Microneedles: A smart approach and increasing potential for transdermal drug delivery system

Abstract

The most widely used methods for transdermal administration of the drugs are hypodermic needles, topical creams, and transdermal patches. The effect of most of the therapeutic agents is limited due to the stratum corneum layer of the skin, which serves as a barrier for the molecules and thus only a few molecules are able to reach the site of action. A new form of delivery system called the microneedles helps to enhance the delivery of the drug through this route and overcoming the various problems associated with the conventional formulations. The primary principle involves disruption of the skin layer, thus creating micron size pathways that lead the drug directly to the epidermis or upper dermis region from where the drug can directly go into the systemic circulation without facing the barrier. This review describes the various potential and applications of the microneedles. The various types of microneedles can be fabricated like solid, dissolving, hydrogel, coated and hollow microneedles. Fabrication method selected depends on the type and material of the microneedle. This system has increased its application to many fields like oligonucleotide delivery, vaccine delivery, insulin delivery, and even in cosmetics. In recent years, many microneedle products are coming into the market. Although a lot of research needs to be done to overcome the various challenges before the microneedles can successfully launch into the market.

Full text

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Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Review
Microneedles: A smart approach and increasing potential for transdermal
drug delivery system
Tejashree Waghule
a
, Gautam Singhvi
a,⁎
, Sunil Kumar Dubey
a
, Murali Monohar Pandey
a
,
Gaurav Gupta
b,⁎
, Mahaveer Singh
b
, Kamal Dua
c,d,e
a
Department of Pharmacy, Birla Institute of Technology & Science (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India
b
School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, 302017, Jaipur, India
c
Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia
d
School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, 2308, Australia
e
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Lot 1 Kookaburra Circuit, New Lambton Heights, Newcastle, NSW 2305, Australia
ARTICLE INFO
Keywords:
Transdermal
Drug delivery
Microneedle
Solid microneedle
Hydrogel microneedle
ABSTRACT
The most widely used methods for transdermal administration of the drugs are hypodermic needles, topical
creams, and transdermal patches. The effect of most of the therapeutic agents is limited due to the stratum
corneum layer of the skin, which serves as a barrier for the molecules and thus only a few molecules are able to
reach the site of action. A new form of delivery system called the microneedles helps to enhance the delivery of
the drug through this route and overcoming the various problems associated with the conventional formulations.
The primary principle involves disruption of the skin layer, thus creating micron size pathways that lead the drug
directly to the epidermis or upper dermis region from where the drug can directly go into the systemic circu-
lation without facing the barrier. This review describes the various potential and applications of the micro-
needles. The various types of microneedles can be fabricated like solid, dissolving, hydrogel, coated and hollow
microneedles. Fabrication method selected depends on the type and material of the microneedle. This system has
increased its application to many fields like oligonucleotide delivery, vaccine delivery, insulin delivery, and even
in cosmetics. In recent years, many microneedle products are coming into the market. Although a lot of research
needs to be done to overcome the various challenges before the microneedles can successfully launch into the
market.
1. Introduction
Hypodermic needles and topical creams are most commonly used
when it comes to delivery of the drug through the skin. Needles are less
accepted by patients due to pain associated with them and topical
creams show less bioavailability. Skin serves as the major barrier for
delivering drug through the topical route. Skin is made up of three main
layers-the outermost stratum corneum, middle epidermis and the
thickest of all, dermis. The stratum corneum layer behaves like a major
barrier as it allows only certain molecules like lipophilic and low mo-
lecular weight drugs to pass through it. The relatively less permeability
of the layer presents many problems in designing topical formulation
[1,2]. Various topical or transdermal delivery systems have been in-
vestigated for improving drug permeation through the skin like nano-
carrier loaded topical creams, transdermal patches, and microneedles
[3,4].
The microneedles (MNs) have been studied by various researchers
for delivering drug through the transdermal route and for overcoming
the limitations of the conventional approaches. Microneedle device
consists of needles of micron size, which are arranged on a small patch.
Considering the problems of the hypodermic needle and the trans-
dermal patch, microneedle drug delivery system was developed and is
thought to be the hybrid of both. The major problem associated with
transdermal technology is that many of the drugs are not able to cross
the skin at the required rate necessary for the therapeutic action.
Researchers have developed a refined technology using microneedles,
which allow hydrophilic high molecular weight compounds to enter
into the stratum corneum. Administration of drugs using the micro-
needle device allows the drug molecules to cross the stratum corneum
layer, thus allowing more drug molecules to enter the skin. The char-
acteristic features of this technology are the faster onset of action,
better patient compliance, self-administration, improved permeability
https://doi.org/10.1016/j.biopha.2018.10.078
Received 12 July 2018; Received in revised form 30 September 2018; Accepted 14 October 2018
⁎
Corresponding authors.
E-mail addresses: gautam.singhvi@pilani.bits-pilani.ac.in (G. Singhvi), gauravpharma25@gmail.com (G. Gupta).
