Micro Needles in Drug Deliveryf

Microneedles in Drug Delivery system 2010-11

1. Introduction

1.1 The concept of minimally invasive drug delivery

A discussion of minimally invasive drug delivery must begin with a consideration of

what invasive delivery means. Administration of drugs via needles and syringes has been

with us for more than a hundred years. For example, the first all-glass syringe patent was

licensed to Becton Dickinson & Co. in 1898. Metal cannula needles on piston syringes

have become the most prevalent ethical device-based drug delivery modality in existence,

with multiple billions being used each year in many health care applications.

Conventional needles, whether on syringes or catheters, represent the preeminent

invasive delivery mode in existence. They are, however, also the most efficient and cost

effective device-based system for administering agents into the systemic circulation and

are presently the general method for delivering polypeptide agents, which are otherwise

proteolyzed by the oral route. The reason, as discovered more than a century ago, is that a

thin, sharp sterile metal pipe is an ideal way to breach the stratum corneum and deliver

agents past the skin barrier into the micro-vascularization of the dermis or lower tissues

and thence into the systemic circulation. Despite this, conventional needle-based delivery

suffers many well-recognized drawbacks, not the least of which is the negative

psychosocial connotation of drug administration via needles. Other problems include the

pain of administration; safety concerns over the possibility of transmission of blood-

borne pathogens; the lack of compliance, the inability or dislike of patients to self-

administer via needles; and the lack of ease of use, especially for younger or elderly

patients. To address these needs, a number of new technologies have arisen or are in

development, whose inventors intend to provide trans-epidermal drug delivery by

circumventing the conventional needle and syringe.1

During recent years, transdermal drug delivery systems have shown a tremendous

potential for their ever-increasing role in health care. This has been mainly attributed to

the favourable properties of lack of first pass metabolism effects of liver, better patient

compliance, steady release profile and lowered pill burden in transdermal system.

However, the transdermal technology have limitations due to the inability of a large

majority of drugs to cross the skin at the desired therapeutic rates because of the presence

of a relatively impermeable thick outer stratum corneum layer. This barrier posed by

Chetan N. Chauhan 1 SSPC, Mehsana


human skin limits transdermal delivery only to lipophilic, low molecular weight potent

drugs.2 Researchers are trying to overcome this hurdle of poor permeability by the

following means:

1) Chemical Means: Chemical means include the prodrug approach and/or use of

chemical penetration enhancers that can improve the lipophilicity, and the consequent

bioavailability.

Chemical approach increases the lipophilicity and therefore increase the permeability of

drugs across skin, whereas the physical approaches disrupt the upper layers of skin

(stratum corneum) and reduce the resistance to the passage of drugs by creating minute

holes in the skin that are large enough for the passage of smaller drug molecules but

probably small enough not to damage the skin.

2) Physical Means: Physical means of transdermal drug delivery comprises of

iontophoresis, electroporation, and sonophoresis.

On the other hand hypodermic needles are effective at bolus delivery of drugs, but cause

pain during insertion and are not ideally suited for delivery over extended periods.

Transdermal patches address these shortcomings.



1.2 Mechanism of skin penetration

The thickness of the stratum corneum is approximately 10 to 20 microns. Therefore the

minimum distance breached by minimally invasive transdermal systems must be about 20

microns. During tissue damage, adenosine triphosphate (ATP) is released from damaged

cells. ATP is a ubiquitous cellular energy storage compound, which when released

extracellularly potentiates input nociceptors (pain receptors) via direct stimulation of

neurons. The effect appears to provide a local signal for tissue destruction, which in turn

stimulates remedial physiological responses such as inflammation, etc. Pain may also

result from tissue distension caused by drug injection, skin damage (and ATP release), or

direct damage to nerves. Researchers are approaching the challenge of pain reduction by

several techniques that are linked by one unifying strategy: limiting the extent of

mechanical insult to skin to the first 50 microns of tissue.

The mechanical stress–strain relationships of skin complicate the practical manipulation

of the stratum corneum, epidermis, and upper dermal layers. The mechanics of skin, and

other soft tissue such as arteries, muscle, and ureter, do not display single-value

relationships between stress and strain and are therefore classified as inelastic materials.

When tissues in this group are held at constant strain, they display stress relaxation, and

when held at constant stress they creep.2, 3

Historically this relationship has required uniaxial application of mechanical force to

breach skin (as in needle penetration), and has made sensation-free clinical manipulation

(containment, preparation, and breach) of skin tissue difficult. In general the new skin

breach technologies described in this communication require either direct uniaxial

application of mechanical energy or thermally/mechanically induced changes in the

physical properties or structure of skin. They differ from classical approaches in that they

attempt to target the epidermis and upper dermal layers devoid of nosiceptors while

gaining access to the circulatory and immune systems via the dermal capillary bed and

epidermis, respectively. If successful, these approaches may greatly reduce or eliminate

the mechanical stimulation of pain responses during delivery.



1.3 Microneedles as a system for minimally invasive transdermal delivery

The development of microneedles for transdermal drug delivery came about as an

approach to enhance the poor permeability of the skin by creating microscale conduits for

transporting across the stratum corneum. Microneedle technology has been developed as

an advanced technique for penetration of large molecular weight and/or hydrophilic

compounds. Micron scale needles assembled on a transdermal patch have been proposed

as a hybrid between hypodermic needles and transdermal patches to overcome the

individual limitations of both the injections as well as patches. Microneedles are so called

because they are of micrometre (millionths of a metre) scale.

