MICROENCAPSULATION FOR THE

THERAPEUTIC DELIVERY OF DRUGS,LIVE

MAMMALIAN AND BACTERIAL CELLS,AND
OTHER BIOPHARMACEUTICS:CURRENT
STATUS AND FUTURE DIRECTIONS

Submitted By:
Munira Muhammadi (01)
Fatema Ilyas (02)
 ABSTRACT
• Microencapsulation is a technology that has shown
significant promise in biotherapeutics, and other
applications.
• This paper is a comprehension review of
microencapsulation and its latest developments in the field.
• It provides a comprehensive overview of the technology and
its primary goals of microencapsulation and discuss various
techniques involved in microencapsulation including
physical, chemical, physiochemical and other methods
involved.
• The limitations and future directions of microencapsulation
technologies are also discussed.
 INTRODUCTION
• Microencapsulation has gained importance in in fields of cells,
tissue engineering, development of drug formulations and oral
delivery system
• The term microencapsule is used for reservoir like structure with a
well-defined core and envelope, having different size, compositions
and functions.
• They can be used to entrap all sorts of substances like solids, liquids,
drugs, proteins, bacterial cells, stem cells and so forth.
• This paper discusses the use of microencapsulated microorganisms
in renal diseases ,cardiovascular diseases ,colorectal cancer
,inflammatory bowel disease, anemia, parathyroid insufficiency,
neurodegenerative diseases and others.
• The use of microencapsulated drug focuses on hormone therapy,
gastrointestinal disorders, diabetes, pulmonary diseases,
periodontitis and hypertension.
GOALS OF MICROENCAPSULATION

• Goals of microencapsulation include:

-Material structuration
-Protection of enclosed product
-Controlled release of encapsulated contents
 MICROENCAPSULATION METHODS

• Techniques used to fabricate microcapsules:

