review on microneedles
TRANSCRIPT
A Review on Mironeedles/ Ghanvat Mitesh
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REVIEW ON MICRONEEDLES
*Ghanvat MD, Gadhave MV, Jadhav SL, Gaikwad DD
Department of Pharmaceutics
VJSM’s, Vishal Institute of Pharmaceutical Education and Research, Ale,(412411)
E-mail ID: [email protected]
Contact No.: 9850216393, 9403968982
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ABSTRACT
Patch-based transdermal drug delivery offers a convenient way to administer drugs without
the drawbacks of standard hypodermic injections relating to issues such as patient
acceptability and injection safety. However, conventional transdermal drug delivery is
limited to therapeutics where the drug can diffuse across the skin barrier.
By using miniaturized needles, a pathway into the human body can be established which
allow transport of macromolecular drugs such as insulin or vaccines. These microneedles
only penetrate the outermost skin layers, superficial enough not to reach the nerve receptors
of the lower skin. Thus, microneedle insertions are perceived as painless.
The thesis presents research in the field of microneedle-based drug delivery with the specific
aim of investigating a microneedle-based transdermal patch concept. To enable controllable
drug infusion and still maintain an unobtrusive and easy-to-use, patch-like design, the system
includes a small active dispenser mechanism. The dispenser is based on a novel thermal
actuator consisting of highly expandable microspheres.
When actuated, the microspheres expand into a liquid reservoir and, subsequently, dispense
stored liquid through outlet holes.
The microneedles are fabricated in monocrystalline silicon by Deep Reactive Ion Etching.
The needles are organized in arrays situated on a chip. To allow active delivery, the
microneedles are hollow with the needle bore-opening located on the side of the needle. This
way, the needle can have a sharp and well-defined needle tip. A sharp needle is a further
requirement to achieve microneedle insertion into skin by hand.
The thesis presents fabrication and evaluation of both the microneedle structure and the
transdermal patch as such. Issues such as penetration reliability, liquid delivery into the skin
and microneedle packaging are discussed. The microneedle patch was also tested and studied
in vivo for insulin delivery. Results show that intradermal administration with microneedles
give rise to similar insulin concentration as standard subcutaneous delivery with the same
dose rate.
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INTRODUCTION
Every drug needs a drug delivery system. Drug delivery is defined as the administration of
the drug into the body through different routes. There are different types of drug delivery
systems developed to administer the drug to the body. Previously, the drug delivery systems
were developed for the traditional routes of administration like oral or parenteral route but in
the last few years many nonconventional routes have been developed such as Transdermal-
through skin, nasal, ocular- through eye, pulmonary- by lungs. In short, many novel drug
delivery systems there have been developed from last few years for the purpose of the
administration of drug to the body to make drug more effective and easy to administer. Every
drug needs the drug delivery system; different drugs are delivered by different routes3.
There are many routes of drug administration invented in recent years. Drugs are used to treat
the diseases using different routes of administration. Each route has its own advantages and
disadvantages. We can use any route to administer the drug into the body as per our
requirements.
There are many routes of drug administration invented in recent years. Drugs are used to treat
the diseases using different routes of administration. Each route has its own advantages and
disadvantages. We can use any route to administer the drug into the body as per our
requirements. Now, we will discuss about the different routes of drug administration which
are generally used.
The different types of drug delivery routes that have been designed to date are as follows.
1. Topical application or local application: - These types of drugs are used by applying on
skin or mucous membrane. Drugs like dusting powder, lotion, paste, ointment or plaster is
used by this type of route. Such type of forms of drugs may also be administered by topical
application like bougie for urethra, pessary for vagina and suppository for vagina and
rectum. The advantages of this route are rapid penetration by skin and reaches into the
systemic circulation, drug absorption at constant rate, avoidance of first-pass effect,
bypassing GI tract. The disadvantages include messy and difficult application, unpleasant
odour and greasy, smudging on application.
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2.Enemata: - The liquid formations of drugs or medicaments are given by rectum in this
route. There are two types of enema - Evacuant enema E.g. Soap water enema. The other
type is Retention enema. E.g. Prednisolone enema for ulcerative colitis.
3.Oral or enteral route: - This route administers most of the drugs. This is the very most
commonly employed route to administer the drug like paracetamol and some antibiotic
drugs.
4.Parenteral route: - In this route, the drugs are given by routes other than alimentary tract
using injections.
5.Injections: - Different routes are used to administer various types of injections including
Intradermal in which the drugs are given into the layers of the skin. E.g. BCG vaccine.
Subcutaneous routes are generally used to administer only non-irritant substances. Insulin
is the most common drug administered by this route. Intramuscular is another route
wherein the drugs are administered into the muscles. This route delivers most of the
vaccines. Soluble substances, mild irritants, suspensions, and colloidal substances are
administered by this route. Using Intravenous routes drugs can be given directly to the
vein. This route is used when rapid onset of action is required. E.g. Furosemide. Intra-
arterial routes are used to administer the drug directly into the arteries. It is used to
produce a sudden high concentration in arterial blood. E.g. antimalignancy compounds.
Intrathecal is a rarely used route wherein drugs are given directly into the subarachnoid
space and act directly on the central nervous system. E.g. Some antibiotics and
antimalignancy drugs4.
However the different type of injections are used to deliver the drug and most of the vaccines
are delivered by intramuscular route by injection and these injections are very painful and
may be create an inflammation of the skin. The another drug delivery system need to be
discovered, especially for vaccine delivery like microneedle that can be used as
transdermally as it is a painless delivery and it has more efficacy than injections.
There are many routes using to deliver the drugs and each route has advantages and
disadvantages. Some drugs need a specific route of administration. Transdermal drug
delivery system has major advantages over the other delivery systems. This drug delivery
system is used by the patch. E.g. Sumatriptan for migraine and atenolol for hypertension.
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Other techniques, which can be used by transdermal, are an Iontophoresis, Electric patch,
Radiofrequencies, Micro needles, Ultrasound that will be given through the skin direct into
the bloodstream to produce quick therapeutic response2.
Need for New Routes of Administration
Above, we saw that there are many routes using to deliver the drugs and each route has
advantages and disadvantages. Some drugs need a specific route of administration.
Therefore it is necessary to invent new routes of drug administration with maximum
advantages with convenience to patients being of utmost importance. By inventing new
routes, drugs might be more effective than their existing route thereby being of help to the
physicians and patients too. In the case of vaccine delivery, we can be delivered it by
intradermal route using new microneedles patch system, which is going to be developed. We
hope that the new microneedles to be a commonest delivery system for the drug delivery,
especially for the vaccine delivery, as it will carry more advantages like painless delivery,
rapid onset of action than other injections and more efficacious drug delivery2.
New Drug Delivery System (NDDS)
Introduction
When the new drug or existing drug is given, altering the formulation and administered
through the different route, this process is called as the novel drug delivery system. One drug
can elicit its different pharmacological responses, when administered by different routes. Its
absorption rate, release of the drug and efficacy may also change5. Pulmonary drug delivery
is also an important route that is used by aerosols, nebulizers, and metered dose inhaler
system. E.g. powder and solutions are delivered by this drug delivery system. The lung route
is used to deliver the proteins and peptides as well as using into the gene therapy which is
used in the treatment of cystic fibrosis. Transdermal drug delivery system has major
advantages over the other delivery systems. This drug delivery system is used by the patch.