Microneedle technique has been successfully used to deliver a variety of compounds

including macromolecules and hydrophilic drugs into the skin. As microneedle system

bypasses the stratum corneum barrier of the skin, permeability enhancement of two to

four orders of magnitude has been observed for small molecules like calcein and also for

the relatively larger compounds like proteins and nanoparticles. The technology that are

long and robust enough to penetrate the layer of the stratum corneum but short enough to

avoid stimulating the nerves has the potential to make the transdermal delivery of drugs

more effective. Therefore, the main aim of the microneedle technology is to combine the

efficacy of the hypodermic needle with the convenience of a transdermal patch.

Figure 1: Layers of the Human Skin



In modern medical applications, there is a need for very small hypodermic needles that

are economical to fabricate. Currently, the smallest needles commercially available, 30

gauge needles, have a 305 mm outer diameter with a wall thickness of 76 mm.

Traditional machining methods make it unfeasible to create needles with a diameter

less than 300 mm. Microneedles on the other hand can be any size and geometry since

they are defined lithographically. Microneedles are designed to be high performance

minimally invasive conduits, through which drug solutions may pass into the body. In

order to be minimally invasive, the needles are designed to be as small as possible.

Needles are also designed to be extremely sharp, with submicron tip radii. This allows

the needles to be effectively inserted into the skin. The stress on the skin is inversely

proportional to the area over which the force is applied.3, 29, 31

Therefore as tip radii decreases the stress imposed at a constant force increases and

allows lower forces to be used for needle insertion. In addition, the small size of the

needles cause less compression of the tissue as needles are inserted which leads to less

compression of pain receptors and a decrease in insertion discomfort. The small size of

the microneedles also decreases the chance that the needle will be inserted close to a

pain receptor. The decrease in tissue damage also decreases the likelihood of infection

occurring at the site of insertion. Internal features of the microneedle, such as in-line

microfilters, which are defined as part of the needle during a lithography step, may also

be used to effectively filter any foreign matter including bacteria from the fluid being

injected. This decreases the chance that a contaminated solution may be inadvertently

injected.

One of the largest barriers to the commercialization of technology is the cost and

effectiveness of producing the technology. Since microneedles are produced in a highly

parallel batch process there is great potential that the individual cost per needle is

lowered. Molded needles which do not sacrifice the mold wafers lead to an increased

cost savings, since the mold may be used over and over. This leads to a high quality

reproducible device that opens up a new option for drug delivery applications that has

few cost and fabrication barriers to being employed in the marketplace.5



2. Advantages & Disadvantages

2.1 Advantages

The major advantage of microneedles over traditional needles is, when it is inserted into

the skin it does not pass the stratum corneum, which is the outer 10-15 μm of the skin.

Conventional needles which do pass this layer of skin may effectively transmit the drug

but may lead to infection and pain. As for microneedles they can be fabricated to be long

enough to penetrate the stratum corneum, but short enough not to puncture nerve endings.

Thus reduces the chances of pain, infection, or injury. 5

In terms of processing there are also many advantages. By fabricating these needles on a

silicon substrate because of their small size, thousands of needles can be fabricated on a

single wafer. This leads to high accuracy, good reproducibility, and a moderate

fabrication cost

Microneedles have a significant advantage over other approaches to transdermal drug

delivery such as electroporation, ultrasonic delivery, or chemical modifiers/enhancers all

of which rely on decreasing the permeation barrier of the stratum corneum, the outermost

layer of the skin. Microneedles mechanically penetrate the skin barrier and allow the

injection of any volume of fluid over time. Microneedles have the ability to be precisely

inserted to inject therapeutics any particular distance below the stratum corneum. This

allows precise localization of a high concentration drug solution in order to obtain

effective absorption into the bloodstream or to stimulate particular clusters of cells in or

near the skin. Therefore, the drug delivery does not depend on transient delivery of

therapeutics across the skin. The delivery is independent of the drug composition and

concentration and merely relies on the subsequent drug absorption into the bloodstream,

which occurs at a much faster rate than permeation of a solution across the skin. This also

allows complex drug delivery profiles. Since drug is actively injected into a patient the

dosage may be varied with time. In addition, by employing multiple needles or effective

fluid control with mixing of solutions multiple drugs may be injected simultaneously

specific to a patient’s personal needs. Needles may also be used to transdermally sample

body fluids for analysis. 4

The extreme miniaturization of fluidic devices enables portable devices for

personalized medicine allowing continuous metabolite monitoring with drug delivery in



response to metabolite levels. This has tremendous advantages over existing

technologies. It allows patients more freedom in their treatment since they are no longer

dependent on a facility to provide an outpatient service which often results in a bolus

injection or a period of intravenous drug delivery while a patient is at the facility with

little or no therapy between treatments. It also allows a lower drug dosage to be injected

over a longer period of time to maintain a constant blood concentration. A bolus

injection on the other hand leads to a rapid increase in blood concentration, often to

toxic levels, followed by a decay period as the drug is metabolized. This time varying

high concentration injection is often responsible for many side effects associated with a

large number of therapeutics. By maintaining a constant blood concentration below

toxic levels, side effects associated with a high concentration bolus injection may be

reduced. Further, the ability of microneedles to deliver therapeutics at a slow,

controlled rate will make unnecessary the injection of a large bolus in the first place.

This allows the delivery of therapeutics to a depth just below the stratum corneum and

yet still above the nerve bed in the skin. A bolus must be injected deeply into the tissue so

it does not leak out the hole punched in the skin to deliver it. Microneedles make this

form of therapeutic delivery unnecessary.

