Microcapsulas. Principios

Critical Reviews™ in Therapeutic Drug Carrier Systems, 33(4), 309–361 (2016)
Overview on Therapeutic Applications of

Microparticulate Drug Delivery Systems
Swarna Bale,a Amit Khurana,a $6KLYD6KDQNDU5HGG\DMandip Singh,b
& Chandraiah Godugua,*

Laboratory of Nano-Biology, Department of Regulatory Toxicology, National Institute of
Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana,
India; bCollege of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee,
Florida
*Address all correspondence to: Dr. Chandraiah Godugu, Assistant Professor, Laboratory of Nano-Biology, Department
of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar,
Hyderabad, Telangana, India-500037; Tel. 040-23073741; Fax: 040-23073751; chandragodugu@gmail.com or
chandra.niperhyd@gov.in
ABSTRACT: Research in novel drug delivery systems is being explored competitively in

order to attain maximum therapeutic effect while minimizing the adverse effects. Despite sev-
eral advancements in pharmaceutical formulations, one of the major challenges still persisting
is sustained drug release. Microencapsulation enacts as an intelligent approach with a strong
therapeutic impact and is in demand globally in medical technology due to its specific and at-
tractive properties, including biocompatibility, stability, target specificity, uniform encapsula-
tion, better compliance, and controlled and sustained release patterns that are responsible for
diminishing the toxicity and dosage frequency. Microparticles are successful delivery systems
that encapsulate both water-insoluble and sparingly water-soluble agents to elicit their efficacy
with a great potential attributed to their unique properties: particle size, shape, structure, drug
loading, entrapment efficiency, porosity, and release profile. Several marketed microparticle-
based formulations are available, including risperidone, buserelin, and octreotide acetate, and
some of them are in clinical trials. The present review highlights the detailed therapeutic ap-
plications of microparticles with advances from the last decade to treat various disease condi-
tions, including cancer, diabetes, cardiovascular diseases, and neurological disorders, as well
as for vaccine delivery, ocular and pulmonary delivery, gene transfer, etc., and exemplifies the
future perspectives in these aspects. One day in the future, microparticle-based formulations
may become broadly researched in drug delivery systems.
KEY WORDS: microparticles, therapeutic benefits, sustained release, drug delivery
I. INTRODUCTION
A controlled drug delivery system is essential to overcome the limitations associated
with conventional therapy and to assist in enhancing the therapeutic efficacy of the ac-
tive compound by releasing drugs from days to months. To attain maximum therapeutic
benefits, it is desired to deliver the drug at right time in the right amount to minimize
adverse effects. One such approach fulfilling the above requirements can be plausible
using microparticles. A microparticlulate drug delivery system (MDDS) entraps solids,
liquids, or gases in size ranging from 1 to 1000 µm in inert polymeric shells, protect-
0743-4863/16/$35.00 ©2016 Begell House, Inc. www.begellhouse.com 309

310 Bale et al.
ing them from the harsh external environment.1 They are administered either directly to
the target organs or through multiple routes, including intraperitoneal, intramuscular,
subcutaneous, intra-organ, and pulmonary delivery. This delivery system particularly
aids in sustained and controlled release of the enclosed particles through gradual diffu-
sion for prolonged periods. Therefore, MDDS is an intelligent approach with a strong
therapeutic impact and is in demand globally in medical technology due to its specific
and attractive properties, including biocompatibility, stability, target specificity, uniform
encapsulation, better compliance, and controlled and sustained release patterns that are
responsible for diminishing the toxicity and dosage frequency. Microparticles enclose
several macromolecules, including vaccines, nucleic acids, and proteins, and control
their release by delivering through multiple routes.2–4 These are successful delivery
systems encapsulating either water-insoluble or sparingly water-soluble active agents.5
MDDS contain two components, a core material enclosing the active ingredient and a
coating material that protects the active material from the harsh external environment
and extends its release as per the requirement. Therefore, based on the disease condi-
tion, target site, and drug to be incorporated, different polymers are used accordingly to
produce better therapeutic efficacy.
The present review describes the classification of MDDS, methods of encapsu-
lation, and evaluation techniques in brief. It encompasses recent updates of MDDS
in different chronic disease conditions, including diabetes, cancer, neurological and
cardiovascular diseases, along with vaccine delivery, immunology, and their use via
inhalation to treat pulmonary diseases. The role of MDDS in ocular delivery and in-
flammatory diseases, including arthritis, psoriasis, and other bone disorders, is dis-
cussed. We also discuss MDDS in clinical trials and propose future perspectives based
on current literature.
A. Classification of MDDS
MDDS are majorly classified as microspheres and microcapsules, as shown in Figure
1. Microspheres are smaller microparticles, spherical in shape with a large surface to
volume ratio that entrap the drug homogenously in the matrix. Microspheres are further
classified as solid and hollow types. Solid microspheres entail numerous therapeutic
applications and hollow types are used as additives. The release rate kinetics follow
first-order diffusion in microspheres because of the absence of a layer during polymer
encapsulation; that is, the active ingredient is dispersed directly in the polymer matrix.
Microcapsules are reservoir systems in which drug is loaded centrally in the polymeric
shell and is released slowly through dissolution and diffusion.6,7 Microcapsule contains
a layer covering the drug and then enclosed by polymeric shell. Based on this property,
they are further categorized as mono-coated, poly-coated, or matrix type depicting the
loading of drug in single hollow chamber, multiple hollow chambers, or in the matrix
within the polymeric shell, respectively. Release of the drug from microcapsules follows
zero-order kinetics. The type of microparticle to be formulated depends on the drug to
be encapsulated and the polymer selected.
Critical Reviews™ in Therapeutic Drug Carrier Systems

Therapeutic Applications of Microparticles 311
FIG. 1: Schematic representation of MDDS classification (A) Microspheres. (B) Microcapsules
B. Advantages and Disadvantages of MDDS

MDDS offer numerous advantages because of their unique properties, including size
and shape. Some of the advantages are explained in brief below. The size of the particles
direct targeted delivery of the drug as in inhalation and ocular delivery. They offer pro-
tection to the encapsulated drug from gastric and other external environments and aid
in sustained and controlled release of the entrapped medicament and are thus useful in
delivering the drugs as explained in the subsequent sections. MDDS enhances the solu-
bility profile of poorly soluble active agents, addressing their solubility. MDDS act as
target-specific delivery system, as evident from direct intratumoral delivery of various
anticancer drugs. MDDS enhances the bioavailability of the loaded drug, thus achiev-
ing effective therapeutic benefits and minimizing side effects. MDDS avoids repeated
drug administration and masks the taste and odor of drugs, thereby imparting better
patient compliance and reducing toxicity concerns. MDDS also assists in delivering
incompatible agents by loading them in a single shell separated by encapsulation. Con-
versely, MDDS has a few disadvantages; for example, it is governed by factors such as
the presence of food, residence time, and the nature of the polymer. Release kinetics of
the active ingredient varies when formulated at different doses. Sometimes, drug may
be delivered at other than the target site due to polymer degradation. Further, the cost
involving in preparing MDDS is significantly higher than the respective standard prepa-
rations and high standardization of the procedure is essential to accomplish reproduc-
ibility of the formulations. These disadvantages can be overcome by altering the design
Volume 33, Issue 4, 2016

312 Bale et al.
of microparticle preparation and using other approaches including targeted delivery,

inhalational delivery, intracranial local delivery for neurological disorders, and so on, as
explained in the following sections.
II. MICROENCAPSULATION
A. Polymers Used for Preparation of MDDS
Before understanding the various methods involved in preparation of microparticles, it
is essential to know the nature of polymers with which microparticles are constructed.
Polymers are important because they modulate the release of drugs from the formula-
tions. They even alter the flow properties by interacting with the particles of the drug.
A broad range of polymers are used to formulate microparticles and are derived from
different sources both natural and synthetic. Natural polymers include gelatin and albu-
min and synthetic biocompatible polymers include carboxy methyl celluloses (CMC),
polylactic acid (PLA), polylactide co-glycolide (PLG), poly[lactic co-glycolic acid]
(PLGA), poly ε-caprolactone (PCL), and polyketals. Molecular weight, biocompatibil-
ity, biodegradability, and nature of the polymer govern the encapsulation of drug. The
entrapment of drug in a polymer should be optimum and should release the drug in the
right place at the right time. Stability, biocompatibility, biodegradability, efficiency of
loading drug at higher concentrations, and ability to release active ingredient in a con-
trollable fashion are considered ideal characteristic features of the polymers. The differ-
ent types of polymers and examples are provided in Figure 2.
FIG. 2: Classification of polymers used in the preparation of microparticles

B. Methods of Microencapsulation
There are different methods used for preparation of microparticles that are classi-
fied as physical, physico-chemical, and physico-mechanical methods. Physical meth-
ods include polymerization; physico-chemical methods include phase separation; and
physico-mechanical methods include solvent evaporation, emulsion, and spray-drying
techniques. The solvent evaporation method is one of the most commonly used encap-
sulation techniques.8 It includes single and double emulsion techniques. Spray drying is
a technique used for sensitive substances to protect them from oxidation. In this process,
the polymer is dissolved in selected organic solvent, followed by dispersion of drug
with homogenization at higher speed, passed through an atomizer under compressed air,
where droplets of micron size are formed.9 Phase separation and coacervation are gener-
ally used for encapsulating water-soluble drugs such as proteins and peptides.10 In this
process, water-soluble drugs are dispersed in the polymer and polymer solubility in the
organic phase is reduced by creating water insufficiency to form the coacervates. Anoth-
er incompatible polymer is then added to the drug dispersed in polymer solution, result-
ing in phase separation of the first polymer, entrapping drug molecules and producing
microparticles. In solvent extraction, a drug is incorporated directly in the organic phase
containing polymer. It involves the same principle as the solvent evaporation technique,
but the difference lies in method of solvent removal. Water-soluble organic solvents
such as isopropanol are used to extract the organic phase in which the polymer and drug
are dispersed. Therefore, the organic phase is removed with water and the efficiency of
solvent extraction depends on proportion of the emulsion to water used for extraction
and solubility of the polymer in the respective organic solvent.
Polymerization is a chemical method of preparation of microparticles, generally
classified into four different types: suspension, emulsion, bulk, and interfacial polym-
erization methods.11 A suitable method has to be selected based on the nature of drug
(i.e., whether the drug is hydrophilic/lipophilic) to incorporate the optimum amount of
drug and to monitor its release rate accordingly. Different methods used in MDDS are
shown in Figure 3 and the majority of them are modifications of three basic techniques:
solvent evaporation, spray drying, and phase separation. A schematic representation of
the respective method used is shown in Figure 4.
C. Parameters Attributing the Efficiency of MDDS

Along with the active ingredient, adjuvants are included in the preparation of micropar-
ticles. To build the matrix of the formulation, polymers are essential. There are various
factors that govern the synthesis and efficacy of microparticles, essential in judging the
entrapment efficiency, which is crucial for the active ingredient to show therapeutic
benefits. These include concentration and molecular weight of the polymer, method of
preparation, solubility of drug and polymer, drug–polymer interactions, rate of solvent
evaporation, agitation speed, phase–volume ratio, etc. In addition, evaluation is a criti-
cal step to be performed after the synthesis of microparticles to ensure its entrapment
efficiency, drug release, and proper synthesis and to ensure that the required physico-

314 Bale et al.
FIG. 3: Various types of encapsulation techniques used for preparation of microparticles
FIG. 4: Schematic representation of methods used to prepare microparticles (A) Solvent evapo-
ration method (B) Single emulsion method (C) Double emulsion method (D) Spray drying and
congealing

chemical properties are achieved. Various evaluation methods with respect to each pa-
rameter are described in Table 1.
TABLE 1: Parameters involved in evaluation of MDDS

Parameter (Particle feature) Evaluation technique
Size Microscopy, sieve analysis, laser light
scattering, coulter counter method, photon correlation
spectroscopy
Crystallinity Differential scanning calorimetry, X-ray diffraction
Shape and surface morphology Freeze fracture microscopy
Porosity and specific area Mercury or helium intrusion potentiometry
Flow properties Angle of repose estimation using fixed funnel and free-
standing cone method
Compressibility index Tapped density method
Thermal properties Differential scanning calorimetry, thermo-gravimetric
analysis, differential thermometric analysis
Degradation of the Attenuated total reflectance Fourier transform infrared
polymeric matrix spectroscopy
Density Multivolume pychnometer
Isoelectric point Micro-electrophoresis
Entrapment efficiency High-performance liquid chromatography
III. THERAPEUTIC APPLICATIONS OF MDDS

MDDS offers a broad range of applications for therapy by loading numerous active
pharmaceutical ingredients. The main aim of any drug formulated as an MDDS is to
achieve local targeted delivery and sustain release of the medication. The extent of
MDDS applications vary from imaging to treating various diseases. Bio-adhesiveness
and permeability enhancement property of polymers aid their application in formulating
microparticles for ocular drug delivery systems. Highly efficient viral and nonviral vec-
tors are formulated as microparticles for achieving gene delivery. MDDS plays a crucial
role in treating diabetes because of the advantage of sustained release, thereby decreas-
ing the frequency of administration of anti-diabetic drugs, avoiding trauma and discom-
fort to the patient. Similarly, it plays a vital role in treating almost all types of tumor
cells by local targeting plausible by delivering potent chemotherapeutics intratumorally.
In addition, microparticles function as effective delivery system in producing probiotics
by preventing their degradation12 and thus have profound applications in many diseases,
as shown in Figure 5. Applications of MDDS in diabetes, immunology, and cancer are
described in detail, as well as other diseases including neurological and cardiovascular
disorders and the advantages of administration of MDDS via specific routes.

