Novel encapsulation systems and processes for overcoming the challenges of polypharmacy

Novel encapsulation systems and processes forovercoming the challenges of polypharmacyMine Orlu-Gul1, Ahmet Alptekin Topcu2, Talayeh Shams2,Suntharavathanan Mahalingam2 and Mohan Edirisinghe2

Available online at www.sciencedirect.com

ScienceDirect

The encapsulation process has been studied to develop smart

drug delivery systems for decades. In particular, micro-

encapsulation and nano-encapsulation approaches have

gained wide interest in the development of particulate drug

delivery and achieved progress in specialties such as nano-

medicine. Encapsulation technologies have evolved through

various platforms including emulsion solvent evaporation,

spray drying and polymer conjugation. Among current

encapsulation methods, electrohydrodynamic and microfluidic

processes stand out by enabling the making of formulations

with uniform shape and nanoscale size. Pressurized gyration is

a new method of combining rotation and controlled pressure to

produce encapsulated structures of various morphologies. In

this review we address key developments in

electrohydrodynamic, microfluidic, their combined and new

approaches as well as their potential to obtain combined

therapies with desired drug release profiles.

Addresses1 School of Pharmacy, University College London, 29/39 Brunswick

Square, London WC1N 1AX, UK2 Department of Mechanical Engineering, University College London,

Torrington Place, London WC1E 7JE, UK

Corresponding author: Edirisinghe, Mohan ([email protected])

Current Opinion in Pharmacology 2014, 18:28–34

This review comes from a themed issue on New technologies

Edited by Gleb B Sukhorukov

For a complete overview see the Issue and the Editorial

Available online 1st September 2014

http://dx.doi.org/10.1016/j.coph.2014.08.001

1471-4892/# 2014 Elsevier Ltd. All rights reserved.

IntroductionThe administration of multiple active pharmaceutical

ingredients in single dosage form is an attractive solution

for overcoming the polypharmacy challenge where

patients can benefit from treatment for several diseases

by the release of drugs contained in one unit. However,

this requires the rapid development of engineering tech-

nologies to encapsulate and control release multiple drugs

contained in single dosage form and this paper summar-

izes our current opinion on this topic.


Electrohydrodynamic processThe electrohydrodynamic (EHD) technique employs an

electrically-driven force in order to construct single or

multilayer particles and fibres in micro and nanometre

scale usually via an electrically charged fluid cone jet.

Modification of different parameters such as flow rate,

medium viscosity, applied voltage, working distance and

needle dimensions modulate the characteristics of the

end products regarding their size, shape and morphology

based on desired outcome (see example in Figure 1). For

example, a volatile liquid such as perfluorohexane (PFH)

can be made to flow through the inner needle while a

polymer solution passes through the outer needle. At

appropriate flow rate and applied voltages typical hollow

core–shell capsules can be mass produced. By increasing

the flow rate of PFH, these can be made monoporous

hollow shell capsules. Moreover, this technique can be set

up as a bench top procedure or used in a portable setting

and in ambient conditions, whereas other conventional

techniques are subjected to high shear stresses, high

temperatures and excessive use of surfactants [1��].According to the aforementioned capabilities and advan-

tages of the EHD technique, it has received considerable

attention in the production of multi-layered drug vehicles

in targeted drug delivery where the release profile of the

active ingredients can be customized accordingly. The

polymeric drug carriers could be prepared with both

natural, such as chitosan, collagen, gelatin and silk fibroin

or synthetic polymers like poly(lactic acid) (PLA), poly(-

lactic-co-glycolic acid) (PLGA), polymethylsilsesquiox-

ane (PMSQ) and polycaprolactone (PCL).

It has been shown very recently that the EHD technique

has the ability to produce particles and fibres of up to four

distinct layers, which further enhances its allure to the

biopharmaceutical industry [2��]. Moreover, different

techniques can be used in order to incorporate the active

ingredients into these nanofibers and nanoparticles such

as blending, surface modification and coaxial process.

