Journal of Controlled Release 178 (2014) 25–45

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Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

Review

Advanced progress of microencapsulation technologies: In vivo and

in vitro models for studying oral and transdermal drug deliveries
P.L. Lam a,⁎, R. Gambari b
a
State Key Laboratory of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
b
Centre of Biotechnology, Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

a r t i c l e i n f o a b s t r a c t

Article history: This review provides an overall discussion of microencapsulation systems for both oral and transdermal drug
Received 30 August 2013 deliveries. Clinically, many drugs, especially proteins and peptides, are susceptible to the gastrointestinal tract
Accepted 17 December 2013 and the first-pass metabolism after oral administration while some drugs exhibit low skin permeability through
Available online 10 January 2014
transdermal delivery route. Medicated microcapsules as oral and transdermal drug delivery vehicles are believed
to offer an extended drug effect at a relatively low dose and provide a better patient compliance. The polymeric
Keywords:
Microencapsulation
microcapsules can be produced by different microencapsulation methods and the drug microencapsulation tech-
Oral drug delivery nology provides the quality preservation for drug stabilization. The release of the entrapped drug is controlled
Transdermal drug delivery and prolonged for specific usages. Some recent studies have focused on the evaluation of drug containing micro-
In vivo study capsules on potential biological and therapeutic applications. For the oral delivery, in vivo animal models were
Skin delivery model used for evaluating possible treatment effects of drug containing microcapsules. For the transdermal drug deliv-
ery, skin delivery models were introduced to investigate the potential skin delivery of medicated microcapsules.
Finally, the challenges and limitations of drug microencapsulation in real life are discussed and the commercially
available drug formulations using microencapsulation technology for oral and transdermal applications are
shown.
© 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2. Challenges to oral and transdermal drug deliveries of conventional routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.1. Oral delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.2. Transdermal delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3. Microencapsulation for drug deliveries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4. Microencapsulation techniques for drug entrapment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.1. Chemical microencapsulation processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.2. Physicochemical microencapsulation processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.3. Mechanical microencapsulation processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5. Stabilization of drugs using microencapsulation technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6. Drug release mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
6.1. Diffusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
6.2. Swelling and dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
6.3. Erodible and degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
6.4. Osmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
7. Recent advances in microencapsulated oral and transdermal drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
7.1. Natural polymer-based systems for drug microencapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
7.1.1. Chitosan-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
7.1.2. Gelatin-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
7.1.3. Alginate-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
7.1.4. Cellulose-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

⁎ Corresponding author.
E-mail address: tcstacey@inet.polyu.edu.hk (P.L. Lam).

0168-3659/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jconrel.2013.12.028
26 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45

7.2. Synthetic polymer-based systems for drug microencapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

7.2.1. Poly(L-lactic acid) (PLA)- and poly(lactic-coglycolic acid) (PLGA)-based systems . . . . . . . . . . . . . . . . . . . . . . . . 37
7.2.2. Poly (vinyl alcohol) (PVA)-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
7.2.3. Poly(ɛ-caprolactone) (PCL)-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
7.2.4. Poly(methyl methacrylate) (PMAA)-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
7.3. Multiple microemulsion systems for drug microencapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
8. Challenges of drug microencapsulation in real life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
9. Commercially available microencapsulated pharmaceuticals for oral and transdermal drug deliveries . . . . . . . . . . . . . . . . . . . . . . . 40
10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