316 Bale et al.
FIG. 5: Therapeutic applications of MDDS and their advantages
A. Role of MDDS in the Management of Diabetes Mellitus

Diabetes is a chronic disease of major global concern. It is forecasted that, in the future,
developing countries will lead the world in diabetic prevalence and India hosts numer-
ous diabetics. Despite several treatment strategies existing for diabetes, the last chance
for saving lives if other treatments fail is pancreatic or islet transplantation. MDDS, par-
ticularly in diabetes, has gained huge attention because repeated dose administration is
avoided, thus preventing the trauma, pain, and injury associated with insult; this method
also sustains drug release and enhances therapeutic efficacy. The application of MDDS
in diabetes is shown in Figure 6 and encapsulation of several anti-diabetic drugs loaded
into microparticles are described in Table 2.
Effective therapy for diabetes in the clinical setting is accomplished using insulin
(INS) administration, either as subcutaneous injections or an intravenous drip; however,
INS administration by these routes may harm the patient and result in injury. Further,
INS is a protein that can be effortlessly digested by gastric enzymes, thereby limiting
its oral bioavailability. Therefore, formulating a delivery system of INS that avoids its
degradation will have practical significance. For example, hydro-gels have been widely
studied as surplus protein carriers. One such approach was reported using pH-sensitive
hydrogel microparticles obtained by polymerization of methacrylic acid and polyethyl-
ene glycol (PEG) dimethacrylates, which released only 25% of INS in an acidic medium
(pH 2.5), followed by a sustained effect that lasted for 10 h in alkaline media, with
INS encapsulation efficiency of 82%.13 Another interesting hydrogel MDDS was for-
mulated using chitosan complexed with PEG and polymethylmethacrylate (PMMA) to
form a matrix and then functionalized with thiol groups by incorporating cysteine onto

FIG. 6: Therapeutic effects and advantages of MDDS in diabetes mellitus
the carboxylic groups of polymer matrix. This system resulted in slow INS release due
to activation of tyrosine kinases triggered by carboxyl groups of the matrix, promoting
controlled and sustained release along with prevention of proteolytic damage of INS.14
Recently, many studies have emerged on composite microparticles, where enclose an-
other formulation to attain specific benefits; examples are discussed below. Burst effect/
initial burst is a key problem associated with DDS, especially in MDDS. To address this,
composite microparticles (microparticle-enclosed nanoparticles) with INS as a model
drug were prepared using the double emulsion extraction technique with hydrophobic
and biodegradable polymers. These particles exhibited significant decrease in INS re-
lease both in vitro (19% in 15 min) and in vivo (582 μU/mL), suggesting the use of com-
posite particles to avoid initial burst and to control the release of drugs progressively so
that better therapeutic efficacy of any drug formulation can be expected.4 Another study
was reported in which INS was fabricated as microparticles using layer by layer nanoas-
sembly of polyelectrolyte films and delivered via the pulmonary route to maintain the
sustained levels of INS. A significant decrease in serum blood glucose levels and an
increase in INS levels suggest these microparticles as a promising tool to treat diabetes
using INS.15 Another study investigated the effect of cyclodextrin on INS release. In that
study, INS-loaded β-cyclodextrin microparticles were prepared using the spray-drying
technique and studied both in vitro and in vivo. It was observed that the release profile in
vitro (50% release in initial 8 h) was correlated with in vivo (50% glucose inhibition in
8 h after administration) and the therapeutic efficacy of the microparticles administered
orally were equivalent to that of subcutaneous injections.16 To allow effective oral INS
delivery, spherical microparticles loaded with INS PLGA-lipid-PEG nanoparticles were

TABLE 2: List of anti-diabetic drugs encapsulated in different MDDS
Drug Polymer Method Significance Reference
318
Palmityl-acylated Exendin-4 PLG w/o/w double emulsification Extension of hyperglycemic effect in 22

vitro and in vivo by binding to both
surface and circulatory albumin
INS PEG dimethacrylate Polymerization Minimum insulin release in acidic 49
medium (18–25%), followed by thera-
peutic effect lasting for 8–10 h in GIT
INS PMMA, PEG, Ionic gelation Improved absorption of insulin across 50
chitosan Caco-2 cell monolayers
INS Oleoyl chitosan Ionotropic gelation Resist gastric degradation, enhanced 19
mucoadhesiveness and permeability
due to hydrophobic interactions
INS Glutamine, chitosan Ionic cross-linking Enhance permeation by 1.52-fold 20

compared with chitosan
INS Carboxymethylated Ionotropic gelation process Prolonged control of hyperglycemia 21
kappa-carrageenan for 12–24 h, protection from hydroly-
sis and proteolysis
PEGylated Exendin-4 PLGA w/o/w double solvent Improved in vivo half-life, stability, 23
evaporation and biological potency and reduced
immunogenic responses by eliminat-
ing acylation
Metformin hydrochloride EC Evaporation and nonsolvent Sustained effect with better release 28
addition profile observed with nonsolvent
addition method, whereas evaporation
resulted in fast glucose reduction
Metformin hydrochloride Pectin w/o emulsion solvent Natural, safe, and economical formula- 31
evaporation tion producing sustained effect for 9 h
Repaglinide Starch Emulsion polymerization Enhanced nasal residence 33
time, improved absorption, and

Bale et al.
bioavailability
TABLE 2: (continued)
Repaglinide EC Aqueous solvent evaporation Prolong control of blood glucose 34
levels for >8 h
Glipizide Galactomannan gum Emulsification cross-linking Significantly reduced fasting and ran- 35
dom blood glucose levels for a longer
period due to strong mucoadhesive

nature
Glipizide HPMC K4M, CMC Simple emulsification phase Entrapment efficiency (69%) and drug 36
separation release (12 h) significant with HPMC
K4M polymer compared with CMC
Gliclazide Isabgol husk, Aqueous ionic Hypoglycemic effect of 37% observed 37
sodium alginate gelation cross-linking considering base glucose levels as
Therapeutic Applications of Microparticles
100% and sustained release of 10 h as

revealed from X-ray imaging
Gliclazide Tamarind seed poly- Ionotropic gelation Better control of glycemic levels in 39
saccharide, alginate vitro correlated with in vivo using
natural, safe, and economic polymer
Glibenclamide Eudragit RLPO Emulsion solvent evaporation Extended release with improved drug 42
stability
Rosiglitazone maleate Sodium CMC, Ionotropic gelation In vitro release of 12 h with good 51
HPMC, carbapol reproducibility of the formulation
934P
Glibenclamide Mucuna gum Emulsion polymerization Microspheres with cross-linking time 52
of 5 h were found as optimum sus-
tained formulation
Nateglinide Cellulose triacetate, o/w emulsion solvent Decrease in dosing frequency, 53
beeswax evaporation enhanced stability, and flow properties
Glipizide Eudragit S w/o/w double emulsion Porous microparticles with release 54
profile extended for 8 h in vitro
EC, ethyl cellulose; GIT, gastrointestinal tract; INS, insulin; PEG, polyethylene glycol; PLG, poly(d,l-lactide-co-glycolide); PMMA,
polymethylmethacrylate
319
320 Bale et al.
prepared using a spray freeze dryer and sustained release of drug was observed for 24
h with a high encapsulation efficiency of 92.3%. The cellular uptake was significantly
high, as evident from Caco-2 uptake studies, and the relative bioavailability of particles
was 12% greater compared with its subcutaneous injection.17 To explore the effect of
conjugated polymers on the permeability and bioavailabilty of INS, undecylenic acid
modified hydrocarbonized porous silica microparticles co-loaded with INS, followed by
surface conjugation with chitosan, significantly improved the absorption and permeabil-
ity of INS. The apparent permeability of these chitosan conjugated microparticles was
improved by 7-fold, whereas the amount of INS permeated was enhanced by 20-fold
across Caco-2/HT-29 cell monolayers compared with unconjugated particles.18 Further,
to protect INS from degradation and to enhance permeability; chitosan was selected as
a polymer for its biocompatible and biodegradable nature. Many reactive functional
groups of chitosan make it a very useful polymer to deliver peptide drugs orally. Re-
sults of one study suggested that chitosan, when complexed with phthalyl poly (ethyl-
ene oxide) loaded with INS, acts as a matrix network of microparticles with extended
release properties compared with chitosan alone.19 To boost the permeability of oral
peptides, hydrophobic groups such as fatty acids (octanyl and oleoyl chloride) were in-
corporated on chitosan and then loaded with INS as microparticles for sustained release
and improved INS efficiency was observed. A similar approach was reported in a study
in which enhanced permeability, mucoadhesivity, and positive charge on chitosan was
imparted using glutamine; this aided in protonation at alkaline pH and thus achieved
prolonged release as an acceptable carrier for INS.20 It was evident from a recent study
that INS release was prolonged for 12-24 h in diabetic rats with lectin functionalized
carrageenan microparticles, exhibiting an encapsulation efficiency of 94.2 ± 2.6% and a
loading capacity of 13.5 ± 0.4%. The sulfate moiety of carboxymethylated carrageenan
particles via ionic interactions binds to amino acids of INS, contributing to increased
stability, loading, and encapsulation efficiency. In addition, lectin functionalization pro-
duced a promising sustained effect.21
In view of the fact that inhalational microparticle system aid in high bioavailability,
Hyun uk Kim et al. developed inhalation delivery of a glucagon-like peptide agonist,
Exendin-4 (palmityl acylated), using albumin-coated porous PLGA microparticles and
observed a profound hypoglycemic effect lasting for about 12 days. This is possible
because of its binding to two types of albumin. First, it bound to the albumin coating
across the drug after release from microparticles and exerted its effect for 7 days, fol-
lowed by binding to albumin of plasma, resulting in a sustained hypoglycemic effect for
5 more days. In terms of inhalation delivery systems, porous microparticles were found
to be more efficient compared with compact microparticles.22 Further, to enhance the
efficacy of Exendin, PEGylated microspheres were formulated, but exhibited limited
acylation due to decreased absorption by conjugated PEG molecules. To enhance the
stability against acylation and to protect from immunogenicity, stable PEGylated micro-
spheres of Exendin-4 were prepared by water-in-oil-in-water (w/o/w) double emulsion
solvent evaporation technique and were found with extended bioactivity, enabling
weekly doses of administration.23 An exenatide microsphere, Bydureon, has been U.S.

Food and Drug Administration (FDA) approved for weekly use as an extended release
product, with limitations including high dose (single dose of 2 mg in humans) and the
complicated procedure involved in its preparation. To address this, simple modifications
such as the use of low-molecular-weight polymers (PLGA RG 502 H), were used to re-
lease the drug encapsulated to its maximum extent. A simple procedure of producing an
oil in water emulsion was practiced that resulted in prolonged release pattern of the drug
with 25 days and 40 days in vivo and in vitro, respectively.24 Another comparative study
was performed on exenatide-entrapped PLGA microparticles prepared by two different
methods: ultra-fine particle processing and spray drying. The results demonstrated that
the microparticles produced by the former method were stable and large, with a sus-
tained release profile for more than a month compared with the latter method, in which
the drug release was for only 2 weeks.25 Efforts were made to prepare composite mic-
roparticles of exenatide in which a nano-formulation was designed using albumin and
dextran cross-linked with sodium trimetaphosphate. Further, to offer gastrointestinal
protection and to deliver the drugs into intestine, these nanoparticles were encapsulated
as microparticles using Eudragit and hydroxy propyl methyl cellulose (HPMC) poly-
mers. This nano-micro-formulation of exenatide enhanced relative bioavailability by
77% compared with the subcutaneously administered drug.26 Inhalation delivery of ex-
enatide microparticles as anti-diabetic therapy was designed in which thiolated and un-
thiolated microparticles were prepared and investigated for studies of uptake and histol-
ogy. Uptake studies revealed that thiolated and non-thiolated exenatide microparticles
differed in uptake efficiency by 4.7- and 2.6-fold, respectively, compared with free drug
administered via the intranasal route.27 Sometimes, when drugs are being used orally,
their bitter taste and fractionated doses affect patient compliance. metformin was encap-
sulated as microspheres using ethyl cellulose (EC) adopting two different approaches:
evaporation and a nonsolvent addition method. Entrapment efficiency was higher with
the latter method and there was a sustained effect lasting up to 10 h in both techniques.28
Another similar study was performed to investigate the influence of pH on the release of
EC microparticles of metformin using the solvent evaporation method and there was
sustained release at an alkaline pH rather than at an acidic pH.29 Carbopol microspheres
of metformin were formulated to accomplish target-specific delivery in the intestine and
were found to be stable sustained release formulations without altered therapeutic effi-
cacy.30 Later, pectin, a natural polymer, was used as an alternative to synthetic polymers
in the preparation of metformin microspheres. A release rate with a 1:1 ratio of drug and
polymer was found to be 98.42, 94.72, 89.04, and 45.96% with pectin, EC, HPMC, and
acrycoat, respectively. This suggests that pectin may be used as a safe and economic
polymer for several extended release micro-formulations with enhanced bioavailabili-
ty.31 Recently, an extensive review on how microparticles overcome the limitations as-
sociated with efficacy of metformin was ascribed by Cetin et al.., addressing reduced
dose frequency, enhanced bioavailability, and decreased side effects, along with signifi-
cant therapeutic efficacy of metformin encapsulated as MDDS.32 To fulfill the needs of
enhanced and rapid absorption and to avoid first-pass metabolism, nasal delivery is
gaining wide significance over oral and parenteral routes due to its surface area and