ElectrospinningElectrospinning, which is an EHD process, enables pro-

duction of fibres using synthetic or natural polymers. It is

attractive in pharmaceutical industry for production of

drug carriers due to its cost efficiency and high production

rate. They offer high surface area to volume ratio [3], high

interconnected porosity where pore size is adjustable [4],

variable surface characteristics [5], possibility of surface

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Novel encapsulation for polypharmacy challenges Orlu-Gul et al. 29

Figure 1

(a)

(b)

(c)

Shell

Core

D

t

Power supply

Inner needle

Syringe1

Syringe2

Outer needleMonitor

CameraRecorder

PFH

PMSQ

10 μm

Current Opinion in Pharmacology

Typical co-axial EHD products. (a) Process illustration, (b) typical hollow

core–shell capsules generated and (c) by increasing the polymer

concentration fibres (not capsules) can be generated.

functionalization [6] and the ability to replicate extra-

cellular matrix composition. Electrospun nanofibers can

highly improve drug diffusion due to their high porous

profile, increase drug uptake by reducing initial burst

release and first pass metabolism, hence reducing

required dosage and the undesired side effects.

ElectrosprayingElectrospraying is another EHD procedure that could be

performed with the same equipment by altering the

processing parameters and choice of materials with suit-

able properties, only this time the end product is in form


of particles that can be taken orally, intravenously,

topically or by inhalation. Alternatively, there are other

conventional routes for fabrication of biodegradable

micro/nanoparticles like solvent evaporation [7], single/

double emulsion [8], spray-drying [9], porous glass mem-

brane emulsification [10] and coacervation (phase separ-

ation) [11]. Nonetheless all the aforementioned processes

have their shortcoming such as polydispersity, low drug

loading efficiency, inability to produce in smaller scales,

integration of high shear stresses and high temperatures,

which can consequently result in denaturation or pre-

mature degradation of the incorporated drugs. However,

the proposed manufacturing technique seeks to overcome

these pitfalls.

Electrohydrodynamic applicationsElectrospun nanofibers have been used extensively in a

variety of new biomedical engineering applications. For

example, the application of these nanofibers is in wound

dressings where wounds are preserved from environmen-

tal threats while helping accelerate the healing process

[12]. Moreover, nanofibers are used in cancer therapy

where a localized and prolonged drug delivery system is

desirable while reducing the possible damage to sur-

rounding tissue and minimizing the unwanted side effect

and also reducing the number of required administration

[13]. In addition to the aforementioned, nanofibers are

used in scaffold construction for delivery of nucleic acids,

for example, DNA siRNA, all down to its appealing

features such as high surface area, high porosity and

interconnected pores which are all favourable to adhesion

and proliferation of cells and transportation of nutrients

and oxygen [4], also cell migration and infiltration are

possible due to the loose bonds in-between the nanofibers

[14]. Last but not least, nanofibers have the ability to

incorporate growth factors, which are widely used to

enhance tissue regeneration by regulating cell prolifer-

ation, migration and differentiation [15].

Compared to fibres, electrospun nanoparticles are con-

sidered to be more recent in development of polymeric

vehicle encompassing drugs. These nanoparticles have

demonstrated higher cellular uptake where particle

adhesion onto cells’ surface is enhanced due to the

existence of surface charges of the particles [16]. More-

over, these nanoparticles have received notable attention

for targeted delivery into the brain where other routes of

drug delivery come short due to low permeability and

inability to cross the blood–brain barrier [17]. Modifi-

cation of different parameters of EHD technique enables

controlling shape, size and thickness of the drug vehicles

and hence adjusting release rate of the active ingredients

as needed. Also these nanoparticles provide means of

smart delivery systems where release profile of the encap-

sulated drugs can be initiated by external environmental

cues such as difference in pH, temperature, magnetic

field or ultrasound [18]. They are also beneficial for


30 New technologies

encompassing drugs that are poorly water-soluble when

administered orally, by shielding the ingredient from

biological processes such as first-pass metabolism [19].

Microfluidic processMicro-materials and nanomaterials research has been

expanding since more than a decade with organic, inor-

ganic [20], polymeric and polymer composites for biome-

dical/pharmaceutical applications [21] for use in drug

delivery systems (DDS). Advanced DDSs are designed,

firstly to deliver specific types of drugs into particular sites

in the body and secondly to release them at a sustained

rate. Targeting is categorized under passive targeting, in

which pH, temperature differences, ultrasound, external

magnetic field is employed or by active targeting, that

depends on antibodies, proteins, peptides to recognize

the target cells. Once a drug is delivered to its target site,

controlled drug release is essential which is viable by

having a uniform particle size and size distribution as

these parameters affect the bioavailability and drug

dosage. However, there exist limitations for the pro-

duction of uniform sized particles using conventional

techniques such as solvent extraction, emulsion-based

methods.