1. Introduction
Advanced technologies in drug delivery turn the challenges into
opportunities of drug deliveries. With the progressive developments
and explorations in technologies, traditional drug delivery routes
are being supplemented by sophisticated and versatile approaches
of drug deliveries. Recently, intensive studies have focused on the inno-
vative technologies to tackle the restrictions of conventional drug deliv-
ery systems. It is highly challenging to develop biopharmaceuticals or
biomedical drugs with an optimal bioavailability and biostability as
well as a maximum therapeutic efficiency. The desired oral dosages
should protect the drugs under unstable biological environments in-
cluding drug degradation induced by the gastrointestinal tract and
first-pass liver effects after oral administration before reaching the
targeted sites, and maximize the drug uptake and absorption in the cel-
lular intestinal regions [1]. The development of topical formulations
should enhance the drug absorption, alleviate the skin disorder by in-
creasing the skin hydration to overcome the low skin permeability,
and promote a prolonged delivery time to the targeted skin sites [2].
In fact, many drugs, such as anticancer drugs with 5–20% oral bioavail-
ability [3], proteins and peptides with less than 1–2% oral bioavailability
[4], are limited in their low bioavailability when they are taken orally
while some patients are found to have immediate and delayed allergy
and site irritation to intravenous injection [5]. As a result, many strate-
gies have been developed for oral and transdermal drug delivery systems
using microencapsulation technologies because these provide some pos-
sible advantages for drug deliveries over conventional routes. Micro-
particulate systems for oral and transdermal drug deliveries are speculat-
ed to improve the drawbacks in the traditional drug dosage forms, and
offer an alternative administration route to enhance the release profile
and improve the bioavailability of drugs. The efficacy of many drugs in
conventional dosage forms, including film coated tablets and hard or
soft gelatin capsules, is often restricted by their limitations to be deliv-
ered to targeted body sites as the drugs may be degraded by the acidic
gastric fluid and this induces irritation to stomach [6]. Therefore,
searching biotechnologies to offer the desired excipients to accomplish
the targeted drug delivery is particularly important.
Medicated-polymeric microcapsules as oral and topical drug deliv-
ery vehicles are believed to minimize the inconveniences and risks dur-
ing oral and intravenous administrations, promote the extension of
drug effect at a relatively low dose, and offer the ease of drug adminis-
tration, resulting in a better patient compliance [7–10]. Microencapsula-
tion, as a micro-packaging technique, involves the manufacture of
microcapsules or microspheres by surrounding the small particles of
solids, droplets of liquids or dispersions of solids in liquids with the
polymeric matrix or shell to give small capsules a variety of applications.
An encapsulated reservoir of core active ingredients is under the con-
trolled release to supply valuable and useful effects for specific end-
uses. The wall material is able to prevent the core active ingredients
from the damages of external environments such as acidity, alkalinity,
evaporation, heat, oxidization, light or moisture. Micro-particulate car-
riers enable the controlled release of core active substances in a targeted
manner, for example, the core ingredients are controlled to be released
all at once or moderately and gradually. Microcapsules are generally
produced within the size ranging from 1 to 1000 μm for enabling the ef-
ficiency of the controlled release profile of core active substances and
extending the shelf life of entrapped substances [10–22]. Microencapsu-
lation has been widely applied to the design and development of drug
delivery systems as microcapsules could protect the drugs from degra-
dation and prevent the body from the potential toxicity induced by
drugs [23]. This review highlights a comprehensive summary of chal-
lenges to conventional oral and transdermal drug delivery routes, micro-
encapsulation techniques for drug deliveries, drug stabilization using
microencapsulation, drug release mechanism of drug loaded microcap-
sules, and advances in oral and transdermal drug deliveries using micro-
encapsulation technologies to overcome these challenges. The challenges
and limitations of drug microencapsulation in real life and the commer-
cially available pharmaceuticals using microencapsulation technology
for oral and transdermal drug deliveries are shown.
2. Challenges to oral and transdermal drug deliveries of
conventional routes
2.1. Oral delivery
Oral delivery is considered as an attractive and preferable route for
drug administration as oral administration provides some advantages
for people, such as ease and full control of drug administration by pa-
tients, together with a high degree of flexibility on dosages [24]. Previous
studies reported that almost all patients preferred oral administration
route of anti-cancer drugs instead of intravenous route. Approximately
80% of patients chose to have an oral chemotherapy treatment for breast
cancer while less than 3% of them favored parenteral route [25]. In anoth-
er study, almost 90% of patients preferred oral chemotherapy for colon
cancer to intravenous treatment [26]. More than 60% of commercially
available drug dosage forms with small molecules are orally adminis-
tered [27]. However, many conventional drugs exhibit poor bioavailabil-
ity when they are taken orally. In oral drug delivery route, impermeable
gastrointestinal epithelium behaves as a physical barrier while peptidase
induced enzymatic degradation acts as a biochemical barrier. The gastro-
intestinal tract, with the total length of approximately 20 ft, is mainly di-
vided into two parts: the upper part involves mouth, pharynx, esophagus
and stomach; and the lower part includes small intestine (duodenum,
jejunum and ileum), large intestine (cecum, colon and rectum) and
anus [28]. More than 90% of nutrients including proteins, minerals, carbo-
hydrates, fats, vitamins and water are absorbed in the small intestine
[28], followed by entering the lymphatic circulation or bloodstream to
the first-pass metabolism (liver). However, when the drug is absorbed
through the bloodstream to the first-pass metabolism, the hepatic
enzymes usually degrade the drug, resulting in low bioavailability and
limited efficacy of the orally administered dosage form. In fact, many
drugs, especially protein and peptide-based medicines, exhibit the oral
bioavailability below 1%. These drugs are difficult to pass through muco-
sal surfaces and biological membranes, and they are being inactivated
 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
because of the stomach juice with strong acid or digestive protease en-
zymes within the gastrointestinal tract. Additionally, drugs are unable
to be effectively absorbed into the systematic circulation due to their
large molecular size, charge issues, and hydrophilic property, resulting
in the tendency to be denaturated and aggregated in the first-pass me-
tabolism [29–32]. Besides the protein and peptides, delivery of anti-
cancer drugs through oral route is also greatly challenged because of
their peculiar physicochemical properties and the physiological barriers
including pre-systemic metabolism and gastrointestinal instability. Oral
bioavailability of some anti-cancer medicines such as doxorubicin, doce-
taxel, paclitaxel and tamoxifen only ranges from 5 to 20% [3,33–36].
2.2. Transdermal delivery
Transdermal delivery is to apply the drugs or medicines to the skin,
the drawbacks of oral administration such as enzymatic degradation
and rapid clearance in the gastrointestinal tract or the first-pass metabo-
lism, therefore, can be avoided. Targeted drug delivery to skin sites
alleviates the physical pain and discomfort, and also promotes the
patient convenience and compliance for drug treatments [37–39].
Although the skin offers a relatively large and readily accessible surface
area for drug adsorption, skin-targeted drug delivery still presents limita-
tions. The human skin is an impermeable barrier that provides a strong
protection against the external substances including bacteria, fungi, vi-
ruses, allergens, dust and large molecules. The skin is mainly composed
of two layers: the underlying layer and the upper basement layer. In
the underlying layer, various types of cells, blood vessels, lymphatics
and nerves are found in a dense network of connective tissue. In the
upper basement membrane, more than 90% of stratified keratinocytes
exist, and keratinocytes undergo the cell differentiation and move up-
ward from the stratum basale, through the stratum spinosum and stra-
tum granulosum, to the outermost layer, the stratum corneum to
finally become corneocytes. Corneocytes grow into anucleated and flat-
tened cells and they are eventually sloughed off [40]. The stratum
corneum, as an outermost layer of epidermis, provides an extremely ef-
fective barrier for the control of drug penetration by an incapability of a
majority of drugs to pass the skin at therapeutic rates and it is also the
main barrier to spread water out of the skin [37,40–42]. The anucleated,
lattened and protein-rich corneocytes of the stratum corneum are thickly
packed within the extracellular lipid matrix [40]. Therefore, the major
challenge of transdermal drug delivery is to overcome the strong barrier
function of the skin as this barrier leads to slow drug penetration rates,
limited drug uptake rate and lack of dosage flexibility or precision.
3. Microencapsulation for drug deliveries
In the 21st century, microencapsulation technology has been
extensively applied to drug deliveries. Biodegradable polymeric micro-
capsules have received great attention as potential drug delivery vehicles
in consideration of their applications in targeted drug delivery.
Microparticles have already been introduced to drug delivery systems
with great success. Microcapsule drug carrier systems possess high poten-
tial for various applications in therapeutic and pharmaceutical fields, such
as anti-inflammation [43–45], antibiotics [46–50], anti-tumor [9,51–56],
proteins [57–61] and vitamins [62–64]. Biopharmaceuticals can be simply
produced by an oil-in-water (o/w) system or a water-in-oil (w/o) system.
Generally, an o/w system refers to the processing emulsion in which the
oil is used as a dispersed phase while the water-soluble/hydrophilic ma-
terial is employed as a dispersed medium during the microcapsule forma-
tion process. However, a w/o system refers to the processing emulsion
which contains the water-soluble/hydrophilic material as the dispersed
phase and the oil as the dispersed medium during the formation process.
Fig. 1 shows the schematic diagrams of an o/wsystem and a w/o system.
For the potential applications, an o/w system could be applied to the
deliveries of oil-soluble agents, including fat-soluble vitamin A, D, E and
K, as well as water-insoluble drugs (e.g. celecoxib). A w/o system could
27
Fig. 1. Schematic diagrams of (a) an o/w system and (b) a w/o system.
be applied to the deliveries of hydrophilic agents, including water-
soluble vitamin B and C, antibiotics, and chemotherapeutic drugs (e.g.
cisplatin).
By using the microencapsulation technology, many benefits can be
found in both oral and transdermal drug deliveries. Microencapsulation
provides a physical barrier to protect the drugs which are liable to
external environments such as acidity, alkalinity, evaporation, heat,
oxidization, light or moisture before drug release in order to improve
the stability of drugs [16]. Curcumin, which is susceptible to oxidants,
light and heat, was protected by gelatin/porous starch microcapsules to
avoid damages and degradation during industrial process. The microcap-
sule-stabilized curcumin still preserved the antimicrobial activities
against foodborne pathogens and spoilage microbe, such as Escherichia
coli (E. coli), Yersinia enterocolitica (Y. enterocolitica), Staphylococcus aureus
(S. aureus), Bacillus subtilis (B. subtilis), Bacillus cereus (B. cereus),
Aspergillus niger (A. niger), Penicillium notatum (P. notatum), and Saccharo-
myces cerevisiae (S. cerevisiae) [65]. Ascorbic acid is considered as an anti-
oxidant agent to stabilize free radicals that lead over time to degenerative
diseases such as cardiovascular diseases and cancer. However, it is highly
unstable and easily degraded. Microencapsulated ascorbic acid was syn-
thesized by using four coating materials including gel, starch, ethyl cellu-
lose and β-cyclodextrin. The results revealed that microencapsulation
could avoid the color change, decelerate the release rate and mask
the acid taste of ascorbic acid. Starch and β-cyclodextrin coated micro-
capsules could delay the degradation of ascorbic acid when they
were stored at 38 °C [66]. Taste marking can be performed by using
microencapsulation systems. Many oral medicines or pharmaceuticals
usually have an obnoxious taste such as bitterness. MicroMask®
technology incorporates a dry-powder micro-particulate approach to
conceal the unpleasant taste or odor of drugs within a specialized matrix
in order to deal with the unwilling patients to take medicines [67].
Berberine was entrapped in the hydroxypropylmethylcellulose micropar-
ticles and the microparticles were then coated with Eudragit E100 in
order to mask the bitter taste of the drug [68]. Microencapsulated drugs
or compounds also improve the drawbacks of conventional drug delivery
routes including poor bioavailability and compatibility, low absorption,
and short half-life. Microencapsulation increases the therapeutic efficien-
cy of drugs and minimizes environmental damages to drugs by making
use of the property of the controlled release. The long-term therapeutic
performance could be enhanced by microencapsulated drugs with an ap-
propriate host response in a specific therapeutic purpose, for example,
chronic disease treatments require a continuous delivery of the drug
[16]. Protein-based drugs, such as insulin, have poor oral bioavailability
and short half-life after administration because they are sensitive to enzy-
matic degradation. For the treatment of iron-deficiency chronic anemia,
patients require at least three to four injections per day to achieve the ap-
proximately normal glycemia level for a long-term period. This causes
discomfort sufferings, inconveniences and low compliance to patients. In-
sulin microcapsules were deposited with multi layers of oppositely
charged Fe3+ and dextran sulfate (DS) in order to offer a longer lasting
performance. The insulin microcapsules greatly improved glucose toler-
ance from 2 h (free insulin) to even 12 h (insulin microcapsules with
28 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
ten bilayers) [69]. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) mi-
croparticles were developed for the ibuprofen delivery. The drug-loaded
microcapsules with multilayer shells of chitosan and sodium alginate
were demonstrated to be more effective to prolong the drug half release
to 62 h with a reduced initial burst when compared with the microcap-
sules without multilayer coverage, with only 1 h of drug half release
[70]. A long-term delivery of erythropoietin was achieved by alginate-
poly-L-lysine-aginate microencapsulated C2C12 myoblasts. The results
showed that the continuous release of erythropoietin could last for
more than 7months [71]. Microencapsulated drug delivery systems pro-
vide various release profiles of drugs or compounds in a controlled man-
ner whether the core drug is released all at once or moderately and
gradually [16]. The release rate of the drug could be affected by the alter-
ation of processing parameters during the microcapsule formation process.
The release profiles of bovine erythrocyte hemoglobin (Hb) from poly(L-
histidine)-chitosan/alginate complex microcapsules prepared with low,
medium and high molecular weight of chitosan were studied. Microcap-
sules prepared with low, medium and high molecular weight of chito-
san showed the initial burst release of Hb of 5.3%, 14% and 9.4% in the
first 30 min and 14.4%, 26.3%, 20.5% after 2 h, respectively. The Hb re-
lease reached 84.8%, 71.4%, and 87.3% from microcapsules prepared
with low, medium and high molecular weight of chitosan after 72 h
[72]. The release profiles of phenacetin loaded gelatin-based microcap-
sules prepared with different poor solvents, including methanol, etha-
nol, and propanol, were investigated. Microcapsules prepared with
methanol were fragile and unacceptable. The results showed that the al-
teration of poor solvent during microcapsule formation process could
affect the drug release rate. Propanol prepared microcapsules possessed
a slower drug release (lower than 34%) than ethanol prepared micro-
capsules (more than 60%) after 24 h [73]. Microencapsulation also
achieves an effective drug concentration at the targeted body sites for
an extended period of time, with minimal systemic exposure. The
local cancer therapy could be achieved by the synergistic effect of radi-
ation and the anticancer drug. The hyaluronic acid/alginate microcap-
sules released the carboplatin in response to radiation, resulting in a
targeted drug delivery to the intratumoral sites. The mice model
showed that the combination of microencapsulated carboplatin and ra-
diation remarkably increased the intratumoral carboplatin concentra-
tion, and the significant increase in carboplatin concentration was
maintained for 48 h after irradiation. Administration of microencapsu-
lated carboplatin did not induce a noticeable increase in the blood
carboplatin level while the free carboplatin highly increased the drug
concentration in blood from 1 to 6 h after administration. The lower
blood carboplatin concentration could reduce the adverse reactions
and side effects of carboplatin [74]. Microencapsulated drugs reduce
the gastrointestinal irritation, potential toxicity and side effects of the
original drugs. DepoMed, Inc. has developed the controlled release
drug delivery technology to improve the side effects of orally adminis-
tered drugs. Reduced irritation system has been designed to reduce
the gastrointestinal irritation induced by certain pharmaceuticals in-
cluding aspirin and many antibiotics. This system is composed of an
outer gelatin capsule for quick decomposition in stomach to deliver
multiple small spherical polymeric pellets containing the active com-
pound [67]. The polymeric controlled release system was designed
to deliver the temozolomide to treat the brain cancer glioblastoma
multiforme in order to reduce the adverse effect of temozolomide.
Temozolomide kills the tumors through the methylation of tumoral
DNA. Methylation leads to DNA damage and activates apoptotic
pathways in the cell cycle, thus resulting in cell death. The potential
cytotoxic effect could be generated during the antitumor process. In
vivo animal results revealed that localized intracranial delivery of temozo-
lomide from microcapsules could permit much higher effective drug
doses and reduce the systemic toxicity, the survival rate of animals
could be eventually extended [75]. Microencapsulation also improves
the handling and the workability of drugs during processing as liquids
can be prepared into powder or solid forms. This makes pharmaceutical
materials to work easily. Park et al. reported the poly(butylene succi-
nate)/poly(ɛ-caprolactone) (PBS/PCL) microcapsules containing indo-
methacin prepared by emulsion solvent evaporation method [76].
Hamishehkar et al. developed insulin-loaded PLGA microcapsules with
respirable size using oil in oil emulsification/solvent evaporation method
[77].
4. Microencapsulation techniques for drug entrapment
Drug microencapsulation can be achieved by using different micro-
encapsulation techniques. The most commonly used microencapsulation
methods for drug entrapment involve: (i) chemical processes (interfacial
and free radical polymerization methods); (ii) physico-chemical
processes (coacervation (phase separation) and ionotropic gelation
methods); and (iii) mechanical processes (fluid bed coating, solvent
evaporation/extraction and spray drying methods). Table 1 summarizes
the microencapsulation methods for drug delivery applications, the
particle size and stability of their resulted microcapsules, advantages
and disadvantages of these methods, as well as examples using these
methods for drug deliveries.
4.1. Chemical microencapsulation processes
Interfacial polymerization refers to the formation of a polymer at the
interface between two liquid phases. The wall of microcapsules is
formed at or on the surface of a droplet or particle by the reactive mono-
mer polymerization. A multi-functional monomer is dissolved in the liq-
uid form of core materials, and the mixture is dispersed to a desired
drop size in an aqueous phase involving a dispersing agent and a
multi-functional amine. The rapid reaction of polymerization then gen-
erates the wall shell of microcapsules [16,23,78]. Free radical polymeri-
zation involves an initiator and a monomer. The initiator molecules are
firstly converted to free radicals by heating, photolysis or electrolysis.
The free radicals then become highly active to obtain electrons
from the molecules of the monomers. The microparticles are formed
through the growth of polymer chains as a result of electron transfer be-
tween the reactive monomers [79]. Drug loaded microparticles are pro-
duced by imbibing the dried microparticles in the drug solution [80–82].
4.2. Physicochemical microencapsulation processes
Coacervation (phase separation) was initially introduced by
Bungenberg de Jong & Kruyt in 1929. It was defined as partial
desolvation of a homogeneous polymer solution into a polymer-rich
phase (coacervate) and a poor polymer phase (coacervation medium)
[83,84]. Coacervation refers to the phase separation in a macromolecu-
lar system in which two phases are formed. The core ingredient is firstly
suspended or dispersed in a solution of wall material in prior to any
droplet formation steps. Coacervation starts by an addition of acid or
salt (pH change), an input of non-solvent to the dispersion, or a temper-
ature change of the emulsion, resulting in a precipitation of wall
material and a continuous coating of wall polymer around the core
droplets. The wall coating of formed microcapsules can be hardened, so-
lidified and stabilized by a polymer crosslinking process through a
change of temperature or an input of crosslinker. Generally, simple co-
acervation needs a single colloidal solute while complex coacervation
implicates more than one colloid [16,23,78,85,86]. Ionotropic gelation
depends on the ability of polyelectrolytes to crosslink in the existence
of counter ions to produce the spherical crosslinked hydrogel beads.
The hydrophilic beads are generated by an addition of drug loaded an-
ionic polymeric drops into an aqueous solution of polyvalent cations.
The diffusion of cations into the polymeric drops leads to a three-
dimensional lattice of ionically crosslinked moiety. The mechanical
strength and permeability of the beads can be enhanced by an input
of polycations or polyelectrolytes to the bead surface [86–88].
Table 1
Microencapsulation methods for oral and transdermal drug deliveries.

Category Microencapsulation Particle Stability Advantages Disadvantages Examples

method size (μm)

Chemical Interfacial 0.5–1000 Based on the types of polymeric • High drug encapsulation efficiency [93] • Difficult to control polymerization • Dimethyl-dodecyl-(5-hydroxy-pentyl)-ammonium bro-
polymerization [91] wall materials used [92] reactions, loss of water soluble drugs mide (antibacterial agent) grafted polyurea microcapsules for
caused by exhaustive washing steps topical delivery [94]
Free radical – [92]; • Insulin (core drug, peptide) loaded poly(methacrylic acid)/
polymerization • More side effects after drug poly(ethylene glycol) microparticles for oral delivery
administration due to an involvement [80–82,95]
of nonbiodegradable wall materials or