322 Bale et al.
highly vascularized epithelium. In agreement with this, repaglinide was encapsulated in

degradable starch microspheres and enhanced bioavailability due to prolonged nasal
residence time was observed compared with repaglinide alone.33 Further, to attain ex-
tended release of repaglinide, it was complexed with resins for their buoyant properties
due to bicarbonate ions and then encapsulated with EC microparticles for potent gastro-
retentive effect lasting for 10 h, with 70% release in initial 6 h.34 The gastro-retentive
effect was achieved in two ways: using a buoyancy process or mucoadhesive polymers.
The half-life (3.4 h) of glipizide constrained for encapsulation to achieve increased ab-
sorption was plausible with gastro-retentive floating systems in which calcium silicate
was used to attain buoyancy and galactomannan gum was used as a biodegradable and
strong mucoadhesive polymer. There was a significant reduction in glucose levels and
altered diabetic parameters compared with its immediate release formulation.35 Interest-
ingly, prolonged release for 12 h was attained when HPMC K4M and CMC were used
as mucoadhesive polymers with a t80 of 240 minutes.36 Glizid MR 60, a marketed sus-
tained-release tablet of glicazide, was formulated as microparticles using isabgol-husk
sodium alginate and was associated with a significant reduction in blood glucose levels
of 37% compared with 95.5% of the marketed drug (considering a diabetic glucose
level as 100%), illustrating the promise of this microparticle.37 In addition, glicazide was
formulated using various polymer combinations including EC as a common adjuvant,
along with HPMC K4M, HPMC K15M, and Eudragit RSPO, resulting in 8 h of pro-
longed effect.38 Glicazide was also loaded with mucoadhesive microspheres using tama-
rind seed polysaccharide in combination with alginate, attaining an entrapment effi-
ciency of 58.12-82.78% and producing sustained release for 12 h in both the stomach
and intestine, thus resulting in a prominent hypoglycemic effect.39 Further, to enhance
the solubility and absorption of glicazide, it was encapsulated together with primary bile
acid using sodium alginate as microcapsules and studied for their potential in in vivo.
The primary bile acid on metabolic activation produces secondary and tertiary bile acid
that can act as effective permeability enhancer. Studies performed on a muscle cell line
(C2C12) using these microcapsules resulted in control of hyperglycemia.40 Using the
same concept, microencapsulation of glicazide in combination with a bile acid deoxy-
cholic acid was prepared using sodium alginate polymer. These particles exhibited co-
lon-targeted delivery with sustained release of drug at pH 7.4 and temperatures of 25°C
and 37°C and also reduced the bead swelling of microparticles.41 To improve patient
compliance, a stable microparticle preparation of glibenclamide was formulated using
biodegradable Eudragit RLPO polymer, resulting in 92.30-98.32% entrapment efficien-
cy.42 Gastro-retentive buoyant microspheres offer a novel delivery platform for treating
diabetes and a key example of this is the design and characterization of floating mic-
roparticles of pioglitazone hydrochloride. Floating in gastrointestinal tract for 12 h was
shown in a buoyancy study and a significant decrease of blood glucose levels was ob-
served in an in vivo pharmacodynamic study performed in rabbits, suggesting that these
floating microparticles may be used as a controlled release formulation to treat diabe-
tes.43 The role of immunosuppressive agents in improving diabetes was studied using a
dual microparticle system consisting of immunosuppressive agents and antigens in com-

bination with PLGA. The dual microparticle system included vitamin D3 and INS B
(9-23) as phagocytosable microparticles and TGF-β1 and granulocyte macrophage col-
ony-stimulating factor (GM-CSF) as unphagocytosable microparticles, modulating the
immune system and offering protection of about 40% by recruiting dendritic cells fol-
lowed by antigen delivery.44 Uncontrolled wound healing in diabetes increases the risk
of primary and secondary complications associated and must be monitored and treated
quickly. In this context, therapeutic efficacy of peroxisome proliferator-activated recep-
tor β/δ agonist GW501516 (GW), due to its potent reactive oxygen species (ROS) mod-
ulation properties, was investigated in diabetic wound healing upon topical administra-
tion. Poly L-lactide (PLLA)-GW, PLGA-GW, and PLLA-PLGA-GW were prepared and
it was observed that the double-layered PLLA-PLGA-GW microparticles exhibited
early and sustained release of GW and improved wound healing significantly compared
with the single-layered particles PLLA-GW and PLGA-GW, emphasizing the role of
release kinetics in improving therapeutic efficacy.45
Natural products are gaining significance as far as therapeutic potential is concerned,
but their efficacy is limited because of their bioavailability and poor pharmacokinetics.
Recent studies of natural products using MDDS are described below. Condensed tan-
nins extracted from sorghum possess α-amylase and α-glucosidase inhibition activities
similar to acarbose. To mask the bitterness of these tannins and to deliver them to the
small intestine, sorghum tannins were entrapped in kafirin microparticles becauase they
are proline rich and offer strong affinity for binding due to their hydrophobicity and the
presence of disulfide cross links. Sorghum tannins entrapped in kafirin microparticles
hampered hyperglycemia both in vitro and in vivo.46 curcumin, due to its poor pharma-
cokinetics, is co-loaded with poly propylene sulfide (PPF), a hydrophobic polymer that,
upon oxidation, turns hydrophilic and releases the entrapped drug on ROS demand.
These microspheres have accelerated antioxidant and anti-inflammatory potential, as
evident from protection of hind limb ischemia by curcumin–PPF microparticles in dia-
betic mice. A significant reduction of in vitro and in vivo ROS levels was observed. Even
blank PPF microparticles accelerated disease recovery, suggesting the synergistic effect
of curcumin–PPF particles in decreasing the progression of ischemia.47 Gongronema
latifolium, a plant used in traditional folk medicine, was investigated for its effect as
anti-diabetic therapy when encapsulated as solid lipid microparticles using fat and phos-
pholipon 90 H. It was observed that the formulation significantly reduced blood glucose
levels more than pure extract and the standard drug glibenclamide, showing it to be a
natural hypoglycemic agent.48
MDDS used with diabetes drugs must address various issues but is associated with
enhanced bioavailability, improved circulation half-life, and effective glucose monitor-
ing due to its sustained effect and also reduces painful frequent administration of injec-
tions/infusions. MDDS enact as an effective, convenient, and successful drug delivery
system for diabetes, controlling hyperglycemia and shows promise as a hypoglycemic
agent to slow diabetic progression and prevent further complications of diabetes, includ-
ing microvascular and macrovascular complications.

324 Bale et al.
B. Vaccine Delivery and Immunology

Multiple strategies to boost immunological responses include reducing organ rejection
reactions, encouraging potent vaccine delivery systems, and targeting specific antigens
using gene delivery without any alterations in the native protein structure. Repetitive im-
munization is essential to produce safe and effective protection from infectious diseases.
To address these issues, polymeric microparticles loaded with adjuvants and antigens
against pathogens are gaining significance with enhanced immune response achieved
with controlled release pattern. A diagrammatic explanation of the application of MDDS
in vaccine delivery is provided in Figure 7.
FIG. 7: Therapeutic effects and advantages of MDDS in vaccine delivery
Apart from target-specific delivery and cell-mediated immune responses, particu-

late carrier systems such as microparticles and nanoparticles have the advantage of
enclosing adjuvants along with antigens, protecting those antigens from degradation
until therapeutic efficacy is achieved at the target site.55 This special property makes
microparticles and nanoparticles more effective at delivering vaccines because of their
strong immune potential due to a synergistic effect of both antigen and adjuvant code-
livery. Another interesting feature of MDDS is modulation of the surface properties,
enhancing uptake and contributing to effective delivery. Several polymers were studied
for their effective adjuvant effect over a number of antigens. PLGA, an FDA-approved
biocompatible and biodegradable polymer, exhibited effective adjuvant effect over an-
tigens and its potential was therefore explored in formulating single-dose vaccines.56
The safety of PLGA and established marketed product records ensured its application in
injectable vaccine delivery.57 In general, to elicit better and strong therapeutic benefits,
antigens are co-loaded with adjuvants that direct and control the intensity of response
of antigens in a delivery system. Accordingly, ovalbumin, a protein antigen, was co-
loaded with adjuvant muramyl dipeptide using PLGA microparticles and prepared and
studied for quantification. That study illustrated that, to achieve a better dose–response

relationship in future vaccination techniques, a selective method quantifying adjuvant

and antigen is essential.58 Further, delivering self-antigens to stimulate immune system
is a difficult task. To overcome this hurdle, a study was performed in which a combina-
tion of a hydrogel-microparticle system enclosing INS self-antigen as a vaccine was
designed to treat diabetes. The hydrogel system used was PuraMatrixTM, consisting of
vaccine adjuvants GM-CSF and cytosine-phosphate-guanine (CpG) to activate immune
cells. As a microparticle formulation, this comprised PLGA as a polymer enclosing de-
natured INS. This specific combinatorial targeting system of vaccine protected 40%
of nonobese diabetic mice from diabetes on three subcutaneous administrations.2 To
avoid immunotolerance, a three-step approach to treat lymphoma using microparticles
was designed. doxorubicin-loaded PLGA microparticles, along with anti-CTLA4 and
anti-OX40 antibodies, were prepared as a formulation and investigated in lymphoma.
Doxorubucin was used to enhance the uptake of tumor antigens by dendritic cells. Fur-
ther, to activate T cells by dendritic cells, anti-OX40 was used and anti-CTLA4 was
used to maintain T-cell responses. This formulation enhanced T-cell accumulation in
tumor cells and significantly eradicated tumor burden.59 The time course response of
PLGA microparticles loaded with antigen in eliciting immunogenic response was inves-
tigated. A 10-week study was designed using PLGA microparticles loaded with 40 µg
of ovalbumin antigen and 16 µg of CpG-ODN adjuvant and the efficacy compared with
Alhydrogel-enclosed ovalbumin. Results revealed sustained and high concentrations of
immunoglobulin G2 (IgG2) antibody titers at day 52; in addition, increased secretion
of interferon-gamma (IFN-γ) for 14 days was observed and the results were in par with
Alhydrogel-enclosed ovalbumin, suggesting the application of MDDS using PLGA to
deliver protein vaccines.60 Versatile mechanisms of immunopotentiation were observed
with vaccines formulated as cationic microparticles. One such approach obtained suc-
cess in effective vaccine delivery when PLG and cetyl trimethyl ammonium bromide
were used as polymers in delivering HIV vaccine consisting of plasmid DNA with p55
gag. This approach resulted in prolonged antigen expression, both at the site of injection
and at the lymph node, and triggered the activation of antigen-presenting cells (APCs)
by recruiting phagocytes at the injection site.61 The efficacy of nonviral vaccines is low
compared with viral vaccines and the use of conventional PLG polymers may not be
sufficient to induce adequate target gene expression. To overcome this, a pH-sensitive
and degradable DNA delivery system was microencapsulated using both PLGA and
poly-β amino ester polymers and was associated with an increase in transfection ef-
ficiency by 3- to 5-fold in stimulating dendritic cells in vitro by MDDS.62 As a novel
attempt, co-delivery of PLGA and polyethyelenimine polymers entrapping DNA was
formulated and immunized intramuscularly and protection of DNA from degradation
was found, boosting the immune response by 2- to 3-fold compared with naked DNA.63
PLGA was surface coated with protamine, imparting a positive charge on the complex,
and evaluated for in vivo immunological efficacy in mice. This formulation exhibited
excess antibody production and T-cell responses due to their enhanced uptake in phago-
cytic cells, whereas in non-phagocytic cells, the combination triggered the transfection
mechanism.64 To combat against tumor and to build antitumor immunity, co-entrapment