E.g. sumatriptan for migraine and atenolol for hypertension. Other techniques, which can be
used by transdermal, are an Iontophoresis, Electric patch, Radiofrequencies, Micro needles,
Ultrasound that will be given through the skin direct into the bloodstream to produce quick
therapeutic response. Microneedles will be used as a transdermally for drug delivery and
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especially for the vaccine delivery. The microneedles will be used as skin patch system by
penetrating into the layer of the skin. The drug delivery through the microneedle might be
common techniques in the next future for the administration of various drugs as well as
vaccines6, 7.
Gene delivery system is used for the treatment of the genetic disorders. Nano drug delivery
systems can be administered the large dose of drug. Combine drug delivery system, which is
used by the combination of drug and medical device. The lab-on-achip is a device is used as
remedies for point-of-care and for the prevention of disease. Nanoparticles and
nanoformulation are showing good response compare to other drug delivery systems.
Nanocapsules can be used for the treatment of cancer. Nanoparticulate drug delivery systems
are using as anti-tumour therapy, antibiotics, anti-hypertensive, gene therapy, and
radiotherapy and for the administration of vaccines and proteins. The drug delivery by the
nasal mucosal route is developing for the administration of the drug via nasal inhalation to
the body or brain. The dendrimer based drug delivery method will be used for the treatment
of AIDS. Hence new drug delivery systems are bringing new way of the treatment of various
diseases, which might make the life easy to live6, 7.
Transdermal Drug Delivery System
Transdermal drug delivery system has been developed 20 years ago. It is a technique used as
topically administration of the drug into the skin by patch which is seen an alternative to
giving to the mouth, intravenous, intramuscular and the other routes of administration.
Nowadays there are many drugs which are using transdermally not only for dermatological
disorder but for various disease. The transdermal drug delivery system has been developed
for the controlled release of drugs through the skin into the systemic circulation. Transdermal
drug delivery system carries some advantages like drug can be administered at a constant rate
for a longer period, bypassing GI tract, first pass effect avoidance, rapid penetration of the
drug into the systemic circulation etc. and some disadvantages like drug can not be given in
condition when the drug is in the large amount, drug has a large molecular size, drug is
highly lipophilic or hydrophilic, drug is sensitive to the skin and drug metabolized into the
skin4. Transdermal drug delivery has proven successful in a number of applications,
including pain management, congestive heart failure and hormone replacement.
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Transdermal administration offers advantages over other delivery techniques, but existing
systems can only be used for a narrow range of compounds that easily pass through the
skin2.
Most of the methods presented in this actually deliver the drug into the skin tissue itself, i.e.
intradermally. However, they are referred to as transdermal techniques since the primary goal
is to achieve systemic distribution. Hence, the skin itself merely functions as a buffer space
for subsequent diffusive spread of the drug into the capillaries and further to the bloodstream.
Skin as the delivery site may be advantageous since it, in the lower parts, contains a dense
vascular network which can promote the uptake of the drug8, 9. There are a number of patches
of different drugs which are going to be developed, of anti-pyretic agents, anti-arrhythmic
agents, anti-histaminic agents, antibiotics, beta channel blockers, calcium channel blockers,
analgesics, anti-hypertensive agents, antiviral agents, hormones, insulin. There are some
drugs that have been marketed and have proved that the transdermal drug delivery system has
advantages over the other routes of administration. E.g. Nicotine patch is most successful
example, which is used to suppress the smoker’s uncontrolled desire of smoke if
continuously applied for 16 hours. Some contraceptives including estrogens – progestin are
used once in a week. Scopolamine patch is used to treat the motion sickness if applied behind
the ear for three days. Fantanyl patch is used for continuous pain relief by applying for 72
hours. Pilocarpine is used for 4 days in the treatment of glaucoma. The clinical trials of these
drugs are going on and might be marketed in short future. We can say that after 20 years, the
transdermal drug delivery system will be a common route of drug administration11.
Marketed and Expected Transdermal Products
There are a number of patches of different drugs which are going to be developed, of anti-
pyretic agents, anti-arrhythmic agents, anti-histaminic agents, antibiotics, beta channel
blockers, calcium channel blockers, analgesics, anti-hypertensive agents, antiviral agents,
hormones, insulin. There are some drugs that have been marketed and have proved that the
transdermal drug delivery system has advantages over the other routes of administration. E.g.
Nicotine patch is most successful example, which is used to suppress the smoker’s
uncontrolled desire of smoke if continuously applied for 16 hours. Some contraceptives
including estrogens– progestin are used once in a week. Scopolamine patch is used to treat
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the motion sickness if applied behind the ear for three days. Fantanyl patch is used for
continuous pain relief by applying for 72 hours. Pilocarpine is used for 4 days in the
treatment of glaucoma. The clinical trials of these drugs are going on and might be marketed
in short future. We can say that after 20 years, the transdermal drug delivery system will be a
common route of drug administration11.
Table 1: Patches of different drugs to be developed12
Compounds TDD technology Development
Alprostadil Gel Preclinical
Buprenorphine Patch Phase III
Dexamethasone Iontophoresis Phase III
Dextroamphetamine Patch Preclinical
Diclofenac Patch Preclinical
Dihydrotestosterone Gel Phase III
Estradiol Gel Phase III
Androgen / Estradiol Patch Phase II
Estradiol / progestin Patch Submitted NDA
Testosterone / Estradiol Patch Phase III
Fantanyl Patch, Iontophoresis Preclinical to Phase III
Flurbiprofen Patch Preclinical
Lidocaine Iontophoresis Phase III
Glucagon-like-peptide-1 Microneedle Preclinical
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Methylphenidate Patch Submitted NDA
Parathyroid Hormone Microneedle Preclinical
Rotigotine Patch Phase III
Testosterone GelPreclinical to Submitted
NDA
Unknown compound for
treatment of
onycomycosis
PatchPhase III
Vaccines (various) Patch Preclinical
Various
(macromolecules)Sonophoresis Preclinical
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MICRONEEDLES – THE NOVEL DRUG DELIVERY SYSTEM
History
The transdermal drug delivery has been developed from recent years. Nowadays there are
different drug delivery systems and different devices are being developed to treat the various
diseases. In this new drug development process, the Microneedle is one of them, which will
be used transdermally. If we will see the history of the needles, on the basis of different
phases, the first phase of the needles was invention, development and refinement of glass
syringes from 1850 to1940. Dr. Charles Gabriel Pravaz and Dr. Alexander Wood were the
first developers of the syringes with needle in 1853, which could be used for piercing the
skin. The second phase included development of single use, sterile, plastic disposable
syringes from 1950 to 1980. We are currently seeing the third phase with the development of
different needles to reduce the risk of transmission of severe diseases. In the near future, the
fourth phase is likely to come which will be based on the invention and development of new
technologies to develop different microneedles, which will be used to administer the drug
and vaccines, minimizing pain and maximizing effectiveness over the existing ones in all
characteristics13.