Other advantages include: 8

Precise volumes of fluid moved rapidly and efficiently

Reduce the amount of drug used

Localize the delivery of potent compounds

Deliver otherwise insoluble or unstable therapeutic compounds

Reduce the chances of missing or erring a dose

Multiple injections can be avoided

Ability to administer the drug at the specific target site

Rapid onset of action

Possible self administration

Efficacy and safety comparable to approved injectable products

Improved patient compliance

Good stability

Cost effective



2.2 Current limitations of microneedles

Biological Response

Future work needs to be performed to determine the biological response to microneedles.

The first response to tissue distress from needle insertion is an inflammatory response at

the insertion site. Also, constriction of capillaries may occur which may affect drug

absorption. During this time tissue edema may also occur, which may affect fluid

delivery from the needles, with the migration of leukocytes to the injury site. Protein

adsorption to the surface of the silicon will promote adhesion of leukocytes to the

needles. However, surface modifications of silicon surfaces to reduce protein adsorption

is an active area of research. Some surface modifiers include: silicon carbide,

polyethylene glycol (PEG), or plasma enhanced chemical vapor deposition (PECVD) of a

Teflon-like fluoropolymer. Any of these coatings could be incorporated into needle

fabrication to improve biocompatibility.

Since microneedles are designed for short term intradermal drug delivery, fibrous

encapsulation is not expected because the needle is not inserted long enough for

encapsulation to occur. However, there is the chance that the body may try to extrude the

needle by pushing it out over time. Therefore, mechanical reinforcement may be required

to keep the needle in place.2

Breakage Versus Piercing Ability

Due to the small size of microneedles, strength and robustness are the major factors in

determining the range of their applications. Needles must be able to tolerate forces

associated with insertion, intact removal and normal human movements if they are to be

integrated into portable biomedical devices. Namely, materials such as silicon are strong

and can easily pierce the skin but they are also brittle materials which fracture easily.

Metal and polymer needles on the other hand are not stiff so they can absorb larger

stresses by plastically deforming. However, this ability also makes piercing the skin more

difficult. Metal deposition also uses thin film processing techniques, and therefore the

metals are mechanically weaker than bulk hardened metals such as stainless steel. A

hybrid microneedle such as the parylene coated silicon needle appears to be most

promising because it balances the advantages of each material. A silicon tip could be held



rigid during insertion and then released allowing the polymer tube to absorb the stress

associated with movement. Since the silicon tip is so much smaller than a whole needle it

will experience smaller stresses and will be less likely to fracture. In addition, even if the

tip does fracture it will be held together by the polymer coating. Another approach is to

develop new polymer processing techniques which can be used to generate needles. If a

semi-crystalline polymer is used, then it may be strong enough to allow needle insertion,

but also have enough of the polymer in an amorphous phase to absorb mechanical stress.

Another way to take advantage of material limitations is to precisely control the stresses

and forces the needle experiences. This could be accomplished by having a

microfabricated insertion actuator to control the insertion force. This could consist of a

microfabricated linear stepper motor or piezoelectric actuator. Both would allow precise

positioning and direct insertion of the needles axially without any bending moment to

deform or fracture the needles. Piezoelectric actuators could also produce ultrasonic

vibrations to decrease the amount of force required for insertion.4



3. Applications

3.1 Diabetes

Microfluidic devices and sampling through a microneedle allows a feedback loop

between a sensor which monitors the glucose levels in the body and a delivery module

which can deliver insulin in a time varying fashion as needed. This more closely

mimics the body’s natural regulation of sugar leading to fewer complications associated

with the treatment.2

3.2 Chemotherapy

When a patient undergoes chemotherapy they often receive a fixed drug dosage in a

session. By delivering the chemotherapeutic agents continuously through a

microneedle, the patient may receive therapy over a longer period of time. It could also

lead to a lower dosage of the toxic drugs, which must be injected at any one time.

Lowering chemotherapy dosages may lead to an overall lessening of the severity of side

effects. By incorporating a longer treatment period with fewer side effects, it could

shorten the overall number of treatments and recovery time to combat the disease.

There are also many cell based therapies which could be delivered continuously

through a microneedle. Antitumor effector cells which attack melanomas have been

extensively studied. These cells have been shown to reduce the size of both solid and

hematologic human tumors. However, if cells are injected intravenously they are not

always localized to tumors and the liver and spleen destroy a large majority of the cells.

If the injection is directly into or around tumors (intralesionally), they will be localized

to attack the tumor. The microneedles do very little tissue damage, so a patient can

receive continuous therapy. Also, the needles have less chance of damaging tumors and

causing the tumor to metastasize than larger needles. 2, 9

3.3 Vaccinations, Pain relievers and Antibiotics

Currently there are many medications, such as the Hepatitus B vaccine, which require

several shots over a period of time. Quite often, people will receive the first or second

shot but fail to return for subsequent shots. Patients also take antibiotics until their

symptoms subside but then do not finish their pills. This is leading to a dramatic

increase in antibiotic resistant bacteria strains. Analgesics such as Sufanta (Sufentanil

Citrate), Sublimaze (Fentanyl Citrate), and Dilaudid (Hydromorphone) have doses of



less than 3 ml per hour. By delivering these pain relievers continuously, a patient can

obtain the benefits of the analgesic without being hindered by a intravenous drip.