P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45

residual solvents [19]
Physico- Coacervation 2–1200 An addition of non-solvent forms • Simple and cheap method for drug encapsulation[16]; • Aggregation of microspheres and • Insulin (core drug, peptide) loaded mucin/sodium alginate
chemical (phase separation) [91] stable coacervates without • High drug encapsulation efficiency and efficient hard scaling-up for mass production (wall) microcapsules for oral delivery [98]
causing agglomeration [96] control of the particle size with a narrower size [97] • Hydrocortisone succinate acid (core drug, steroid
distribution [92] hormone)/5-fluorouracil (core drug, anticancer agent)/
phyllanthin (core drug, plant bioactive) loaded chitosan
(wall) microcapsules for oral and topical deliveries [12,14]
• Fucoxanthin (core drug, xanthophyll) loaded fish gelatin–
gum arabic (wall) for oral delivery [99]
Ionotropic gelation – Low mechanical strength due to • No requirement of organic solvents or elevated • Relatively fast release of drug due to • Curcumin-phytosome (core drug, plant bioactive) loaded
permeable hydrogel membrane temperatures; the low mechanical strength [92] chitosan (wall) microspheres for oral delivery [100]
of microspheres [92] • Prevention of liable drug damages such as proteins; • Egg yolk immunoglobulin (core drug, antibody) loaded
• Simple, fast and cost-effective method [92] chitosan/alginate (wall) microcapsules for oral delivery [101]
• Insulin (core drug, peptide) loaded chitosan/alginate
microcapsules for oral delivery [102,103]
Mechanical Fluid bed coating 20–1500 Based on the thickness of the • Total control over the drying temperature; • Relatively longer duration (up to 2 h) • Berberine HCl (core drug) loaded hydroxypropyl–
[91] coating layers [78,91] • Lower operation cost [104] involved in the drying process [104]; methylcellulose microparticles coated with Eudragit E100
• Agglomeration/sticking of particles (wall) for oral delivery [68]
during coating [105] • Diclofenac sodium (core drug, anti-inflammatory agent)
loaded Eudragit RS30D (wall) microcapsules for oral delivery
[106]
Solvent 0.5–1000 Microcapsules prepared with • Useful method for the delivery of small drug • Low drug encapsulation efficiency • Cidofovir (core drug, antiviral agent) loaded poly(lactide-co-
evaporation/ [91] solvent extraction result in higher molecules [92] and high cost [92]; glycolide) (PLGA) microcapsules for topical delivery [107]
extraction porosities than those produced by • More side effects after drug • Human recombinant insulin (core drug, peptide) loaded
solvent evaporation [85] administration due to an involvement poly(D,L-lactide-co-glycolide) (PLGA) (wall) microcapsules
of non biodegradable wall materials or for topical delivery [108]
residual solvents [94] • Carvedilol (core drug, antihypertensive agent) loaded
Ordered mesoporous carbon (wall) microparticles for oral
delivery [109]
Spray drying 5–5000 High stability [110] • Low operation cost, good stability and retention, and • Particle agglomerations and larger • Cidofovir (core drug, antiviral agent) loaded poly(lactide-
[91] easy scaling-up for mass production [110,111]; sized microcapsules [91]; co-glycolide) (PLGA) microcapsules for topical delivery [107]
• No limitation of polymer choices, high encapsulation • Loss of input materials, change of • Ibuprofen (core drug, anti-inflammatory agent) loaded
efficiency, time-efficiency, useful for heat-sensitive drug polymorphism of spray-dried drugs, gelatin (wall) microcapsules for oral delivery [113]
entrapment such as proteins or peptides due to an and limited amount of polymer and • Soft mannitol/lecithin agglomerates containing
involvement of mild temperatures [112] drugs being encapsulated [92]; pantoprazole (core drug, proton-pump inhibitor) loaded
• No uniform microcapsules [110] Eudragit S100 (wall) microparticles for oral delivery [114]

29
30 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
4.3. Mechanical microencapsulation processes
Fluid bed coating refers to a process that solid drug particles are
suspended on a jet of air followed by spraying a liquid coating on the
drug particles, and the coated wall is solidified through solvent evapora-
tion or cooling procedures [78,85,86]. Wurster in 1953 developed the
coating technique by using a coating chamber with a cylindrical nozzle
and a perforated bottomplate for spraying the coating material on the
core particles [89]. Solvent evaporation/extraction forms the microcap-
sules by dissolving or dispersing the core drug in the coating polymer
solution, followed by the dispersion of core-wall solution in a liquid
vehicle with agitation [78,86]. The coating material then shrinks around
the core drug to produce the microcapsules by removal of the solvent
from the polymer droplets either by solvent evaporation (by heat or
reduced pressure), or by solvent extraction (with a third liquid which
is a precipitant for the polymer and is miscible with both water and
solvent) [85]. Spray-drying method was industrially employed since
1927 [90]. The core particles are firstly dispersed in a wall polymer solu-
tion and then sprayed into a hot chamber. The wall material solidifies
onto the core particles because the input solvent evaporates and there-
fore the microcapsules can be formed in a polynuclear or matrix type.
Spray-drying is normally used for encapsulating labile drugs due to its
short contact time in the drier. Spraying drying can be applied with
the use of supercritical carbon dioxide for the entrapment of sensitive
drugs such as proteins [16,23,78,85].
5. Stabilization of drugs using microencapsulation technology
Drug stability refers the capability of a drug formulation in a spe-
cific container/closure system to preserve its own properties and
therapeutic effects throughout the period of storage and usage
[115]. In fact, many drugs are liable to chemical and physical degra-
dation due to the fragility of their molecular structure. Chemical deg-
radation (pH, moisture, oxidation) and physical degradation
(temperature, light) of drugs may alter their pharmacological func-
tions, leading to a changed therapeutic efficiency and toxicological
consequences [116]. For examples, β-lactam antibiotics, especially
penicillin, easily degrade in the presence of acidic aqueous condi-
tion [117]. Vitamin C is susceptible to oxidation [118]. Protein-
based drugs are highly unstable to pH and temperature variations,
moisture and oxidation [119]. Nifedipine, epirubicin and idarubicin
are sensitive to light [120,121]. The drugs should be stable to remain
their quality until the time of usage. The drug quality could be kept
by using the microencapsulation technology which provides a qual-
ity protection of drugs using the polymeric micro-carriers. Microen-
capsulation offers a quality maintenance and preservation of
susceptible drug molecules to stabilize the sensitive drugs from the
external environment. Pharmaceuticals are conjugated or embedded
in the polymeric wall materials of microcapsules or microparticles
for the drug stabilization and the controlled drug release [122]. Ther-
apeutic agents could be prevented from interacting with the external
molecules which may deteriorate the nature of drugs and lead to an
inefficiency of their bioactivity. Crosslinked polymer chains in the
wall matrix or wall shell of microcapsules could delay the drug disso-
lution under gastrointestinal fluids by forming the diffusion barrier
to stabilize and protect the inner drugs. The polymeric wall of micro-
capsules is subject to the initial hydrolysis and enzymatic cleavage
which lead to the scission of polymer chains [123]. Drugs could be
covalently bound to the polymer chain or backbone to produce a
drug-polymer conjugate for a prolonged delivery of unstable drugs
such as proteins. The first polymer–protein conjugate SMANCS
(Zinostatin stimalamer®) was developed in 1990 and available com-
mercially. Maeda and Konno synthesized the conjugate which
consisted of an anti-tumor protein neocarzinostatin (NCS) covalent-
ly bound to two polymer chains of styrene-co-maleic anhydride
(SMA). The clinical study showed that a majority of hepatoma
patients treated with SMANCS had tumor shrinkage (95%) and de-
creased α-fetoprotein levels (86%) [124–126]. G4-polyamidoamine
(PAMAM) dendrimer–ibuprofen conjugates were produced through
ester, amide, and peptide linkages. Amide- and ester-linked conju-
gates were shown to be relatively stable under the cathepsin B buffer
and diluted human plasma release mediums [127]. A novel paclitaxel
conjugate was synthesized by using valine–citrulline dipeptide (Val–
Cit), a substrate of Cathepsin B (C B ), and p-aminobenzylcarbonyl
(PABC) as a spacer, to link polyethylene glycol (PEG) and paclitaxel
for the enhanced antitumor activity [128]. Protein stabilization
could be achieved by a suitable polymer for microencapsulation sys-
tem to reduce the protein aggregation [129,130] and minimize the
water content of proteins [131]. Protein inactivation and aggregation
could occur easily during the harsh encapsulation procedures [132].
A stabilization method was developed for the encapsulation of γ-
chymotrypsin and HRP in Poly( D ,L -lactic-co-glycolic) acid (PLGA)
microspheres with the use of PEG as a protein stabilizer. Co-
lyophilizing of γ-chymotrypsin with PEG before PLGA encapsulation
resulted in a significant decrease in the formation of buffer-insoluble
aggregates during microencapsulation process, with only 8% protein
aggregation, as compared with lyophilizing of γ-chymotrypsin in
PLGA microspheres, with more than 30% aggregation and loss of
half activity [133]. Glycol chitosan (GC) was incorporated into
PLGA microparticles in order to stabilize lysozyme as a model pro-
tein. The viscous GC in an aqueous phase for lysozyme entrapment
suppressed the protein hydration and declined the protein leakage
during microcapsule formation process. Microcapsules with a higher
amount of GC remained the bioactivity of protein, with more than
95 wt.% of lysozyme remaining for 28 days, whereas the control mi-
crocapsules revealed a great decrease in protein bioactivity, with
about 92 wt.% after only 7 days [134].
Many antibiotics become unstable under gastrointestinal environ-
ment after oral administration, resulting in low bioavailability. The
antibiotic stabilization could be accomplished by the combination of a
non-toxic polymeric material and the antibiotic to stabilize the antibiotic
under aqueous conditions. Crosslinked polymeric complex could give
a protective coating against the harsh environment of the stomach and
increase the chemical stability of acid-degradable moieties/drugs [135].
A gastro-mucoadhesive chitosan/alginate system was designed to stabi-
lize and protect the antibiotic amoxicillin under the gastric condition
after oral administration. Microencapsulated amoxicillin was demon-
strated to be highly stable under the simulated gastric fluid, with the
drug degradation of only 7.6% after 8 h, when compared with the plain
amoxicillin, with 90.9% drug degradation [136]. Clarithromycin loaded
Eudragit L100 microcapsules were developed in order to increase the
drug stability and avoid the fast dissolution of drug after oral administra-
tion. Eudragit L100 microcapsules did not show significant changes in
the drug content of acidic suspension of optimal batch. The prepared for-
mulation revealed a good stability for 14 days [137]. The drugs used for
the treatment of Acquired Immunodeficiency Syndrome (AIDS) includ-
ing lamivudine and stavudine are unstable with short half-life after oral
administration. Both drugs became stable at 40 °C with 75% RH for
about 3 months with less drug loss when they were encapsulated within
the cellulose-based microcapsules [138,139]. Microencapsulation tech-
nology has also been applied to other therapeutic compounds to enhance
their half-life and stability. Ubiquinone-10 (CoQ10), a vitamin-like lipo-
philic compound used in the pharmaceutical industries, is vulnerable
to light, oxygen and temperature. CoQ10 microcapsules prepared with
20% gum arabic as the wall material resulted in a high increase in the
drug half-life of 693 min when compared with the free CoQ10, with
the half-life of 111.17 min for at 30 ± 2 °C under UV light [140].
Nattokinase (NK), an effective fibrinolytic enzyme, was entrapped in
high molecular weight γ-polyglutamic acid in sodium form (Na-γ-
PGA) microcapsules in order to improve the temperature and pH stabil-
ity. NK became more stable over a broad range of pH (from 2.0 to 12.0),
at higher temperatures (50 °C and 60 °C) and under acidic conditions
Table 2
Summary of polymeric material-based microencapsulation systems for the applications of oral and transdermal drug deliveries.

Polymeric materials Delivery Entrapped drugs Biomedical applications References

route

Chitosan Oral Curcumin Curcumin-phytosome loaded chitosan microspheres had a prolonged half life and improved oral absorption of curcumin when compared with those of curcumin [100]
phytosome and curcumin loaded chitosan microspheres.
Chitosan Oral Celecoxib Microcapsules had a better inhibition of cyclooxygenase-2 protein expression from mice hepatocytes than free celecoxib. [160]
Chitosan Oral Hydrocortisone succinic ACTH concentration in microcapsule mice plasma was more than 40% lower than that of water control. [12]
acid
Chitosan–alginate Oral IgY Microspheres effectively protected the IgY antibodies against ETEC-induced diarrhea in older pigs. [101]
Chitosan Oral Insulin Phytic acid-crosslinked chitosan capsules improved the intestinal absorption of insulin and remarkably reduced blood glucose levels in diabetic mice when [161]
compared with tripolyphosphate-crosslinked chitosan capsules.
Chitosan–alginate Oral Insulin Blood glucose concentration in diabetic rats could be significantly reduced and stably maintained for a prolonged period after administration of insulin loaded [102]
microspheres when compared with the free insulin.
Chitosan Transdermal Miconazole nitrate/ Drug release raised with an increase in pressure from 0.028 to 5 kg. [162]
clotrimazole
Chitosan Transdermal 5-FU Microencapsulated 5-FU had a stronger growth inhibition of human keratinocytes than free 5-FU. 5-FU could be released from microcapsule treated textiles on an [12]

