into
CS/g-PGA nanoparticles to form an ionically cross-linked
network. Comparing with CS/g-PGA nanoparticles, the multi-
ion-cross-linked nanoparticles could retain more insulin. With
the addition of MgSO4 and TPP, the cumulative amount of
insulin released were significantly reduced at pH 2.5 and pH
7.0, while a fast release of insulin was observed at pH 7.4
(simulating the pH in the body fluid at intercellular spaces),
which means insulin were more likely to be released from the
multi-ion-cross-linked nanoparticles after they were infil-
trated into mucus layer (Lin et al., 2008). Since SC injection
of insulin often produces peripheral hyperinsulinemia in
individuals. In another study, it was found that oral admin-
istration of aspart-insulin-loaded chitosan/g-PGA nanoparti-
cles could achieve a slower but longer hypoglycemic effect
without producing hyperinsulinemia. Oral administration of
aspart-insulin-loaded chitosan/g-PGA nanoparticles at insulin
doses of 30 IU/kg produced a hypoglycemic effect similar to
subcutaneous injections of neutral protamine Hagedorn
insulin (NPH-insulin) at insulin doses of 5 IU/kg. Moreover,
the SC injection of aspart-insulin solution (5 IU/kg) produced
a better hypoglycemic effect than SC injection of NPH-
insulin solution with the same dose (Sonaje et al., 2010a,b,c)
(Figure 3).
Starch-based nanoparticles
As one of the better known natural and biodegradable
biopolymers, starch has attracted much attention because of
its gelling and film forming properties. Zhang et al. (2013)
obtained a pH-responsive copolymer made of starch nano-
particles as backbone and poly(L-glutamic acid) (PGA) as
graft chains. The result of in vitro insulin release experiment
showed that the grafted copolymer had excellent pH-
responsive property due to the introduction of pH-responsive
Figure 3. (a) Blood glucose level versus time profiles and (b) plasma
insulin level versus time profiles of test diabetic rats following the
administration of different insulin formulations (Sonaje et al., 2010a,b,c).
PGA chain. Insulin released from the copolymer in artificial
gastric juice (pH ¼ 1.2) more slowly than that in artificial
intestinal liquid (pH ¼ 6.8). In another study, hydrophobic
starch acetate was conjugated with polyethylene glycol (PEG)
to from an amphiphilic polymeric derivative. Being pH-
sensitive, the PEGylated starch acetate nanoparticles are
capable of opening the tight junctions. Moreover, work of
adhesion for PEGylated starch acetate nanoparticles was also
significantly higher at 595.7 mN mm than starch acetate
(179.1 mN mm) and chitosan (144.4 mN mm), which means
PEGylated starch acetate nanoparticles showed a high
mucoadhesiveness (Minimol et al., 2013).
Synthetic polymers
Since the natural polymers come from different preparation
technologies and different sources, which may lead to a
variety of physicochemical properties (Sonia & Sharma,
2012). However, the structure and physicochemical properties
of synthetic polymeric carriers could be well-controlled, and
thus their drug release properties and biological behaviors
could be modified to change.
PLGA
Poly(lactide-co-glycolide) (PLGA) is widely studied for
biological applications owing to their biodegradability and
 6 Y. Y. Luo et al.
Downloaded by [Xiang Yuan Xiong] at 02:11 07 August 2015
Figure 4. (a) Short model of PLGA. (b) Interaction of the insulin with a
PLGA model of near 1500 Da. In this figure the histidine are shown in
space filling, the glutamate in ball and stick (Lassalle & Ferreira, 2010).
biocompatibility (Cui et al., 2007; Lassalle & Ferreira 2010;
Reix et al., 2012). Generally speaking, the PLGA copolymers
were synthesized from lactic acid and glycolic acid through
the ring-opening polymerization. The hydrophobic inter-
actions between insulin and PLGA appear to be responsible
for the entrapment of insulin in PLGA nanoparticles (Lassalle
& Ferreira, 2010). The contact between insulin and the short
model of PLGA is illustrated in Figure 4. However, the
hydrophilicity of insulin makes them incapable of being
entrapped by hydrophobic PLGA matrices. In a previous
study, insulin was encapsulated in PLGA nanoparticles via