Introduction
Microneedles can be defined as the solid or hollow cannula with an insertion length of
approximately 20 to 1500μm and the external diameter of no more than approximately
300μm. However, earlier needles were used for parenteral route only, now it will be used as
transdermal drug delivery system using patch system. Today, most of the scientists are trying
for the innovations in the different transdermal drug delivery system. The drug delivery by
using the microneedles is an alternative approach to administer the drug across the stratum
corneum. The microneedle is also a new drug delivery system to be used as transdermally
that will be applied as a skin patch system2.
The microneedles made up from silicon, glass, metals or biodegradable polymers. The
microneedles have been fabricated by the Micro-Electro-Mechanical System (MEMS). It is a
skin patch system, which is applied on the skin using microneedles to deliver the drugs and
vaccines because of the microneedles, will provide a quick response disrupting the stratum
corneum. The microneedles have been design to penetrate into the skin about the depth of
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200μm. On the application of microneedles by patch system, they create the holes in the skin
so that the molecules of the drug can penetrate across the skin and administration of drug can
improve. Microneedles are much thinner than the diameter of our hair and it’s painless on the
application. It will be used for the instant systemic response and enhance the vaccine
delivery12.
Figure 1: Microneedle with blue colour (electron micrograph close up).
Advantages
There are some advantages of using microneedle as a transdermal drug delivery system like
the microneedles can improve the administration of the drug by penetrating into the
uppermost layer (stratum corneum) of the skin which will be better than the existing drug
delivery systems and the absorption of drug will be increased. The microneedles penetrate
into the outer layer of the skin with the drug and drug diffuses into the deeper area of the skin
and reaches into the systemic circulation. The new therapeutic compounds can administer by
this technique, this technique could be used to deliver the drug continuously as requirement
of body. Pain is not caused on the application of the microneedles because of microneedles
are much thinner and they only penetrate in the upper layer. The drug which contain
unpleasant odour cannot be taken by orally but it can be possible through the microneedles as
it will be Easy to use, increase the patients compliance, self medicament is possible, frequent
dosage is not required, first pass effect can be avoided, the constant communication between
the part of the body (beneath of the skin) and drug reservoir could be provided by this
system, microneedles also used for the extraction of the body fluid or blood12.
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A microneedle-based drug delivery system may feature all the favorable properties that made
the classical transdermal patch a success. Like the ordinary patch, the system would be easily
attached to, for instance, the upper arm and worn for a shorter time while medicating. The
advantages of such a system are:
1) Pain-free administration: Microneedles with a length of a few hundred micrometers, only
penetrates the superficial layers of the skin where the density of nerve receptors is low. As
a consequence, insertion of microneedles into skin is perceived as painless.
2) Easy to use: Like an ordinary transdermal patch, an envisioned system can be applied by
the patient himself virtually without any training. However, to achieve this, special
insertion tools and procedures are highly unwanted. Hence, the insertion force of the
microneedles needs to be low and the insertion procedure needs to be reliable and robust.
If this is achieved, it is reasonable to believe that the system, for certain medication, can
be sold over the counter (OTC).
3) Discreetness: Incorporating a microneedle-array with a planar and compact dosing system
yields a patch-like, unobtrusive device that can be discreetly worn under clothing.
4) Continuous release: An unobtrusive device may be worn for longer times, thus enabling
continuous and sustained delivery at therapeutic levels.
5) Controlled release: Drug release through a separate mechanism allows the release rate to
be precisely controlled. This may be accomplished through integration of passive
elements, e.g. flow restrictors or membranes, or active devices. Active dosing systems
offer the possibility to modulate the delivery in time and in amplitude. Even more
advanced, active elements permit the use of closed-loop systems.
6) Safer handling: Microneedles protruding a few hundred micrometers from a surface pose a
far less risk of accidental needle sticks than hypodermic needles do. Since microneedles
do not reach into the blood, the risk of transmission of blood-borne pathogens is also
further reduced1.
Disadvantages
This system carries some disadvantages too. The needle made of silicon and if the silicon left
under the skin after removing the patch, it may create problems. The needles are very small
and much thinner than the diameter of hair so the microneedle tips can be broken off and left
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under the skin therefore problems may be developed. Local inflammation may cause, if the
drug level is high under the skin. Skin irritation or allergy may create in case of sensitive
skin. The designs of microneedles are difficult to apply on the skin therefore proper
application is needed and self administration is not easy. The solid silicon microneedles
fabrication technique includes silicon wafers and clean room process, which are quite
expensive12.
Types
The different types of microneedles there have been developed as transdermal drug delivery
systems. Each microneedle has its own quality, which is advantages in different way and they
have been designed as requirement. The different types of microneedles are etched by
different materials; the first type of the microneedle is single-tip microneedles that have a
sharp tip. These types of microneedles are in straight shape, 200μm in length. It contains
sharp tip with different angles of 15 degree, 30 degree, 45 degree and 75 degree. The second
type of Quadruplet microneedles and the third type of microneedle is hollow microneedles.
The quadruplet and hollow microneedles are good in strength and not very expensive
respectively. The following figure represents different microneedles images used for the
transdermal drug delivery system14.
A classification for microneedles usually used in literature is based on the fabrication
process: in-plane or out-of-plane microneedles. In-plane microneedles are fabricated with the
shaft being parallel to substrate surface. The advantage of this arrangement is that the length
of the needle can be very accurately controlled. A disadvantage is that it is difficult to
fabricate two-dimensional arrays. Out-of-plane microneedles on the other hand, protrude
from the substrate and are straightforward to fabricate in arrays. Instead, the length and high
aspect-ratios become significant challenges in the fabrication of these kinds of needles.
Another useful point of distinction is whether the microneedles are solid or hollow. Hollow
needles with a needle bore, or lumen, allow an active liquid transport through the
microneedle1.
Microneedles have been used in many different applications, ranging from neurostimulation
to gene delivery into individual cells. A common goal is to create a pathway to an object by
physically circumventing some kind of barrier. In most applications this barrier is the skin.
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The rationale of using microneedles, as opposed to macroscale devices, is motivated either
by the size of the target or the benefit of piercing in a minimally invasive manner1.
1.Solid microneedles
Solid microneedles were designed to create micron-size pores in the tissue, which act as
direct pathways allowing drug molecules or particles to transport into the tissue. These
microneedles tend to have sharp tips and have good mechanical strength. They could be
mass-produced at low cost16.
a.Silicon microprobes
In the early phase of microneedle development, pyramidal silicon microprobes were found15.
Using a spin casting method, a photoresist is placed onto a silicon-dioxide coated wafer; the
wafer is then brought in contact with a photomask and is exposed to UV light. The
transferred pattern (from photomask to photoresist) is then etched into the silicon dioxide
masking layer. The photoresist is then removed and the wafer is anisotropically wet-etched in
potassium hydroxide solution to create arrays of pyramidal probes. With the goals of
delivering genetic materials to cells, these microprobles are ten to hundreds of microns in
height and have very sharp tips. These structures were used to transfect DNA into cells of
plants and mammals16(as shown in Figure 2).