P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45

intact mice skin.
Chitosan Transdermal Vitamin E Microencapsulated vitamin E significantly increased the skin moisture and elasticity, and also reduced the skin wrinkle and roughness. [163]
Gelatin Oral Ibuprofen Microcapsules caused a significantly higher initial plasma concentration in rats, Cmax and AUC of ibuprofen than the free ibuprofen. [113]
Gelatin–agar Oral Gallic acid Microcapsules were more effective in an oral treatment of acute liver and kidney toxicity in mice than the free gallic acid after an overdose of acetaminophen. [11]
Gelatin Transdermal Vitamin A palmitate Vitamin A palmitate was released at a much slower rate from microspheres containing gel than the conventional plain vitamin A palmitate gel in rat skin. [187]
Gelatin–agar Transdermal Berberine Microcapsules had a better anti-S. aureus activity than the free drug. Berberine could be released from microcapsule treated textiles on nude mice skin. [11]
Gelatin–agar Transdermal Phyllanthus urinaria Microcapsules improved the anti-A. niger activity when compared with the free herbal extract. [188]
Alginate Oral Insulin After 5 h, blood glucose lowering effect caused by micro-particles in diabetic rabbits was equal to that induced by the subcutaneously administered insulin [99]
solution.
Alginate Oral Isoniazid Microspheres could be detected in the intestine of adult Wister rats after 24 h. [199]
Alginate–chitosan Oral Metronidazole Microcapsules had a better eradication of H. pylori infection in mice than the suspension form of free MZ. [200]
Alginate–sweet potato Oral Glipizide Microcapsules possessed a slow, complete and extended release of glipizide, as well as a good mucoadhesive property in the in vitro wash-off test. [201]
starches
Alginate–sodium Oral Gliclazide Microencapsulated drug had a prolonged hypoglycemic effect (2–16 h) in diabetic albino rats when compared with the free drug (0.5–10 h). [203]
carboxymethyl cellulose
Alginate–methyl cellulose Oral Gliclazide Gliclazide-loaded microcapsule-treated alloxan-induced diabetic albino rat group showed a significant hypoglycemic effect when compared with the free drug. [204]
Ethylcellulose Oral Salbutamol sulfate Oral bioavailability of microcapsules was demonstrated by young healthy human volunteers. [205]
Ethylcellulose Oral Clarithromycin Microcapsules did not decrease the bioavailability and had a better therapeutic performance with a prolonged drug release in healthy volunteers. [206]
Trehalose/hydroxyethyl Transdermal Vancomycin Microencapsulated vancomycin could be useful for topical applications on the potential microbial contamination on skin wounds. [207]
cellulose
PLA Oral Insulin Insulin loaded PLA microcapsules were capable of lowering the blood glucose level in the diabetic rat. [214]
PLGA Oral Amifostine Half of amifostine from PLGA microcapsules was released after the first 6 h, and 92% of amifostine was further released after 12 h. [215]
PLGA Oral Plasmid DNA Microcapsules loaded with plasmid DNA could induce the immune system to produce the corresponding fish-anti-LCDV antibody which could be detected in [216]
the sera of Japanese flounders.
PLGA Transdermal Acyclovir Acyclovir reservoir in the porcine skin basal epidermis treated with microparticles was higher than that of control suspension after 88 h, suggesting that PLGA [217]
microparticles could improve acyclovir topical therapy as the drug retention in the basal epidermis.
PLGA Transdermal Cidofovir Higher amount of cidofovir was found in the basal epidermis treated with microparticles than that of control solution, revealing that cidofovir-loaded micro- [218]
particles could increase the drug retention in the basal epidermis.
PLGA Transdermal Human recombinant Released insulin from PLGA microspheres stimulated a rapid cell migration following an induced scratch as fresh insulin over 23 days, suggesting a high level of [108]
crystalline insulin sustained bioactivity.
Locust bean gum-PVA Oral Buflomedil HCl Microspheres could offer a controlled release of buflomedil HCl with short half life and high water solubility. [221]
Lepidium sativum-PVA Oral Simvastatin Microspheres could provide a controlled release of simvastatin from the crosslinked polymer matrix. [222]
Gum ghatti-PVA Oral Ranitidine HCl Microsphere prepared with higher amount of glutaraldehyde and PVA resulted in a higher mucoadhesivity and a slower drug release. [223]
PCL Oral Bovine serum albumin Bovine serum albumin protein could keep unchanged with no aggregates during the encapsulation process. [227]
PCL Oral Manidipine Drug loaded PCL microparticles could reduce the mean arterial pressure variation up to 24 h after phenylephrine injections when compared with the pure drug [228]
dihydrochloride and drug loaded poly(3-hydroxybutyrate-co-3-22 hydroxyvalerate) microparticles.
Eudragit® L100-55 Oral Anti-VP8 IgY Microcapsules had the retention of more than 95% of IgY activity after 6 h incubation in SGF when compared with the free IgY, with a significant decrease (86%) [233]
in IgY activity after 30 min. In vivo weaned pig model revealed microencapsulated IgY exhibited a much higher stability after oral administration.
Eudragit® L30 D-55 Oral Vibrio cholerae C7258 Oral administration of 3.5 mg microencapsulated vibrio cholerae C7258 inactivated strain showed an appropriate protection of the bacteria which induced the [234]
inactivated strain production of high levels of vibriocidal titers in adult rats as compared to the same amount of non-encapsulated one.