Delivery of all of these medications in a continuous fashion greatly simplifies the

therapy. A patch device could be applied once a day or every few days and supply the

patient with enough medication for a given time period. In addition, the drug could be

kept in a lyophilized powder. The powder would be reconstituted with water, dosed,

and delivered as needed by the patient. 2

3.4 Catheterized Instrumentation

Microneedles may be placed on the end of a catheter for intervascular delivery. The

needle could be used to breach blood vessel walls in order to inject precise dosages of

drugs to the surrounding tissue. They may be used to inject clot-dissolving drugs

directly into a coronary arteriosclerosis such as alteplase (a genetically engineered form

of one of the body's own plasminogen activator proteins) or Streptokinase (a

plasminogen activator produced by streptococcus bacteria)20

3.5 Blood glucose measurements

Recent advancement involves the instrument in which a patient will load the cartridge

into the electric monitor and simply press the monitor against the skin. This action will

cause the microneedle to penetrate the skin and drain a very small volume of blood(less

than 100 nanolitres) into the disposable. Chemical agents in the disposable react with the

glucose in the blood to give a colour. The blood glucose concentration will be measured

either electrochemically or optically and the resultant value displayed on the monitor.

The use of hollow microneedles allows the delivery of medicine, insulin, proteins or

nanoparticles that would encapsulate a drug or demonstrate the ability to deliver a virus

for vaccination. An assay of needles can be designed to puncture the skin and deliver the

drug much like a nicotine patch for individuals who are trying to quit smoking.38

3.6 Skin therapy

Microneedle skin therapy is s till in testing development but it seems to show much

promise. Microneedle therapy is a way to rejuvenate the skin without destroying the

epidermis. It is similar to laser treatment but with less damage. Microneedles penetrate

the epidermis and break away old collagen strands. The collagen strands that are

destroyed create more collagen under the epidermis. This leads to youthful looking skin.



The only disadvantage of this method is that it causes blood oozing, which laser

treatments do not. It does however have advantages such as: increased collagen, non sun-

sensitivity upon treatment, no breaking of the epidermis, lower cost, and ease of

application.20

3.7 Eye Treatment

Microneedles can be used to deliver drugs to the eye through a minimally invasive

procedure. The needles used to penetrate the eye only go as deep as half a millimetre into

the eye tissue. This means that the needles do not penetrate far enough to cause as much

damage as traditional needles. As a result, they can be applied to the eye using only local

anaesthetic. This technique has the potential to revolutionise the way of treating common

eye conditions such as glaucoma, macular degeneration and diabetic retinopathy.

Other applications of microneedles include: 26, 24, 39

Cell manipulation.

Interconnection between microscopic and macroscopic fluidic systems.



4. Classification – Types & Approaches

Microneedles can be classified into various types as shown below:

4.1 Types of Microneedles:

Figure 2: Classification of Microneedles

4.1.1 Solid Microneedles

Solid microneedles are 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 can be

mass-produced at low cost. These are of various types and as shown above, can be

fabricated from various materials: 9, 15, 22

4.1.1.1 Silicon Microprobes 18, 27

In the early phase of microneedle development, pyramidal silicon microprobes were

found. 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 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. 28, 41

4.1.1.2 Silicon microneedles

Figure 3: 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. Silicon is

preferred material for fabrication because it has the following characteristics.16, 43

Silicon is abundant, inexpensive, and of high purity and perfection

Silicon processing is highly amenable to miniaturization

Photolithographic patterning allows for rapid evaluation of design ideas

Batch-fabrication results in high volume manufacturing at low unit cost

Silicon is also a biocompatible material (essential for blood testing)

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.

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 compared to conventional

hypodermic needle insertion, and no subjects reported any adverse reactions.

4.1.1.3 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 subject.18, 36

4.1.1.4 Polymer microneedles

Polymers have also been used to form arrays of microneedles. In comparison to silicon

counterparts, polymer microneedles offer the mechanical advantage of improved

resistance to shear induced breakage. Unfortunately, this comes at the cost of reduced

sharpness at the tip of the microneedle due to low modulus and yield strength of the

polymers. Chemically, biodegradable polymers allow additional functionality of the

microneedles themselves. Rather than simply piercing the skin to create pathways for

therapeutic molecules, the microneedles themselves become drug depots implanted in the

skin.2, 34

4.1.2 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;

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. As expected these benefits come at the cost of increased

complexity.

Figure 4: Hollow Microneedles

4.1.2.1 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 combination. 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 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. 10, 18



4.1.2.2 Metal hollow microneedles

Hollow metal microneedles can be creating using laser micromachining (Davis 2003).

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 electrodeposition of a thin metal

coating onto the mold. 18, 21

4.1.2.3 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 precisely. 40, 44

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 enzyme. 21



4.1.3 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 developed. 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. 30, 37

Microneedles made out of maltose mixed with ascorbate were developed for transdermal

delivery of drugs. 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 reported. 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

compounds 19

4.2 Delivery Strategies

A number of delivery strategies have been employed to use the microneedles for

transdermal drug delivery. These include:

4.2.1 Poke and patch approach

This method uses microneedles to make holes and to apply a transdermal patch to the

skin surface.5 Transport can occur via diffusion or possibly iontophoresis if an electric

field is applied.



Insulin delivery using poke and patch approach:

Insulin was delivered to diabetic hairless rat’s in-vivo. Microneedle arrays were inserted

into the skin using a high velocity injector and shown by embed fully within the skin. A

solution of insulin was placed on the top of the microneedle array and left in place for 4

hours. Over this time period blood glucose levels steadily decreased by as much as 80%.

Insulin placed on the skin surface without microneedles did not have any significant

effects. 5, 20

4.2.2 Coat and poke

Another approach is coat and poke where the needles are first coated with the drug and

then inserted into the skin. There is no drug reservoir on the skin surface; the entire drug

to be delivered is on the needle itself.