Figure 2: A single silicon microprobe fabricated by anisotropic silicon etching and used to
deliver genes to plant and mammalian cells.
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b. Silicon microneedles
The simplest forms of the microneedles are solid spikes. Besides being solid, their unifying
characteristics include being very sharp and usually had fairly simple fabrication schemes.
Using a deep-reactive ion etching method, silicon microneedles were fabricated. The
fabrication steps include depositing a chromium masking layer onto a silicon wafer,
patterning it using photolithography into dots with the size of the desired needle base. The
wafer is etched with an oxygen/fluorine plasma mixture to create the high aspect ratio silicon
microneedles. These needles were used to create micron-scale holes in the skin through
which molecules can be more easily transported. Henry et al. (1998) conducted the first
study to determine if silicon microneedles could be used to increase transdermal drug
delivery. The penetration of microneedles through the upper layer of skin (stratum corneum)
created direct pathways for molecules that would not normally be able to diffuse through skin
barrier due to size or water solubility. These microneedles were demonstrated to increase the
permeability of in vitro human epidermis by 3-4 orders of magnitude28 (as shown in Figure
3).
Figure 3: Arrays of solid silicon microneedles used in transdermal drug delivery study and
demonstrated enhancement of dermal permeability.
In a follow-up study, McAllister et al (2000) showed that epidermis permeability to calcein,
fluorescently-tagged bovine serum albumin (BSA) and nanospheres can be increased up to
10,000 fold after treatment with silicon microneedles. In addition, Kaushik et al. (2001)
tested the pain level associating with the insertion of silicon microneedle arrays into human
skin in vivo. The study showed that the microneedles caused an insignificant amount of pain
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compared to conventional hypodermic needle insertion, and no subjects reported any adverse
reactions. In a separate study, Chabri et al. (2004) inserted silicon microneedles into human
epidermal sheets in vitro and delivered pDNA (LPD), a nonviral gene therapy vector, into the
tissue28.
c. Metal microneedles
Metal is considered a better alternative material for microneedles since it has good
mechanical strength, is relatively inexpensive and can be fabricated with ease. Solid,
stainless steel microneedles can be made by a laser-cutting technique. The resulting needle
structures are bent out of the sheet, and electropolished. The needles can be in either single
microneedles or multi-needle array form. Martanto et al (2004) used stainless steel solid
microneedles to deliver insulin to diabetic hairless rats in vivo. Needle arrays were inserted
into the rat skin using a high-velocity injector. A solution of insulin was placed on top of the
microneedle arrays and left in place for 4 h. Over this time period, blood glucose level
steadily decreased by as much as 80% compared to the control subject28 (as shown in Figure
4).
Figure 4: Solid stainless steel microneedle arrays used in an insulin delivery test using
diabetic rats in vivo.
Recently, a new delivery method associated with metal microneedles was developed. Using a
formulated coating solution, different sized molecular compounds ranging from micro-
(sodium fluorescein, sulforhodamine, etc.) to macro- (proteins, DNA, etc.) can be coated
onto the shafts of either single metal microneedles or multi-arrays of microneedles26. After
insertion into the tissue, the naturally hydrophilic-coating instantly dissolves off the
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microneedle shafts and creates drug depots within the tissue to provide sustained release(as
shown in Figure 5).
Figure 5: Images of coated solid metal microneedles.
2. Hollow microneedles
Skin permeability can be dramatically increased by the holes created from solid microneedles
insertions. However, it is still necessary to have more controlled and reproducible transport
pathways to delivery drugs into the tissue. The fabrication of hollow microneedles that allow
transport through the hollow shaft of the needle was based on this need. The inclusion of a
hollow lumen in a microneedle structure expands its capabilities dramatically and can offer
the following advantages: the ability to deliver larger molecules and particles; deliver
material in a convective transport fashion (for example, pressure-driven flow) instead of
passive diffusion; and minimize the cross-contamination of the deliverables and its
surrounding. A variety of hollow microneedles has been fabricated and has demonstrated
success in transdermal drug delivery.
a. Silicon hollow microneedles
The most logical technique for the inclusion of a lumen in the silicon spikes presented is the
addition of an etching step to form a fluidic channel using standard photolithography and
isotropic-anisotropic etching combination18. The fabrication steps include coating silicon
dioxide on a silicon wafer, patterning the backside of the wafer and etching through the wafer
stopping on the upper oxide layer to define the needle lumen. Silicon nitride was then
deposited, and a larger circular mask was patterned on the front side and underetched to
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create the tapering effect of the microneedle. After both silicon dioxide and silicon nitride
layers were removed, symmetrical and asymmetrical needle structures can be achieved by
adjusting the relative position of the isotropic and anisotropic etching axis. The hollow
silicon structures have been created in three-dimensional arrays out of the substrate plane. An
extension of the solid pyramids of Hashmi was found to effectively withdraw blood through
the lumen by capillary action17. (as shown in Figure 6)
.
Figure 6: Arrays of symmetric silicon hollow microneedles used in fluid injection
experiments.
Also, an extension to the solid silicon spikes of Henry was found to deliver both larger
particles (700 nm Nanospheres) and dye to chicken thighs under pressure driven flow18 (as
shown in Figure 7).
Figure 7: Arrays of hollow silicon microneedles used for transdermal liquid transport.
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b. Metal hollow microneedles
Hollow metal microneedles can be creating using laser micromachining. Microneedles with
straight walls (i.e. that is not tapered) are fabricated using molds with cylindrical holes
created either by reactive ion etching (RIE) through silicon wafers or lithographically
defining holes in SU-8 photoresist polymer. A thin coating of metal was then
electrodeposited onto the molds to produce the desired microneedles. Tapered hollow needle
was fabricated either by obtaining a mold from a silicon master or laser drilling tapered holes
into polymer sheets, followed by electrode position of a thin metal coating onto the mold.
Davis et al. (2004) have demonstrated the insertion test using the resulting hollow, metal
microneedles28 (as shown in Figure 8).
Figure 8: An array of hollow, metallic microneedles used for skin insertion test.
The study reported that less insertion force was required since the interfacial area of the
needle that is in contact with the skin was reduced. Additionally, these microneedles offered
stronger mechanical stability. As a follow-up study, Martanto et al (2004) delivered insulin
into hairless, diabetic rats in vivo using these hollow microneedle arrays. After 4 hours of
delivery, the blood glucose levels of the rats were reduced to 47% of their original value,
which indicated the successful transdermal delivery.
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c. Glass hollow microneedles
Hollow, glass microneedles can be quickly produced with different geometric parameters for
small-laboratory use. These needles are physically capable of insertion into the tissue without
breaking, having a larger drug loading dose and permitting visualization of the deliverables.
Thin glass capillaries were placed within a micropipette puller, and could have either a blunt
or a beveled tip, which allowed ease of needle insertion into the tissue. Coupling with an
insertion apparatus, the insertion depth of the needle into the tissue can be controlled
precisely28.