double-emulsion solvent evaporation method to improve the
loading capacity. 11.31% insulin loading capacity was
obtained for the insulin-loaded PLGA nanoparticles. After
oral administration of nanoparticles with an insulin concen-
tration of 30 mg/kg to diabetic rats, a 50% reduction in blood
glucose level was observed within 8 h (Yang et al., 2012).
However, the slight negative surface charge of PLGA
nanoparticles exhibit weaker bioadhesive abilities compared
with positive-charged nanoparticles. Cationic modifications,
such as chitosan-coat had been used to improve the bioavail-
ability of insulin-loaded PLGA nanoparticles. As a result,
compared with the PLGA nanoparticles, CS-coated PLGA
nanoparticles reduced the initial burst, and showed a stronger
mucosal adhesion, thus prolonged the resistance time and
increased the bioavailability of insulin (Zhang et al., 2012).
Drug Deliv, Early Online: 1–10
Concanavalin A was used as a target ligand to enhance the
lymphatic absorption of oral insulin formulations. After oral
administration of Concanavalin A-conjugated PLGA nano-
particles (20 IU/kg), the blood glucose lever reduced from
about 260.17 to 196.33 mg/dL in 3 h, and hypoglycemic effect
lasted for the next 24 h, while oral PLGA nanoparticles loaded
with the same dose of insulin cannot reach the same effect
(Hurkat et al., 2012).
PLA
Vesicles self-assembled from amphiphilic polymers are cap-
able of encapsulating both hydrophilic and hydrophobic drugs
due to their hydrophilic shell and hydrophobic core in aqueous
solutions (Kita-Tokarczyk et al., 2005; Xiong, 2006). Xiong
et al. explored the use of Pluronic/poly(lactic acid) (PLA)
vesicles as oral insulin carriers. Pluronic/PLA copolymer was
obtained by attaching PLA segments to both ends of Pluronic
copolymer by a ring-opening polymerization (Figure 5). PLA
was highly hydrophobic, while the hydrophobicity of PPO was
weaker and PEO was hydrophilic, so the Pluronic/PLA
copolymer could self-assemble to vesicles in water (Figure 6).
According to their studies, after orally treating with
insulin-loaded PLA-F127-PLA vesicles at insulin doses of
50 IU/kg, the blood glucose of the diabetic mice reduced from
18.5 to 5.3 mmol within 4.5 h, and this effect lasted for an
additional 18.5 h (Xiong et al., 2007). Pluronic P85/PLA
(PLA-P85-PLA) vesicles were also explored to carry insulin
for oral administration. After oral administration of insulin-
loaded PLA-P85-PLA vesicles at insulin doses of 200 IU/kg
to the diabetic mice, the glucose level reached the minimum
after 2.5 h. The blood glucose level increased slowly after
10.5 h and was maintained at a low level (32.5% of initial
blood glucose concentration) for at least an additional 14 h
(Figure 7) (Xiong et al., 2013).
PCL
Poly("-caprolactone) is a biodegradable polyester synthesized
from"-caprolactone by a ring-opening polymerization
(Jugminder & Chawla, 2002). Polymeric nanoparticles
composed of biodegradable poly("-caprolactone) and poly-
cationic non-biodegradable acrylic polymer (EudragitÕ RS)
were used for oral regular human insulin and aspart-insulin
delivery. When aspart-insulin-loaded PCL/EudragitÕ RS
nanoparticles were administered orally to diabetic rats at the
dose of 50 IU/kg, the maximum plasma glucose level
reduction (52%) was observed at 8 h after administration
(Damge et al., 2010). Comparing with oral administration of
regular insulin-loaded PCL/EudragitÕ RS nanoparticles,
which working only for 6–8 h, the hypoglycemic effects of
aspart-insulin-loaded PCL nanoparticles lasted for 12–24 h
(Damge et al., 2007). This may be because the monomeric
aspart-insulin can be taken up by the intestinal mucosa more
easily than regular human insulin (Damge et al., 2010).
PEA
L -Lysine/L -Leucine-based poly(ester amide) with pendant
COOH groups was synthesized by He et al. (2012) for oral
insulin delivery. The PEA copolymer with benzyl ester
 DOI: 10.3109/10717544.2015.1052863 Review of biodegradable polymeric systems for oral insulin delivery 7
Figure 5 The synthesis scheme of
PLA-P85-PLA block copolymer (Xiong
et al., 2013).
Downloaded by [Xiang Yuan Xiong] at 02:11 07 August 2015