A variation on this method is the dip and scrape where microneedles are first dipped into

the drug solution and then scrapped across the skin surface to leave behind the drug

within micro abrasions created by microneedles.5

Protein vaccine delivery using coat and poke method

Examination of microneedles to deliver ovalbumin as model protein was done using coat

and poke method. Antigen release from the needle surface was found to occur quickly

where upto 20mg could be released in five sec. 20

4.2.3 Biodegradable microneedles

It involves injecting the drug through the needle with a hollow bore. This approach is

more reminiscent of an injection than a patch.



5. Microfabrication

MEM is an acronym for Microelectromechanical systems. These gained popularity in the

1960’s in the microelectronics industry when sensors were integrated with the electronic

circuits. These are systems that have either mechanical or electric devices typically

containing sub millimeter feature sizes. Slowly, the field of MEMS became distinct

division from microelectronics and commercial products became available.

They are used to make pressure, temperature, chemical and vibration sensors, light

reflectors and switches as well as accelerometers for airbags, vehicle control, pacemakers

and games. The technology is also used to make inkjet print heads, microactuators for

read/write heads and all-optical switches that reflect light beams to the appropriate output

port.13, 35

5.1 General fabrication of microneedles

The various patterns used in depositing layers and doping regions on the substrate are

defined by a process called lithography. 45

Simply put, the lithography process generally consists of the following steps.

A layer of photo resist (PR) material is first spin-coated on the surface of the wafer.

The resist layer is then selectively exposed to radiation such as ultraviolet light,

electrons, or x-rays, with the exposed areas defined by the exposure tool, mask, or

computer data.

After exposure, the PR layer is subjected to development which destroys

unwanted areas of the PR layer, exposing the corresponding areas of the

underlying layer.

Depending on the resist type, the development stage may destroy either the

exposed or unexposed areas. The areas with no resist material left on top of them

are then subjected to additive or subtractive processes, allowing the selective

deposition or removal of material on the substrate.

Photo resist materials consist of three components:

A matrix material (also known as resin), which provides body for the photo resist

The inhibitor (also referred to as sensitizer), which is the photoactive ingredient

The solvent, which keeps the resist liquid until it is applied to the substrate.


http://www.siliconfareast.com/masks-reticles.htm


Most lithography based MEMS fabrication processes are either additive or subtractive. In

general the following processes are used in the block building processes.

Patterning and masking a region for deposition, depositing the material and removing

the mask.

Depositing a material, masking a region for removal and stripping away the material

for deposition.

On a fundamental level these processes include deposition of the materials (additive),

etching of the materials (subtractive) thus enabling the process of patterning. These are

described below:

5.1.1 Etching Processes

Definition of Etch:

A category of lithographic processes that remove material from selected areas of a die.

Examples are nitride etch and oxide etch

Figure 5: Outline of etching process


http://www.chemicool.com/definition/oxide_etch.html

http://www.chemicool.com/definition/nitride_etch.html

http://www.chemicool.com/definition/die.html

http://www.chemicool.com/definition/material.html


There are two basic categories of etching processes:

Wet etching

Dry etching.

In the former, the material is dissolved when immersed in a chemical solution. In the

latter, the material is sputtered or dissolved using reactive ions or a vapor phase etchant.

Table 1: Comparison of Dry and Wet etching processes

5.1.1.1 Wet Etching

Wet Etching is an etching process that utilizes liquid chemicals or etchants to remove

materials from the wafer, usually in specific patterns defined by photoresist masks on the

wafer. Materials not covered by these masks are 'etched away' by the chemicals while

those covered by the masks are left almost intact.14,15

A simple wet etching process may just consist of dissolution of the material to be

removed in a liquid solvent, without changing the chemical nature of the dissolved

material. In general, however, a wet etching process involves one or more chemical

reactions that consume the original reactants and produce new species.

A basic wet etching process may be broken down into three basic steps:

Diffusion of the etchant to the surface for removal;

Reaction between the etchant and the material being removed;

Diffusion of the reaction byproducts from the reacted surface



Due to the chemical nature of this etching process, a good selectivity can often be

obtained, which means that the etching rate of the target material is considerably higher

than that of the mask material if selected carefully.

Some single crystal materials, such as silicon, will have different etching rates depending

on the crystallographic orientation of the substrate. This is known as anisotropic etching

and one of the most common examples is the etching of silicon in KOH (potassium

hydroxide), where Si <111> planes etch approximately 100 times slower than other

planes (crystallographic orientations). Therefore, etching a rectangular hole in a (100)-Si

wafer will result in a pyramid shaped etch pit with 54.7° walls, instead of a hole with

curved sidewalls as it would be the case for isotropic etching, where etching progresses at

the same speed in all directions. Long and narrow holes in a mask will produce v-shaped

grooves in the silicon. The surface of these grooves can be atomically smooth if the etch

is carried out correctly, with dimensions and angles being extremely accurate.

Wet etching is generally isotropic, i.e., it proceeds in all directions at the same rate. An

etching process that is not isotropic is referred to as 'anisotropic.' An etching process

that proceeds in only one direction (e.g., vertical only) is said to be 'completely

anisotropic'.

Lateral etch ratio (RL) = Horizontal etch rate

Vertical etch rate

Isotropic Etching: RL = 1

Anisotropic Etching: 0<RL<1

Directional Etching: RL=0


http://www.answers.com/topic/crystallography


Figure 6: Illustration of Isotropic,Anisotropic and directional etching

Reduction-oxidation (redox) reactions are commonly encountered in wafer fab wet

etching processes, i.e., an oxide of the material to be etched is first formed, which is then

dissolved, leading to the formation of new oxide, which is again dissolved, and so on

until the material is consumed.