McAllister et al. (2003) used single glass microneedles inserted into the skin of diabetic
hairless rats in vivo to deliver insulin during a 30-min infusion period. The needles had a tip
radius of 60 μm and were inserted into the tissue of a depth of 500-800 μm. The results
indicated an up to 70% drop in blood glucose level over a 5-h period after the insulin was
administered. Using single, beveled-tip microneedles, Martanto et al. (2006) examined the
effect of different experimental parameters on microinfusion through hollow glass
microneedles into human skin in vitro. The study reported that partial retraction of the needle
within the tissue increased delivery flow rate 10-fold compared to that without retraction.
Infusion rates could also be increased at a greater insertion depth, a larger infusion pressure,
a beveled-tip instead of a blunt tip and the addition of hyaluronidase enzyme28 (as shown in
Figure 9).
Figure 9: A single, beveled-tip, hollow glass microneedle used in microinfusion within
human cadaver skin.
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3. Other types of microneedles
Besides solid and hollow microneedles, various other types of microneedles were fabricated
using different materials such as biodegradable polymers, polysilicon and sugar with
additional functionalities. Because of their biocompatible nature with the tissue,
biodegradable polymer microneedles were developed19. These needles were fabricated by
initially making master structures using lithography-based methods, creating inverse
structures from the master molds, and finally producing replicate microneedles by melting
biodegradable polymer formulations (i.e. poly-lactic acid, PLA, or poly-lactic-co-glycolic
acid, PLGA) into the molds. The resulting microneedles can be loaded with molecules,
drugs, DNA or proteins. Unlike solid and hollow microneedles, polymer microneedles
themselves serve as the drug implants after insertion into the tissue. Park et al. (2006)
inserted the microneedles loaded with calcein or bovine serum albumin (BSA) into full
thickness human cadaver skin. Strong images of the fluorescent model drugs were detected
over 200 μm deep from the skin surface. Additionally, the in vitro release profiles of calcein
and BSA ranged from hours to months depending on the formulations19 (as shown in Figure
10).
Figure 10: Solid biodegradable polymer microneedles with calcein encapsulated at the
needle tips used for in vitro transdermal insertion test.
Ito et al. (2006) prepared microneedles encapsulated with erythropoietin (EPO) for
percutaneous administration of EPO into mice in vivo. Under room temperature, EPO
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solution was added to high concentration of polymer solution (dextrin, chondroitin sulfate or
albumin) and microneedle were prepared by forming thread with polypropylene tips. The
results suggested the effectiveness and usefulness of microneedles for administration of EPO.
Microneedles made out of maltose mixed with ascorbate were developed for transdermal
delivery of drugs20. The lengths of these needles were ranging from 150 μm to 2 mm. A
clinical experiment was performed to test the biosafety and basic tolerance of these
microneedles. The tests showed the sugar-based microneedles spontaneously dissolved and
released ascorbate into epidermis and dermis of human skin. No dermatological problems
were reported28 (as shown in Figure 11).
Figure 11: An array of 500 μm microneedles made out of maltose and used in transdermal
insertion test.
Aside from being a drug delivery tool, microneedles can also be used as a biosensor. One
major reason for loss of biosensor activity is through the settling of large molecular weight
compounds onto the sensor and affecting senor signal stability. A microdialysis microneedle
is fabricated that is capable of excluding large MW compounds21.
Dimension
The dimensions of the microneedles are different as their types. The solid tip microneedles
and hollow microneedles have different dimension. Solid microneedles are fabricated in 750-
1000 μm in length, 15º-20º tapered tips angle and 190-300 μm bases area. The masks of
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microneedles are designed to 400-600 μm triangles length, 70-100 μm conduits diameter, and
25-60EA/5 mm2 arrays density. The tips of microneedle are in various shapes like triangular,
rounded, or arrow like structured22.
The hollow microneedles arrays are fabricated with lumen diameter of 30 μm and height of
250 μm. The center-to-center the distance of the hollow microneedles array is 150 μm. The
axis of lumen is fabricated with the distance of 10 μm to the axis of outside column23.
Constitution
The microneedles have been produced by using different materials like glass, silicon and
metal like stainless steel, titanium or nickel iron. Polymers have also been used in order to
manufacture the microneedles. The solid polymer microneedles have been produced by using
plastic like polycarbonate and paralyne, and the biodegradable polymers such as polylactic
and polyglycolic acid. The silicon is frequently used with the PDMS reservoir to hold the
drug. The different types of microneedles are fabricated by using various fabrication
methods. The microneedles are 10-200μm in length and in varying tip diameters. There are
some fabrications methods have been developed for the microneedles like surface
micromachining, silicon isotropic etching, and silicon bulk micromachining. The modified
bulk silicon method and the micromold plating method have been used recently to develop
the three dimensional hollow microneedles which are used to increase the transdermal drug
delivery rates. The inclined LIGA process has been also used for the fabrication of the
microneedles. The microneedles are also synthesized using etching techniques such as
chemical, physical etching techniques and standard lithographic procedure. The dry and wet
etching techniques are also used to develop the microneedles22.
General Fabrication Techniques
Typical MEMS fabrication techniques include very precisely controlled deposition and
etching of materials. By utilizing differences in selectivity to the etchant between different
types of materials, structures can be formed in a controlled manner. The structures to be
fabricated are defined by a two-dimensional pattern. This pattern is transferred from an
original photomask to a photosensitive film on a substrate by photolithography. The substrate
is typically a silicon wafer with a thickness of 300–700 _m. Also in case that polymer
replicated microdevices are desired, a common method is to fabricate the master device in
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silicon due to the precision achievable through silicon micromachining. Once a structure is
defined on the substrate, materials can be etched with respect to each other. By consecutively
redepositing, patterning and etching materials, intricate three-dimensional structures may be
created1. Common techniques to add material to the substrate are spin coating, physical vapor
deposition (e.g. evaporation or sputtering) or chemical vapor deposition (CVD).
Etching may be accomplished through wet etching (dipping into liquid solution) or dry,
plasma-based, etching. In plasma-based etching a gas is excited into a reactive state, enabling
reactions between the gas and the substrate to take place. By controlling the gas pressure, the
relative amount of ions over reactive radicals can be adjusted, which in turn affects the
degree of isotropy of the etch. An electric field (bias) may accelerate the ions and further
increase the directivity of the etch. Such an anisotropic plasma-based etch is referred to as
Reactive Ion Etching (RIE) 1.
Fabrication
Fabrication of microneedles can be done in number of different way using different materials
to develop a range of different geometries for both solid and hollow Microneedles2.
Fabrication of solid microneedles:
The design and fabrication technologies of solid microneedles have been varied considerably
from laboratory to laboratory. The investigators have been fabricated the microneedles
employing the silicon microchip lithographic technique, which adapted from the
semiconductor industry for the fabrication of solid and microneedles and microneedle arrays.