Figure 6. (a) TEM micrograph of PLA-P85-PLA nanoparticle vesicles in water. (b) The possible schematic microstructure of PLA-P85-PLA vesicles
(Xiong et al., 2013).

pendants was prepared by solution polycondensation of three

monomers, and the structure of L-Lysine/L-Leucine-based
PEA-COOH is illustrated in Figure 8 (He et al., 2012). Insulin
was encapsulated in PEA microspheres by a solid-in-oil-in-oil
technique using N,N-dimethyformamide(DMF)/corn oil as
solvent pairs. As a result, the release of insulin was pH-
dependent and the hydrophobicity of PEA-COOH micro-
spheres can be adjusted by the level of leucine components,
thus improving the stability of the drug delivery system and
enhancing the overall absorption of insulin. Oral administra-
tion of insulin-loaded PEA-COOH microspheres to strepto-
zotocin-induced diabetic rats at a dose of 60 IU/kg, the plasma
glucose levels reduced to 49.4% within the first 5 h of
administration, and this effect lasted for 8 h (He et al., 2012).
Arginine-based PEA (Arg-PEA) was also introduced in their
research; the structure of Arg-PEA is shown in Figure 8.
By adding Arg-PEA to form PEA-COOH/Arg-PEA blend Figure 7. The blood glucose level versus time profiles following oral
administration of physiological saline to control animals, insulin free
microspheres, the hypoglycemic effects could be further PLA-P85-PLA vesicles, insulin-loaded PLA-P85-PLA vesicles (50, 100
improved (He et al., 2013). and 200 IU/kg), and subcutaneous injection of free insulin (5 IU/kg).
Results are means ± S.D. of five animals per group. Significant
difference from negative physiological saline control (*p50.05;
Conclusions and future perspectives **p50.01) (Xiong et al., 2013).

Though oral insulin delivery systems show promise in recent

years, this work needs further study before clinical testing. improved via different method (Li et al., 2013). However, the
Since insulin is a hydrophilic carrier, the insulin has been bioavailability of orally administered insulin remains low
modified to enhance its physicochemical and biological compared with SC injections. In addition, maintaining the
stability. The loading efficiency of insulin should also be physicochemical and biological stability of insulin in the GI
 8 Y. Y. Luo et al.
Figure 8 Chemical structures of the poly(ester
amide)s. (a) L-Lysine/L-Leucine-based
PEA-COOH. (b) Arginine-based Arg-PEA
(He et al., 2013).
tract is necessary, especially when mucoadhesive systems
were used to prolong the residence time (Wong, 2010).
Furthermore, potential insulin alternatives, such as psyllium
polysaccharides (Singh & Chauhan, 2009), chalcone (Hsieh
et al., 2012), glucagon-like peptide-1 (Ahn et al., 2013), can
Downloaded by [Xiang Yuan Xiong] at 02:11 07 August 2015
be added to the oral dosage form in order to avoid the risk of
insulin overdose. A successful oral insulin delivery system
should be biocompatible and biodegradable, keeping the
stability of insulin during the absorption, and ultimately
improving the bioavailability of insulin.
Declaration of interest
The authors would like to acknowledge the financial support
from the National Natural Science Foundation of China
(No. 21264009 and 31360376), the Natural Science
Foundation of Jiangxi Province (No. 20132BAB206034), the
Scientific and Technological Landing Project of Higher
Education of Jiangxi Province (No. KJLD13071) and the
Cultivation Project for Academic and Technical Leaders of
Major Disciplines of Jiangxi Province.(No. 20153BCB22009).
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