Biomedicine & Pharmacotherapy 109 (2019) 1249–1258
0753-3322/ © 2018 Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T

and efficacy [2]. In addition to improved therapeutic advantages, mi-
croneedles give highly accurate reproducible results with minimum
inter-subject variability in bioavailability. Though it has many ad-
vantages it also possesses some limitations. There is the possibility of
skin irritation or allergy to sensitive skin. Since the needle size is very
small and thinner as compared to the thickness of hair, breaking of
microneedle tips may take place which if remained inside the skin, can
cause problems. These limitations are very rare and can be overcome
with advanced material selection for microneedles. The main objective
of developing this technology is to create larger transport pathway of
micron size which is larger than molecular dimensions and smaller than
holes by hypodermic needles, to disrupt the stratum corneum to allow
large molecules to pass through thus increasing the permeability [5].
Conventional methods like electric methods- iontophoresis and elec-
troporation, chemical/ lipid enhancers create pores of nanosize which
improve the permeability up to some extent but fail for large molecules
[6]. A comparative discussion is compiled for various transdermal drug
delivery systems in Table 1. The drug delivery by various transdermal
systems is presented in Fig. 1. The topical cream spreads only on the
skin surface. It has been reported that only 10–20% of total drug loaded
in cream is being permeated through the skin [3]. In case of a trans-
dermal patch, the drug has to pass the stratum corneum barrier thus it
also shows less bioavailability. Addition of permeation enhancer in the
transdermal patch can improve the drug permeation but up to a very
limited extent [4]. The hypodermic needle goes deep into the dermis
where pain receptors are present. Thus it can deliver 90–100% of the
loaded drug but it is very painful which results in poor patient com-
pliance. Microneedle patch bypasses the stratum corneum barrier and
delivers the drug directly into the epidermis or upper dermis layer
which delivers 100% of the loaded drug without pain [5].
2. Mechanism of drug delivery
The delivery of the drug through the topical route follows the dif-
fusion mechanism. In the microneedle drug delivery system, the skin is
temporarily disrupted. A microneedle device is made by arranging
hundreds of microneedles in arrays on a tiny patch (the same as that of
a normal transdermal patch available in the market) in order to deliver
sufficient amount of drug to give a required therapeutic response. It
pierces the stratum corneum thus bypassing the barrier layer. The drug
is directly placed in the epidermis or upper dermis layer which then
goes into the systemic circulation and shows a therapeutic response on
reaching the site of action [6,7]. Mechanism of drug delivery through
microneedles is depicted in Fig. 2.
3. Dimensions of microneedles
Microneedles can be formulated in varying sizes depending on the
type of microneedle and the material used. Since the epidermis is up to
1500 μm thick so the needle length of up to 1500 μmissufficient to
release the drug into the epidermis. Needles larger in length and thicker
in diameter can go deep into the dermis, damage the nerves and cause
pain [5]. Mostly they are 150–1500 microns long, 50–250 microns
wide, and have 1–25 microns tip thickness. As discussed earlier the
need for microneedle device is to create micron size transport pathway,
the diameter of needles is kept between few microns. Microneedle tips
Table 1
Comparison between topical cream, transdermal patch, hypodermic needle, and microneedle drug delivery systems.
Topical cream Transdermal patch Hypodermic needle Microneedle
Description Emulsion/ emulgel/
cream/ ointments
Adhesive patch to be placed on the
skin
Fine, hollow tube having a sharp
tip with small opening at the end
Micron size needles are aligned on the
surface of a small patch
Onset of action Slow Slow Faster Faster
Pain Painless Painless Painful Painless
Bioavailability Poor Insufficient Sufficient Sufficient
Patient compliance Less Better Less Better
Self-administration Possible Possible Not possible Possible
Mechanism of drug delivery Permeation through
skin pores.
Drug has to cross stratum corneum
barrier, thus poor diffusion of large
molecules
Drug placed directly in the
dermis
Bypass stratum corneum and drug placed
directly into epidermis or dermis hence
enhanced permeability
Fig. 1. Comparison of topical cream, hypodermic needle, microneedle patch and transdermal patch.
T. Waghule et al. Biomedicine & Pharmacotherapy 109 (2019) 1249–1258
1250

can be cylindrical, triangular, pointed, pentagonal, octagonal and are
available in many more shapes [7].
4. Microneedle fabrication material and its properties
4.1. Silicon
The first microneedle was made from silicon in the 1990s [6]. Si-
licon is anisotropic in nature and has a crystalline structure. Its prop-
erties depend on the alignment in the crystal lattice, which shows dif-
ferent elastic moduli (50 to 180 GPa) [8–10]. Its flexible nature allows
producing needles of different sizes and shapes. Its attractive physical
properties make it a versatile material. Silicon substrates can be pre-
cisely manufactured and are capable of batch production. The cost of
silicon and its time-consuming complex fabrication process limits its
use in microneedle. In addition, there are some biocompatibility issues,
as silicon is brittle, some part may break and remain in the skin thus
causing some health issues [8].