These techniques include reactive-ion etching and silicon-vapor deposition. There are some
fabrication processes in place to develop a microneedle. There is some etching techniques
also used like dry and wet etching technique for the microneedles. The etching process is
done by silicon wafer; acid-etched technique from the titanium sheet, the chemical etched
technique is also used to make the microneedles24.
The solid microneedles have been fabricated in different way like solid silicon microneedles,
solid metal microneedles, solid polymer microneedles etc. The most of the microneedles
have been fabricated for solid silicon microneedles because of easier to fabricate and have
mechanical strength more than hollow microneedles. The solid metal microneedles have been
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fabricated by different metals like steel, titanium and nickel iron. The proper
microfabrication technology for the fabrication of solid metal microneedles has not been well
developed. The solid polymer microneedles have been fabricated by engineering plastic like
polycarbonate and paralyne, and biodegradable polymers like polylactic and polyglycolic
acid. The solid polymer microneedles have been fabricated by using clean room fabrication
technique, using molding or other microreplication techniques. This fabrication process of
solid microneedles generally involves the steps to develop the microneedles like laser
cutting, cleaning and bending the microneedles and the electropolishing. By following these
steps of fabrication microneedles are fabricated24, 25.
1. Laser cutting of the microneedles is done by the stainless steel sheet by the use of infrared
laser. When it was used, operated at 1000HZ, 20 J/cm2 energy density and 40%
attenuation of laser energy to cut the microneedles. The cutting speed was 2 mm/s and the
removing air constant pressure was 140 kPa.
2. During the laser cutting, the slag and oxides is deposited on the microneedles so cleaning
is needed. The cleaning is done by the detergent and rinse from the water. And then it is
need to bend at 90o angle by the aid of #9 single edged razor blades.
3. The electropolishing of the microneedles is required to clean the edge and to make the tips
of microneedle sharp. The electropolishing is done by the solution, which contains
glycerine, ortho-phosphoric acid (85%) and water in a ratio of 6:3:124, 25.
The different types of microneedles are fabricated by the various fabrication methods. The
microneedles are 10-100μm or no more than 1500μm in length and in varying tip diameters.
There are some fabrications methods have been developed for the microneedles like surface
micromachining, silicon isotropic etching, and silicon bulk micromachining. The modified
bulk silicon method and the micromold plating method have been used recently to develop
the three dimensional hollow microneedles which are used to increase the transdermal drug
delivery rates. The inclined LIGA process has been also used for the fabrication of the
microneedles. The microneedles are also synthesized using etching techniques such as
chemical, physical etching techniques and standard lithographic procedure26.
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Fabrication of hollow microneedles
Hollow microneedles have been fabricated in two different ways that hollow metal
microneedles and hollow silicon microneedles. Hollow microneedles contain a hollow
internal bore so it has been carried additional advantages over the solid microneedles. The
hollow metal microneedles have been fabricated by using different metals like stainless steel,
palladium, and nickel. The hollow microneedles can be applied to the skin on the base of the
transdermal patch. The use of the hollow microneedles can improve the drug delivery
because the bore of hollow microneedles provides a known, predictable and unchanging
pathway for transportation of the drug. The hollow silicon microneedles have been fabricated
by using silicon by clean room lithography and etching techniques. The hollow silicon
microneedles are as good as hollow metal microneedles25.
Figure 12: A schematic representation of fabrication process used in making the hollow
microneedle array.
The above figure - “The process consists of (Figure 12-a) isotropic etching of outside shape
for needle tips by STS ICP equipment with mask patterned in photolithography (Figure 12-b)
thermal growth of a silicon oxide layer after removal of photoresist mask (Figure 12-c)
patterning of both top silicon oxide layer in outside shape of needle and back oxide layer in
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reservoir (Figure 12-d) coating of a photoresist and pattering of the inner channel on the
photoresist and oxide layer (Figure 12-e) lumen etching by DRIE (Figure 12-f) outside shape
of needle and lumen etching by DRIE after removal of photoresist (Figure 12-g) backside
reservoir etching by DRIE (Figure 12-h) removal the oxide layer resulting in the fabricated
hollow needle array”23.
Coating
For the coating of the microneedles different drug molecules are used like proteins, DNA,
peptides etc. by using the novel- micron scale, dip coating process and specially formulated
solutions that made for the coating. Coating solution contains 1% (W/V)
carboxymethyalcellulose sodium salt, 0.5% lutrol F-68 NF and the drug model/
biopharmaceutical. The drug model consist of 0.01% suforhodamine, 0.01% calcein, 3%
vitamin B, 1% bovine serum albumin, 0.5% plasmid DNA, 10% barium sulphate particles,
1.2% 10μm diameter latex beads and 8.2% 20μm diameter latex bead. Microneedle is dip-
coated into the 20-30μl coating solution by horizontally dipping. There are two devices used
for the coating rows of microneedles by dip coating process. First device is the coating
solution reservoir which consists of two laminated parts: 1) bottom plate and 2) cover plate
made of polymethaylmethacrylate. This device is used to prevent the access coating liquid to
the microneedles shaft and to prevent the contamination of the base. The second device is the
micropositioning dip coater which used to enable three dimensional alignments and also used
to dip the microneedle rows by inserting into the dip holes. There are three linear-
micropositioners were used. This technique of coating the microneedle arrays is similar to the
coating of rows of microneedles26.
Drug Reservoir
The microneedles array system contains a drug reservoir system to hold the drug, like the
deformable PDMS (polydimethylsiloxane) is used as the drug reservoir for the suspension of
lyophilized drug. From which the drug is released at constant rate by microneedle array into
the skin. The PDMS is chemically bonded with the silicon. Then silicon coating is molded
with the monolayer of hexamethyldisilazane (HDMS), so the PDMS can remove from that
mold and activate in the low power oxygen plasma. Then the backside of the microneedle
array is bonded with PDMS. The suspension is filled between the gap of PDMS and silicon
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layer of the microneedle array and release at the constant rate on application on the skin. The
hollow type of microneedles contain bore which necessary for the administration of the drug.
The bores are 5-70μm in size and they designed as the requirement. The formulation
technique of the hollow microneedles which contain bore is expensive and it’s difficult to
make and very costly. Its sharp tips are very difficult to make therefore its not easy to use.
It’s difficult to insert into the patient’s skin. The central bore which plugged by the skin
tissues on the application. Because of the length of the bore of hollow microneedle, the drug
is diffused vary slowly by the outermost layer stratum corneum and the drug delivery may
become slow into the systemic circulation. It is a disadvantage of the hollow microneedles18.
Penetration
The human skin is made of the three different layers; the uppermost layer is stratum
corneum, which is 15-20μm in thickness, the epidermis and dermis. The mechanism of the
microneedle insertion into the skin is very critical to its practical application. Needles with
the correct geometry and physical properties, such as strength, are able to penetrate the skin
provided the penetration force is less then the breaking force of the needle or tip. Each person
has different thickness of these layers. The skin penetration and the microneedle penetration
depth have been demonstrated by the skin distribution technique. The experiments of the skin
distribution technique has shown that the uncoated microneedles are penetrated the first
90μm of the skin and coated microneedles are penetrated 70μm of the skin. However the test
is shown the various depth of penetration with different design and range of epidermis and
dermis and the coating of the microneedles are slightly affected to the penetration into the
skin. The stratum corneum has thickness of 15-20μm therefore it has been proved that the
microneedles, if they are coated or uncoated, they past the stratum corneum of the skin27 (as
shown in Figure 13).