326 Bale et al.
of ovalbumin and CpG in PLGA microparticles was investigated and resulted in a strong
immunostimmulatory response of a 2-fold improvement in survival period, thus pre-
venting tumor aggressiveness.65
Interestingly, a study revealed the efficacy of vaccination in a neurodegenerative
Alzheimer’s disorder in which Aβ peptides were entrapped in PLG microspheres and
evaluated both in vitro and in vivo. The in vivo study revealed a sustained effect of oral
immunization for a period of 24 weeks in mice by producing excess anti-Aβ antibod-
ies and in turn eliciting a potent immune response. Different Aβ peptides were loaded
in PLG, including the B-cell epitope (Aβ 1-12), a T-cell epitope (Aβ 29-40), and full
length (Aβ 1-42), with entrapment efficiencies of 70.46%, 60.93%, and 65.98%, re-
spectively.66 Recently, protein-based vaccines have been gaining significance in tar-
geting cancer because they are safer and thus considered an alternative approach to
traditional vaccines. To target cancer and mimic the tumor microenvironment, acid-
degradable microparticles comprising a protein antigen and immunostimulatory CpG
DNA adjuvant were co-loaded and found to be effective against tumor in MO5 mela-
noma model in mice.67
Imiquimod, a toll-like receptor-7 (TLR-7) agonist, was loaded in pH 7.4 stable acet-
ylated dextran microparticles and elevated expression of various cytokines was found
in the macrophages, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta
(IL1-β), and IL-6, compared with its free drug, suggesting a promising immunostimu-
latory effect of MDDS in vaccine delivery systems.68 Although several adjuvants are
used in vaccines, they are restricted due to their solubility and toxicity parameters. To
surmount these problems, immune-potentiator-loaded microparticles were formulated
and exhibited enhanced efficacy. In this context, FDA-approved imiquimod and PLGA
were loaded together as a formulation and found to be a robust adjuvant.69 Interestingly,
another polymer, PLA, was used for vaccine delivery to avoid repeated immunizations.
Filarial vaccine-loaded PLA microparticles were prepared and administered as a single
dose in mice and strong cellular and humoral responses were observed, as evident from
the antibody titer of 50,000 and 64,000 when loaded with PLA-TV and PLA-FEP, re-
spectively, suggesting the use of PLA microparticles as an effective drug carrier systems
to deliver vaccines.70 Further, a comparative study was performed to illustrate the ad-
juvanticity of traditional alum and PLA microparticles loaded with INS split vaccine.
Alum augmented humoral immune responses by increasing the concentration of antigen
at injection site, whereas PLA microparticles improved both humoral and cellular im-
mune responses by draining antigens into lymphnodes, showing PLA to be effective as
an adjuvant in modulating immunogenicity.71 Even chitosan microparticles were recent-
ly investigated as carriers for delivering immune-contraceptive vaccines.72 A stable and
safe vaccine consisting of Pasteurella multocida-loaded alginate microparticles used
as a subcutaneous administration was investigated for hemorrhagic septicemia in mice.
The formulation was stable for 6 months at room temperature and 4°C, with an in vitro
release profile of 30 days, and protected the mice from altered immune responses.73
Vibrio cholera-loaded cellulose acetate phthalate microparticles were prepared using a
spray dryer to form gastro-resistant powder and investigated at concentration of 30 and

60 mg with and without alginate in the formulation. It was observed from the results that
alginate-containing microparticles had similar effect to that of suspension, suggesting
the retention of efficacy of microparticles in the powder form of the vaccine.74
Alpha crystalline, a heat shock protein obtained from Mycobacterium tuberculosis,
was encapsulated in starch microparticles consisting of starch-binding domain tag fu-
sion protein to enhance immobilization and investigated for immunogenicity in mice.
Notably, results obtained suggest that IFN-γ secretion was elevated and a large amount
of IgG2 antibody was produced due to immunostimulatory responses, revealing a role
of the adjuvant in immobilization.75
Influenza is a dreadful disease without any specific treatment other than a recom-
mended yearly vaccine. To avoid this, influenza virus A/PR/34/8 H1N1 was loaded
together with polymer Eudragit S and trehalose in a matrix form and formulated as
microparticles. Surprisingly, elevated levels of IgG were observed, offering effective
protection over the virus.76 To enhance the uptake of vaccine by M cells, Aleuria auran-
tia lectin was used and formulated in a single step into microparticles of multiple poly-
mers, including Eudragit, PMMA, and HPMC acetate succinate loaded with vaccine
and albumin as a model protein using the spray-drying technique.77 Albumin micropar-
ticles, when covalently bonded with maleic anhydride-dimethyl acrylamide, were found
to exhibit adjuvant nature against hepatitis B as a mucosal vaccine delivery system.78
Aplha-galactosylceramide is a antigen for natural killer cells and has a role in activating
immune responses in cancer. This antigen was microencapsulated along with ovalbumin
and higher levels of IgG and IgA antibody production were observed for greater than 3
months on sublingual administration. In addition, Th1-related antibodies were 20-fold
higher in the formulation compared with the free drug, clearly showing the sustained
effect of the formulation.79 Tumor lysate serves as a source of tumor-related antigens
and is expected to possess significant immunoboosting capacity. Still greater efficacy is
obtained when tumor lysate is combined with adjuvant in a formulation. Numerous pre-
clinical studies were performed, with promising results obtained, and provide a scope
for entrapping several chemotherapeutics in combination with this effective tumor lysate
particulate system, resulting in superior antitumor efficacy.80 To overcome the M-cell
intestinal barrier, BmpB (membrane protein B of Brachyspira hyodysenteriae) vaccine
was loaded in porous PLGA microparticles, followed by coating with chitosan in conju-
gation with M-cell-targeting peptide CKS9 as a complete formulation. This resulted in
attaining complete immunity involving Th1 and Th2, increasing IgA and IgG antibodies
and stressing oral delivery of the formulation.81 Another study was investigated using
tumor lysate vaccine enclosed in PLGA microparticles injected subcutaneously in mice
with metastatic breast cancer induced by 4T1 cells. After the sixth day of induction, mice
were injected with vaccine microparticles, followed by a booster dose on the 11th day.
The ooster dose included a TLR-stimulating adjuvant, along with tumor lysate vaccine
microparticles. The results of the study revealed a reduction of lung tumor burden by
42% without inducing any sort of autoimmunity.82
As reported in diabetes, composite microparticles also find application in deliver-
ing vaccines. Recently, nanoporous MDDS has started gaining momentum in vaccine

328 Bale et al.
delivery due to its simple method of preparation. Using this approach, a study was per-
formed in which a hydrogen bond was produced between a polymer and tannic acid
and then used for loading antigens, which can serve as a potent vaccine carrier aiding
in activating both humoral and cell mediated immunity.83 A similar study was based
on the application of nanoporous polyelectrolyte microparticles as a vaccine carrier.
Solid microparticles of antigen were prepared using polyelectrolytes and mannitol as a
porogen using the spray-drying method of encapsulation because of its scalability. On
redispersion of particles, released antigen was presented to CD8T cells by dendritic cells
in in vitro and in vivo results revealed strong humoral and cellular immune responses
in mice.84 Rather than polymeric microparticles, inorganic calcium carbonate (CaCO3)
was used to formulate microparticles due to its unique properties, including biocom-
patibility, natural minerals, and porogens. Peptide nanofiber exhibiting self-adjuvant
properties was encapsulated in CaCO3 microparticles and investigated for oral vaccine
delivery. Results of the study revealed that the composite particles penetrated efficiently
through the mucosal barrier and produced significant IgA mucosal antibody responses
compared with standard adjuvant cholera toxin B.85 Reports from a recent study sug-
gest that porous microparticles of CaCO3 and mannitol were potential in delivering the
antigen via the oral route. Results showed that prepared porous microparticles were ef-
ficiently internalized by Caco-2 and HT-29 cells and upregulated stimulatory molecules
in intestinal cells. In vivo studies are yet to be performed in developing these particles as
promising carrier candidates.86
Although immunizations are increasing annually with the growing population, the
risk associated with the use of needle vaccines includes infection and the transmission of
blood-borne pathogens, adding to the global burden of disease. Therefore, a needle-free
method of vaccination using antigen-loaded composite microparticles was designed.
This needle-free system, prepared by spray drying, consists of sugar-based micropar-
ticles enclosing cationic mesoporous silica nanoparticles, which in turn are loaded with
antigen ovalbumin. Multiple advantages of this specific system were revealed, includ-
ing: (1) the microparticle size range of the final formulation allowed its use as an epi-
dermal powder immunization, (2) nanoparticles were distributed finely in microparticles
without aggregation on redispersion, (3) ovalbumin retained its stability by adsorbing on
cationic shell of nanoparticle, and (4) delivery of ovalbumin in the nano size range made
it easy to recognize by the immune system. Therefore, composite microparticles exhibit
therapeutic versatility in when used in vaccination.87Another study explored the po-
tential of potassium-doped hydroxyapatite microparticles as antigen carriers to prepare
needle-free formulations. Diptheria toxin CRM197-loaded potassium-doped hydroxyapa-
tite microparticles were formulated as a needle-free dermal preparation and investigated
for their in vitro and in vivo effects. The release profile from in vitro studies and in vivo
immunogenic responses were similar and comparable to that of existing clinical stan-
dard alum-adsorbed CRM197 delivered intramuscularly.88 From the above key findings,
it is clear that microparticles play a crucial role in immunology and have emerged as a
promising delivery approach for vaccines. Some of the microparticles enclosing vac-
cines are described in Table 3.

C. Role of MDDS in the Management of Cancer

Many types of treatment exist for cancer, including surgery, standard chemotherapy,
radiation therapy, immunotherapy, and targeted therapy. The treatment to be given de-
pends on the specific type of cancer and how advanced it is. Very rarely, one can find
monotherapy to be the mainstay for cancer because combinational treatments have ad-
vantages. However, the side effects of anticancer drugs limit the use of several standard
chemotherapeutics. For example, cardiotoxicity and nephrotoxicity are associated with
conventional chemotherapeutics such as doxorubicin and cisplatin respectively.89,90 Fur-
thermore, effective drugs are even more toxic. To address these toxicity problems, tar-
geted therapies have emerged in which the drug acts at a particular molecular target that
is more associated with the cancer. Currently, targeted therapies are considered a cor-
nerstone in anticancer drug development as they are the most precise treatment, being
prepared by collecting information from the patient and treating the disease accordingly.
Nevertheless, target therapies pose many disadvantages because of this individualiza-
tion of therapy. The expression of the genes with the same target can be different from
individual to individual and treating the same target for different types of cancer is not
possible; therefore, continuous therapeutic monitoring is required on an individual ba-
sis. Despite such achievements, maintaining the required concentration of chemothera-
peutics in tumor cells for prolonged time periods is difficult. Furthermore, drug can be
leaked into the surrounding tissues due to the lack of a lymphatic system in cancer cells.
Therefore, to elicit a better response, the drug has to be circulated in the body without
producing adverse effects.91 Various approaches to the use of MDDS in decreasing tu-
mor progression are described in Figure 8.
Immunotherapy is one of the alternatives to chemotherapy and is gaining enormous
attention specifically in cancer therapy. However, the antibodies administered may be sub-
ject to phagocytosis, so their efficacy is limited. To solve this problem, immunomodula-
tory antibodies can be entrapped as MDDS. For example, in one study, the antibodies
anti-CD40 and anti-CTLA-4 were individually encapsulated as microparticles in the size
range of 12-15 µm to avoid their being engulfed by phagocytes. Their efficacy in colon
carcinoma (MC-38 cells) was significant and lasted for about 30 days compared with
the same dose in incomplete Freund’s adjuvant, proving that microparticles as immuno-
therapy exert long-lasting and nontoxic effects.92 Curcumin, a safe and traditional natural
product well known for its multiple potent activities, including antioxidant, anti-inflamma-
tory, and anticancer properties, is limited due to its poor bioavailability. Any formulations
that enhance the bioavailability of curcumin would emerge as a weapon to treat many
of diseases. Curcumin fabricated with PLGA microparticles were prepared and showed
significant inhibition of MDA-MB-231 breast cancer xenografts due to down-regulated
expression of VEGF and inhibition of angiogenesis at a single subcutaneous dose com-
pared with repeated administration of curcumin alone.93 Several lines of evidence suggest
the use of PLGA as an effective polymer in cancer therapy. Exemplifying this, PBFT and
PFTTQ are two polymers with unique properties, including strong green fluorescence and
high near infrared absorption, respectively, that were conjugated and formulated as PLGA
microparticles and studied for their efficacy in the MCF-7 breast cancer cell line and NIH-

Table 3: List of drugs encapsulated as MDDS to improve performance of immune system
330
Drug Polymer Method Significance Reference

HIV vaccine encoding PLG + cetyl tri- Modified solvent evapo- Formulation exhibited serum antibody levels 61
plasmid DNA p55 gag methyl ammonium ration process and cytotoxic lymphocyte activity with a 2-fold
bromide difference compared with plasmid DNA; elicited
multiple immunostimulation mechanisms
HIV vaccine DNA prime/ PLGA Modified solvent evapo- Released intact cargo without any degradation 63
MVA boost regime ration process in vitro for 2 weeks and significantly improved
immunological performance 2- to 3-fold greater
than free drug in vivo
Protamine PLGA Micro-extrusion-based Microparticles enabled increased uptake via 64
w/o/w solvent phagocytosis, so improved immunogenic
extraction responses were observed
Β-amyloid protein PLG w/o/w double emulsion Stimulated strong immune response for 24 weeks 66
solvent evaporation by inducing anti-Aβ antibodies
Imiquimod Dextran o/w emulsion Significant increase in the expression of TNF-α, 68
IL-6, and IL-1β reveals the immunostimulatory
effect and offers better protection from disease
Influenza A/PR/34/8 Eudragit-S + Spray drying Functions as oral mass vaccination that reduces 76
H1N1 trehalose the cost and frequency of the vaccination
virus
BSA Maleic anhydride Cross-linking/ Covalant modification explored the potential of 78
polymerization BSA as mucosal vaccine
α-galactosylceramide and PLA Double emulsion Antibody production was 20-fold higher by 79
ovalbumin α-galactosylceramide and ovalbumin micropar-
ticles compared with ovalabumin alone; immu-
nogenic responses persisted for greater than 3
months