When an isotropic etchant eats away a portion of the material under the mask, the etched

film is said to have 'undercut' the mask. The amount of 'undercutting' is a measure of an

etching parameter known as the 'bias.' Bias is defined as the difference between the

lateral dimensions of the etched image and the masked image or simply it is the

difference in the lateral dimensions between the features on the mask and the actually

etched pattern. Thus, the mask used in etching must compensate for whatever bias an

etchant is known to produce, in order to create the desired feature on the wafer. Smaller

RL results in smaller bias.



Another important consideration in any etching process is the 'selectivity' of the etchant.

An etchant not only attacks the material being removed, but the mask and the substrate

(the surface under the material being etched) as well. The 'selectivity' of an etchant

refers to its ability to remove only the material intended for etching, while leaving the

mask and substrate materials intact.

Selectivity, S, is measured as the ratio between the different etch rates of the etchant for

different materials. Thus, a good etchant needs to have a high selectivity value with

respect to both the mask (Sfm) and the substrate (Sfs), i.e., its etching rate for the film

being etched must be much higher than its etching rates for both the mask and the

substrate.

Despite the resolution limitations of wet etching, it has found widespread use because of

its following advantages:

Low cost;

High reliability;

High throughput; and

Excellent selectivity in most cases with respect to both mask and substrate materials

Automated wet etching systems add even more advantages:

Greater ease of use;

Higher reproducibility; and

Better efficiency in the use of etchants.

Of course, like any process, wet etching has its own disadvantages. These include the

following:

Limited resolution;

Higher safety risks due to the direct chemical exposure of the personnel;

High cost of etchants in some cases;

Problems related to the resist's loss of adhesion to the substrate;

Problems related to the formation of bubbles which inhibit the etching process where

they are present;

Problems related to incomplete or non-uniform etching.



Silicon (single-crystal or poly-crystalline) may be wet-etched using a mixture of nitric

acid (HNO3) and hydrofluoric acid (HF). The nitric acid consumes the silicon surface to

form a layer of silicon dioxide, which in turn is dissolved away by the HF. The over-all

reaction is as follows:

Si + HNO3 + 6 HF H2SiF6 + HNO2 + H2 + H2O.

Silicon dioxide may, as mentioned above, be wet-etched using a variety of HF

solutions. The over-all reaction for this is:

SiO2 + 6 HF H2 + SiF6 + 2 H2O.

Water-diluted HF with some buffering agents such as ammonium fluoride (NH4F) is a

commonly used SiO2 etchant formulation

Wet etching of aluminum and aluminum alloy layers may be achieved using slightly

heated (35-45 deg C) solutions of phosphoric acid, acetic acid, nitric acid, and water.

Again, the nitric acid consumes some of the aluminum material to form an aluminum

oxide layer. This oxide layer is then dissolved by the phosphoric acid and water, as more

Al2O3 is formed simultaneously to keep the cycle going.

5.1.1.2 Dry Etching

Dry Etching is an etching process that does not utilize any liquid chemicals or etchants

to remove materials from the wafer, generating only volatile by products in the process.

Dry etching may be accomplished by any of the following:

Through chemical reactions that consume the material, using chemically reactive

gases or plasma (plasma etching)23

Physical removal of the material, usually by momentum transfer (physical sputtering

and ion beam milling)

A combination of both physical removal and chemical reactions. (Reactive ion

etching)

Dry etching refers to the removal of material, typically a masked pattern of

semiconductor material, by exposing the material to a bombardment of ions (usually a

plasma of reactive gases such as fluorocarbons, oxygen, chlorine, boron trichloride;

sometimes with addition of nitrogen, argon, helium and other gases) that dislodge

portions of the material from the exposed surface.

The main purpose of developing dry etching is to achieve anisotropic etching.


http://en.wikipedia.org/wiki/Helium

http://en.wikipedia.org/wiki/Argon

http://en.wikipedia.org/wiki/Nitrogen

http://en.wikipedia.org/wiki/Boron_trichloride

http://en.wikipedia.org/wiki/Chlorine

http://en.wikipedia.org/wiki/Oxygen

http://en.wikipedia.org/wiki/Fluorocarbons

http://en.wikipedia.org/wiki/Plasma

http://en.wikipedia.org/wiki/Ions

http://en.wikipedia.org/wiki/Semiconductor


Figure 7: Illustration of dry etching

Plasma etching, a purely chemical dry etching technique, basically consists of the

following steps:

Generation of reactive species in a plasma;

Diffusion of these species to the surface of the material being etched;

Adsorption of these species on the surface;

Occurrence of chemical reactions between the species and the material being etched,

forming volatile byproducts;

Desorption of the byproducts from the surface; and

Diffusion of the desorbed byproducts into the bulk of the gas.

The reactive species used in dry chemical etching must be selected so that the following

criteria are met:

High selectivity against etching the mask material over the layer being etched;

High selectivity against etching the material under the layer being etched;



High etch rate for the material being removed;

Excellent etching uniformity.

They should also allow a safe, clean, and automation-ready etching process.

Unfortunately, most etching techniques that employ purely chemical means to remove

the material (whether through wet or dry etching) do not exhibit high anisotropy. This is

because chemical reactions can and do occur in all directions. Thus, chemical reactions

can attack in the horizontal direction and consume a portion of the material covered by

the mask, a phenomenon known as 'undercutting.'

If maximum anisotropy is of utmost concern, then dry etching techniques that employ

physical removal of material must be considered. One such technique is physical

sputtering, which involves purely physical removal of material by bombarding it with

highly energetic but chemically inert species or ions. These energetic ions collide with

atoms of the material as they hit the material's surface, dislodging these atoms in the

process.

Targeting the layer to be etched with incident ions that are perpendicular to its surface

will ensure that only the material not covered by the mask will be removed.