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Figure 13: Penetration of microneedles into the skin.
The microneedle arrays are used to deliver the drugs as well as vaccines. The skin is made of
three layers; stratum corneum the outermost layer with thickness of 15-20μm, the epidermis
that has thickness of 500-1000μm. So the microneedle should be robust, sharp and have a
small diameter to penetrate the skin layers and some force is necessary to induce the
microneedle into the skin. The coated or uncoated microneedles are penetrated about first 70-
90μm of the skin. The nerve should not be contact with the needles so the microneedle length
should be controlled by the needle base and nerve contact can be minimized. Because of skin
flexibility and random blood vessels distribution, the high aspect ratio and microneedles with
array system is necessary. To avoid the skin damage and pain associated with the application
of the microneedles, each needle must have small-penetrated area. The solid microneedles
are applied on the skin and it’s removed before the drug penetrates into the circulation
because the solid microneedles plugged the skin on the application. The solid microneedles
are used only to create the holes into the skin therefore the drug can penetrate easily22.
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Table 2: Microneedle Patches of Some Drugs.
Sr. No. Drug Use
1. Flufenamic acid A non-steroidal anti-inflammatory agent
2. Lidocaine HCl Anesthetic
3. Methyl nicotinate causes dilation of blood vessel & increases blood
flow velocity
4. Insulin In Diabetes mellitus
5. Naltrexone A potent mu-opioid receptor antagonist
6. Glucagon Enzyme
7. Parathyroid hormone Hormone
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RESULT AND DISCUSSION
As we have seen before that nowadays the novel drug delivery system is going to develop
different drug delivery systems. The microneedle is a novel drug delivery system intended
for transdermal administration.
Manufacturing of Microneedles
After reviewing entire literature about the microneedles, there has been various fabrication
techniques used in order to fabricate different types of microneedles. Some complex
technologies have been used for microneedles fabrication that involved state of- the-art-
clean-room technology. This was such a technique, which will be costly to produce
microneedles and may not be robust enough on the application as a skin patch system.
Despite some fabrication designs have been easy to follow. Microneedles have been
inexpensive enough and it will be helpful for single use. Better clinical application and
commercial success will be concerned with the use of microneedles as it is a disposable
medical device.
Microneedles have been manufactured by different technologies and its manufacturing cost
will depend strongly on the application. The microneedles cost will be much less than one
dollar and it should be or preferably it will be less than five or ten cents in order to have a
great potential. The microneedles have been fabricated by different types of fabrication
methods, which developed by microfabrication research community have been silicon based.
The microelectronic clean room technology has been used in order to fabricate different type
of microneedles shapes by using different lithography. The microneedles industries have
been fabricated various types of microneedles by using different fabrication technology but
in the case of clean room technology, the clean room equipment and its operation are still
quite expensive. The microneedles can be produced by using inexpensive microneedle
fabrication technology. Although the silicon based fabrication technique may be quite
expensive, the rest technologies are cheap to fabricate. The metal microneedles can be
fabricated by using electroplating fabrication technique that is more than century old.
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Microneedle Design
By considering different designs of microneedles, there are number of various constraints can
be balanced, if the designs of microneedles will be optimized. Geometry of the microneedles
is most important consideration and it should be desired. The effective geometry of
microneedles needs to be produced by using cost effective and large scale manufacturing of
different types microneedles. Microneedles have been made by using different materials like
glass, metal silicon and biodegradable polymers. The glass and silicon microneedles can be
broken on the application due to the lack of proper application. The broken microneedles can
be remaining into the skin so it may be create problems. The tips of microneedles much
thinner than the diameter of hair and it can be broken into the skin during insertion.
Microneedles should be made by using materials, which is strong enough. It should not be
broken during insertion into the skin and should be safe for the skin. Microneedles should not
be damaged the drug and it should fabricated easily and by using cheap microneedle
fabrication technology so the patients can be applied the microneedle patch themselves
without fear of braking needles. The microneedles should be strong enough to avoid
breakage.
Microneedles have already a geometry small enough to avoid pain but it should be large
enough to insert easily into the skin in order to produce desired pharmacological effects of
applied drugs and desired amount of antibody in case of vaccine delivery. The microneedles
should be a device, which can be able to give all the facilities like drug storage, needle
insertion and better patient convenience. The microneedles must deliver the appropriate drug
dose with the appropriate pharmacokinetics.
According to the literature review, there is not a single design which optimizes all the aspects
of the microneedles. To fulfill the best compromise, the specific drug therapy and capabilities
of available technology will be needed simultaneously. Examples if bolus delivery of a sub-
milligram drug dose will deliver by using solid polymer or metal microneedles by coating
over the needles, it will be delivered vary easily. Because microneedle contain limited
amount of drug for coating so the small drug dose will lend on the application of solid
microneedle patch, which will be very easy to deliver the drug and easy and strong enough to
manufacture it than hollow microneedles. Whenever the larger dose of drug needs to be
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delivered by microneedles for a long time, it will be possible by infusion, which can be done
by hollow microneedles. The clinical value of this system will justify more expense and the
design of hollow microneedles coupled with a pump will be difficult.
Strength and Limitations of Microneedle
There are many researches of transdermal drug delivery systems are going to develop novel
delivery techniques. Various microneedles have been produced in order to administer drug
and vaccine delivery. Because the transdermal drug delivery by microneedles have given a
very exciting opportunity with the combination of the efficacy of needle-based delivery and
patient’s acceptance of various transdermal methods.
The solid and hollow microneedles have been used to increase the skin permeability across
the stratum corneum, which is the outer most layer of skin. Microneedles have been used by
coating drug on the surface of needles tips or using drug reservoir (Paradimethylsiloxane)
patch system. By using this drug reservoir patch, microneedles can be used to deliver not
only small molecule of the drug but can be used to deliver the lipophilic drug and
macromolecules like DNA and proteins or peptides too. The drug with high molecular weight
can also be delivered by coating or encapsulating small dose of that drug. The delivery of
drug can be made more rapid than traditional adhesive patch by using hollow microneedles.
According to the literature review, the microneedles as a novel drug delivery system has very
good power to prove it self but there are more work need to be done to make it perfect or
more effective before FDA approval and commercialization are realized. Although as above
discussed about design and manufacturing of microneedles are optimized, more work will be
required to make microneedle better. Microneedle patches system need to be a complete
microneedle-based system, which can be reliable for patients. The design of the microneedles
should be easy and reliable therefore untrained clinicians or patients can apply the
microneedle patches easily where self medicament may be desirable. As the microneedle
patches are new drug delivery system, the performance of drugs or vaccines and its safety
will need to be comprehensively tested during its preclinical and clinical evaluations.