Bale et al.
Table 3: (continued)
Protein B of Brachyspira PLGA + chitosan w/o/w double emulsion Oral vaccine delivery of Bmp B induced both 81
hyodysenteriae (BmpB) solvent evaporation Th-1 and Th-2 immune responses and thus

reduced frequency of vaccine administration
Denatured insulin PLGA w/o/w double emulsion Protected 40% of nonobese diabetic mice from 2
solvent evaporation diabetes with three subcutaneous administrations
Alpha crystalline Starch Immobilization on starch Increased immobilization of adjuvant and pro- 75
microparticles using duced immunostimulatory responses as evident
starch binding domain from high concentrations of IFN-γ and IgG2
tag fusion protein antibody

Vibrio cholera Cellulose ace- Spray drying Retention of efficacy in powder form of vaccine 74
tate phthalate
microparticles
Ovalbumin Silica nanoparticles Spray drying Needle-free formulation for effective epidermal 87
and sugar based powder immunization for easy recognition by
microparticles immune system
Ovalbumin-KFE8 CaCO3 micropar- Precipitation of mic- Penetrated efficiently through mucosal barrier 85
ticles and nanofibers roparticles in presence ofand produced significant IgA mucosal antibody
peptide nanofibers responses compared with standard adjuvant
cholera toxin
Tumor lysate vaccine PLGA Double emulsion solvent Reduction of lung tumor burden by 42% without 82
evaporation inducing any sort of autoimmunity
PLG, polylactide co-glycolide; PLGA, poly(lactic co-glycolic acid); BSA, bovine serum albumin; PLA , poly(lactic acid); TNF, tumor necrosis factor; IL,
interleukin; o/w, oil in water; w/o/w, water in oil in water
331
332 Bale et al.
FIG. 8: Therapeutic effects and advantages of MDDS in cancer
3T3 normal cells. Interestingly, the conjugated formulation selectively reduced the growth
of MCF-7 cells due to its potential of light to heat conversion without inducing toxicity in
normal cells and is therefore attractive for use in cancer cell image-guided phototherapy.94
The efficacy of most the anticancer drugs is limited due to the resistance of tumor
cells and immunotolerance toward the drug. To address this, immunization has been
introduced in this setting. In situ immunization is a phenomenon in which immunotoler-
ance is counteracted due to the involvement of APCs such as dendrites that are capable
of recognizing a wide range of tumor antigens and thus induce cytotoxicity in tumor
cells. Applying this phenomenon, doxorubicin was loaded together with oligodeoxy-
nucleotides (CpG) as biodegradable PLGA microparticles and the formulation inhibited
the growth of B and T lymphocytes. Doxorubicin induced the death of cancer cells,
whereas CpG aids in presenting antigens to APC.95 To surmount these issues, formula-
tions have emerged and microparticles are a great advance in the treatment of cancer,
having applications in almost all types.
1. Breast Cancer
Breast cancer is the most common type of invasive tumor in women. As per the 2015
statistics of the American Cancer Society, it was observed that ~231,840 new cases of

invasive breast cancer were reported and, of these, ~40,290 women were prone to death
due to the aggressive nature of this cancer type. Metastasis of breast cancer presents a
challenge in cancer research because of its high invasive potential to multiple organs,
including liver, brain, and bone. Standard therapies recommended for breast cancer to
date include chemotherapy, hormonal therapy, and surgery. All of these treatments fail
to produce a good quality of life. When breast cancer patients are subjected to these
treatments, promising efficacy can be observed, but lasts only for a short period of time
because tumor cells enter into the G0 phase during treatment and, later on, the recurrence
of tumor leads to mortality.
Often, breast cancer treatment involves surgical intervention or frequent harsh, in-
jectable drug administrations. To enable the sustained effect of the drugs and to de-
crease the surgical risk and dosage frequency, entrapment of drug in formulations can be
a better approach. Several chemotherapeutics used for breast cancer are being loaded in
microparticles to attain potent therapeutic efficacy and better patient compliance. Inject-
able microparticles in the range of 1–10 µm of prodigiosin, synthesized from the bacte-
rium Serratia marcescens, were prepared using PLGA and polyvinyl alcohol polymers
and investigated for their efficacy against breast cancer and obtained promising results
with intratumoral delivery.96 Lapatinib is a dual tyrosine kinase inhibitor used as an ac-
tive drug in breast cancer and several other solid tumors. To improve its potency in this
particular cancer, it was entrapped in PLA microspheres surface coated with collagen
and was found to be effective in mammary tumor-selective targeting.97 Microcapsules
of gold nano shells in a breast cancer mouse model, with the assistance of ultrasound
imaging and photothermal therapy, revealed a significant decrease of tumor progression
with a temperature rise of 70°C within 8 min. After 17 days of treatment, the tumors
were completely cured in six of seven mice. To elicit effective a local and sustained
effect in breast cancer, mitoxantrone-encapsulated albumin microspheres were intra-
tumorally injected at a higher dose and significantly improved the survival rate with
diminished systemic toxicity.98 Biodistribution and therapeutic efficacy of 131I-loaded
gelatin microspheres were studied in a xenograft model. Tumor retention of radioactiv-
ity was higher in the treatment group (19.93 ± 5.24% after 16 days) and tumor growth
was significantly inhibited because of its intratumoral sustained delivery.99 Although
MDDS exhibits a broad size range of 1–1000 µm, the use of specific sizes can result in
therapeutic efficacy through optimization. Glucose oxidase is loaded in alginate–chito-
san microparticles and tested for in vitro and in vivo efficacy against MDR breast cancer
cells. Results suggest that a particle size of 4 µm produced better cytotoxicity on tumor
cells (both MDR and wild-type cells) via production of ROS, contributing to membrane
damage and lipid peroxidation.100 Breast cancer metastases such as into the brain, liver,
and bone are observed at a high incidence. A comparative study was performed inves-
tigating the effect of doxorubicin and temozolomide with intracranial implantation and
systemic administration in adenocarcinoma of brain metastasized from breast cancer.
Doxorubicin and temozolomide were individually loaded into a biocompatible and in-
ert liquid crystal polymer as microcapsules and were found to be safe, efficacious, and
superior to free drugs.101 PCL microspheres encapsulated tamoxifen with a mean size of

334 Bale et al.
27–47 µm and an entrapment efficiency of 61–67% resulted in effective cytotoxicity of

MCF-7 breast cancer cells.102 PLA microspheres loaded with cytokines including IL-12,
TNF-α, and GM-CSF was investigated for their efficacy in MT-901 tumors. Inside the
tumor, excess recruitment of CD8+ cells and polymorphonuclear cells was observed,
halting tumor growth. In addition, the activation of antitumor T cells resulted in boost-
ing the immune response in breast cancer.103 The development of numerous micropar-
ticles entrapping different chemotherapeutics is in progress to elicit local and targeted
drug delivery, thereby eliminating the side effects associated with the standard effective
chemotherapeutics, producing a better quality of life and a prolonged survival rate for
breast cancer patients.
2. Prostate Cancer
Prostate cancer is common in elderly men (above 60 years) and is the highest cause of
mortality in this age group.104 In early stages of the disease, radiation therapy is gener-
ally practiced. However, due to delayed diagnosis, the inhibition of androgens using
hormonal treatment based on palliative therapy is recommended.105 Earlier, estrogens
were used, but were banned due to cardiovascular complications. A decade ago, lu-
teinizing hormone releasing hormone (LHRH) was prescribed as the mainstay of treat-
ment for prostate cancer and showed a sustained effect of 1–3 months.106 LHRH analogs
improved the symptoms of prostate cancer patients but did not eradicate cancer com-
pletely and frequent relapses were reported. Later, many analogs of LHRH, including
leuprorelin acetate, goserelin, and triptorelin, were developed as improvements in the
treatment of prostate cancer. In Europe, leuprorelin acetate at a dose of 3.75 mg capable
of elucidating effect for 1 month was introduced and was successful in decreasing the
progression of prostate tumors, stressing the role of a controlled release formulations.
Later, several molecules were encapsulated and screened for their activity against pros-
tate cancer.
Microcapsules of the somatostatin analog RC-160 and the LHRH antagonist SB-75
were formulated and investigated for their effects against the progression of prostate
cancer. It was found that SB-75 alone and in combination with RC-160 was effective in
suppressing tumor growth and volume, but RC-160 alone did not inhibit prostate tumor
growth.107 Cancer stem cells are responsible for the resistance and metastasis of conven-
tional chemotherapeutics. It is essential to grow these cells for a thorough understanding
of cancer treatment and therapy and it takes 10 days to form stem cell colonies. This
can be minimized to 2 days by loading the prostate cancer cells in 3D microcapsules
comprising of alginate hydrogel.108 PTEN is a tumor suppressor found to be inactivated
in prostate cancer cells, thereby resulting in resistance. Therefore, PTEN plasmid DNA
is loaded into microspheres consisting of cationized gelatin hydrogels and has been
found to be an effective treatment strategy. Moreover, when these microspheres were
administered along with irradiation therapy and studied in radiation-resistant prostate
cancer cells (PC3-Bcl-2), the results were exciting. A profound efficacy in tumor regres-
sion was achieved with the combination compared with microspheres and irradiation
alone.109 Delivery systems such as micro-RNA and small interfering RNA (siRNA) ap-

proaches are also gaining significant momentum in current cancer research. One such
example of siRNA delivery was reported in which survivin gene-expressing siRNA was
entrapped in microcapsules and its effect against prostate tumors evaluated. On deliver-
ing surviving-expressing siRNA to PC3 prostate cancer cells, inhibition of anti-apop-
totic protein was found and resulted in decreased tumor growth.110 Although there are
multiple controlled release delivery systems for delivering potent molecules to control
prostate tumors, the MDDS approach remains the best, as observed from the literature.
More research is required to enhance its scope further.
3. Other Cancers
Apart from the breast and prostate cancers, MDDS can be applied in all types of cancers,
including lung cancer, renal cancer, glioma, etc., as described in Table 4. Drugs intended
to treat the glioma type of cancers must cross the blood–brain barrier (BBB) and possess
high lipophilicity. However, many potent drugs lack the ability to penetrate the BBB be-
cause of P-gp efflux pumps; for example, paclitaxel has poor penetration properties. For
this reason, these drugs have to be administered intracranially, but this method of direct
administration into into the brain is associated with infections. To achieve therapeutic
benefits via intracranial administration, controlled release formulations such as MDDS
and implants have been designed. In this approach, paclitaxel-entrapped microparticles
have been formulated and tested against brain tumors and the sustained effect lasted for
several weeks without producing any sort of brain infections.111 Although different de-
livery systems have been used for cisplatin, the sustained effect was limited to 14 days;
however, fabrication of cisplatin with PLA microparticles resulted in extended release of
the drug for 75 days in in vitro conditions.112 Hybrid nanoporous microparticles loaded
with the standard chemotherapeutic doxorubicin were developed using CaCO3 and folic
acid coupled with lambda carrageenan, producing a bifunctional formulation with de-
creased toxicity and enhanced cancer cell targeting. Further investigation in the MG-63
osteosarcoma cell line revealed the anticancer efficacy of the doxorubicin formulation
after 24 h of treatment, with a significant reduction in cell viability.49 Malignant me-
sothelioma is an aggressive intracavitary tumor that initiates from mesothelial cells of
different origin such as pleura, peritoneum, and pericardium. To treat this rare tumor,
doxorubicin entrapped as acid-prepared mesoporous microspheres (APMS) was for-
mulated and, surprisingly, tumor number, size, and weight were significantly inhibited:
3-fold greater with APMS-doxorubicin compared with doxorubicin alone.113 The cyto-
toxic efficacy of doxorubicin was enhanced and its cardiotoxicity was minimized when
it was formulated as PLGA microparticles studied in C6 glioma cancer cells. Further, its
release profile was based on copolymers used either pluronic P105 or PLLA in combi-
nation with PLGA. PLLA altered the particle size, whereas pluronic enhanced entrap-
ment efficiency ~2-fold compared with PLGA alone.114 The antiproliferative effects of
arginine, an essential amino acid in breast and gastric cancers, have been shown.115,116 To
investigate its outcome on lung cancer, arginine conjugated with albumin microspheres
was tested in different lung cancer cell lines, including A549, CRL-2081, and MAK9.
Arginine microspheres mitigated tumor growth, migration, and cell proliferation in all