4.2. Metal
The main metals used are stainless-steel and titanium. Palladium,
nickel, palladium-cobalt alloys are also used [11]. They have good
mechanical properties and good biocompatibility. Metals are strong
enough to avoid breaking, thus more suitable as compared to silicon for
microneedle production. The first metal used in the production of mi-
croneedle was stainless steel [12]. Titanium is a good alternative to
stainless steel [8,13].
4.3. Ceramic
Alumina (Al
2
O
3
) is mainly used because of its chemical resistance. It
forms a stable oxide because of the highly energetic ionic and covalent
bonds between Al and O atoms [14]. Other types of ceramics used are
calcium sulfate dihydrate [Gypsum (CaSO
4
0.2H
2
O)] and calcium
phosphate dihydrate [Brushite (CaHPO
4
.2H
2
O)] [5]. In recent years an
organically modified ceramic called Ormocer®has been used. It is a
three-dimensionally cross-linked copolymer [15]. A polymer with dif-
ferent properties can be produced by using different organic units
during polymerization. Mainly they are produced using a micro-
molding technique. Ceramic slurry is cast into a micro-mold. Micro-
moulding techniques are cheaper processes, and also have the potential
for scale-up [8].
4.4. Silica glass
Varying geometries can be produced on small scale using glass.
Silica glass is physiologically inert but brittle in nature [16]. Bor-
osilicate glass which is made up of silica and boron trioxide is more
elastic. They are mostly fabricated manually, thus are less time efficient
[17]. Glass MNs are not used now commercially, but only for experi-
mental purposes [8].
4.5. Carbohydrate
Maltose is one of the most common sugars used [18]. Other sugars,
such as mannitol, trehalose, sucrose, xylitol and galactose, poly-
saccharides can also be used [19]. Carbohydrate slurries are moulded
by making use of silicon or metal templates. The drug-loaded carbo-
hydrate mixture is casted into the moulds to get the microneedles [20].
The time-based dissolution of carbohydrate regulates the drug release
inside the skin. Carbohydrates are cheap and safe for the human health
but degradation at high temperatures makes the fabrication process
difficult [8].
4.6. Polymer
A wide variety of polymers including poly (methyl methacrylate)
(PMMA) [21], polylactic acid (PLA) [22], poly (lactic-co-glycolic acid)
(PLGA) [23], polyglycolic acid (PGA) [17], poly (carbonate) [24],
cyclic-olefin copolymer, poly (vinylpyrrolidone) (PVP) [25], poly (vinyl
alcohol) (PVA) [25], polystyrene (PS) [26], poly (methyl vinyl ether-co-
maleic anhydride) [27], SU-8 photoresist [28] are reported for micro-
needles preparation. Mostly, dissolving or biodegradable and hydrogel-
forming microneedles arrays are made from these polymers. Micro-
needles fabricated with these polymers have less strength than other
materials but are tougher than glass and ceramics [8,9].
5. Types of Microneedle
Different types of microneedles fabricated and investigated for their
application in drug delivery are solid, coated, dissolving, hollow, and
Fig. 2. Mechanism of drug delivery by microneedle device: (1) Microneedle device with drug solution; (2) Device inserted into the skin; (3) Temporary mechanical
disruption of the skin; (4) Releasing the drug in the epidermis; (5) Transport of drug to the site of action.
T. Waghule et al. Biomedicine & Pharmacotherapy 109 (2019) 1249–1258
1251

hydrogel microneedles. Different types of microneedles with their un-
ique properties are displayed in Fig. 3. Each type of microneedle has its
own way of delivering the drug into the epidermis. Some are used just
to create pores in stratum corneum, some are precoated with the drug
solution on their surface, some are dissolvable and some are prefilled
with the drug solution [29–32].
5.1. Solid microneedles
Solid microneedles are mostly used for pre-treating the skin by
forming pores. Pointed tips of the needles penetrate into the skin; create
channels of micron size, through which the drug directly enters the skin
layers on the application of a drug patch, thus increasing the permea-
tion. The drug is taken up by the capillaries to show a systemic effect. It
can be used for a local effect also [29]. Solid microneedles deliver the
drug with passive diffusion to skin layers [1,30]. Narayanan et al fab-
ricated solid silicon long and tapered microneedles using tetra-
methylammonium hydroxide etching process. Microneedles with an
average height of 158 μm and base width of 110.5 μm were successfully
fabricated [33]. Later he also fabricated the gold-coated solid silicon
microneedles with the dimension of 250 μm in height, the base width of
52.8 μm, the aspect ratio of 4.73, tip angle and diameter of 24.5° and
45 μm. The results demonstrated improved bioavailability and me-
chanical strength [34]. Li et al studied polylactic acid microneedles and
found that biodegradable polymer solid microneedles have sufficient
mechanical strength to pierce the stratum corneum and can enhance the
absorption of the drug. The microneedles having 800 μm depth and
density of 256 MNs per cm
2
was found to enhance the drug permeation
[35]. Stainless steel microneedles are also studied by various re-
searchers. Enhanced delivery of captopril and metoprolol tartrate was
studied after application of stainless steel MN arrays [1].