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32 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
(pH 5 and 1.2) as opposed to the free NK. Microencapsulated NK also had
more protective bioactivity than the free NK [141].
6. Drug release mechanisms
6.1. Diffusion
Drug release can be done by drug diffusion from polymeric reservoir
microcapsules or polymeric matrix microcapsules. In the reservoir sys-
tem, the drug is entrapped within the core reservoir by a polymeric
wall shell. The drug first partitions into the polymeric wall of microcap-
sules from the core reservoir, and then diffuses out to other side of the
wall shell in the medium. When the core reservoir is saturated and a
constant concentration gradient of the drug is remained in the wall
shell, the rate of drug flux is constant. This results in zero order drug re-
lease. The drug release rate maintains constant as long as the internal
and external concentrations of core drug and the concentration gradient
through the wall shell are constant. Finally, the drug concentrations in
the core reservoir and in the wall shell fall below saturation, the release
rate of drug declines [23,142]. Kooiman et al. [143] reported the devel-
opment of oil-filled poly(L-lactic acid) (PLA) terminated with 1H–1H
perfluoro-octan-1-ol microcapsules for the ultrasound-triggered deliv-
ery of lipophilic drugs. Hexadecane oil was used as the core drug carrier
reservoir with cyclodecane gas, while the absorbing dye Sudan Black, as
a hydrophobic molecule, was selected to mimic a lipophilic model drug.
Sudan Black release was efficient for half oil-filled microcapsules since
75 ± 6% of the amount encapsulated was released with the oil. The
remaining Sudan Black was retrieved from the bottom fraction, suggest-
ing that it stayed with the shell. In the matrix system, the drug is firstly
encapsulated in the polymeric matrix of microcapsules and the drug re-
lease is achieved by diffusion through the matrix. This system involves
the initial burst release of drug from the wall matrix surface. The drug
release rate depends on the physical properties of polymer used for
the matrix wall. Generally, the hydrophobic polymers delay the release
and diffusion of the drug from microcapsules [23,142]. Jeong et al. [144]
investigated the drug release of papaverine loaded PCL microparticles.
There was a small initial burst release of papaverine from microcapsules
due to the drug encapsulated near the surface of hydrophobic PCL wall.
The subsequent drug diffusion through the amorphous region of PCL
wall matrix into the release medium was delayed. The characteristics
of PCL also had an influence on the drug release rate. Lower PCL concen-
tration (2.5 wt.%), higher molecular weight (80 K) of PCL and less per-
fectly shaped crystalline lamellae of PCL wall matrix also contributed
to a faster rate of drug release.
6.2. Swelling and dissolution
Swelling involves the water uptake by a polymer system and the poly-
mer system then increases in its volume. Swelling of a polymer is closely
related to the drug dissolution from the polymer system. When swelling
happens in the drug loaded polymeric matrix, the water enters the poly-
meric matrix and the polymer system swells by the uptake of water. At
this stage, the drug dissolution occurs, the entrapped drug gradually dis-
solves and then diffuses through the swollen polymeric matrix to the re-
lease medium [23,142]. The swelling rate of the polymer system can be
governed by the properties of polymeric materials. Generally, the drug-
polymer formulation contains a hydrophilic polymer with low density
of crosslinking chains, water penetration leads to a rapid swelling of the
polymer, resulting in the faster drug dissolution from its present solid
phase to the release medium [142,145]. Fundueanu et al. [146] synthe-
sized the cellulose acetate butyrate (CAB) microcapsules containing
sulfopropylated dextran microspheres loaded with tetracycline HCl. The
drug release was governed by the wall shell rupture of CAB microcapsules
under the pressure caused by the swelling of the encapsulated dextran
ion exchange resins. The force induced by swelling then broke the more
resistant wall of microcapsules, resulting in self-propelled drug release.
Kim and Park [147] reported that the tulobuterol release from PCL/
Eudragit RS 100 microcapsules was faster than that of PCL microcapsules
in the succinic acid release medium because the hydration level increased
in the presence of Eudragit RS 100. The increased hydration level of mi-
crocapsules might be associated with the fact that the quaternary ammo-
nium groups of Eudragit RS 100 interacted with the carboxyl group of the
succinic acid. With the higher hydration level, the swelling and dissolu-
tion of microcapsules increased. This increased the drug diffusion from
the microcapsules through an increased permeability of the microcapsule
wall. Kulkarni et al. [148] investigated the relationship between the re-
lease of diltiazem HCl and the crosslinking extent of gellan gum/egg albu-
min microcapsules. Diltiazem HCl was first bound to a cation exchange
resin Indion 254® before microencapsulation in order to reduce bitter
taste of drug and increase the stability by protecting the drug from hydro-
lysis. The drug-resin complex showed an extended dissolution up to 3 h
when compared with the free drug (1 h). The crosslinked microcapsules
could prolong the drug release up to 15 h. A decrease in microcapsule
swelling was promoted by a higher amount of glutaraldehyde which
may produce a stiffer polymer network during microcapsule formation
process. This reduced the water adsorption and the volume of the poly-
meric matrix. The drug transport through the polymer was then retarded.
6.3. Erodible and degradation
Erosion and degradation of a drug delivery system should involve the
nontoxic, biodegradable and biocompatible polymeric materials. The
drug is homogeneously mixed with the polymer in the microencapsula-
tion system. Erosion and degradation of the polymeric wall of microcap-
sules highly decrease the distance between the drug molecules and the
microcapsule surface. This results in the drug release without transport.
However, the hydration process is usually quicker than the erosion and
degradation of polymeric matrix of microcapsules, causing diffusion
and release of the entrapped drug through micro-pores of microcapsules
induced by water uptake. The polymeric matrix begins to be eroded and
degraded but the encapsulated drug molecules still maintain in the inte-
rior of microcapsules. Eventually, the entrapped drug is released once the
polymeric matrix disintegrates [23,142,149]. Zhu et al. prepared the
felodipine-loaded PLA/polymerized-N-maleoylchitosan (p-NMCS) core–
shell microcapsules and the drug release mechanism was studied. The re-
sults showed that the drug release of p-NMCS microcapsules was driven
by a diffusion process, while the drug release of PLA/p-NMCS microcap-
sules with high ratio of PLA to p-NMCS (not less than 1/1) was propelled
by a combined diffusion and degradation process. The encapsulated
felodipine was slowly released from the PLA/p-NMCS core–shell micro-
capsules as a result of PLA degradation [23,150]. Erosion or degradation
of the polymeric matrix could be induced by pH or enzymatic hydrolysis
which leads to the release of entrapped drug [151]. The release of 5-
Aminosalicylic acid from the crosslinked chitosan–sodium cellulose sul-
fate–sodium polyphosphate microcapsules in the simulated colonic
fluid (pH 6.4) with glucanglucanohydrolase and phosphate buffer
(pH 6.4) was discussed [152]. The micro-pores could be found in the
surface of microcapsule film which was subject to the simulated co-
lonic fluid (pH 6.4) with glucanglucanohydrolase after 12 h because
of enzymatic erosion or degradation of microcapsule film. The swell-
ing of microcapsules was reduced and the erosion or degradation
was increased due to the presence of enzyme in the release medium.
With an increased erosion or degradation, the drug holding capacity
of microcapsules was decreased. This resulted in more amount of
drug release after 12 h when compared with the microcapsules in
phosphate buffer (pH 6.4) medium.
6.4. Osmosis
Drug release related to osmosis refers to the movement of water
molecules down the concentration gradient through the semiperme-
able wall shell of microcapsules until there is a balance between both
 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
sides. The rate of drug (osmolyte) flowing across the wall shell of micro-
capsules depends on the drug concentration and property, the perme-
ability of wall shell and temperature. Release medium passes through
the microcapsule wall and dissolves the entrapped drug, causing a con-
centration gradient which attracts more water inside [23,142]. Osmotic
pumping happens when the osmotic pressure, induced by water ab-
sorption, propels the transport of the drug [149,153]. In the osmotically
related drug release mechanism, the osmotic flux of water passes across
the wall and dilutes the drug solution inside the microcapsules. This re-
sults in swelling, microcracks, and eventually the rupture of microcap-
sules. When cracks are formed, drug solution leaks through them and
interconnects microcapsules that have been already ruptured [154]. A
biodegradable micro-osmotic pump was developed for the controlled
release of basic fibroblast growth factor (bFGF). The bottom layer of
the device contained a reservoir for drug storage and micro-channels
for drug release. Another layer of the 85/15PLGA was considered as a
semi-permeable layer. When the device was immersed in an aqueous
condition, osmotic pressure drove water into the reservoir and the
internally-built pressure started to drive the drug (bFGF) through the
micro-channels [155]. Another biodegradable device was constructed
for the controlled release of ciprofloxacin-HCl (CIP). This device
consisted of osmosis and diffusion mechanisms to release CIP for
short-term therapies. The poly(glycerol-co-sebacic acid) (PGS) was lo-
cated in a tubular geometry with solid drug powder packed into its
core and a micro-orifice was drilled through its wall in order to expulse
the drug from the device. PGS acted as a semipermeable material for the
elementary osmotic pump to accomplish the release of CIP [153].
7. Recent advances in microencapsulated oral and transdermal drug
delivery systems
In fact, microcapsule-based drug delivery systems offer many
benefits to drug delivery, targeting and release. Their great potential
to integrate with conventional drug dosages leads to the emergence
of effective micro-medicines for oral and topical treatments. The use
of natural and synthetic polymers as drug carriers in the microencap-
sulation systems is possible to improve and enhance the drug stabil-
ity in biological environments including the gastrointestinal tract
and the first pass metabolism after oral administration, as well as
skin layers during transdermal administration. This also increases
the drug entrapment efficiency, and utilizes drug targeting, release,
absorption and interaction with targeted body sites. Recently, some
novel microencapsulation systems have been developed in order to
provide more choices for drug entrapment. Table 2 summarizes the
polymeric material-based microencapsulation systems for oral and
transdermal drug deliveries evaluated by in vivo and in vitro models.
7.1. Natural polymer-based systems for drug microencapsulation
7.1.1. Chitosan-based systems
Chitosan is a cationic linear polysaccharide composed of β(1–4)
linked glucosamine with N-acetylgucosamine. It is originated from ex-
tensive deacetylation of chitin existed in shells of crustaceans. There
are different obtaining procedures that can affect the soluble properties
of chitosan. Chitosan must be dissolved in the media with acidic pH, and
using 1 to3% aqueous acetic acid solution to solubilize chitosan is very
common. This is because chitosan contains the amino group which is
water-insoluble, positively charged, and only soluble at the state of
pH b 6. Chitosan processes many advantages in microcapsule forma-
tion. Chitosan is a natural polymer which is biodegradable,
biocompatible, non-toxic and safe. It is able to control the release profile
of active ingredients [10,12–15,90,156,157]. Chitosan is a mucoadhesive
polymer that increases residence time at the site of drug adsorption and
the half time of drug clearance, and thereby improving the drug
bioavailability [158,159]. A higher degree of deacetylation (N 65%) can
increase the charge density, and eventually improve the drug
33
transportation [158]. Chitosan is considered as a safe material for
microcapsule-based oral drug delivery carrier that protects the liable
drug from the gastrointestinal environment in a number of previous
studies. Zhang et al. [100] developed the curcumin-phytosome loaded
chitosan microspheres for oral administration. The pharmacokinetics
study showed that the half-life of curcumin-phytosome loaded chitosan
microspheres (3.16 h) was longer thanboth curcumin-phytosome
(1.73 h) and curcumin loaded chitosan microspheres (2.34 h). The re-
sults revealed that curcumin-phytosome loaded chitosan microspheres
exhibited a better sustained drug release and an improved oral absorp-
tion of curcumin than others. The study suggested that a carrier combin-
ing chitosan microspheres and phytosomes, could be a more promising
vehicle for oral administration of curcumin. Cheng et al. [160] reported
the chitosan-based microcapsules containing celecoxib as a cyclooxy-
genase 2 inhibitor. The possible therapeutic activity of celecoxib con-
taining microcapsules on mice was investigated after oral
administration by examining the immunohistochemistry section of
the liver. The celecoxib containing chitosan microcapsules showed a
better inhibition of cyclooxygenase-2 protein expression from mice he-
patocytes when compared with an oral administration of free celecoxib.
Plasma liver functional enzyme markers and histochemistry analysis re-
vealed that chitosan-based micro-particulate system did not have toxi-
cological adverse effects on the mice hepatocytes. Lam et al. [12]
developed the chitosan-based microcapsules to deliver hydrocortisone
succinic acid through oral administration. The potential of chitosan-
microencapsulated hydrocortisone succinic acid for oral application
was demonstrated using ACTH assay from C57BL/6 mice. The mean
ACTH concentration in drug loaded chitosan microcapsule mice plasma
was detected to be approximately 42.2% lower than that of water con-
trol. Li et al. [101] reported the use of chitosan–alginate microcapsules
to protect the egg yolk immunoglobulin (IgY) against K88 + ETEC
(enterotoxigenic E. coli)-induced diarrhea using an in vivo pig model.
Chitosan–alginate microspheres could effectively protect the IgY anti-
bodies from gastric inactivation after oral administration, resulting in
an enhanced protection against ETEC-induced diarrhea in older pigs.
Since the protein- and peptide-based drugs were highly susceptible to
the gastrointestinal environments, some efforts were put on this area.
Lee et al. [161] compared the therapeutic performance between phytic
acid- and tripolyphosphate-crosslinked chitosan capsules for insulin de-
livery. Phytic acid-crosslinked chitosan capsules resulted in an im-
proved intestinal absorption of insulin and significantly decreased
blood glucose levels in diabetic mice when compared with the
tripolyphosphate-crosslinked chitosan capsules. Zhang et al. [102] ex-
amined the chitosan–alginate microcapsules for the oral delivery of in-
sulin. The blood glucose concentration in diabetic rats could be
significantly reduced and stably remained for 96 h after oral adminis-
tration of insulin loaded microspheres when compared with the free in-
sulin (Fig. 2). The results suggested that the alginate–chitosan
microspheres could be a potential carrier of protein or peptide drugs
in oral administration.
Transdermal delivery of drugs using chitosan microcapsules as car-
riers has also been investigated. Yuen et al. [162] reported the potential
use of chitosan-based microcapsules for the topical delivery of two
antifungal agents, miconazole nitrate and clotrimazole, for the tinea
pedis treatment. The release rates of two drugs were investigated
under different pressures from 0.028 to 5 kg at different pH values
from 5.5 to 8.5. The drug release increased with an increase in pressure