Table 4: List of drugs encapsulated as MDDS in treating cancer
Drug Polymer Indication Method Significance Ref
Paclitaxel PLGA Brain tumor o/w solvent Enhanced solubility and release rate of paclitaxel due to 120
336
extraction altered geometry was observed in diethylnicotinamide

release medium in vitro for several weeks
Paclitaxel PLGA, PLLA, Glioma Electrospray Cytotoxicity of microparticles in C6 glioma cell line was 121
PCL fabrication high with microparticles compared with Taxol and sustained
release for >30 days in vitro
Cisplatin PLA, PLGA Glioma Solvent evaporation PLA/PLGA (30/70) microparticles of cisplatin resulted in 112
sustained release for >75 days and reduced initial burst in
vitro, whereas other delivery systems enclosing cisplatin
released the drug for <14 days
Temozolomide PLGA Glioma Emulsifying-solvent Cell growth was inhibited entire time course tested (>72 h) 122
evaporation method with microparticles, whereas only temozolomide in powder
form halted cell growth and only up to 12 h
Gemcitabine BSA Renal cancer Sonochemical Significant improvement of anticancer potential with 118
preparation microparticles was observed compared with native drug in
RCC, 786-O cells using thymidine incorporation
assays
Holmium 166 Acetylacetonate Renal cancer Solvent evaporation Novel minimally invasive technique for renal cancer with 119
technique feasibility for imaging using CT, MRI, and SPECT
Arginine BSA Lung cancer Water/organic Arginine–albumin microspheres consisting of arginine with 117
solvent emulsion high concentration inhibited tumor growth in A-549, MAK-
system 9, and CRL-2081 lung cells, whereas free arginine promoted
lung cell proliferation
Doxorubicin Porous PLGA Metastatic w/o/w double emul- Potent inhalation anticancer therapy with significant reduc- 123
lung cancer sification method tion of number of tumors and tumor volume in vivo and
88.8% cytotoxicity after 24 h in vitro in B16F10 melanoma
cells
EphrinA1 BSA Lung cancer Emulsification Significant inhibition of focal adhesion kinase with micro- 124
chemical spheres compared with recombinant EphrinA1 alone and
cross-linking effective inhibition of cell migration and colony formation

Bale et al.
in A-549 cells
PLGA: poly(lactic-co-glycolic acid), PLLA: poly-L-lactide, PCL: polycaprolactone, BSA: bovine serum albumin
three cell lines of lung cancer, as evidenced from decreased levels of EphrinA1 (EphA2),
an oncogenic protein. Another interesting finding was that arginine in free form of the
same concentration activated tumor growth, but when used as microspheres, it eradi-
cated tumors by creating an arginine-rich surface on microspheres.117 The effect of gem-
citabine microspheres of bovine serum albumin (BSA) prepared using a sonochemical
method on the renal cancer cell line 786-O was investigated and significant inhibition
of renal tumor growth was found.118 Holmium-166 microspheres were prepared with
acetylacetonate and injected intratumorally in orthotopic renal tumors. These micro-
spheres have the potential to enact as both a therapeutic and imaging system due to their
emission of beta particles and gamma rays, conferring the advantages of microparticles
as theranostics in cancer.119 MDDS is a versatile technique and has huge potential in the
future to improve cancer therapy while lessening systemic toxic effects.
D. Neurological Disorders
Achieving efficacy of a drug in the central nervous system is a challenging prospect
for neurologists because of the lack of efficient permeability properties that makes it
incapable of crossing the BBB. However, new strategies have emerged to deliver drugs
directly into the central nervous system. For the first time in the 1960s, it was reported
by Folkman and Long that digoxin was delivered in to the myocardium via an implant
formulation of a silicone rubber device using a polymeric carrier.125 Then, several stud-
ies were performed using different formulation approaches in treating neurologic dis-
orders in which implants of the desired drug were administered surgically. However,
one surgery is not enough for prolonged periods and repeated administration of such
implants is required. To avoid this, drugs can be entrapped as microparticles, followed
by administration as implants using injections, thereby acting as a local and targeted
delivery system and preventing frequent administrations of medication. In this way,
risks associated with surgeries can be eliminated and patient comfort and compliance
are improved.126
Parkinson’s disease is a neurodegenerative disorder hallmarked by a loss of nigros-
triatal dopaminergic neurons. There are standard treatments available, but there is a
need to develop new formulations. Levodopa is considered the gold standard to treat
Parkinson’s, but its long-term use is associated with dyskinesia. Currently, continuous
dopaminergic stimulation therapy is practiced to halt disease progression and to delay
the onset of side effects. To trigger the dopaminergic system on a continuous basis, the
microparticles approach can be effective due to the extended release of the drug for
a prolonged period of time. Rotigotine-loaded PLGA microspheres were designed to
evaluate their neuroprotective role by administrating them intramuscularly once daily
for 15 d and potent effects were observed in diminishing disease progression.127 To en-
hance the stability and uptake of dopamine by the brain, solid-lipid microparticles using
tristearin were formulated and administered via nasal administration and were found to
be a promising tool for dopamine delivery.128
Stem cell therapy holds great promise in eradicating all diseases, including neu-
rodegenerative disorders and especially Parkinson’s disease. Human neural stem cells

338 Bale et al.
and marrow-isolated multilineage inducible cells possess neuroregenerative properties

and, when adhered with neurotrophin-3-loaded active microspheres, offer neuroprotec-
tion on release with enhanced cell survival and differentiation in an ex vivo organo-
typic model.129 Another study reported that neurotrophic factor derived from a glial cell
line (GDNF) was responsible for stimulation of dopaminergic and other motor neurons.
Clinically, administration of GDNF is possible via catheter implantation but is associ-
ated with limitations such as safety and efficacy. To avoid these complications, PCL
microspheres entrapped with GDNF were prepared and a sustained effect was observed
for ~25 days when injected into selected regions of brain.130 Selegiline-hydrochloride-
entrapped chitosan microspheres were prepared using glutaraldehyde as a cross-linking
agent and, when administered nasally, was found to be safe from toxicity in studies in
Parkinson’s disease. In vitro studies reported strong mucoadhesive strength and better
swellable properties of selegiline microspheres.131
Alzheimer’s disease is another neurodegenerative disorder associated with declined
cognition and the inability to manage routine daily life. In an attempt to deliver drug
into brain tissue to treat Alzheimer’s disease, magnetic microparticles of chitosan loaded
with tacrine were developed and administered intravenously by placing a magnet at
the target site. The results revealed that the concentration of microparticles in the brain
were significantly higher compared with its free drug and the dose required to elicit
the effect was minimized, thereby reducing the dose-related toxicity.132 Donepezil was
formulated as PLGA microparticles for its sustained effect of ~1 week after subcutane-
ous administration and proved efficacious in an in vivo model of Alzheimer’s disease.133
Neurotrophic factor is essential for the proper growth, functioning, and maintenance
of neurons.134 Nerve growth factor (NGF) is one such neurotrophin that monitors the
neurons of the basal forebrain. Administration of NGF decreased the neuronal death
and thus diminished the progression of Alzheimer’s disease.135 However, its short half-
life and failure to cross the BBB because of its size and polarity limits its application.
Therefore, NGF entrapped in hollow fibrin microspheres coated with polystyrene were
prepared and assessed for neuronal outgrowth assay in PC-12 cell lines. In this in vivo
study, neuroprotection was achieved and sustained for 14 days compared with NGF
injection alone, which released NGF for only 4 days.136
Several oral medications are available for epilepsy, but 30% of cases are uncured
with those currently available.137,138 Micro-injections and implants are therefore pre-
ferred to bypass the BBB and deliver the drug directly at the site of origin of the sei-
zures. In this way, the dose required to elicit the effect can be reduced, which in turn
mitigates the side effects associated with drugs.139,140 Because microsphere implants
avoid surgical intervention, brain damage and infections can be further reduced.141 A
typical method of electro-jetting was used in preparation of strong hydrophobic core
polymer shell microcapsules loaded with lacosamide, in which the respective polymer
controls the release profile of the drug. In addition, intracranial administration of several
standard chemotherapeutics was made plausible using MDDS. With this method, the
surveillance of cancer patients can be improved and thus contribute to treating brain
tumors. MDDS may serve as depot formulations, implants, and injectables in treating

various neurological disorders.
E. Cardiovascular Disorders
Heart-related disorders, including ischemia, myocardial infarction, atherosclerosis, and
hypertension, are life-threatening conditions occurring mostly in developed and devel-
oping countries and novel therapies are always welcome. For the myocardial infarction,
growth factors in a preclinical state of research were found to promising, but their ef-
ficacy was not consistent in clinical trials.142,143 The failure of growth factors in clinical
trials can be ascribed to their instability and short life span. To prevent this, stable,
highly concentrated growth factors must be administered and this can be feasible using a
controlled drug delivery system. In the last decade, several attempts were made to entrap
vascular endothelial growth factor (VEGF) and fibroblast growth factor in different for-
mulations, including nanoparticles, liposomes, microparticles, and gels.22,144–146 PLGA
microparticles as carriers of a drug delivery system were investigated for their potential
cardioretention effect in a myocardial ischemia rat model. Microparticles of different
sizes (2, 5, 14, and 30 µM) were administered to rats and the best retention effect and re-
sponse were observed with particles of 5 µM for about 3 months. Particles of 30 µM got
obstructed in the needle and few particles reached the infracted site, whereas particles of
2 µM were engulfed by phagocytes and a decreased response was observed. Therefore,
PLGA microparticles of 5 µM can be used to load the drugs that can treat myocardial in-
farction with sustained effect.147 Vascular inflammation was targeted in a murine model
of atherosclerosis in which two ligands were used to target E-selectin and VCAM-1,
formulated as spheroidal microparticles, emphasizing the significance of the effect of
particle shape, size, and biodistribution in developing a formulation required to target
atherosclerosis.148 In myocardial infarction, excess production of oxidative stress results
in the death of cardiomyocytes and a complete balance of endogenous antioxidants must
be maintained. To achieve this, one of the most important endogenous antioxidants,
super oxide dismutase (SOD), can be given externally, but is limited by its poor pharma-
cokinetic behavior that can be enhanced through protein modification. To extend its re-
lease, SOD was entrapped as MDDS using polymer poly (cyclohexane-1, 4 diyl acetone
dimethylene ketal) of the polyketal class. The formulation exhibited significant cardio-
protection, as evident from echocardiography and other assessed cardiac parameters in
treating myocardial ischemia compared with SOD protein alone. Moreover, formulated
SOD scavenged both intracellular and extracellular superoxides, thereby decreasing the
apoptosis of cardiomyocytes and reversing the ischemic condition.149
Carvedilol is an antihypertensive drug also prescribed for congestive heart failure
and available on the market as an immediate release tablet, but its effect is limited due
to its poor bioavailability of 25–35% as a result of rapid first-pass metabolism.150 To
enhance its bioavailability and stability and to attain sustained release, carvedilol mi-
croparticles were prepared using a blend of polymers comprising of poly (3-hydroxy-
butyrate-co-3-hydroxyvalerate) and polycaprolactone and significant sustained release
was observed both in vitro and in vivo; therefore, this method can be used to potentiate
the effects of carvedilol as an antihypertensive agent.151 Captopril , a water-soluble anti-

340 Bale et al.
hypertensive drug, exhibits dose-dumping and initial burst release effects. To overcome
this, microparticles of captopril were developed using cellulose propionate polymer and
tested in vivo. The half-life of captopril is 6–8 h, which results in its needing to be ad-
ministered three times per day, but in vivo results indicated that there was a decrease in
systolic blood pressure even after 24 h on oral administration of captopril formulation,
an evidence of sustained effect.152 Thymosin β4 (Tβ 4) is a peptide essential for survival
and growth of cardiomyocytes.153 Its long-term administration is always preferred be-
cause Tβ 4 reverts the cellular events that had taken place during ischemia and thus can
recover the cardiac tissue from damage. Therefore, microspheres of Tβ 4 were formu-
lated using PLGA to achieve a sustained effect and to overcome cardiac ischemia.154 To
attain revascularization of cardiac tissue after myocardial ischemia, a pro-angiogenic
factor, VEGF, was encapsulated as PLGA microparticles and a significant sustained ef-
fect was observed for 1 month or longer. The results revealed that, even after 1 month of
administration of VEGF microparticles, a remarkable angiogenesis and arteriogenesis
was observed, as evident from increased levels of small-caliber caveolin-1 vessels and
α-smooth muscle actin-positive vessels, respectively, showing the positive results of the
formulation compared with free VEGF.155 It is clear that the MDDS approach is effective
at treating cardiovascular disorders along with the above-mentioned disease conditions.
F. Other Applications
In general, MDDS is not limited to a specific disease or disorder and is indeed applica-
ble to all types of disease conditions. MDDS as gene therapy is currently receiving wide
attention. The applications of MDDS in other disease conditions apart from the above
described diseases are described in Table 5. Discussed are the applications of MDDS in
various disease conditions including psoriasis, arthritis, and bone disorders, and the role
of MDDS as a probiotic and theranostic agent is also shown. Microparticles are consid-
ered as effective and feasible encapsulation techniques with wide potential therapeutic
applications in treating multiple disorders.
IV. DELIVERY OF MDDS THROUGH SPECIFIC ROUTES