5.2. Coated microneedles
The microneedles are surrounded with the drug solution or drug
dispersion layer [1]. Subsequent dissolution of drug from the layer
takes place and the drug is delivered quickly. The amount of drug that
can be loaded depends on the thickness of the coating layer and the size
of the needle which is usually very less [29]. Baek et al loaded lidocaine
on poly L-lactide (PLLA) microneedle arrays. The loaded lidocaine re-
leased rapidly in phosphate buffer saline and was found to be stable for
3 weeks [36]. Coated microneedle also explored for delivery of multiple
agents through same formulation. Li et al coated each microneedle with
different formulations and drugs thus allowing co-delivery of multiple
agents with different properties. These delivered water soluble and
water insoluble dyes simultaneously [37]. Chen and co-workers coated
PLA microneedles with sulforhodamine B and found the drug delivery
efficiency to be approximately 90%. The in-vitro studies in mice con-
firmed the continuous drug delivery [38].
5.3. Dissolving microneedles
Dissolving microneedles are fabricated with biodegradable poly-
mers by encapsulating the drug into the polymer. After inserting mi-
croneedle in the skin, dissolution takes place which releases the drug.
The application involves only a single step as the microneedle is not to
be removed out after insertion as in other cases. The polymer gets de-
graded inside the skin and controls the drug release. The bio-accept-
ability and dissolution of the polymer inside the skin make it one of the
best choices for long-term therapy with improved patient compliance
[1]. Effective needle drug distribution is an important factor which
faces problems while developing dissolving microneedles. Hence,
polymer-drug mixing is a critical step in such fabrication [30]. Chen
and his group developed tip dissolving microneedles which showed
rapid and efficient drug delivery without skin irritation [39]. Dissolving
microneedles take time to dissolve and complete insertion is difficult.
Zhu et al developed rapidly separating microneedles mounted on solid
microneedles which gave sufficient mechanical strength to the micro-
needles and approx 90% delivery efficiency was observed in 30 s [40].
Wang et al introduced the addition of bubbles to the dissolving mi-
croneedles to prevent drug diffusion in the entire microneedles. These
were found to achieve about 80% of drug delivery efficiency in 20 s
[41]. Separable arrowhead microneedles were developed by Chu et al.
Sharp polymer tips encapsulated with the drug were mounted on blunt
metal shafts which separate or dissolve on insertion in the skin within a
few seconds. These modifications in dissolving microneedles showed
that possibilities of the rapid drug delivery with controlled release ki-
netics [42].
5.4. Hollow microneedles
Hollow microneedles have an empty space inside which is filled
with the drug dispersion or solution. They have holes at the tips. On
inserting into the skin, the drug is directly deposited into the epidermis
Fig. 3. Different types of microneedles (a) Solid mi-
croneedles use poke with patch approach, are used for
pre-treatment of the skin; (b) Coated microneedles use
coat and poke approach, an coating of drug solution is
applied on the needle surface; (c) Dissolving micro-
needles are made of biodegradable polymers; (d)
Hollow microneedles are filled with the drug solution
and deposit the drug in the dermis.
T. Waghule et al. Biomedicine & Pharmacotherapy 109 (2019) 1249–1258
1252

or the upper dermis layer. Mostly it is used for high molecular weight
compounds such as proteins, vaccines, and oligonucleotides [1]. The
drug flow rate and release pressure can be adjusted if the drug is to be
given by a rapid bolus injection. These microneedles are capable of
administering a large dose of the drug as more amount of drug can be
accommodated into the empty space inside the needle. Maintaining a
constant flow rate is essential here [32]. Increase in the microneedle
bore can increase flow rate but lead to reduced strength and sharpness.
Sometimes a metal coat is applied on the microneedle to increase the
strength of the microneedle but this can make the needles sharp [1].
Mishra et al developed hollow microneedles aligned on the silicon
substrate having a length of 500–600 μm and 100 μm outer diameter.
The flow rate of 0.93 μls
−1
was achieved at 2 K Pa pressure difference
[43]. Maaden and co-workers fabricated fused silica hollow micro-
needles using hydrofluoric acid etching. These microneedles were able
to inject very less amount of vaccine into the skin in an automated
manner thus overcoming the drawbacks of the hypodermic needle [44].
Interestingly Suzuki and colleagues developed hollow microneedles
which were mimicking the action of mosquitoes and the designed mi-
croneedles showed improved penetration in the skin [31].
5.5. Hydrogel-forming microneedles
This type of microneedle is recently developed. Super-swelling
polymers are used to make microneedles. The polymers constitute the
hydrophilic structure which makes it capable of taking up a large
amount of water into their three-dimensional polymeric network. These
polymers swell when inserted into the skin due to the presence of the
interstitial fluid. This leads to the formation of channels between the
capillary circulation and the drug patch. Before needling, these mi-
croneedles are just used to disrupt the skin barrier. On swelling, they
behave as a rate controlling membrane. They have flexibility in size and
shape. Easy sterilization and intact removal from the skin are the un-
ique properties of such microneedles [45]. Migdadi et al studied hy-
drogel-forming microneedles to administer metformin transdermally so
as to decrease the gastrointestinal side effects associated with the oral
delivery. Results demonstrated the improved permeation and bioa-
vailability of the drug with designed microneedles [46]. Cross-linked
polymers are also utilized for fabricating swellable microneedles for
drug delivery.