As an important method for nano/micro fabrication,

microfluidics is the field of science focusing on the

manipulation of solutions on the micrometer range for

the production of specific materials in a confined space.

Figure 2

Micr ofluidics

Micropar�c les

Microcapsules

Microgels

Classes of materials available for fabrication using microfluidic devices. PGA


Microfluidics is becoming an increasingly important tool

for researchers, because it allows production of uniform,

monodisperse nano-particles and microparticles with

enhanced control over particle size, size distribution,

shape, morphology and composition. These benefits

enable increased drug loading, ability to regulate variation

in composition, achieve attachment of ligands to carriers.

The inherent advantages are the minimization of material

use, facileness of the fabrication, cost effectiveness and

general portability of the systems.

Microfluidics offers a pathway for the generation of three

types of biomaterials that can be used for drug delivery

(see Figure 2); microparticles, microcapsules and micro-

gels. As pharmaceutical science aims to localize the effect

of the drug to the site of therapy (‘magic bullet’), targeting

is of increased importance. Delivery of commonly used

drugs is a possibility by adoption of biodegradable poly-

mers, such as thermoplastic aliphatic poly(esters). PLA is

one of the most commonly used polymers, with its di-

block or triblock copolymers with glycolic acid poly(gly-

colide) (PGA), PCL and PLGA. Approved by Food and

Drug Administration (FDA) for drug delivery, they are

biocompatible, biodegradable and non-toxic versatile

tools [22] having mechanical stability for use with

proteins, peptides, vaccines and similar molecules [8].

In fact, monodisperse, Paclitaxel (PTX) loaded poly

(L-lactic acid) (PLLA) microspheres produced using a

microfluidic chip are indicative of higher drug-loading,

Polymeric PEG, PC L, PLA,PGA, PLGA

Bio-polymers Chitosan, Alginate,Gela�n, Pec�n

CompositesPol ymer-Au, Ag,

QDs, Fe3O4

Inorgani c Silica

Vesic les Pol yme rsome s,Liposomes

Bio-polymers Chitosan, Alginate,

Polymeric PLA, PLLA, EC

PDMm pNP Im


is poly(glycolic acid). Others are defined in text.



encapsulation efficiency and sustained release behavior in

comparison to published papers [23].

The copolymerization of lactides and glycolides in PLGA

has received much attention as it improves the biode-

gradability in comparison to homopolymers, thus

enabling a wide range of use in many medical applications

including but not limited to delivery of macromolecules,

anti-inflammatory agents, peptides, hormones [24,25].

In a typical microfluidic device, two parameters of import-

ance are: Geometry of the channels (see Figure 3) and

type of device material (ranging from polymers to inert

silica, glass). A T-junction device works by introducing a

dispersed phase through a microchannel, while a continu-

ous phase flows perpendicularly, both phases meet at the

junction, break past the outlet to result in a droplet. Each

droplet contains bubbles, evaporation of the solvent

induces breakup of the bubbles to result in generation

of microparticles (evaporation induced self-assembly).

The junction can be adapted for use with both hydro-

philic and hydrophobic polymers. As texture is a direct

consequence of interfacial stability, the surface

morphology of the microparticles can be tuned from

smooth to rough surfaces, by changing the solvent con-

stitution, thus changing the evaporation rate [26].

Biopolymers include naturally occurring carbohydrate

based polysaccharides, such as cellulose, alginate, pectin

and chitosan, which are inherently water soluble, non-

toxic, biodegradable and biocompatible. Alginates sub-

tracted from seaweeds are popularly used in drug delivery

[27] and cell encapsulation [28]. Monodisperse alginate

hydrogel microbeads are produced with high uniformity

and control over size, shape in a T-junction microfluidic

device [28]. The higher degree of control with a narrow

size distribution (<%5) is decisive on the clearance rate of

Figure 3

(a) (b)

(c) (d)


Schematic of commonly used types of microfluidic devices, (a) T-

junction, (b) Y-junction, which can also be modified to a V-junction, (c)

co-flowing and (d) flow-focusing.


the Ca-alginate-drug complex from the body and specific

drug dosage [29].