The interaction of microneedles materials like metal, silicon, or different polymers with any
drugs molecules or vaccines will need to be conformed performing various evaluation study.
Microneedles have already expected to be safe as a delivery system but its safety and
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efficacy studies regarding all aspects of microneedles need to be conformed in its clinical
evaluation programme.
Certain limitation for microneedles are that the microneedles can deliver large doses of drugs
as required to treat particular disease but that dose can treat the respective disease and may
cause adverse effects to the skin. As per previous discussion, the immune stimulatory
properties of the skin will be more effective in case of vaccine delivery but this immune-
stimulatory properties can be neutralized the effects of other drugs. Because of immune-
stimulatory properties of the skin, massive antibody may be produced on the vaccine delivery
and it can be harmful to the body.
In Vitro Preclinical Evaluation
The main aims of these in vitro tests were to determine optimization of microneedles,
penetration force, strength of microneedles, delivery efficacy etc. The in vitro preclinical
evaluation was carried out by using mediums and the cadaver skin of human and pig with the
administration Rhodamine B or black ink using microneedles arrays in order to perform
needle breakage test. These injecting materials were kept PDMS, which is the microfluid
chip. The in vitro testing was also performed by coating microneedles in cadaver skin of
human and pig. Vitamin B, calcein and sulforhodamine were used in order to coat the
microneedles. In this in vitro test, the Rhodamine B and black ink were injected by
microneedle microfluid chip in 1% of agarose gel and Petri dish containing methanol
respectively. In these in vitro tests, the different types of microneedles have been used like
microneedles with 8.5 and 15 tip taper angles and isosceles triangle microneedles with 9.5
and 30 tip taper angles. In these experiments, it was difficult to measure the microneedles
shaft deflection at the end. The considerable matter in these tests is that the silicon shafts can
be used as cantilever beams in place of microneedles shaft order to deliver the study
solutions because the silicon shafts are movable as they are fixed at one end and free to rotate
from other end. Using these silicon shafts, the little bit effective and valuable results than
microfluid shaft can be achieved. Some errors of theoretical calculations of penetration force
and bending force can be developed from microneedles shaft width.
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In Vivo Preclinical Evaluation
The in vivo preclinical evaluation of microneedles was performed on animals like mice and
guinea pig in order to determine the delivery efficacy, penetration force, bending force and to
evaluate the skin toxicity testes using vaccine delivery. The microneedles were tested on
animals for different purpose and it will get the positive results as per objectives. But the
thickness and properties of the skin of animals and human are different. So penetration will
not be applied on human skin, which was applied to animal skin. If it happens, microneedles
will break off or bend or human skin may get damage. So various microneedles properties
like penetration force and bending force will not recognized after in vivo preclinical
evaluation. Although these properties will establish using animal, on human skin, it will be
changed.
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CONCLUSION
This thesis presents a fully integrated microneedle-based transdermal drug delivery system
and development work towards the same.
The microneedles require a very low insertion force to be inserted into skin,
potentially allowing arrays with hundreds of such microneedles to be inserted into
skin by hand without any aids.
The microneedles can penetrate human skin in vivo at clinically relevant sites.
The microneedles can be hermetically sealed through thin membranes and be opened
at the time of delivery by applying pressure or inserting the sealed needles into skin
tissue.
The microneedles can be fabricated with high process yield.
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SUMMARY
Every drug needs a drug delivery system. There are different types of drug delivery systems
developed to administer the drug to the body. Every drug needs the drug delivery system;
different drugs are delivered by different route. Transdermal drug delivery system has major
advantages over the other delivery systems. This drug delivery system is used by the patch.
Transdermal Drug Delivery System:-
Transdermal drug delivery system has major advantages over the other delivery systems.
This drug delivery system is used by the patch. Microneedles will be used as a transdermally
for drug delivery and especially for the vaccine delivery. Nano drug delivery systems can be
administered the large dose of drug. Combine drug delivery system, which is used by the
combination of drug and medical device. Transdermal drug delivery system has been
developed 20 years ago.
Microneedles
The drug delivery by using the microneedles is an alternative approach to administer the drug
across the stratum corneum. The different types of microneedles there have been developed
as transdermal drug delivery systems. The second type of Quadruplet microneedles and the
third type of microneedle is hollow microneedles. The following figure represents different
microneedles images used for the transdermal drug delivery system.
Solid microneedles
b. Silicon microneedles
c. Metal microneedles
2. Hollow microneedles
a. Silicon hollow microneedles
b. Metal hollow microneedles
c. Glass hollow microneedles
3. Other types of microneedles
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Fabrication of solid microneedles
The solid microneedles have been fabricated in different way like solid silicon microneedles,
solid metal microneedles, solid polymer microneedles etc. The most of the microneedles
have been fabricated for solid silicon microneedles because of easier to fabricate and have
mechanical strength more than hollow microneedles.
Fabrication of hollow microneedles
Hollow microneedles have been fabricated in two different ways that hollow metal
microneedles and hollow silicon microneedles. The use of the hollow microneedles can
improve the drug delivery because the bore of hollow microneedles provides a known,
predictable and unchanging pathway for transportation of the drug. The hollow silicon
microneedles are as good as hollow metal microneedles.
Manufacturing of Microneedles
The microneedles must deliver the appropriate drug dose with the appropriate
pharmacokinetics. Various microneedles have been produced in order to administer drug and
vaccine delivery. Microneedles have been used by coating drug on the surface of needles tips
or using drug reservoir (Paradimethylsiloxane) patch system.
A Review on Mironeedles/ Ghanvat Mitesh
39
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A Review On Mironeedles/ Ghanvat Mitesh D./T.Y.B.Pharm/2008-0942
APPENDIX I
List of tables
Table no. Name of Caption Page No.
1. Patches of different drugs to be developed 8
2. Microneedles Patches of some drugs 31
A Review On Mironeedles/ Ghanvat Mitesh D./T.Y.B.Pharm/2008-0943
APPENDIX II
List of Figures
FigureNo.
Title PageNo.
1. Microneedle with blue colour. 12
2. A single silicon microprobe fabricated by anisotropic silicon etchingand used to deliver genes to plant and mammalian cells.
16
3. Arrays of solid silicon microneedles used in transdermal drug deliverystudy and demonstrated enhancement of dermal permeability.
17
4. Solid stainless steel microneedle arrays used in an insulin delivery testusing diabetic rats in vivo.
18
5. Images of coated solid metal microneedles. 18
6. Arrays of symmetric silicon hollow microneedles used in fluid injectionexperiments.
20
7. Arrays of hollow silicon microneedles used for transdermal liquidtransport.
20
8. An array of hollow, metallic microneedles used for skin insertion test. 21
9. A single, beveled-tip, hollow glass microneedle used in microinfusionwithin human cadaver skin.
22
10. Solid biodegradable polymer microneedles with calcein encapsulated atthe needle tips used for in vitro transdermal insertion test.
23
11. An array of 500 μm microneedles made out of maltose and used intransdermal insertion test.
24
12. A schematic representation of fabrication process used in making thehollow microneedle array.
28
13. Penetration of microneedles into the skin 30