6. Methods of delivering drug
Various methods can be used to deliver the drug into the epidermis
layer. One approach is to poke the skin with the microneedles to create
holes, followed by removal of the microneedle and application of the
drug-containing patch over it. This creates a direct transport pathway
for a drug to travel into the skin. The electric field can be applied for
better effect. The second approach is to cover the microneedle surface
with a coating layer containing the drug. The coated microneedles are
inserted into the skin where drug dissolution takes place from the
coating [6]. The third approach is to dip the microneedles into the
solution containing drug and scrape the needles on the skin. The drug is
left behind into the abrasions. Another approach is to incorporate the
drug into a biodegradable polymer and fabricate the microneedles from
the mixture. One can design a hollow microneedle where the drug so-
lution can be filled into the hollow space of the microneedles [8,34].
7. Fabrication techniques
The selection of fabrication or manufacturing method for micro-
needles depends on the type, geometry and the material of the micro-
needle [29]. Various techniques used for different type of microneedles
are mentioned in Table 2 [47–49].
8. Evaluation of microneedles
8.1. Characterization methods
The drug can be loaded onto or into the microneedles either in
suspension/dispersion form or encapsulated form (liposomes, nano-
particles, nanoliposomes) [37]. The drug can be coated with the
polymer solution or can be applied as a patch. Various physicochemical
characterizations including particle size, polydispersity index, viscosity,
and zeta potential can be evaluated for loaded drug depending on the
type of formulation used in the microneedles [50]. Drug release, ad-
hesion, permeation tests are performed for a patch which is applied
after pre-treatment. The size, internal structure, and crystallinity of the
liposomes or nanocarriers can be performed using a dynamic light
scattering, X-ray scattering, and transmission electron microscopy
technique. Stability studies of drug dispersion and microneedles can be
studied at a different temperature, pH and simulated in-vivo physio-
logical conditions (cell line or tissues). Other tests like solubility stu-
dies, drug content, in-vitro release tests, and biocompatibility studies
are also performed on designed microneedle [5,15].
8.2. Dimensional evaluation
Various methods are used to evaluate the needle geometry and to
measure the tip radius, length, height of the microneedle. Most
common methods are optical or electrical microscopy. Analysis of a 3D
image gives a better picture of needle geometry and helps in quality
control. Scanning Electron Microscope (SEM) and confocal laser mi-
croscope have been used for this purpose. SEM produces an image of a
sample by making use of a focused beam of electrons which interact
with the atoms in the sample while scanning and produce various sig-
nals which give information about sample surface topography and
composition. Confocal laser microscope produces high-resolution
images [51,52].
8.3. Mechanical properties or insertion forces
A microneedle must be sharp and slender enough so that it can
easily penetrate into the skin and also be strong enough so that it does
not break when inside the skin. Mechanical tests which are performed
on microneedles are given in Table 3. Two important factors for a safe
and efficient design of microneedles are the force at which the micro-
needle loses its structural integrity and the insertion force. The ratio of
these two forces is called as the ‘safety factor’. The ratio is preferred to
be as high as possible [53].
8.4. In-vitro skin permeation studies
Diffusion cell apparatus is used to find the permeation of the drug
through the skin. Pig ear skin is mostly used in the experiment which is
mounted between the receptor and donor compartment. The cumula-
tive permeation profiles of microneedle treated and untreated skin are
compared [54].
8.5. In-vivo animal model studies
Hairless rats can be used for the study. A suitable technique to an-
esthetize the animal shall be used. One of the parameters considered is
trans-epidermal water loss (TEWL) which is measured before and after
micro needling. Delfin Vapometer is used to measure this parameter
[54].
T. Waghule et al. Biomedicine & Pharmacotherapy 109 (2019) 1249–1258
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9. Patient compliance and safety
9.1. Skin recovery process
When a microneedle device is inserted into the skin and removed
after the treatment, it leaves behind holes of micron size. It may take
time to reseal these pores. These holes need to be resealed quickly,
otherwise may cause infection. The time taken by the skin to recover its
barrier properties is important. Pore resealing can be studied by elec-
trical impedance measurement. It can take 2–40 hrs to recover de-
pending on whether the skin is occluded or not and also the geometry of
the needle. TEWL and tissue staining can also be used to study pore
resealing [29,30].
9.2. Skin irritation
The normally used transdermal injections even show a small swel-
ling around the site. This is because the skin layer is disrupted while a
foreign material is being inserted into the skin [29].
9.3. Skin irritation and infection
As the skin is exposed to various environmental stresses, skin carries
various defense mechanisms to protect itself. In case of sensitive skin,
use of microneedles can cause mild to moderate skin irritation or al-
lergy. Redness, pain, swelling can be seen. Itching can cause patient
discomfort [55]. Holes caused by inserting microneedles into the skin
can be a site of infection unless the needles are sterile. Although the
pores created by microneedles are very small as compared to that of a
hypodermic needle, thus show less microbial penetration [29].