An example for inorganic–polymeric composites (see

Figure 2), CdSe/ZnS quantum dots (QDs) are encapsulated

into uniform PLGA biocompatible microparticles using a

microfluidic chip [30]. Furthermore, there are instances of

QD-tagged drug delivery systems and QD encapsulated in

PLGA used for in vivo medical imaging [31]. Moreover, Ca-

alginate microparticles are employed for encapsulation of

Au-nanoparticles [32] with a polydispersity of 5%. Mag-

netic Fe3O4 nanoparticles [29] can also be combined with

QDs. The aim is that by using Fe3O4 QDs composite

microvehicles for use in smart drug delivery are manufac-

tured. Lastly, silica, the most abundant inorganic material

in the earth’s crust is a chemically inert, biocompatible

substance that can be adopted for use in drug delivery. In

fact, Lee et al. [33] developed a one-step in situ method that

involves an ethanol sol and a solvent diffusion induced self-

assembly to produce monodisperse mesoporous silica

microspheres with a 2D hexagonal structure.

Microcapsules, fabricated by layer by layer techniques

(LbL) generally suffer from low encapsulation efficien-

cies but have found a versatile platform in droplet-based

microfluidics, as they benefit from narrow size distri-

bution, strict control over size and low amounts of

reagents used (of the order of microliters). Monodisperse,

uniform microcapsules can be produced in microfluidic

devices by droplet or double emulsion templating

through evaporation induced solidification [34]. In prep-

aration of a polymer microcapsule, oil-in water (O/W)

droplets are used which are then solidified. Hydrophobic

PLLA microcapsules are fabricated using PLLA polymer

solution with 3% vol. dodecane in dichloromethane

(CH2Cl2) and an aqueous solution of poly(vinylalcohol)

(�1% wt.) as an emulsifier in the dispersed phase. PLLA

biodegradable microcapsules with stable walls containing

a hydrophobic model drug were fabricated after evapor-

ation of dichloromethane [35], a novel approach with a

potential future use in drug delivery.

Vesicles, microscopic subdivisions surrounded by a thin

membrane are generally self-assembled from either syn-

thetic (polymersomes) or phospholipid(liposomes)

amphiphilic molecules. Polymersomes are comprised of

diblock copolymer vesicles with amphiphilic additives, as

in poly(ethyleneglycol)-b-polylactic acid (PEG-b-PLA)

prepared in a microcapillary device using a W/O/W

double emulsion approach [36]. On the other hand, lipo-

somes contain an inner aqueous core for encapsulation of

a hydrophilic drug while a hydrophobic drug is incorpor-

ated into the lipid bilayer. An ethanol injection based

method that can be scaled up is chosen for encapsulating a

hydrophobic Beclomethasone dipropionate (BDP) and a

hydrophilic drug (cytarabine, Ara-C) in liposomes for

administration via the pulmonary route [37].


32 New technologies

Microgels are polymer particles at micrometer scales with

a high degree of cross-links within the three-dimensional

polymer network, that can swell or shrink upon their

surrounding’s water content, thus offering reversible

changes in pore sizes and diffusion of drugs. Therefore,

there is a considerable interest in microgels, with stimuli-

responsive poly(N-ispropylacrylamide), able to encapsu-

late polystyrene microparticles, QDs and magnetic nano-

particles and release them upon a gradient change in

temperature [38].

Novel processesIn recent years, there has been tremendous progress in

new technological development for controlled drug

release system where improved efficacy, reduce toxicity,

and improved patient compliance are needed to improve

human health.

Microbubbles are also becoming increasingly important

as pharmaceutical carriers and can be produced using

microfluidic methods, and more recently by taking

advantage of co-axial EHD principles [39]. It is now even

Figure 4

(a) (b

(c)

Typical products formed through pressurized gyration (a) nanofibres, (b) mi


possible to combine microfluidic and EHD principles to

obtain microbubbles at various size scales [40] and

although this method has not been fully adapted for

biomedical applications, it is very likely that this will

happen in the near future. However, compartmentalising

microbubbles, which are stable over long periods of time

(months), for polypharmacy applications is a much more

challenging task compared with particle, capsules and

fibres. However, the use of such bubbles in combination

with diagnostic engineering platforms such as ultrasound

offers a very formidable way of diagnosing and treating

disease, for example, tumours, and is a hot topic of

research at present [41].