-Chemical methods
-Physical methods
-Physiochemical methods
1.Chemical Methods Of Microencapsulation
• Chemical methods of microencapsulation include:
 Solvent evaporation-requires heat in which the core material
dissolves in the coating solution followed by the agitation in liquid
vehicle to obtain desired microcapsule size.
 Interfacial polycondensation-involves Schotten-Baumann
reaction between an acid chloride and compound containing active
hydrogen atom. These two polymeric reactants meet and form thin
walls at the microcapsule interface.
 Interfacial cross-linking-also involves Schotten-Baumann
reaction in which bifunctional monomer containing active hydrogen
atoms are replaced by biopolymer(protein) during
encapsulation.the membrane of microcapsule is formed by the
reaction of an acid chloride with functional groups of protein at the
interface of emulsion.carbohydrates and starch added for increased
modulation of biodegradability and physical properties.
 In situ polymerization-reactants are polymerized together to
form the particle surface
 Matrix polymerization-involves the embedding of the core
material in a polymeric matrix during particle .
2.Physical Methods Of Microencapsulation
• Physical methods of microencapsulation include:
 Spray drying-an emulsion is prepared by the dispersion of oil-core
material or water soluble active ingredient into concentrated coating
material. This emulsion is then atomized into spray of droplets
using rotating disks and then heated to allow water to evaporate,
yielding dry microcapsules. Used for encapsulation of proteins and
microorganisms
 Fluid-bed coating(pan coating)-used to encapsulate
pharmaceuticals into coated particles or tablets. Oldest procedure in
which solid particles are mixed with a dry coating material using
liquid spray that is heated to surround the particle cores.
 Centrifugal extrusion-a microencapsulation technique that
involves the use of a spinning extrusion head made up of concentric
nozzles. The microcapsule core and coating materials are pushed
through the nozzles forming a flow that splits into droplets
following clearing the nozzle. The solidification of droplets can be
undertaken using cooling and gelation.
 Vibrating nozzle(vibrating jet)-in this the liquid material
encapsulated is extruded through the nozzle at a specific flow rate,
forming a laminar jet. Uses permanent sinusoidal force at
determined frequencies forming microcapsules of uniform
distribution . The solidification of microcapsules can be undertaken
using cooling and gelation.
 Spinning disk(rotational suspension separation)-in this a
mixture is formed with a material for the internal core of the
microcapsule and liquid microcapsule coating material and
dispersion is done through turning disk followed by the
solidification using cooling and gelation. Purification is done to
isolate microcapsules from coating material particles.
3.Physiochemical Methods Of Microencapsulation
• Physiochemical methods of microencapsulation include:
 Inotropic gelation-ability of polyelectrolytes to cross-link in
presence of counterions, leading to gelation. Forms 3D lattice due to
the diffusion of cations into polymeric drops.
 Coacervation(phase seperation)- oldest and most used
technique which involves the addition of Salt or alcohol into
polymeric mixture, promoting the liquid-liquid phase separation
and the formation of coacervate polymer droplets.
 Supercritical fluid technology-forms particles by rapid
depressurization or by exceeding the saturation point of solute by
dilution, as well as combination of both these processes.
 MICROENCAPSULATED MICROORGANISMS
• Microencapsulation has been widely used for the encapsulation and
immobilization of microorganisms.
• Bacterial cell encapsulation occurs naturally as bacteria proliferate
and produces exopolysaccharides, high-molecular-weight polymers
composed of sugar residues.
• Early research used microencapsulation for immobilization of
bacterial cells in food and dairy industry.
• In recent years microencapsulation of probiotic cells has been used
for treatment of number of gastrointestinal and other health
disorders.
• Research focused on microencapsulation of probiotics have been
successful in
-Renal failure
-Cardiovascular diseases
-Colon disorders
1.Microencapsulated Microbes In Renal Failure
• A research by Prakash in which Encapsulated E-colli cells
were administrated orally to uremic rats which
successfully lowered the levels of plasma urea and
ammonia back to normal levels, also preventing renal
failure.
• This research also highlighted microencapsulation as a
method to isolate the delivered microorganisms through
GIT transit until excretion, eliminating safety issues with
delivery of microorganisms.
• These microencapsulated yeasts cells decreased urea levels
by 18% during 8 week treatment period demonstrating the
efficiency of formulation as a therapeutic for eliminating
elevated levels of metabolites present in renal failure
2.Microencapsulated Microbes In
Hypercholesterolemia And Cardiovascular Diseases
• Garofalo investigated the use of microencapsulated
p.pectorium with alignate-polylysine and open pore agar
which shows significant cholesterol depletion activity.
• Jones used (bile salt hydrolase)BSH-active microencapsulated
microorganisms for lowering blood serum cholesterol.
• These formulation can contribute to a significant cholesterol
lowering effect in cardiovascular diseases.
• Jones further used the yogurt formulation of APA
microencapsulated BSH-active which was shown to reduce low
density lipoprotein cholesterol(LDL),and non-high-density
lipoprotein(HDL) cholesterol in hypercholesterolemic patients
more efficiently than traditional probiotic therapy and other
cholestrol-lowering ingredients.
3.Microencapsulated Lactobacilli In Colon Diseases
• Urbanska investigated the antitumorigenic properties of
APA microencapsulated l.acidophilus that carry germline
apc mutation which spontaneously develop numerous
pretumoric intestinal neoplasms.
• This probiotic led to a significant reduction in number of
adenoms and gastroinstestinal neoplasias in treated
animals,suggesting that this microencapsulated bacteria
could have a role in successful colon cancer therapeutic.
• APA microencapsulated l.acidophilus also used to suppress
intestinal inflammation in mice,for potential applications in
chromic inflammatory gut dieseases such as IBS and IBD.
• The mictoencapsulated formation also lowered cytokine
levels and increased colonic epithelial cell survival.
MICROENCAPSULATED MAMMALIAN CELLS
• Delivery of mammalian cells promotes regeneration of organs like
liver, pancreas, heart, kidney but unfortunately it also raises a
number of challenges in in vivo delivery like:
-Immune rejection by host
-A loss in cell survival due to aggregation and impaired nutrition
-Impaired cellular function due to inadequate gene expression
-A requirement for a large amount of readily available cells
-Shortage of human cell donors
• Microencapsulated cells can provide an alternative approach to
resolve the these obstacles.
• The most significant research with regard to microencapsuation in
cell based therapies focus on applications of
diabetes and hepatic disease.
1.Microencapsulated Pancreatic Cells To Treat Diseases