9.4. Pain
The microneedles do not reach the pain receptors which are deep
into the dermis, thus cause less pain as compared to that of a hypo-
dermic needle. The intensity of pain depends on the number of mi-
croneedles on a patch, length of the microneedle and the tip angle or
needle shape [29]. Gill et al confirmed that microneedles cause less
pain than a 26-gauge hypodermic needle. Lesser the microneedles
length and number on the patch, less is the pain associated with the
therapy [56].
10. Applications
10.1. Oligonucleotide delivery
Oligonucleotides are short DNA or RNA molecules. Delivering oli-
gonucleotide to their intracellular site of action is difficult. Therefore
various techniques to enhance the delivery were discovered. An attempt
to deliver 20-merphosphorothioated oligodeoxynucleotide was made
using the microneedle approach. Solid microneedles made up of
stainless steel or titanium were tried to deliver oligonucleotides using
the poke with patch approach. More amount of drug was found to reach
the site of action as compared to the intact skin. Using iontophoresis
along with microneedle approach gave better results than iontophoresis
alone [2,57].
10.2. Vaccine therapy
A vaccine is a biological preparation. It provides active acquired
immunity to a particular disease. Vaccine constitutes a killed or wea-
kened form of disease-causing micro-organism, its toxins or one of its
surface proteins. Vaccine therapy stimulates the immune system of the
body and provides protection against the future micro-organism en-
counter. Microneedle approach was found to be effective in vaccine
therapy [29,30].
DNA vaccine was delivered using microneedle. Immune responses
seen were much better than that of the normal injections [58]. An at-
tempt to develop a microneedle patch which can be used for adminis-
tering influenza vaccine was also made [59]. A less dose is required
when the drug is administered using hollow microneedles as compared
to intramuscular injection. Administration of anthrax and rabies vac-
cine using hollow microneedles was also studied [8]. Ogai and collea-
gues fabricated hollow microneedles from poly-glycolic acid to enhance
the vaccination efficiency by the intradermal route. The precise de-
livery of the drug in the upper dermis provides enhanced immunity.
After the vaccination, the antibody titers were significantly higher with
Table 2
Fabrication techniques for different types of microneedles [47–49].
Type of microneedle Fabrication techniques
Solid microneedle
Silicon microneedle Silicon dry-etching process,
Isotropic etching, Anisotropic wet etching,
Dicing a silicon substrate and then acid etching.
Three-dimensional laser ablation,
Metal microneedles Laser cutting, Wet etching,
Metal electroplating methods.
Polymer microneedles Photolithography.
Ceramic microneedles Ceramic micro moulding and sintering lithography.
Coated microneedles Dipping or spraying the microneedles with an aqueous solution of increased viscosity to retain more formulation during drying and which contains a
surfactant, the active agent and a stabilizing agent.
Microneedles can be dipped one time or more than one time into a coating solution, each individual microneedle can be dipped into a microwell
containing drug solution or a film of drug solution previously formed on the roller can be applied.
Layer-by-layer coating techniques.
Dissolving microneedles Micro moulding.
Hollow microneedles Micro-electromechanical systems (MEMS) techniques-laser micromachining, deep reactive ion etching of silicon, an integrated lithographic
moulding technique, deep X-ray photolithography, wet chemical etching and micro-fabrication.
Table 3
Mechanical characterization tests [29,53].
Parameter Tests
Insertion force Dye marking,
Force-displacement tests
or Electrical measurements
Insertion depth Histological cryosectioning and staining,
confocal microscopy and
Optical tomography
Failure force Pressing the device on a rigid surface,
Displacement force tests
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intradermal vaccination with microneedles as compared to sub-
cutaneous injection on 15th day [60]. Dissolving microneedles were
also investigated for intradermal vaccination [61].
10.3. Peptide delivery
Peptides are enzymatically degraded when administered through
the oral route. Transdermal delivery avoids this but less amount of
peptide is able to cross the skin. Peptide delivery through microneedles
can help overcome poor skin penetration of the peptides. Desmopressin
is a synthetic form of vasopressin, a potent peptide hormone. It is used
to replace low levels of vasopressin. This medication is used to treat
diabetes insipidus, bedwetting in young children and hemophilia A. Use
of microneedle approach to deliver desmopressin was studied which
showed that microneedle delivery was safe and more efficient as
compared to other routes [2]. Cyclosporin A is a water-insoluble and
high molecular weight cyclic peptide which is used to treat various skin
diseases. Dissolving microneedles containing cyclosporine A with the
dimension of 600 μm in length and 250 μm wide were prepared by
molding process. Fabricated microneedles with 10% cyclosporine A was
pressed into the porcine skin for 60 min which showed dissolving of
approx 65% of microneedle with 34 ± 6.5 μg drug delivery [62]. In
one study, GAP- 26 which is a gap junction blocker loaded polyethylene
glycol diacrylate based microneedles were fabricated by Liu et al for
delivering peptides through swelling effect. The designed microneedles
showed improved permeation of loaded peptide which confirmed with
the inhibition of the proliferation of keloid fibroblasts and the collagen I
expression [63].