Another novel process, known as pressurized gyration

[42�], utilises simultaneous centrifugal spinning and

solution blowing to prepare drug loaded systems such

as nanofibres and microparticles (microbubbles, and

microcapsules) (see Figure 4). This novel technique

makes use of the destabilising centrifugal force and the

dynamic fluid flow against the stabilising surface tension

of the mixture solution of the polymers and drugs at the

)

100 µm

100 µm


crobubbles and (c) microcapsules.



orifice to fabricate very rapidly the desired product. The

product size, size distribution and morphology could be

controlled by varying the concentration of the polymer/

drug solution (in effect viscosity and surface tension),

rotating speed and the working pressure. In addition, the

drug could be coated on nanofibres or microparticle

system or embedded within nanofibres or microparticle

system. The large surface area of the nanofibres enables

efficient solvent evaporation and favours the formation of

amorphous dispersion to offer site-specific release of the

drugs to the body. A wide variety of drugs regardless of

the molecular weight can be loaded on biodegradable

microparticles to deliver sustained release of drugs from

each individual microparticle. The relative ease in design

and formulation of microparticulate delivery systems

through pressurized gyration offer unique advantages,

greater uniformity and reproducibility.

Bringing science into practice — delivercombined therapies by novel encapsulationThe advances in sophisticated encapsulation engineering

significantly raises hope in controlled and targeted deliv-

ery of drug molecules and biological therapeutics. In

particular, the experimental set-up of EHD, microfluidic

processes and their combination genuinely offers new and

vast potential in developing multi-drug formulations

encapsulating multiple drugs. The multiple channel

design of these processes may allow introducing multi

polymeric drug solutions enabling the control of compo-

sition and desired drug release. Combined drug therapies

are often required by special patient populations. The

comorbid patients are prescribed up to five or more

medicines’, often called as polypharmacy. The difficulty

in managing complex drug regimes’ can negatively

impact patient adherence. The currently licensed fixed

dose combination (FDC) products may help patients on

multiple prescriptions. However current preparation

methods are not fully equipped to provide desired release

characteristics of all drugs loaded into single dosage

forms. The advanced geometry of EHD and microfluidic

system should be further explored for the preparation of

combined therapies. This would enable the effective

delivery of multiple therapies to patients with comorbid-

ities. Undoubtedly older people would benefit most from

the advances in this field.

ConclusionsThe electrohydrodynamic and microfluidic based

methods, their combined use and other new methods

such as pressurized gyration for particular combined drug

delivery systems are still at its early phases, yet there has

been an enormous growth and interest in the develop-

ment of DDS based on microfluidics. This is not surpris-

ing once benefits of engineering designs are taken into

account, with a wide variety of drug delivery vehicles

offering control over size, structure, composition and

importantly higher drug loading with sustained release.


The potential areas for improvement lie in the scalability

of the methods which are currently on micro-milligram

range. There are studies to overcome this, for example, by

integration of multiple microfluidic units simultaneously

running in parallel to each other, manufacturing on the

kg-scale is possible for potential pharmaceutical appli-

cation. In parallel, EHD methods are faster and can

produce multi-layered capsules with, theoretically, no

limit in the number of layers. The combination of micro-

fluidics and electrohydrodynamics offer exciting possibi-

lities for the preparation of carriers with a variety of fluid

and solid chambers while pressurized gyration can be

used as a one-pot generator of many encapsulated pro-

ducts with very high yield and size control. What is more

to the point, the novel microencapsulation methods have

great potential in facilitating the preparation of combined

therapies hence responding to the need of older people

with comorbidities.

It is crucial to realize that most of the above described

work has been proven on a laboratory scale and in some

instances backed-up by only in vitro experiments. The

translation of these technologies to mass production and

to in vivo scenarios requires considerable attention in both

scale up and understanding to detail and mechanisms.

Conflict of interest statementNo conflict of interests.

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42.�

Mahalingam S, Edirisinghe M: Forming of polymer nanofibers bya pressurised gyration process. Macromol Rapid Commun2013, 34:1134-1139.

A new process combining pressure and rotation to mass produce finefibres has been invented and this is featured on the journal cover page.

































































































































Novel encapsulation systems and processes for overcoming the challenges of polypharmacy

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