Unfortunately, such a purely physical process is also non-selective, i.e., it also attacks

the mask layer covering the material being etched, since the mask is also directly hit by

the bombarding species. For this reason, physical sputtering has never become popular

as a dry etching technique for wafer fabrication.

A good balance between isotropy and selectivity may be achieved by employing both

physical sputtering and chemical means in the same dry etching process. Reactive ion

etching is one such process that involves both physical and chemical means to remove

material.18, 19

Reactive ion etching (RIE)

Reactive ion etching (RIE), is sometimes referred to as reactive sputter etching (RSE),

consists of bombarding the material to be etched with highly energetic chemically

reactive ions. Such bombardment with energetic ions dislodges atoms from the material

(just like purely physical sputtering), in effect achieving material removal by sputtering.

In reactive ion etching (RIE), the substrate is placed inside a reactor in which several

gases are introduced. Plasma is struck in the gas mixture using an RF power source,



breaking the gas molecules into ions. The ions are accelerated towards, and react at, the

surface of the material being etched, forming another gaseous material. This is known as

the chemical part of reactive ion etching. There is also a physical part which is similar in

nature to the sputtering deposition process. If the ions have high enough energy, they can

knock atoms out of the material to be etched without a chemical reaction. It is a very

complex task to develop dry etch processes that balance chemical and physical etching,

since there are many parameters to adjust. By changing the balance it is possible to

influence the anisotropy of the etching, since the chemical part is isotropic and the

physical part highly anisotropic the combination can form sidewalls that have shapes

from rounded to vertical.

RIE is a chemical-physical etching process capable of providing highly anisotropic etch

profiles with good selectivity.9–12 Anisotropy is attributed to ionic bombardment which

is basically a physical phenomenon. On the other hand, selectivity is a chemical

phenomenon that occurs on the surface to be etched due to the chemical reaction of the

active radicals and the neutral species present in the plasma thereby producing loosely

bound compound. This compound is then pumped away from the etched surface due to

physical bombardment of energetic ions present in the plasma. The degree of anisotropy

and selectivity depends on a larger number of parameters such as etch, pressure, radio

frequency (RF) power, gas flow rate and the type of reactant gas or their combinations

used. Plasma etching process was optimized for photo-resist removal using oxygen

plasma and the etching end point was determined by in-situ monitoring of the emission

spectral lines of different species present in the plasma.45

Deep reactive ion etching (DRIE)

A special subclass of RIE which continues to grow rapidly in popularity is deep RIE

(DRIE). In this process, etch depths of hundreds of micrometres can be achieved with

almost vertical sidewalls. The primary technology is based on the so-called "Bosch

process", named after the German company Robert Bosch which filed the original patent,

where two different gas compositions are alternated in the reactor. Currently there are

two variations of the DRIE. In the 1st Variation, the etch cycle is as follows: (i) SF6

isotropic etch; (ii) C4F8 passivation; (iii) SF6 anisoptropic etch for floor cleaning. In the

2nd variation, steps (i) and (iii) are combined.



Both variations operate similarly. The C4F8 creates a polymer on the surface of the

substrate, and the second gas composition (SF6 and O2) etches the substrate. The polymer

is immediately sputtered away by the physical part of the etching, but only on the

horizontal surfaces and not the sidewalls. Since the polymer only dissolves very slowly in

the chemical part of the etching, it builds up on the sidewalls and protects them from

etching. As a result, etching aspect ratios of 50 to 1 can be achieved. The process can

easily be used to etch completely through a silicon substrate, and etch rates are 3-4 times

higher than wet etching.

In addition to sputter-removal, the bombarding ions used in RIE were chosen so that

they will chemically react with the material being bombarded to produce highly volatile

reaction byproducts that can simply be pumped out of the system. This is the reason

why RIE is widely used in wafer fabrication - it achieves the required anisotropy (by

means of sputter-removal) and the required selectivity (through chemical reactions).

Table 1 presents some examples of the process gases usually employed in the reactive

ion etching of common wafer materials.19

Material to be

EtchedExamples of Gases Used in the RIE

PolysiliconCF4; SF6; Cl2; CCl3F; etc. (w/ or w/o

oxygen)

Al; Al doped with Si,

Cu, TiCCl4; CCl4+Cl2; BCl3; BCl3+Cl2

Tungsten Fluorinated Gases

Refractory SilicidesFluorinated plus Chlorinated Gases

(w/ or w/o oxygen)

TiN; TiC Same as Al Etch

Table 2: Examples of Gases Used in the RIE of Common Wafer Materials



5.1.2 Deposition processes

Commonly used deposition processes are: Electrodeposition, Sputter deposition, Physical

Vapour Deposition (PVD) and Chemical Vapour Deposition (CVD). The Chemical

Vapor Deposition Process is a very intricate process which takes place in several steps.

5.1.2.1 Electrodeposition

It is the deposition of the material initiated and propogated by an electrochemical

reaction. Most commonly the term is used to identify the deposition of various metals on

to a substrate via electroplating. However in general it refers to the deposition of the

organic or inorganic substances by reactions driven externally by applying potential

(electroplating) or by in situ potential generated by chemical reactions (electrode-less or

electrode plating)

5.1.2.2 Electroplating

The general principle guiding electroplating is the reduction of a metal species onto a

desired part. The part is immersed in an electrolyte bath and an external power source

supply electrons for the reduction to occur. The anode can serve as both a electrode for

carrying the current as well as a source for replenishing the ions in the electrolyte bath.

The first practical electroplating bath was created in 1843. Metal microneedles are

formed by the deposition of nickel into molds. This includes electroplating nickel to form

microneedle itself and electroless plating of seed layer to polymer molds.