10.4. Hormone delivery
Insulin is a peptide hormone. The medication is used to lower the
high blood sugar levels. Delivering insulin using microneedle was found
to lower blood glucose levels more efficiently [64]. Li et al fabricated
solid microneedles and studied the effect on blood glucose levels in
diabetic mice on delivery of insulin. The results demonstrated the re-
duced blood glucose level to 29% of the initial level at 5 h which
confirmed the improved permeability of insulin to the skin using mi-
croneedle [35]. Ye and co-workers investigated microneedles in-
tegrated with pancreatic β-cell capsules which sense the blood glucose
levels and secrete the insulin. But the patch was not found to function
effectively. Thus microneedle matrix containing synthetic glucose
signal amplifiers (GSAs) was developed which was consist of nanove-
sicles containing glucose oxidase, α- amylase and glucoamylase en-
zymes. These amplifiers showed the secretion of insulin from the β-cells
capsules [65]. The results of clinical study conducted for parathyroid
hormone (I-34) coated microneedles demonstrated the 3 times shorter
T
max
and 2 times shorter apparent T
1/2
compared to conventional in-
jection therapy [66]. These studies indicated that microneedle can be
utilized efficiently for the hormonal therapy. Further, these can also be
modified for sustained action with the use of suitable polymers [67].
Additionally, iontophoresis in combination with microneedles can also
be explored for delivery of various hormones [68].
10.5. Cosmetics
Microneedle use in cosmetics is gaining importance; especially to
improve the skin appearance and to treat skin blemishes and scars. An
attempt to deliver some cosmetic active ingredients like ascorbic acid,
eflornithine, retinyl retinoate was made using the microneedle ap-
proach [8]. Melanin was incorporated into phosphatidylcholine lipo-
somes (nanoliposomes) which showed increased solubility in lipids.
Amount of pigment that reached deep near the hair structures was
found to be more on application by an e-roller [69]. Enhanced delivery
of melanostatin, rigin and pal-KTTKS was also investigated through the
use of microneedles [70].
10.6. Lidocaine delivery
Lidocaine is used for local anesthesia. Administering lidocaine
through microneedle causes less pain as compared to hypodermic in-
jection and thus shows better patient compliance [29].
Baek et al coated the microneedle tips with lidocaine. These mi-
croneedles showed consistent in vitro skin penetration and enhanced
delivery of the drug in 2 min. Hence, microneedles can be used for pain-
free and rapid local anesthesia [36]. In one study, microneedles coated
with PEG-lidocaine dispersions showed improved drug delivery within
3 min compared to the topical formulation [1].
10.7. Pain therapy
Meloxicam loaded polymeric microneedles were prepared using
polydimethylsiloxane molds. The in-vitro permeation studies showed
approx 100% drug release in 60 min. The drug deposition was found to
be 63.37% and improved transdermal flux of 1.60 μg/cm
2
/hr was ob-
served. The permeation increased 2.58 times compared to free drug
solution [71]. Neuropathic pain is usually difficult to treat. The avail-
able treatments are not able to provide sufficient pain relief and show
certain side effects. Dissolvable microneedles were explored for treating
neuropathic pain. These delivered selective calcitonin gene-related
peptide (CGRP) antagonist peptide and showed high specificity against
the receptors. The analgesic microneedle patch showed no skin irrita-
tion and side effects. About 75% microneedle dissolved within 20 min
on the application [72]. The effective delivery of therapeutics through
microneedle has opened the huge opportunities for the industries for
pain management.
10.8. Ocular delivery
Many posterior segment indications can be treated by targeting drug
delivery. Iontophoresis was used to deliver nanoparticles through the
suprachoroidal space. Without iontophoresis, the particles were found
to localize at the injection site. When combined with microneedles
more than 30% of nanoparticles were delivered to the posterior seg-
ment of the eye [73].
10.9. Cancer therapy
Cancer affects many people every year in the world and cancer
treatment faces lots of challenges. Microneedles have been investigated
for various anticancer drugs delivery. Self-degradable microneedles
were investigated for melanoma treatment by delivering anti-PD-1
(aPD1) in a sustained manner. Anti-PD-1 and glucose oxidase loaded
pH-sensitive dextran nanoparticles were delivered through microneedle
[74]. A topical cream containing 5-fluorouracil is used to treat basal cell
carcinoma. The permeability of 5-fluorouracil was enhanced up to 4.5
times when the cream was applied on the skin treated with solid mi-
croneedles. Significant inhibition of tumour growth further confirmed
improved efficacy using microneedles [75]. Bhatnagar et al investigated
the delivery of chemotherapeutic agents- tamoxifen and gemcitabine
through microneedles for the treatment of breast cancer. Localized
delivery of these drugs would help to reduce the side effects [76].
Polymeric microneedles were also investigated for skin cancer and lo-
calized delivery of anticancer drugs [77].