and the release of drugs had no significant difference at different pH
values. Lam et al. [12] demonstrated the topical delivery of 5-FU using
chitosan-based microcapsules. Chitosan-based microcapsules contain-
ing 100 μg/mL of 5-FU resulted in a stronger growth inhibition of
human keratinocytes when compared with the free drug. The skin
cells with both untreated control (Fig. 3a) and blank microcapsules
without drugs (Fig. 3b) showed a high integrity of cellular morphology
while cells with both 5-FU microcapsules (Fig. 3c) and free 5-FU
(Fig. 3d) had certain degree of cellular damage. The 5-FU microcapsules
34 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
Fig. 2. The serum glucose concentration after oral administration of insulin-free and
insulin-loaded (100 IU/kg) alginate–chitosan microspheres to STZ-induced diabetic rats.
Statistically significant difference from insulin-free microspheres: *p b 0.05; **p b 0.01.
(Adapted with permission from [102]).
exhibited a stronger cell inhibitory effect than the free 5-FU (Fig. 3e).
This might be due to the sustained release of 5-FU from microcapsules,
resulting in a continuous therapeutic effect against the growth of skin
keratinocytes. In vitro drug delivery model also showed that 5-FU
Fig. 3. Growth inhibition towards skin keratinocytes: (a) untreated control; (b) blank mi-
crocapsules; (c) 5-FU microcapsules; (d) 5-FU; (e) percentage of cell viability. Each exper-
iment was done in triplicate and a mean value was obtained while three independent
experiments were performed. Results are shown as mean ± SD from their mean values
of these three independent experiments. (Adapted with permission from [12]).
could be released from chitosan-based microcapsule treated textiles
on the intact mice skin model. Yenilmez et al. [163] prepared the vita-
min E containing chitosan microspheres for topical delivery. In vivo
study conducted on human cheeks and crows' feet skin demonstrated
that the vitamin E microspheres significantly increased the skin mois-
ture and elasticity, and reduced the skin wrinkle and roughness.
Chitosan is regarded as a promising candidate for oral drug delivery
due to its mucoadhesive property. Chitosan-based micro-particulate
system containing drug loaded oil is believed to be useful in oral drug
delivery. Most conventional drugs have poor bioavailability and absorp-
tion when they are orally administered because of drug degradation
under the gastrointestinal environment and the first-pass metabolism.
Therefore, many drugs are required to be taken frequently in high
doses in order to achieve an effective therapeutic level. Frequent
drug administration in high doses can induce toxicity and other side
effects [164]. As a result, the optimal drug formulation prepared with
mucoadhesive chitosan might minimize the in vivo drug degradation,
offer a drug release over an extended period of time and also reduce
the potential toxicity of drugs. Mucosal membranes are the moist sur-
faces of wall linings existing in various body cavities including eyes,
nostrils, buccal cavity, respiratory, gastrointestinal and reproductive
tracts. These membranes offer the lubrication and control the moisture
content of the cell epithelial surfaces [165–167]. Mucoadhesion is con-
sidered as an attractive interaction at the interface between a drug
and a mucosal membrane [166]. Mucoadhesive property of a pharma-
ceutical formulation can be accomplished by introducing hydrophilic
polymers with good sticking ability during the formation process. Chito-
san has both primary amine and hydroxyl functional groups which en-
hance hydrogen bond formations such as \OH and \COOH [168]. The
linear molecule of chitosan displays enough chain flexibility and its sur-
face energy characteristics prefer to spread into the mucosal surface.
The chitosan conformation depends on its ionic strength. All of them
determine the mucoadhesion activities [168–171]. Chitosan has an ex-
cellent mucoadhesion among various polymers and it possesses the
mucoadhesive activity due to the ionic interaction between the posi-
tively charged primary amino groups in chitosan and negatively
charged sialic acid and sulfonic acid substructures of the mucus in cell
membrane [158,172,173]. This interaction extends the residence time
at the site of drug absorption due to the increased contact with the ab-
sorbing mucosa, leading to a steep concentration gradient to favor drug
absorption and localization in specified regions to enhance the drug bio-
availability [174,175]. Previous studies have shown that the presence of
chitosan demonstrated an improved mucoadhesion [167,176–179].
Chitosan has also been reported to enhance the mucosal permeation
which resulted in the improvement on drug adsorption [180]. There-
fore, chitosan is considered as a suitable polymer to produce the
micro-carriers for oral drug delivery to protect the susceptible drugs
such as protein- and peptide-based medicines from the gastrointestinal
environment for increasing drug bioavailability and drug adsorption.
Oral delivery of chemotherapy still remains challenges in pharmaceuti-
cal and therapeutic fields. Chemotherapeutic drugs are generally ad-
ministered through intravenous injection and this results in patient
discomfort and inconvenience. Oral administration of chemotherapy
can significantly damage the esophagus, stomach as well as other or-
gans. The availability of oral chemotherapeutic dosage forms would
greatly improve the life quality and compliance of patients with mini-
mal disruption of activities of their daily living [3,181]. The dual protec-
tion of the chemotherapeutic agent could be provided by an internal oil
phase together with a chitosan-based micro-carrier. It is believed that
the internal oil phase of microcapsules might protect the anti-cancer
drug from the gastrointestinal environment during oral administration.
The chitosan wall shell of microcapsules might be gradually dissolved in
the stomach. The bile might emulsify the oil into smaller oil droplets
which are called “micelles”. These micelles are believed to protect the
chemotherapeutic agent from the gastrointestinal environment and
thereby avoiding the drug to attack the gut lining (Fig. 4). Since the
 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
Fig. 4. Schematic diagram of the acidic degradation of chitosan-based microcapsules con-
taining drug loaded oil in stomach and the bile emulsification process of drug containing
micelles.
nutrients especially lipids and fats are absorbed in the small intestine
followed by entering the lymphatic circulation, the drug containing
micelles might then enter the lymphatic circulation directly without
the influence of the first-pass metabolism. The drug bioavailability and
drug adsorption would be greatly enhanced by using the oil containing
chitosan-based microcapsules for oral drug delivery.
7.1.2. Gelatin-based systems
Gelatin is a derived protein substance from collagen which is
isolated from the boiled connective tissues, tendons, bones and skins
of animals, usually fishes, cows and pigs [182]. Gelatin is widely applied
to pharmaceutical areas as it is a natural polymer which is biodegrad-
able, biocompatible and non-toxic. Gelatin is able to produce a high
drug loading, and it is easy for administration and removal in physiolog-
ical environments [183]. Apart from tryptophan and low in methionine,
cystine and tyrosine, all the amino acids exist in gelatin [184]. The amino
acid composition in gelatin varies from one source to another and main-
ly consists of great amounts of glycine, proline and hydroxyproline
[185]. Gelatin is a gelling agent that is soluble in hot water and subse-
quently capable of forming strong, transparentelastic and elastic ther-
moreversible gels and flexible films on cooling below about 35 °C.
Generally, there are two types of gelatins, Type A and Type B. Type A gel-
atin is produced by soaking skin or bones in a diluted acidic medium
followed by extraction at acidic pH while Type B gelatin is solubilized
at near neutral pH at about 60–90 °C [186]. Gelatin exhibits the desired
properties which make it preferable for drug delivery applications. In
micro-particulate oral drug delivery, Li et al. [113] formulated a novel
gelatin microcapsules for the encapsulation of ethanol and ibuprofen
using a spray drying method. The ibuprofen-loaded gelatin microcap-
sules led to a significantly higher initial plasma concentration in rats,
Cmax and AUC of ibuprofen than the free ibuprofen powder, revealing
that the drug from gelatin microcapsules resulted in more effective ab-
sorption after oral administration. Lam et al. [11] designed a
formaldehyde-free gelatin/agar microcapsules for the oral delivery of
gallic acid. The in vivo mice disease model (Fig. 5) revealed that the oral-
ly administered gallic acid loaded gelatin/agar microcapsules were
helpful to alleviate the damages of acute liver and kidney toxicity in
mice after an overdose administration of acetaminophen compared
with the free gallic acid. The free drug induced the death of 2/3 mice
whereas all microcapsule-treated mice did survive. This might be due
to the high dose administration of free gallic acid which might lead to
the adverse effects and drug toxicity. However, the microencapsulated
gallic acid within the gelatin/agar micro-carrier might promote the
sustained drug release over a prolonged period of time and this might
reduced the adverse side effect after a high dose of oral administration.
35
Fig. 5. H and E histochemical analysis of liver and kidney sections from the survival mice
treated with APAP alone (on day 1) followed by single dose daily of deionized water, gallic
acid loaded microcapsules, or gallic acid from day 2 to 4. In water control group, all the
liver sections exhibited necrosis whereas 2 of 3 the kidney sections exhibited necrosis
and only mouse 1 showed a certain degree of cellular integrity in its kidney section. It
should be also noted that 1 of 3 the liver and kidney sections (mouse 2) from the micro-
capsule treated group exhibited necrosis while those mice treated with gallic acid exhib-
ited necrosis. (Adapted with permission of The Royal Society of Chemistry [11]).
Gelatin-based micro-particulate systems have also been used in
transdermal drug delivery. Wakode and Baja [187] reported the use of
gelatin microspheres to increase the stability of vitamin A palmitate
for transdermal delivery. In the rat skin release model, vitamin A palmi-
tate was released at a much slower and linear rate from the gelatin
microspheres containing gel when compared with the conventional
plain vitamin A palmitate gel. Lam et al. [11] reported the synthesis of
a formaldehyde-free gelatin/agar-based microencapsulation system
for topical delivery of berberine. The Minimum Inhibitory Concentra-
tions (MICs) and antibacterial tests proved that berberine loaded
gelatin/agar-based microcapsules exhibited a better growth inhibition
towards S. aureus when compared with the original drug. The drug de-
livery model (Fig. 6) demonstrated the delivery of berberine from mi-
crocapsule treated textiles on nude mice skin. Berberine has the
fluorescent property. If the treated skin site showed the fluorescent ef-
fect after the topical treatment, the berberine could be released from
the microcapsules, delivered on the skin surface and absorbed by the
skin. As the treated site of nude mice skin showed the fluorescent effect,
this result suggested that the drug loaded gelatin-based microcapsules
could be a useful vehicle for topical drug delivery. Lam et al. [188] also
studied the anti-A. niger activity of Phyllanthus urinaria (P. urinaria)
loaded gelatin/agar-based microcapsules. This novel green gelatin–
agar microencapsulation system with water extract of P. urinaria was
shown to exhibit an improved anti-A. niger activity when compared to
the free herbal extract.
Gelatin/agar-based micro-particulate system could be used for
transdermal drug delivery. The skin is considered as an ideal biological
site with a readily accessible and large surface area for drug administra-
tion. Transdermal drug delivery can avoid the disadvantages of oral ad-
ministration including enzymatic degradation and rapid clearance in
the gastrointestinal tract and the first-pass metabolism, and overcome
the drawbacks of intravenous injection including pain, discomfort, and
36 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
Fig. 6. The nude mice skin experiment was performed to demonstrate the possible delivery
of berberine HCl from microcapsule fabricated cotton: a. nude mouse; b. nude mouse skin
treated with microcapsule fabricated cotton samples; c. nude mouse skin treated with mi-
crocapsule fabricated cotton after 24 h; d. nude mouse skin under UV illumination and e. re-
lease of berberine HCl from microcapsule fabricated cotton after 24 h. For b, c, and d, the left
sample represents the microcapsule without drugs and the right sample represents the ber-
berine HCl loaded microcapsules. The data in panel (e) represent the average from in vitro
release of berberine HCl loaded microcapsule experiments ± SD from three independent
experiments. (Adapted with permission of The Royal Society of Chemistry [11]).
inconvenience of patients [142]. However, the skin is a major barrier of
drug delivery. Therefore, an effective therapy would tackle the chal-
lenges of topical drug delivery to deliver the required amount of drug
dosages into the treated skin sites. Gelatin is an amphoteric polymer
that simultaneously has cationic and anionic functional groups. Gelatin
was reported to exhibit relatively poor mucoadhesive characteristics
like non-ionic polymers due to its amphoteric property and self-
neutralization of cationic and anionic charged within its structure [166].
Gelatin solidifies to form crystalline regions within the amorphous ma-
trix at room temperature [189]. Gelatin displays a thermoreversible
property. The chain of gelatin partially renatures, and forms interchain
and intrachain collagen-like triple-stranded helices at below 30 ºC
while the helices remelt and gelatin returns to its random coil configu-
ration at higher than 40 °C [190]. The average skin temperature ranges
from 29.19 to 35.90 °C between the slightly warm or slightly cool and
neutral conditions [191]. The crosslinked gelatin network could swell
under the release solvent and allow the egress and diffusion of the
entrapped drug [192]. The polymer chain relaxation of drug loaded gel-
atin matrices occurred and the gelatin network started to swell, causing
an increase in the matrix volume and smaller pores in gelatin matrices.
This action generated spaces between the polymer chains, resulting in
the release of the entrapped drug [192]. The free volume in a polymer
network might be considered as a volume fraction of molecular-sized
holes which were accessible for diffusion [193]. Therefore, the gelatin-
based system might allow the sustained release of entrapped drugs by
attaching on the skin for topical application. The polymer chains of mi-
crocapsules might relax when subject to the moisture and heat generat-
ed from the skin, permitting diffusion of the entrapped drugs from the
micro-pores or macromolecular network of the matrix carrier through
the stratum corneum into the epidermis. The drug might then be
absorbed in the capillary network before entering the peripheral circu-
lation (Fig. 7). Lam et al. [194] investigated the washing fastness of ber-
berine loaded chitosan and gelatin/agar microcapsules containing
textile fabrics. The results revealed that gelatin/agar-based microcap-
sules containing the internal water phase of berberine maintained rela-
tively higher amount on cotton fabrics and exhibited better antibacterial
activity even after 20 washing cycles when compared with chitosan mi-
crocapsules having the core oil phase of berberine. Therefore, gelatin-
based system would be more suitable for the delivery of topically ap-
plied medicines.
Fig. 7. Transdermal drug delivery from gelatin-based matrix microcapsules.
7.1.3. Alginate-based systems
Alginate, as an anionic linear polysaccharide containing 1,4-linked
D-mannuronic acid and L-guluronic acid residues, is obtained from
brown seaweed using a dilute alkaline extraction. The resulting solution
is treated with mineral acids and finally converted to sodium alginate
[195,196]. Sodium alginate is a natural, biocompatible, biodegradable
and hydrophilic polymer. It has been applied to micro-particulate