• Delivery of insulin has proven promising for the treatment of type I

diabetes but unfortunately the use of these immunosuppressive
drugs prevent rejection of implanted PIC predisposes patients to
infections and increases risk of cancer development in post
transplant period.
• Microencapsulation can act as a barrier shielding the delivered
pancreatic cells from the host’s defence, eliminating the need for
immunosuppressive drugs.
• Islet cells were encapsulated which showed to increase insulin
when stimulated with glucose.
• The transplanted encapsulated islet cells maintained
normoglycemia for 3 weeks demonstrating the potential of
microencapsulation for treatment of type I diabetes.
• Microencapsulated PICs injected directly into the peritoneal cavity
and the omental pouch without any immunosuppressive drug
administration unlike free PICs and were also able to maintain
normal glucose level for over 100 days following transplantation .
• Omer used encapsulated NIPCCS and non encapsulated NIPCCs in
the control group which showed that microencapsulation
successfully provides the encapsulated islet cells with immune
protection without need for immunosuppression. Showed
improvement in ratio of B cells
• Microencapsulation can also be used for human
xenotransplantation.as it decreases the insulin level by 30% and
demonstrates the potential of survival of microencapsulated
xenogenic PIC transplanted without the need for
immunosuppression.
2.Microencapsulated hepatic Cells To Treat liver
Diseases
• Orthotropic liver transplant is currently the only effective
treatment for end stage liver disease but due to shortage of
organs ,requirement for immunosuppressive therapy and
numerous complications limit the overall effectiveness of
transplantation.
• So encapsulated hepatocytes were transplanted into rats
with heapatic failure and remained viable following 35 days.
• A recent study demonstrated the regeneration of liver cell in
BAlB/C mice with acute liver failure by 70% hepatectomy
using a mixture of microencapsulated rat hepatocytes and
human fetal liver stromal cells with basal basal fibroblast
growth factor whichenhanced survival rates by over 86%.
3.Other Applications Of Microencapsulated
Mammalian Cells
• Zhang used the microencapsulated Chinese hamster
ovarian cells in Srague-Dawley rats as a therapeutic for
ischemic heart diseases and showed significant
improvement in cardiac function and demonstrated a
decline in fractional shortening and left ventricular
enlargement.
• Microencapsulation has also found use in parathyroid
replacement and in treatment of severe anemia and
neurodegenerative diseases.
• Microencapsulation has also shown great potential for
the development of cancer therapy allowing to bypass
the issue of immune rejection.
 MICROENCAPSULATED DRUGS AND OTHER
PHARMACEUTICS
• Microencapsulation has greatly enhances pharmaceutics
research in terms of drug delivery devices.
• This interdisciplinary field comprising polymer science
and emulsion technology has not only covered
encapsulation of drugs but also of peptides , proteins and
DNA/RNA therapeutic molecules for controlled release
studies.
• The phenomenon of sustained controlled release of drug
not only protects the drug from degradation but also
protects the body from potential toxic effects of the drug.
• Most o the commonly used polymers for drug
applications are PLA and PLGA.
1.Microencapsulation Of Biological Agents, Food
Supplements, Enzymes, and Antibiotics
• Biodegradable and biocompatible polymers, such as
PLGA have been used to encapsulate biologically active
agents such as risperidone (antipsychotic).
• Likewise, encapsulation of food supplements, such as
vitamins and oil substances, has also been performed
using emulsion technology.
• A study performed by Ratnakar Tandale in 2007,
showed the encapsulation of vitamin C and gallic acid,
as model antioxidants, in whey protein.
• These antioxidants were encapsulated using spray
drying and freeze drying methods. The study
determined the highest encapsulation ratio of vitamin
C: why protein: gallic acid.
• Another study demonstrated microencapsulation of
protein loaded chitosan nanoparticles by spray drying
for pulmonary delivery of drugs.
• They characterized the micro particles for size and
aerodynamic properties.
• The results showed a protein loading efficiency of 65% to
80% with its release 75% to 80% from nanoparticles
within 15 minutes.
• Zheng demonstrated the successful oral delivery of
clarithromycin in chitosan-alginate-ethyl cellulose
microspheres for the treatment of peptic ulcers caused
by Helicobacter pylori.
2.Microencapsulation Of Anticancer Drugs
And Genes
• Microencapsulation has also been used to deliver
anticancer agents.
• A recent study demonstrated the advantage of
ionotropic gelatin to encapsulate a drug, verapamil HCI
in a blend of sodium alginate, hydroxypropyl
methylcellulose and hydroxymethylcelluose polymers.
• Other bioactive molecules such as peoteins and
DNA/RNA , that are more prone to denaturation, have
also been encapsulated by solvent exchange.
• Likewise, DNA has been encapsulated under reduced
shear, to maintain its integrity, for oral delivey
applications.
3.Microencapsulation Of Proteins And Hormones

• Microencapsulation technology has also enabled the oral

delivery of high-molecular-weight proteins. Due to their
high molecular weight, these molecules are poorly
absorbed by the blood stream and are also sensitive to
degradation by the acidic environment of GIT.
• A study by Deluca demonstrated the encapsulationof
insulin using blend of acryloyl hydroxyethyl starch
(AcHES) hydrogel microparticles with PLGA, an
interesting alternative to subcutaneous injectionfor the
management of type 1 diabetes.
• This application provided a high efficiency into the
microparticles and provided a sustained release of the
active agents.
• As per the literature, microencapsulation techniques, such
as spray drying, phase separation, and emulsion techniques
pose a limitation in pharmaceutical applications, where the
therapeutic molecules may degrade due to thermal and
chemical exposure involved during the encapsulation
process.
• Thus, alternative methods for encapsulation are being
explored to avoid such limitations.
• One study proposed, introduced the use of a high-voltage
electrostatic field to encapsulate bovine serum albumin, a
model protein, in sodium alginate microcapsules of
<100um. In size with 80 hours of controlled protein release.
• This study brought a new dimension for the
microencapsulation of protein and peptide-based
pharmaceutics.
CHALLENGES AND FUTURE OUTLOOKS
• Given the importance of microencapsulation in various disease
applications the technology needs to be further enhanced. One aspect
that seems critical is the targeted delivery using triggered release of
encapsulated contents due to external trigger factors.
• It is also clear that, for each microcapsule formulation, the types and
physical and chemical properties of the microencapsules must be
optimized.
• Optimization may involve a number of variables, including the type of
microencapsulation process, the encapsulation materials used, and the
therapeutic loading capacity.
• Keeping this characteristics in mind, it is also evident that the future
success of microencapsulation must look at the optimization of the
methods behind the fabrication of microcapsules. Specifically,
characteristics such as permeability, mechanical stability, cell viability,
controlled release, targeted drug delivery, drug stability etc.
Thankyou!