11. Approved products
The first microneedle product was derma roller. Many microneedle
products are coming in the market and are approved for medical and
cosmetic use [2,29,78]. Some of them are mentioned in Table 4. Many
companies in Germany, US, Europe, Japan are selling microneedle
products [9].
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12. Clinical trials and safety
A lot of pre-clinical studies were carried out on microneedles and
were found effective in many aspects but only a few gain successes in
human subjects. Kaushik et al conducted the first study for micro-
needles in human subjects in the year 2001. The aim was to find
whether the silicon microneedles are small enough to prevent pain as
compared to a 26-gauge hypodermic needle. The microneedles were
applied to the forearm of the 12 male and female healthy volunteers
selected for the study. The study concluded that the pain caused by the
microneedles was less than that caused by the hypodermic needles
[79]. Arya and co-workers conducted trials to find whether micro-
needles cause local skin reactions and acceptable by patients or not. The
study was conducted on 15 human subjects. The study demonstrated
that the microneedles did not cause any swelling, pain or erythema at
the site of application of the patch. The patients were able to self-ad-
minister the patches by hand without the need of the applicator. The
human subjects preferred these more than the conventional needles
[80]. The randomized clinical trial was conducted on 21 men to in-
vestigate the enhanced delivery of lidocaine after pretreatment with
microneedles. Topical 4% lidocaine cream produced anesthesia after
60 min of the application. With the microneedles pre-treatment, an-
esthesia was produced within 30 min. [81]. An open trial was con-
ducted on 10 patients for hyaluronic acid-based microneedle patch to
investigate the therapeutic effects to treat psoriasis. Calcipotriol-beta-
methasone ointment was applied on the skin. Microneedle patch was
applied over this once every day for a week. The one-week application
significantly reduced the psoriatic plaques and thus was found efficient
compared to the conventional cream application [82].
13. Current research, challenges, and future trends
The first microneedle was made up of silicon. A study was con-
ducted to explore if microneedle can be used to deliver drugs through
the skin more efficiently or not. Initially, the permeation studies were
done on cadaver skin to see if large molecules like albumin, insulin can
pass through the skin on using microneedles. Further studies confirmed
better delivery of large molecules by microneedles. Currently, many
new exciting microneedle concepts are coming out which will be of
great help in the future [2].
Microneedle approach is being applied to a number of drugs, but it
has to encounter various challenges before it can release to the market.
A lot of studies have to be conducted to get it clinically approved. The
main problems associated with the microneedles technology include,
skin allergy, redness and irritation. A limited amount of drug can be
loaded into the microneedle. Passing hydrophilic and large compounds
through the skin is a major challenge. A proper material has to be se-
lected in the fabrication of these needles, which has adequate me-
chanical strength and insertion force. The main objective is to increase
the permeation without causing pain. It could be difficult for a patient
to first poke with a needle and then apply the patch. There is a chance
of infection if the skin pores do not close after application [1].
A number of technologies are developing to deliver the drug
through the skin. Various modifications have been investigated in the
conventional microneedles. 3M's hollow microneedle is one of them.
This emerging technology is flexible enough and can be used to ad-
minister some hundreds of milligrams of proteins, which go directly
into the systemic circulation [83]. Combination of ultrasound and
transdermal drug delivery is also studied in order to further increase the
drug permeability [84]. Thus, microneedles can be fabricated with a
variety of modifications in order to smartly deliver the drug through the
skin providing a new direction and revolution in the field of trans-
dermal drug delivery systems.
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Product name Company name Description of the product Use
Dermaroller®Dermaroller®Germany,
White Lotus
A cylindrical roller with solid or metal microneedles,
0.2–2.5 mm in length.
Improve skin texture,
treat scars and hyperpigmentation.
C-8 (Cosmetic type) The Dermaroller Series by
Anastassakis K.
A needle length of only 0.13 mm (130 μm) Used to enhance penetration of topical
agents.
CIT-8 (Collagen Induction
Therapy
The Dermaroller Series by
Anastassakis K.
A needle length of 0.5 mm (500 μm) Used in collagen induction and skin
remodeling.
MF-8 type The Dermaroller Series by
Anastassakis K.
A needle length of 1.5 mm (1500 μm) Treat scars.
MS-4 The Dermaroller Series by
Anastassakis K.
A Small cylinder, 1 cm length, 2 cm diameter, and 4 circular
arrays of needles which are 1.5 mm in length
Used on facial acne scars
MicroHyala®CosMed transdermal drug
delivery
Dissolving microneedle patch with hyaluronic acid Wrinkle treatment
LiteClear®Nanomed skincare Solid silicon microneedles are used as pre-treatment and then
drug applied topically.
Treats acne and skin blemishes
Soluvia®SanofiPasteur Europe Hollow microneedle
attached to a syringe
Influenza vaccination
h-patch Valeritas Small adhesive machine like patch is used To deliver drugs in subcutaneous tissue
(insulin)
Microstructured transdermal
system
3M Hollow microneedle To deliver biologics and other small
molecules
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