formulations for drug delivery because of its bioadhesive, gelation and
pH responsive properties [99,197]. Sodium alginate can form hydrogels
with multivalent cations such as Ca2+, Ba2+ or Fe3+ [198]. Generally,
spherical alginated-based microcapsules or microspheres are produced
by directly dripping the sodium alginate solution into CaCl2 solution
[198]. Builders et al. [99] developed the mucinated sodium alginate
microcapsules for oral delivery of insulin. The efficacy of microencapsu-
lated insulin was examined using a diabetic rabbit model. The blood glu-
cose lowering effect induced by the orally administered insulin-loaded
microparticles prepared with three parts of sodium alginate and
one part of mucin after 5 h was equal to that produced by the subcuta-
neously administered insulin solution. It was believed that mucinated
sodium alginate microcapsules could be an effective alternative for
oral delivery of insulin. Rastogi et al. [199] reported the synthesis of
alginate microspheres for the oral delivery of isoniazid. The isoniazid
loaded alginate microspheres were orally administered by adult Wister
rats. Gamma-scintigraphic studies were conducted to determine the
location of microspheres in rat body after oral administration. The
presence of microspheres could be marked in the intestinal lumen 4 h
post-oral administration. Microspheres could also be detected in the in-
testine after 24 h although the percent of radioactivity had significantly
decreased. Ishak et al. [200] investigated the performance of chitosan-
coated floating alginate beads for oral delivery of micronized Metroni-
dazole (MZ) using a Helicobacter pylori (H. pylori)-induced mice
model. The histopathological assay showed that groups receiving MZ
in the form of floating alginate beads at 10, 15 and 20 mg/kg possessed
a better eradication of H. pylori infection in mice than that of the suspen-
sion form of free MZ. The in vivo H. pylori clearance study also revealed
that 15 mg/kg MZ loaded floating alginate beads showed 100% clear-
ance rate while 20 mg/kg MZ containing suspension resulted in only
33.33%. Sandhya et al. [201] designed the glipizide mucoadhesive
microcapsules coated with alginate and sweet potato starches
which were suitable for oral drug delivery. The developed microcap-
sules exhibited a slow and complete release of glipizide over a
prolonged period of time and a good mucoadhesive property in the
in vitro wash-off test.
 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
7.1.4. Cellulose-based systems
Cellulose is a linear polysaccharide originated from natural sources
including cotton, hemp, wood and other plants. It is highly crystalline
due to the extensive intramolecular hydrogen bonds. β-Glucose mole-
cules condense through β(1 → 4)-glycosidic bonds to lead to cellulose
[196,202]. Cellulose has been reported as a wall material of microcap-
sules for oral and transdermal deliveries in several studies. Prajapati
et al. [203] studied the hypoglycemic performance of alginate–sodium
carboxymethyl cellulose or carbopol 934P microcapsules with gliclazide
entrapment. The in vivo diabetic albino rat assay demonstrated that the
alginate–sodium carboxymethyl cellulose microencapsulated drug had
a prolonged hypoglycemic effect (2–16 h) when compared with the
oral administration of the free drug (0.5–10 h). Pal and Nayak [204]
reported the development of gliclazide-loaded alginate–methyl cellulose
microcapsules with good mucoadhesion. In vivo alloxan-induced diabet-
ic albino rat model showed that significant hypoglycemic activity could
be noted in gliclazide-loaded microcapsule group after oral administra-
tion. Murtaza et al. [205] reported the synthesis of ethylcellulose
tabletted microparticles for oral delivery of salbutamol sulfate. The in-
vitro drug release test showed that an initial rapid release of salbutamol
sulfate from the tabletted microparticles was observed, followed by a
slow and prolonged drug release over 12 h. The in vivo study with the in-
volvement of young healthy human volunteers demonstrated the bio-
availability of drug loaded microcapsules after oral administration. The
drug could be detected in the human plasma samples. Hu et al. [206] re-
ported the development of clarithromycin (CLM) loaded ethyl cellulose
microcapsules for oral drug delivery. The pharmacokinetic study showed
that CLM dry suspension containing microcapsules did not decrease the
bioavailability and did possess a better therapeutic performance for
prolonging the release behavior significantly in healthy volunteers.
Giandali et al. [207] showed the synthesis of vancomycin loaded treha-
lose/hydroxyethylcellulose microspheres for topical drug delivery. The
developed microspheres might keep the treated skin site dry and pro-
vide the sustained release of vancomycin. The vancomycin loaded micro-
spheres were suggested to be useful for topical applications on the
potential microbial contamination on skin wounds when there were ex-
tensive injuries in skin and damages in skin barriers.
7.2. Synthetic polymer-based systems for drug microencapsulation
7.2.1. Poly(L-lactic acid) (PLA)- and poly(lactic-coglycolic acid) (PLGA)-
based systems
PLA and PLGA have been used for drug microencapsulation due to
their biodegradable, biocompatible and non-toxic properties, and they
have been approved by the Food and Drug Administration for human
use [208,209]. PLA is linear aliphatic polyester synthesized from lactic
acid monomers which are obtained by the fermentation of biomass,
such as corn or wheat, or waste products, such as whey or molasses
[210]. However, the hydrophily of PLA is unsatisfactory, resulting in a
slow decomposition rate [211]. PLGA is depolymerized in the presence
of water. The hydrolysis reaction cleaves the ester bonds of polymer
chains [212]. PLGA allows the controlled drug release from its pas-
sive degradation in aqueous environments such as living tissues
[85,212,213]. PLA and PLGA have been reported for micro-particu-
late oral and topical drug deliveries. Ma et al. [214] developed the
orally administered PLA microcapsules in order to protect insulin
from proteolytic enzymes in the gastrointestinal tract. The in vivo di-
abetic rat model showed that the insulin loaded PLA microcapsules
were capable of lowering the blood glucose level. Sixty-eight percent
of diabetic rat blood glucose level was reduced by 68.5 ± 11.7% and
21% of diabetic rat blood glucose level was decreased by 39.7 ± 6.6%.
The results suggested that PLA microcapsule could be used as a car-
rier to protect insulin from proteolytic degradation in the gastroin-
testinal tract and ensure the bioactivity of insulin after the passage
through the intestinal tract. Mandal et al. [215] designed the PLGA
biodegradable microcapsules for the potential oral delivery of
37
amifostine. In vitro release study showed that about half of amifostine
was released during the first 6 h, and the drug continued to release,
with 92% of amifostine release after 12 h. The developed PLGA
microcapsule could be a carrier for the orally active controlled-release
of amifostine. Tian et al. [216] prepared the PLGA microcapsules con-
taining plasmid DNA (pDNA) against lymphocystis disease virus
(LCDV). In vivo fish model demonstrated that oral administration of
microcapsules containing the pDNA could induce the immune system
to produce the corresponding fish-anti-LCDV antibody which could be
detected in the sera of Japanese flounders. The results implied that
PLGA microcapsules were effective as oral carriers for the transfer of
pDNA. Santoyo and co-workers [217] reported the PLGA microparticles
loaded with acyclovir against viruses of the Herpes group. The skin
penetration study using a porcine skin model showed that there was
no noticeable difference between the quantity of the drug in the basal
epidermis with microparticles and with acyclovir suspension at 6 and
24 h. However, the acyclovir reservoir in the basal epidermis with
microparticles was higher than that with the control suspension after
88 h. This could be probably due to the controlled drug release pro-
duced by the vector in the basal epidermis. The PLGA microparticles
could improve acyclovir topical therapy as the drug retention in
the basal epidermis could be increased. This group [107] further inves-
tigated the topical drug penetration of cidofovir loaded PLGA micropar-
ticles against herpes viruses. Although the skin penetration assay using
a porcine skin model revealed that the amount of drug penetration was
higher with the drug solution than with microparticles after 24 h, the
amount of cidofovir found in the basal epidermis was much higher
with microparticles than with the control solution. The results sug-
gested that cidofovir-loaded microparticles could increase the drug re-
tention in the basal epidermis and reduce its penetration through the
skin. Hrynyk et al. [108] developed the human recombinant crystalline
insulin (hRcI) loaded PLGA microcapsules for the topical wound healing
treatment. In vitro scratch assay showed that insulin released from
PLGA microspheres over 23 days stimulated a rapid cell migration fol-
lowing an induced scratch as fresh insulin, suggesting a high level of
sustained bioactivity.
7.2.2. Poly (vinyl alcohol) (PVA)-based systems
PVA is a water-soluble synthetic polymer with biocompatible, biode-
gradable, nontoxic and excellent mechanical properties [218,219].
Crosslinked PVA is able to swell in aqueous conditions to offer a
controlled delivery of drugs [220]. Kaity et al. [221] synthesized a
novel interpenetrating polymer network microspheres of locust bean
gum (LBG) and PVA for oral controlled release of buflomedil HCl using
glutaraldehyde as the crosslinking agent. An increase in the amount of
PVA and glutaraldehyde decreased the wake uptake and drug release
because of the low water uptake capacity of PVA and the increased
rigidity of microcapsule network by glutaraldehyde. The developed
microspheres could be a potential candidate for providing a controlled
release of drugs with short half-life and high water solubility. Jain and
coworkers [222] developed the glutaraldehyde crosslinked Lepidium
sativum (Ls) and PVA interpenetrating polymer network microspheres
to provide a controlled drug release to improve the bioavailability
and half-life of simvastatin after oral administration. In vitro release
study showed that an increase in the amount of glutaraldehyde or
PVA could lead to a denser polymer network of microspheres which
resulted in a slower drug release from the polymeric matrix. This
group [223] further produced the interpenetrating polymer network
of gum ghatti (Gg) and PVA microspheres using glutaraldehyde as a
crosslinker for the oral controlled release of ranitidine HCl. The results
showed that an increase in the amount of glutaraldehyde or PVA
resulted in a higher mucoadhesivity and a slower drug release.
Microspheres with a higher proportion of Gg:PVA (1:4) and a higher
amount of glutaraldehyde (3.5 mL) had the highest mucoadhesivity
82.33 ± 0.57% in the in vitro wash off test and the slower drug release
in the release study, when compared with microspheres prepared
38 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
with Gg:PVA (1:2) and 1.5 mL glutaraldehyde, with the lowest
mucoadhesivity 62.66 ± 0.57% and the faster drug release.
7.2.3. Poly(ɛ-caprolactone) (PCL)-based systems
PCL is considered as a promising candidate for controlled drug
delivery due to its biodegradable, biocompatible, non-toxic characteris-
tics [76,224,225]. The high crystallinity and hydrophobicity of PCL
result in a relatively slow biodegradation rate and an unsuitable micro-
environment for tissue growth [226]. Benoit et al. [227] reported the
development of bovine serum albumin loaded PCL microparticles
which were suitable for oral vaccine delivery. The study confirmed
that the protein could maintain unchanged without the presence of ag-
gregates during the encapsulation process. Barboza et al. [228] devel-
oped the PCL and poly(3-hydroxybutyrate-co-3-22 hydroxyvalerate)
(PHBV) microparticles for the oral controlled release of manidipine
dihydrochloride (MAN). The in vivo rat model revealed that MAN load-
ed PCL microparticles could reduce the mean arterial pressure variation
up to 24 h after phenylephrine injections when compared with the pure
drug and MAN loaded PHBV microparticles. The orally administered
PCL microparticles containing MAN were suggested to promote a
long-lasting antihypertensive effect.
7.2.4. Poly(methyl methacrylate) (PMAA)-based systems
PMAA is a biocompatible ionizable hydrophilic polymer [229–231].
Crosslinked PMAA network is capable of swelling in water and its swell-
ing behavior highly depends on the pH value because of the ionization/
deionization of the carboxylic acid groups. The \COOH groups are not
ionized and the PMAA network remains at its collapsed state at low
pH of less than 5.5, whereas the \COOH groups are ionized and the
charged COO− groups repulse each other at high pH of 5.5–7.4, resulting
in the swelling of PMAA [231,232]. Eudragit® L100-55 is an anionic
methacrylic acid–ethyl acrylate copolymer which provides a coating of
microparticles with gastro-resistant property. Kovacs-Nolan et al.
[233] reported the development of anti-VP8 IgY loaded Eudragit®
L100-55 microcapsules to increase a protective efficacy under gastroin-
testinal conditions after oral administration. The in vitro stability study
demonstrated that a significantly more activity was preserved by micro-
encapsulated IgY (a 35%w/w enteric polymer coating resulted in the re-
tention of greater than 95% of IgY activity after 6 h of incubation in SGF)
than non-encapsulated IgY, with very little retention of IgY activity
(a significant decrease (86%) in IgY activity after 30 min of SGF expo-
sure). The in vivo stability test of the IgY using a weaned pig model
also revealed that there was a positive correlation (r = 0.996) between
the IgY activity and the amount of IgY in different regions of the gastro-
intestinal tract for the microencapsulated IgY. However, the amount of
non-encapsulated IgY in the gastrointestinal tract did not correlate as
well with IgY activity (r = 0.615) and the result showed high quantities
of IgY yet low IgY activity, suggesting that the antibodies were present,
but they lost their activity. The results demonstrated that the
microencapsulated IgY with a pH-sensitive methacrylic acid copolymer
(Eudragit® L100-55) could protect the antibodies from gastric
inactivationto promote an effective control of HRV infection.
Eudragit® L30 D-55 is an aqueous dispersion of an anionic
polymethacrylate and it is able to provide the microcapsules with
gastro-resistant effects. G. Año et al. [234] synthesized the vibrio
cholerae C7258 inactivated strain (VC) embedded Eudragit® L30
D-55 microcapsules. The results obtained from the immunogenicity
assay of microparticles using an oral inoculation adult rat model
showed that the oral administration of 3.5 mg of microencapsulated
VC achieved an appropriate protection of the bacteria which induced
the production of high levels of vibriocidal titers. This suggested the
possibility of using lower doses of microencapsulated VC to achieve a
suitable immune response. However, VC alone at 3.5 mg did not in-
duce an immune response. The developed microcapsules could
offer a low cost and easily produced oral vaccine, which would be
helpful to be administered to young children.
7.3. Multiple microemulsion systems for drug microencapsulation
A water-in-oil-in-water (w1/o/w2) multiple emulsion system con-
sists of the internal (w1) and external (w2) phases, which are chemically
alike, as well as an intermediate immiscible (o) phase which physically
separates the two alike phases [235]. The formation of a stable multiple
emulsion involves a two-step emulsification process, where in the first
step a water-in-oil emulsion (w1/o) is initially formed, which is
then re-emulsified in an aqueous phase (w2) with a combination of
emulsifiers and/or stabilizing agents [236]. Therapeutic drugs could be
encapsulated in the internal (w1) phase and the intermediate immisci-
ble (o) phase of the multiple emulsion using microencapsulation
technology for both oral and topical drug deliveries. The w/o/w
micro-particulate system could be developed by a micro-emulsion. A
microemulsion is defined as a single optically isotropic structured solu-
tion containing water, oil and surfactant [237]. By applying the