A. Pulmonary Delivery
The delivery of drugs via the pulmonary route is associated with promising benefits
compared with other conventional administration routes because of its large surface
area, high permeability and vascularization, and the negligible thickness of the blood–
alveolar barrier. Pulmonary delivery is mostly preferred and considered as effective in
delivering potent drugs to treat respiratory diseases, including chronic obstructive pul-
monary disease, pneumonia, tuberculosis, and cystic fibrosis. In addition to targeting
respiratory disorders, the pulmonary route is also used to deliver drugs with poor oral
bioavailability and to enhance systemic effects of drugs.171 Despite the exceptional prop-
erties of the delivery of drugs via the pulmonary route, including fast onset of action,
local drug delivery, reduction of dose, decreased side effects, and escape from first-pass
metabolism, there is an urgent need to develop controlled release formulations to avoid

frequent administration, to maintain a constant level of drug, and to improve patient

comfort and compliance.172,173 Furthermore, major challenges that controlled drug de-
livery system prevents include macrophage uptake, mucociliary clearance, and degra-
dation by metabolic enzymes of the medicament administered. Particles greater than
6 µm are generally prone to mucociliary clearance and particles ranging from ~1–3
µm undergo phagocytosis by macrophages.174,175 Moreover, some cytochrome P450 en-
zymes are expressed even in lungs and contribute to the degradation of drug, caus-
ing its inactivation.176 However, size is the vital factor in deciding the efficacy of drug
during pulmonary delivery and microparticles thus can play a prominent role due to
their micron size. This facilitates their feasibility in treating both respiratory-related
disorders and also other disorders in which bioavailability and systemic absorption are
major concerns. MDDS with a size range of 1–5 µm are suggested to for pulmonary
accumulation. However, even particles with sizes of 1–2 µm are cleared by phagocytes
and therefore the half-life of drugs are still shortened. This led to the development of
large, porous MDDS with low density and enhanced efficiency of aerosolization. These
particles, due to their large size and porosity, prevent phagocytosis clearance and re-
duce particle interactions.177 The porosity is achieved using substances called porogens.
Although the efficiency of drugs is increased in large porous MDDS, its release is not
sustained. Therefore, to prepare an extended controlled release formulation, swellable
MDDS were developed. These MDDS particles with varied sizes of 0.5–5 µm are easily
inhaled in the dry condition and, when accumulated in the lung, its moist surface causes
the particles to swell, thereby solving two problems at once: decreased phagocytosis by
macrophages and sustained release of drug from the swelled particles.
In a model of metastasis of melanoma tumor, porous doxorubicin entrapped PLGA
microparticles were administered for controlled release via pulmonary inhalation and
the results suggested a decrease of tumor progression by these particles, as evidenced
from the reduced number of lesions.178 A study was performed in which BSA, an osmot-
ic agent, was used as a porogen to prepare PLGA-loaded INS and VEGF microparticles.
Controlled release for 2 weeks was achieved without producing any burst effects and
the porous nature imparted was uniform, stressing the role of BSA in sustained delivery
for loading various proteins and peptides.179 A pharmacokinetic study was performed in
guinea pigs to investigate the absorption of porous rifampicin microparticles and found
that only half of the oral dose was required to produce systemic effects via pulmonary
route. Likewise, even after achieving systemic concentrations, some amount of drug
was detected in the lungs, emphasizing the potential benefits of pulmonary drug deliv-
ery.180 Porous microparticles for INS were prepared using emulsification combined with
the supercritical carbon dioxide precipitation method in which polylactic acid was used
as a polymer and ammonium bicarbonate as a porogen. In vitro data showed the pre-
pared microparticles to be the stable, safe, highly sustainable, and bioactive compared
with INS alone. In vivo studies have yet to be performed, but based on the in vitro results
obtained, these particles can have a beneficial role as hypoglycemic agents when admin-
istered through the pulmonary route.157 Hollow porous microparticles enclosing lipids
targeting lung are called “PulmoSpheres” and are used as an effective vehicle carrier to

342
Table 5: List of drugs encapsulated as microformulations to treat different disease conditions

Rotigotine PLG Parkinson’s disease Emulsion Improved parkinsonism 127
score, protected neurons with
antioxidants. and significantly
decreased cytokine production
Tacrine Magnetic chitosan Alzheimer’s disease Emulsion cross-linking Concentration of formulation 132
in brain is significantly greater
than free drug
VEGF PLGA Myocardial Solvent Sustained release of VEGF for 146
ischemia extraction/evaporation >1 month in vitro and in vivo
SOD 1 protein Polyketal Myocardial Double emulsion Sustained effect of the 149
ischemia formulation decreased both
intracellular and extracellular
superoxides and improved the
function of myocardium
Carvedilol Poly(3- Hypertension Simple emulsion PCL–carvedilol microparticles 151
hydroxybutyrate- resulted in prolong antihy-
co-3- pertensive effect than PHBV
hydroxyvalerate) carvedilol formulation
[PHBV],
PCL
Captopril Cellulose Hypertension Solvent evaporation Formulation decreased systolic 152
propionate blood pressure for 24 h in vivo
compared with standard drug
Thymosin β 4 peptide PLGA Myocardial Double emulsion High peptide encapsulation 156
ischemia (98%) and processed in dif-
ferent range of sizes so that
parenteral delivery could be
amenable

Bale et al.
INS PLLA Pulmonary delivery Emulsion-combined pre- Explored the sustained 157
for diabetes cipitation of compressed potential, safety, and stability
CO2 anti-solvent of insulin microparticles via
pulmonary delivery without
losing therapeutic potential in
diabetes

Sunitinib PEG, PLLA, Ocular Single o/w Long-term inhibition of ocular 158
PDLLA neovascularization emulsion solvent neovascularization by sup-
evaporation pressing angiogenesis sus-
tained for 210 days
Dexamethasone Poly(ester amide) Ocular delivery Emulsion Exhibited high encapsula- 159
solvent evaporation tion efficiency (85%) with an
extended release for 3 months

Ofloxacin PLG + gelrite Ocular delivery o/o emulsion solvent Improved bioavailability 160
evaporation by 11.7-fold compared with
marketed available eye drops,
reduced repeated instillations,
and provided better patient
compliance
Dexamethasone PLGA Arthritis Double emulsion-sol- Significant reduction of 161
21-acetate vent evaporation synovial inflammation was
observed from the fourth
day of microparticle injec-
tion and sustained its effect
for 3 months; target-specific
delivery
Thrombin-related pep- Poly propylene Osteoporosis Double emulsion solvent Single administration (300 μg) 162
tide (TP508) fumarate + PLGA extraction of microparticles significantly
enhanced bone formation as
evident from microcomputed
343
tomography
344
Lidocaine PLGA Peripheral tinnitus Homogenization Consistent high concentrations 163
solvent evaporation of lidocaine particles in peri-
emulsification lymph for 3 days was observed
in vivo on topical application;
significantly inhibited periph-
eral tinnitis
Clobetasol Propionate PLGA Psoriasis o/w emulsion solvent Clobetasol in PLGA micro- 164
evaporation spheres delayed the cargo
release and exhibited sustained
effect compared with commer-
cial product
Osteogenic pro- Alginate/chitosan Spinal fusion Ionic gelation Avoids initial burst and 165
tein- Nell-1 (Nel-like released 15% of cumulative
molecule-1) cargo for 30 days; suitable car-
rier for osteogenesis
Doxorubicin Chitosan–dextran Osteosarcoma Coacervation Reduced side effects, 166
sulfate decreased tumor volume and
metastasis, and significantly
inhibited bone lysis
Cyclopentyladenosine Mannitol-lecithin/ Ischemia Spray drying Cerebrospinal fluid concentra- 167
chitosan tions of nasal administered
microparticles were 2-fold
higher compared with its
administration via systemic
route

Bale et al.
VEGF PLGA Nerve regeneration w/o/w double emulsion Initial burst of 67% in 24 168
solvent h followed by release of
evaporation 0.34% drug daily for 4 weeks
revealed using human umbili-
cal vein endothelial cell prolif-
eration assay
SOD Polyketal 3 + PVA Lung fibrosis Solid in oil in water SOD microparticles retained 169
double emulsion therapeutic effect and
decreased progression of fibro-
sis; devoid of inducing toxic
effects
Fluorofenidone PLGA Acute lung injury Solvent evaporation Lung distribution of micropar- 170
ticles were 4.6-fold higher
compared with the drug in its
solution form
PLG/PLGA, poly(d,l-lactide-co-glycolide); VEGF, vascular endothelial growth factor; SOD 1, superoxide dismutase 1; PLLA, poly-L-lactide; PEG,
polyethylene glycol; PDLLA, poly-D,L-lactide; PHBV, poly(3-hydroxybutyrateco-3-hydroxyvalerate); PVA, polyvinyl alcohol
345
346 Bale et al.
deliver immunoglobulins. Antibody IgG entrapped with lipid dipalmitoylphosphatidyl-

choline, a component of lung surfactant, was loaded in these PulmoSpheres for its pas-
sive immunization, which was achieved by stimulating both local and systemic immune
responses and thus may be used to treat respiratory-related syndromes.181 Pulmonary
delivery is not restricted to treat respiratory disorders, but has possibilities in all chronic
disorders and is also applicable to treating cancer. Despite several advances in cancer
treatment, the efficacy of most of chemotherapeutics is limited by their adverse side
effects, resistance to treatment, dose of the drug required, and selectivity due to which
combinatorial approach is being given more prominence.90 doxorubicin and paclitaxel
are the standard anticancer drugs used to treat various tumors.182,183 To produce a syner-
gistic effect and to reduce toxicity, both doxorubicin and paclitaxel were formulated as
PLGA nanoparticles and administered through the pulmonary route, but uncontrolled
aerodynamic properties of the particles compromised the efficacy of formulation.184,185
To obtain efficient aerosolization, porous microparticles of the same combination were
formulated using polymer PLGA. Testing in a tumor model of B16F10 pulmonary me-
tastases revealed the promising and significant synergistic effects of the combination
that provides a scope for future clinical application.186
Exubera, an INS inhalational formulation, is frequently used to control hyperglyce-
mic conditions in both type 1 and type 2 diabetes. This pulmonary INS delivery system
offers a high level of safety and better patient compliance.187 The Mannkind Corporation
developed a dry powder preparation of INS called Afrezza (INS technospheres), which
was found to be an effective and patient-friendly medication.188 In terms of transepithe-
lial transport, INS-like growth factor 1 peptide was compared with INH and a transport
model was extrapolated. Therefore, pulmonary delivery of INS growth factor-1 was
made possible using silk fibroin and trehalose in an ex vivo human lung model.189 Mic-
roparticles delivered via the pulmonary route may emerge as an attractive approach very
soon in future to treat respiratory-related and other diseases even.
B. Ocular Delivery
Ocular drug delivery is an exciting approach to treat eye-related disorders. Limitations
pertaining to ocular delivery of drugs include lachrymal drainage and irritation that
cause damage to the eye and sometimes may result in loss of vision. Due to lachrymal
drainage, the residence time of drug in the eye is short and penetration into the cornea
is low, at about 1–3% of the dose administered.190,191 For this reason, drug to corneal
contact should be prolonged for therapeutic efficacy and, to fulfill this criteria, poly-
mers can be used. Polymers should be bioadhesive, nonirritating, and nontoxic. MDDS
is a fascinating method for the preparation of ophthalmic products because, once the
particles have permeated the cornea, lachrymal drainage can be delayed due to the size
of particles and thus longer retention time is achieved, decreasing the elimination of the
drug and promoting a sustained effect. Using this method, promising therapeutic bene-
fits are achieved, but caution should be taken that the drug does not produce any sort of
irritation or toxic effects. A study was performed in which CMC and polyvinyl alcohol
(PVA) in their sodium salt form were used as polymers to prepare adrenaline-loaded

microparticles and the prepared formulation was swellable with good interpenetrated
network and safe to use in ophthalmic delivery systems.192 Another study used chitosan
as a polymer to for ocular delivery. Chitosan was selected for its high permeability
and strong mucoadhesive nature has been used in many studies.193 PVA is a surfactant
that offers chemical resistance and possesses good physical properties.194 Therefore,
chitosan in combination with PVA was used as a polymer mixture to encapsulate pilo-
carpine for ophthalmic delivery based on results of in vitro studies; the in vivo effect
has to be evaluated further.195 Recently, a study was reported based on atropine sulfate
microparticles investigated for mydriatic and cyclopegic effect using a rabbit model
and compared with marketed atropine sulfate. Results of both in vitro toxicity and in
vivo studies suggested that the formulation of strength 0.66% prepared using albumin
and chitosan polymers was superior to the available marketed 1% atropine solution,
revealing the potency and importance of MDDS.196
Ocular neovascularization is commonly observed in diseases including diabetic
retinopathy and age-related macular degeneration.197,198 Sunitinib, an anti-angiogenic
drug belonging to the class of receptor tyrosine kinases, was loaded as microspheres
using a mixture of polymers consisting of PLLA, poly-(D, L-lactide) (PDLLA), and
PEG, the latter of which has a vital role in altering release kinetics. These micropar-
ticles released drug for ~210 days, with initial burst at 24 h, using both diffusion and
erosion as release mechanisms. The in vivo effects of this formulation were studied us-
ing a chicken chorio-allantoic membrane assay and findings of both in vitro and in vivo
studies revealed significant neovascularization of the formulation on intravitreal injec-
tion.158 Polyesteramide was used as a novel biodegradable polymer to investigate as a
carrier in ophthalmic delivery. Dexamethasone was loaded as cargo and microspheres
were formed using polyester amide as polymeric system. In vitro and in vivo rabbit
model release studies indicated that the formulation can be sustained for 90 days and
a cytotoxicity study revealed the safety of the formulation. In addition, biodistribution
of the formulation performed in Sprague-Dawley rats on intravitreal administration
confirmed its sustainability. The outcome of the study stresses on use of polyesteramide
as a carrier in ophthalmic delivery systems.159 Ofloxacin eye drops exist on the market,
but a delivery system is preferred to overcome its poor bioavailability and low perme-
ability. Considering this, PLGA microspheres of ofloxacin were prepared, which then
integrated in gel formulation and were associated with a 11.7-fold increase in bioavail-
ability when tested in rabbits compared with marketed eye drops.160 As a whole, the
significance of MDDS in ocular drug delivery is prominent due to prolonged retention
time, enhanced bioavailability and permeability, and avoidance of repeated adminis-
trations, all of which decrease the irritation caused by these drugs and increasing the
safety of the formulation.
V. MDDS IN CLINICAL TRIALS