microemulsion vehicles, both hydrophilic and oil-soluble agents could
be solubilized so as to achieve a cooperative function for a specific ther-
apeutic use [41]. Previous studies reported the synthesis of w/o/w
microemulsion systems. Kawakatsu et al. [238] reported the develop-
ment of w/o/w emulsion for producing microcapsules. In the w/o sys-
tem, pectin, as a polysaccharide, was used as an internal water phase
while oleic acid or triolein containing Span 20, Span 80 or TGPR were
used as an oil phase. The w/o/w emulsion was then produced by feeding
w/o emulsion through the micro-channels into an external water phase
containing 3 wt.% of Tween 20. Foster et al. [239] designed the w/o/w
emulsion for microcapsule formation which was suggested to be
applied to oral drug delivery, cell encapsulation, protein evolution
and gene therapy. In this system, a biocompatible and biodegradable
amphiphilic diblock copolymer poly(ethylene glycol)-b-poly(c-methyl
e-caprolactone) was used as the internal water phase; volatile oil was
applied as the oil phase; and PVA was employed as the outer water
phase. Cai et al. [240] developed the polystyrene hollow spheres using
the w/o/w multiple emulsions. Sodium lauryl sulfate, as an internal
water phase, was suspended in polystyrene dissolved benzene and
1,2-dichloroethane. The w/o emulsion was then poured to the PVA
which was used as the outer water phase. Liu et al. [241] reported the
synthesis of PLA/PLGA microcapsules loaded with recombinant human
insulin using a w1/o/w2 multiple emulsion. The inner water phase
(w1) consisted of recombinant human insulin while the oil phase (o) in-
volved a mixture solvent of dichloromethane (DCM) and toluene con-
taining PLA/PLGA and Arlacel 83. The outer water phase (w2) was
composed of PVA and sodium chloride which were dissolved in water.
The multiple microemulsion systems possess the advantages for both
oral and topical drug deliveries. Oral drug delivery using the multiple
microemulsion reduces the transient drug overload, resulting in a de-
crease in local adverse side effects [242]. Microemulsion declines the
first-pass metabolism and remains the plasma drug level for a
prolonged period of time [243]. Microemulsion also possesses some
benefits for transdermal drug delivery. An increase in drug concentra-
tion in the skin is achieved due to a large amount of drug incorporated
in the formulation. An increased thermodynamic stability of the drug
may enhance its partitioning into the skin. The components of
microemulsion may act as permeation enhancers to decrease the diffu-
sional barrier of the stratum corneum, leading to an increase in the per-
meation rate of drug through the skin [244,245]. Cournarie et al. [246]
compared the insulin loaded w/o/w multiple microemulsion prepared
with either Miglyol® 810N or fish oil using a two-step process. The mul-
tiple microemulsion consisted of an inner aqueous phase of 71% of an
aqueous solution of insulin (2.8 mg/mL) containing 0.18% of NaCl; an
oil phase of 25% of oil (either Miglyol® 810N or fish oil), 4% of Abil®
EM-90; and an external aqueous phase of Arlatone® F127G (1%). This
study suggested that the combination of Miglyol® 810N and fish oil
was proposed to prepare the multiple microemulsion in order to obtain
the benefits of Miglyol® 810N (small globules formation and higher sta-
bility) and fish oil (beneficial therapeutic effects) for oral administration.
 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
Shahiwala et al. [247] developed the squalane oil-containing w/o/w mul-
tiple emulsion for the oral immunization of ovalbumin (OVA). Oral im-
munizations of squalane oil-containing w/o/w multiple emulsion
resulted in a much higher systemic IgG and mucosal IgA responses
when compared with the nasally treated groups. The results revealed
that squalane oil-containing w/o/w multiple emulsion formulations
could significantly improve the local and systemic immune re-
sponses after oral administration. The developed system could be a
better alternative to the mucosal delivery of prophylactic and therapeu-
tic vaccines. Paul et al. [248] developed the w/o/w multiple emulsions
for acyclovir entrapment to enhance its oral bioavailability. The in vivo
rat model showed that an extended drug release was obtained from
w/o/w multiple emulsions, resulting in a better oral bioavailability
when compared with the drug solution. Tirnaksiz and Kalsin [249] de-
veloped the formulation of topical w/o/w multiple microemulsions
with the globule size ranging from 20 to 37 μm. The inner water phase
included 0.03% sodium chloride and 1.5% caffeine in distilled water,
the oil phase involved 30% liquid paraffin and 2 or 4% lipophilic surfac-
tant (Abil®EM90), and the outer water phase contained 1, 2 or 4%
Tetronic®908 in distilled water. An initial rapid release of caffeine
followed by a much slower rate of drug release could be shown. The op-
timal multiple emulsion involving Tetronic®908 (1%) in the outer aque-
ous phase and Abil®EM90 (2%) in the oil phase was considered as a
potential dosage form of prolonged drug release. Schmidts et al. [250]
reported the development of a topically used w/o emulsion, w/o/w
emulsion, multiple emulsion and submicron emulsion for the
DNAzymes delivery to treat inflammatory diseases such as atopic der-
matitis. The w/o emulsion involved the aqueous phase (5 wt.% glycerol,
0.3 wt.% MgSO4, 0.14 wt.% potassium sorbate, 0.07 wt.% citric acid and
63.9 wt.% distilled water) and the oil phase (3.0 wt.% triglycerol
diisostearate, 1.2 wt.% isopropyl palmitate, 1.2 wt.% Cetostearyl
Isononanoate, 0.2 wt.% soy lecithin and 24.6 wt.% hydrophobic basis
gel). For the w/o/w emulsion, the inner aqueous phase consisted of
0.065 M MgSO4 solution containing the DNAzyme, the oil phase
contained 15.8 wt.% heavy paraffin oil, 4.0 wt.% sorbitan oleate and
0.2 wt.% soy lecithin, and the outer aqueous phase was composed of
1.0 wt.% Steareth-20 and 58.7 wt.% preserved water. The multiple emul-
sion was produced by mixing the appropriate quantities of the compo-
nents and the DNAzyme at room temperature. The oil phase contained
7.20 wt.% Labrasol®, 4.80 wt.% Plurol Oleique®, 2.50 wt.% cetostearyl
isononanoate and 2.50 wt.% isopropyl palmitate, and the water phase
was composed of 2.49 wt.% glycerol, 16.60 wt.% propylene glycol,
0.30 wt.% MgSO4 and 63.21 wt.% distilled water. For the submicron
emulsion, the water phase (a blend of Oleth-3 and Oleth-10 in total
6.0 wt.%, 3.0 wt.% glycerol, 0.3 wt.% MgSO4 and 75.3 wt.% preserved
water) and oil phase (5.0 wt.% Coco-Caprylate/Caprate, 5.0 wt.%
cetearyl isononanoate, 5.0 wt.% Ethyl oleate) were heated separately
to 70 °C and then mixed together. Oleth-3 and Oleth-10 were used to
adjust the HLB values of 10, 11 and 12 for three different submicron
emulsions. The stability test showed that w/o/w emulsion and w/o
emulsion had the higher DNAzyme stability over 3 months as compared
with submicron emulsion and multiple emulsion. The skin penetration
studies using the porcine skin model showed that the submicron emul-
sion (HLB 12) exhibited the highest DNAzyme penetration for both in-
tact (untreated) and impaired (with a simulated impaired barrier of
atopic dermatitis skin) skin after 24 h, followed by the multiple emul-
sion with the second highest DNAzyme uptake. DNAzyme uptake from
submicron emulsion to the skin revealed that components such as
ethyl oleate, interacted with the stratum corneum, resulting in an in-
crease in DNAzyme penetration as compared to skin with impaired bar-
rier (a reduced stratum corneum). The low DNAzyme uptake by w/o/w
emulsion and w/o emulsion might be associated with the higher stabil-
ity which delayed the release of the entrapped DNAzyme. However, the
oily membrane of w/o/w multiple emulsion broke down under shear
during topical application, resulting in the successful release and skin
penetration of DNAzyme, as well as the higher cellular uptake of
39
DNAzymes. This study concluded that the w/o/w multiple emulsion
was helpful to transport the DNAzyme across the skin and into epider-
mal cells of the atopic dermatitis affected skin. An interesting w1/o/w2
multiple microemulsion system has been developed for the potential
applications of oral and transdermal drug deliveries (Lam's unpublished
data). Gelatin was used as an internal water phase (w1) containing a bio-
medical agent. The oil phase (o) was a vegetable oil while the outer
phase (w2) was chitosan. Fig. 8 shows this w1/o/w2 microemulsion sys-
tem. The developed emulsion system is speculated to be a drug carrier
for both oral and topical applications for specific disease treatments.
8. Challenges of drug microencapsulation in real life
Drug microencapsulation possesses a significant potential for phar-
maceutical and therapeutic fields in future as it provides the sustained
and controlled release of pharmaceutical agents for various medical
applications. However, microencapsulation technology still faces the
existing obstacles and limitations in drug deliveries. This results in a dis-
tance between drug microencapsulation and clinical practice in real life.
The challenge involves the scale-up of drug microencapsulation process
to achieve the high reproducibility of the microencapsulated drug
formulations. Technical, quality, ethical and economic issues should be
considered when the mass production of pharmaceuticals using micro-
encapsulation technology is implemented. Technical considerations
may include the features and requirements of a microencapsulated
pharmaceutical product that should be specified and identified before
the design of a drug formulation. For examples, the microencapsulated
protein should be planned to prolong the drug bioactivity after oral ad-
ministration using a low permeable and biocompatible polymeric ma-
trix for drug entrapment. Precise characterization of drug loaded
microcapsules is fundamental to the development of a pharmaceutical
formulation for the disease treatment. For the therapeutic applications,
the physical, chemical and therapeutic properties of microcapsules
should be carefully examined and identified. Drug entrapment efficien-
cy of microcapsules is closely related to the drug doses and therefore it
should be cautiously controlled to avoid an overdose administration of
the drug. Particle size of microcapsules could alter the total surface
area for the drug release. The stability of microcapsules should be ma-
nipulated in order to produce the microencapsulated pharmaceuticals
with a clinically acceptable shelf life. The materials involved in the mi-
crocapsule formation should be standardized in terms of chemical com-
positions, purification and reaction situations so as to achieve the
biosafety and efficiency requirements consistently and minimize the
product variability in different laboratories [251,252]. Additionally, the
Fig. 8. A w1/o/w2 multiple microemulsion system.
40 P.L. Lam, R. Gambari / Journal of Controlled Release 178 (2014) 25–45
quality control should be necessary to produce the microencapsulated
medicine with an acceptable quality. Ethical approval of a pharmaceuti-
cal product should be obtained to demonstrate the safe use of drug load-
ed microcapsules as being supported by the results of animal
experiments and clinical trials. The operational procedures of drug mi-
croencapsulation should be simplified to increase the efficiency of pro-
duction, and thus reducing the production time and cost. All of these
steps are fundamental to the application of drug microencapsulation
technology for clinical therapies in the real life.
9. Commercially available microencapsulated pharmaceuticals for
oral and transdermal drug deliveries
Although the challenges and limitations of drug microencapsulation
exist, there are some successful microencapsulation products which
have been commercially available in the market. For the microencapsu-
lated oral drug delivery systems, Bayer Inc. has developed the CIPRO®
Oral Suspension which consists of ciprofloxacin microcapsules and
strawberry flavored diluent medium for oral administration to treat
the microbial infections [253]. Micropharma Ltd. has launched the
Cardioviva™ that contains the alginate-poly-L-lysine-alginate microen-
capsulated probiotic Lactobacillus reuteri NCIMB 30242 for oral adminis-
tration. The clinical study reported that the Cardioviva™ could
effectively lower the cholesterol level after a 6 week treatment period
[254]. Ther-Rx Corp., a branded-drug subsidiary from KV Pharmaceuti-
cal Co., has marketed the Micro-K® Extencaps® which is an oral formu-
lation of microencapsulated potassium chloride for the treatment of
hypokalemia [255]. Mayne Pharma International has developed the
taste masked Paracetamol (Nopap™) powder and tablets which can
mark the unpleasant taste of the drug, enhance the drug stability and
provide a sustained drug release after oral administration [256].
Novartis Int. AG has invented the Sandimmun Neoral®, an oral formula-
tion of Cyclosporin A, using the microemulsion technology for the treat-
ment of rheumatoid arthritis. The clinical study reported that the
microemulsion formulation improved the drug bioavailability, resulting
in a reduced requirement for increased doses over time [257]. Roche has
marketed the Fortovase® microemulsion formulation for the oral deliv-
ery of Saquinavir and Abbott Laboratories has also developed the
Norvir®, an oral microemulsion dosage of ritonavir for the treatment
of Human Immunodeficiency Virus (HIV) [258]. For the microencapsu-
lated topical drug delivery systems, Tagra biotechnologies Ltd. has syn-
thesized the Tagravit™ microcapsules for topical delivery of vitamins
(A, E and F) onto the skin. Tagravit™ microcapsules significantly im-
prove the stability of vitamins by protecting the vitamins from the ex-
ternal environments [259]. DS Laboratories, Inc. has invented the
Trioxil® (bisazulene gel) in a carrier agent of natural encapsulated gin-
seng and hamamelis extracts as well as arnica for topical delivery.
Trioxil® acts for 12 h to inhibit the Propionibacterium acnes bacteria
and fungi after applying onto the skin [260]. Table 3 shows the commer-
cially available microencapsulation products for oral and transdermal
drug deliveries.
Table 3
Commercially available microencapsulation products for oral and transdermal drug deliveries.
Product name Core active ingredient Dosage route
CIPRO® Ciprofloxacin Oral
Cardioviva™ Lactobacillus reuteri NCIMB 30242 Oral
Micro-K® Extencaps® Potassium chloride Oral
Nopap™ Paracetamol Oral
Sandimmun Neoral® Cyclosporin A Oral
Fortovase® Saquinavir Oral
Norvir® Ritonavir Oral
Tagravit™ Vitamin A, E and F Transdermal
Trioxil® ginseng and hamamelis extracts, arnica Transdermal
10. Conclusion
Recent advances in microencapsulation systems for the applications
of oral and transdermal drug deliveries are summarized in this review.
The use of micro-particulate systems for producing biopharmaceuticals
and micro-medicines has shown to have a great potential in pharma-
ceutical and medical industries. The desired formulations should protect
the drugs under unstable biological environments, such as drug degra-
dation induced by the gastrointestinal tract and first-pass liver effects
after oral administration, overcome the low skin permeability when
the drugs are administered through transdermal route, and promote a
prolonged drug delivery to the targeted body sites. Micro-particulate
systems for oral and transdermal drug deliveries are believed to over-
come the flaws in the conventional drug dosage forms They also leave
an alternative administration route to improve the drug release profile,
and enhance the bioavailability and stability of the drug dosages. In fact,
the synthesis and development of microencapsulation systems for drug
delivery are mature. However, the actual applications and usages of
these microencapsulation systems remain to be limited. Although
some progress has been made in recent studies, few previous studies in-
vestigated the possible biological effects and therapeutic activities from
in vitro and in vivo models. The next challenge will be the bridging of the
synthesis and potential applications of medicated microencapsulation
systems.
Acknowledgment
Parts of this work were extracted from P.L. Lam's thesis. The authors
would like to acknowledge the support of the Innovation Technology
Commission and Research Grants Council, The Hong Kong Polytechnic
University. Prof. R. Gambari is supported by AIRC.
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