There are number of marketed products in different type of disease conditions based on
microformulations. Some of the examples of marketed microparticles include Sandos-

348 Bale et al.
tatine LAR depot (octreotide) and Somatuline LA (lanreotide) for treating acromegaly:
Plenaxis (abarelix), Zoladex (goserelin acetate), Eligard (leuprolide acetate), and De-
capeptyl (triptorelin) for prostate cancer; Zoladex (goserelin acetate) for breast cancer;
Arestin (minocycline) for periodontitis; Suprecur MP (buserelin) for endometriosis;
Risperdal consta (risperidone) for psychosis; and Bydureon for diabetes. The therapeu-
tic benefits of these products encouraged continued research on microparticles and their
further advancements. With consistent efforts, several drugs are now formulated as mi-
croparticles, were successful in preclinical trials, and then entered into clinical trials to
prove their efficacy; examples follow. Holmium-166 (166Ho)-PLLA microspheres were
designed to explore their effect on radioembolization in liver cancer with proven results.
Later, the formulation was extended to study in liver metastasis to explore its safety
profile and a clinical study was performed with 15–24 patients having unresectable liver
metastasis. Results of the study suggest that eight patients were successfully treated with
the formulation.199 Another study was performed based on the delivery of doxorubicin
(Oncogene microspheres) via the intra-arterial route to treat hepatic cancer. To deter-
mine whether yttrium 90 glass microspheres are safe, radioembolization of this formula-
tion was practiced in hepatocellular carcinoma.200 Yttrium 90 microspheres, also known
as TheraSphere, emit high-energy beta radiation and achieve promising therapeutic ben-
efits in patients with hepatocellular carcinoma using radioembolization. Moreover, the
formulation was found to be safe and well tolerated. A clinical study is in progress to
determine the safety of SIR spheres along with the antiangiogenic drug regorafenibin
in patients with metastatic colorectal cancer.201 Another Phase III, multicenter, random-
ized double-blind study is currently investigating the safety and efficacy of lanreotide
microparticles in cancer related to peritoneum at a dose of 30 mg and complete results
of the study will be reported soon.202 Some of the recent clinical trials of microparticles
collected from www.clinicaltrials.gov.in are shown in the Table 6. MDDS continues to
gain significance in clinical trials.
VI. FUTURE PERSPECTIVES

Today, many MDDS formulations exist on the market to treat different disease condi-
tions. In the past decade, research in MDDS has undeniably improved, but there are
obstacles, including scalability by formulating MDDS as generic strategies that impede
the effectiveness of MDDS. However, MDDS is emerging as an exciting approach to
treat any disease condition and is a limitless tool to overcome the hurdles associated
with conventional therapy. Several features of microparticles enable their potential in
formulation design. Furthermore, some of the parameters that are given utmost sig-
nificance in consideration of microparticles as therapy include nature of drug/active
compound, polymer, solvent, method used, and disease condition. Accordingly, MDDS
are given as injectables, implants, depots, and gels. Although MDDS are administered
in different forms, one of the major purposes remains the achievement of sustained ef-
fect of the entrapped drug without loss of therapeutic efficacy. MDDS offer a reduction
in the frequency of administration, mitigation of side effects, local and targeted drug

Table 6: List of drugs entered into clinical trials to combat cancer (www.clinical trials.gov.in)
Microparticle Indication Phase Trial No.
Lanreotide Peritoneal neoplasms Completed (Phase III) NCT00216372

Doxorubicin-loaded Embozene® Tandem™ Hepatocellular carcinoma Completed (Phase III) NCT01798134
Holmium 166 microspheres Liver metastasis Phase I NCT01031784
SIR-Spheres (Yttrium-90 microspheres) Colorectal cancer Completed (Phase I) NCT00972036
doxorubicin, superabsorbent polymer microsphere Hepatocellular Carcinoma Completed NCT01116635
(Phase II)
TheraSphere® Yttrium-90 microspheres Cholangiocarcinoma Phase II NCT01912053
Regorafenib SIR-Spheres Colorectal neoplasms Phase II NCT02195011
DT-LM (Docetaxel) Advanced cancer Phase I NCT01611961
Holmium-166 polylactic microspheres Liver neoplasms Phase II NCT01612325
HepaSphere/QuadraSphere Microspheres Hepatocellular carcinoma Phase III NCT01387932
Oncozene-DEB-TACE Hepatocellular cancer Recruiting NCT02141906
HAI-90Y radio embolization Colorectal cancer Phase III NCT01895257
Yttrium 90 glass microspheres Unresectable hepatocellular carcinoma Completed (Phase II) NCT00589030
Holmium-166 microspheres Neuroendocrine tumors Phase II NCT02067988
Perflutren lipid microspheres Breast cancer Phase 4 NCT01817374
SIR-Spheres® (Yttrium microspheres) Ocular melanoma Phase I NCT01893099
SIR-Spheres® (Yttrium 90 microspheres) Uveal melanoma Phase II NCT01473004
349
350 Bale et al.
delivery, and better patient compliance. Contribution of MDDS to the biomedical field
is enormous and covers all research areas of interest, namely, cancer, diabetes, vaccine
delivery, vascular system, nervous system, etc. There are several potent neutraceuti-
cals with therapeutic potential that is limited by pharmacokinetics. Encapsulating such
compounds as MDDS by modifying the use of polymers and methods of encapsulation
could lead to significant therapeutic benefits with enhanced safety, bioavailability, and
reduced side effects.
Although the major focus and primary goal of MDDS in drug discovery has been
related to attaining sustained release of the medication, the size of particles in MDDS
should not be ignored. Particles of micron size offer advantages for drug delivery via the
inhalational route to enhance systemic bioavailability. Therefore, delivery of microparti-
cles entrapping any drug for any disease can be significantly achieved via the pulmonary
route so that better patient compliance can be achieved. One of the best outcomes ex-
pected to be achieved with MDDS is in the preparation of porous microparticles, a fea-
sible technique in which a limited dose of the active compound exerts maximum thera-
peutic benefits by diminishing side effects. Further, an interesting and feasible strategy
in MDDS is the preparation of composite microparticles. These particles, in which a
microformulation is fabricated with a nanoformulation have significance in chronic dis-
ease conditions. There are many examples of composite microparticles that have been
discussed above in the therapeutic applications for diabetes, cancer, and vaccine de-
livery. The inclusion of nano and microformulations as a single drug delivery system
contributes to sustained release, targeted delivery, reduced side effects, and enhanced
therapeutic efficacy simultaneously. Further, MDDS could play a vital role in gene de-
livery (delivery of siRNA, miRNA, and shRNA). Added to this, MDDS has applications
in probiotics and theranostics. In the future, inhalational application of MDDS to treat
chronic disease conditions and MDDS as composite microparticles will emerge and be
associated with improved therapeutic benefits. Based on the strong evidence from the
literature, available marketed products, and ongoing clinical trials, MDDS will continue
to gain prominence as an effective and sustained targeted drug delivery system in the
near future, encapsulating both natural traditional compounds and synthetically derived
molecules to treat chronic diseases.
VII. CONCLUSIONS
Multiple advantages of MDDS facilitate them as potent carriers in therapeutic targeting.
This delivery system address the drawbacks of conventional therapy and plays a vital
role in attaining desired bioavailability, enhanced permeability, and targeted drug deliv-
ery. Particles of micron size, once reaching the target site, cannot diffuse back through
the membrane and thus accomplish maximum retention at the target and have promising
results. Systemic side effects are minimized and single administration provides relief for
a longer time, improving the quality of life for patients, the most essential requirement
of therapy. Although many marketed microformulations exist, there is an urgent need
to develop MDDS for several drugs for a wide range of diseases to achieve maximum

therapeutic efficacy. One day in the future, MDDS may be considered the gold standard
of research in drug delivery systems.
ACKNOWLEDGMENTS
The authors are thankful to all of the research teams who contributed in the field of ther-
apeutic applications of microparticle drug delivery system. We acknowledge financial
support from the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers,
Government of India; technical assistance from Indian Institute of Chemical Technology
(CSIR-IICT), Hyderabad, India. We acknowledge Rahul B. Chavan, Rajesh Thippara-
boina, and Anjali Jain (Research Scholars, NIPER-Hyderabad) for valuable suggestions.
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Critical Reviews™ in Therapeutic Drug Carrier Systems, 33(4), 309–361 (2016)

Overview on Therapeutic Applications of

ABSTRACT: Research in novel drug delivery systems is being explored competitively in

KEY WORDS: microparticles, therapeutic benefits, sustained release, drug delivery

0743-4863/16/$35.00 ©2016 Begell House, Inc. www.begellhouse.com 309

Critical Reviews™ in Therapeutic Drug Carrier Systems

FIG. 1: Schematic representation of MDDS classification (A) Microspheres. (B) Microcapsules

B. Advantages and Disadvantages of MDDS

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of microparticle preparation and using other approaches including targeted delivery,

FIG. 2: Classification of polymers used in the preparation of microparticles

Critical Reviews™ in Therapeutic Drug Carrier Systems

C. Parameters Attributing the Efficiency of MDDS

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FIG. 3: Various types of encapsulation techniques used for preparation of microparticles

Critical Reviews™ in Therapeutic Drug Carrier Systems

TABLE 1: Parameters involved in evaluation of MDDS

III. THERAPEUTIC APPLICATIONS OF MDDS

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FIG. 5: Therapeutic applications of MDDS and their advantages

A. Role of MDDS in the Management of Diabetes Mellitus

Critical Reviews™ in Therapeutic Drug Carrier Systems

FIG. 6: Therapeutic effects and advantages of MDDS in diabetes mellitus

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Palmityl-acylated Exendin-4 PLG w/o/w double emulsification Extension of hyperglycemic effect in 22

INS Glutamine, chitosan Ionic cross-linking Enhance permeation by 1.52-fold 20

Critical Reviews™ in Therapeutic Drug Carrier Systems

Volume 33, Issue 4, 2016

100% and sustained release of 10 h as

Critical Reviews™ in Therapeutic Drug Carrier Systems

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highly vascularized epithelium. In agreement with this, repaglinide was encapsulated in

Critical Reviews™ in Therapeutic Drug Carrier Systems

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B. Vaccine Delivery and Immunology

FIG. 7: Therapeutic effects and advantages of MDDS in vaccine delivery

Apart from target-specific delivery and cell-mediated immune responses, particu-

Critical Reviews™ in Therapeutic Drug Carrier Systems

relationship in future vaccination techniques, a selective method quantifying adjuvant

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Critical Reviews™ in Therapeutic Drug Carrier Systems

Volume 33, Issue 4, 2016

Critical Reviews™ in Therapeutic Drug Carrier Systems

C. Role of MDDS in the Management of Cancer

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Drug Polymer Method Significance Reference

Critical Reviews™ in Therapeutic Drug Carrier Systems

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tag fusion protein antibody

FIG. 8: Therapeutic effects and advantages of MDDS in cancer

Critical Reviews™ in Therapeutic Drug Carrier Systems

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27–47 µm and an entrapment efficiency of 61–67% resulted in effective cytotoxicity of

Critical Reviews™ in Therapeutic Drug Carrier Systems

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extraction altered geometry was observed in diethylnicotinamide

Critical Reviews™ in Therapeutic Drug Carrier Systems

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and marrow-isolated multilineage inducible cells possess neuroregenerative properties

Critical Reviews™ in Therapeutic Drug Carrier Systems

various neurological disorders.

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IV. DELIVERY OF MDDS THROUGH SPECIFIC ROUTES

Critical Reviews™ in Therapeutic Drug Carrier Systems