The bath is a solution of nickel sulfate, nickel chloride, and boric acid and the reaction

governing the deposition is:

Ni 2+ + 2e- Ni0

The anode is typically nickel foil which is dissolved from its ground state to replenish the

ionic species consumed in the bath. An external power supplies the electrons to reduce

the nickel species.

5.1.2.3 Elecroless plating

It occurs in a manner similar to electroplating as described above. However a chemical

reducing agent is present in the solution instead of electricity.


http://www.answers.com/topic/physical-vapor-deposition

http://www.answers.com/topic/physical-vapor-deposition

http://www.answers.com/topic/sputter-deposition


Electroless plating of nickel used sodium hypophosphate as the reducing agent. Another

area of interest with regard to electroless plating is the ability to plate onto insulating

surfaces since the necessicity of the substrate serving as an electrode is obviated.

5.2 Specific Processes used in the Fabrication of Microneedles.

5.2.1 LIGA

LIGA is a german acronym that stands for Lithographic, Galvanoforming and

Abforming. This translates into lithography, electroplating and molding.

In general, the process includes the following procedure:

To form a mould using lithography

Electroplate into this mould to form a metallic structure

To remove the mould and reveal a completed structure.

If the desired parts are polymeric, the metal structures serve as the mould for the

polymeric parts.

In the past this was accomplished using polymethyl methacrylate and X-ray lithography

but later this technique was later broadened to include many other types of lithography

and mould materials. While standard lithography offers patterning in the lateral

dimension, the LIGA process offers projection in the vertical direction. 19

5.2.2 Laser Micro Machining

Three-dimensional arrays of hollow and solid microneedles have been fabricated using

laser micromachining techniques. Ultraviolet (UV) and infrared (IR) laser machining was

used to create molds for electrodeposition of metals. Mold materials included polyimide,

polyethylene terephthalate, and titanium. IR laser machining was also used to cut solid

needle designs directly from stainless steel. The mechanical stability and insertion

characteristics of hollow microneedles were tested. The force necessary for insertion was

found to vary linearly with the interfacial area of the microneedle.

The ability to crete three dimensional structures of similar quality in a single , dry step is

often reason enough to adopt laser fabrication technique. The primary disadvantage of

laser patterning is the serial nature of the process. Where lithography offers batch

fabrication, laser ablation requires each feature to be patterned individually.18,19



5.3 Packaging of Microneedle-Based Drug Delivery Systems

Handling by patients or healthcare workers in the macroscopic world is an inherent

challenge confronting microdevices that perform biomechanical functions directly on

tissue. The current state of microfabrication technology allows the construction of precise

architectures with the limitation of physical fragility. This is especially true of hollow

high-aspect-ratio parts like microneedles. Although advances in surface-smoothing and

coatings technologies are likely to improve device robustness, it is likely that the

packaging of the microdevice will play a most important role in the development of

procedures for their use. Integration of the microdevice in a larger system that will be

handled by the practitioner and connection to a fluidic system and reservoir for solution

or dry-powder-based formulations is not a trivial undertaking. It is not unreasonable to

assume that device package as a whole “enables” the use of the microdevice, and that the

entire drug delivery package will need to be developed for testing well in advance of

clinical trials. However, the current state of development is largely focused on developing

scaleable microfabrication processes and efficacious architectures for the microdevice.1,2



6. Commercial Microneedle Technology

A decade after the first microneedles were reported, many commercial technologies have

come into the market including the Macroflux technology, h-patch, Micro-Trans and

many more (as shown in the table)

Table 3: Commercial Microneedle technologies

6.1 Macroflux technology

Macroflux transdermal patch technology has been developed to deliver

biopharmaceutical drugs in a controlled, reproducible manner that optimizes

bioavailability and efficacy without significant discomfort for the patient. Macroflux

technology incorporates a titanium micro projection array affixed to a polymeric adhesive

back. The array has an area of up to 8 cm2 and contains as many as 300 micro projections

per cm2 with individual micro projection lengths of <200 m. The maximal adhesive

patch size is 10 cm2. A coating process is used to apply drug to the tip of each micro

projection in the array. When the patch is applied to the skin, the drug-coated micro

projections penetrate through the skin's barrier layer into the epidermis. Drug is absorbed

by the micro capillaries for systemic distribution. The rate of absorption is promoted by

the high local drug concentration around the micro projections and the large surface area

provided by the patch array.



Following are the salient features of Macroflux:

Systemic Approach

The Macroflux patch and application system are shown in Figure below. When the

applicator is pressed onto the skin, it self-actuates to release the patch with the correct

force and timing (in milliseconds). This reusable, spring-loaded applicator ensures

reproducible patch application and uniform penetration of Macroflux microprojections

through the stratum corneum layer. The patch-application system is easy to use, requiring

no special training.

Figure 8: Figure illustrating ease of application of Macroflux

Efficient Tip Coating Process

With many traditional patch technologies, only a small percentage of drug is actually

delivered from the patch reservoir into the skin. In the current environment of cost

containment and disposal risks, this is undesirable, particularly for the more expensive,

potent biopharmaceuticals. In order to maximize the efficiency of drug incorporation into

the patch and to ensure the precision of drug transport to the skin, a coating process has

been developed that applies the drug formulation just on the tips of the Macroflux

microprojections.



Rapid Delivery & High Bioavailability

Macroflux patches can provide rapid and efficient delivery of therapeutic agents. In the

HGP model, time to maximum plasma drug concentration (Tmax) of hGH occurred

sooner with hGH coated on Macroflux patches than with subcutaneous injection, and

bioavailability was similar

Scientists at ALZA have also demonstrated that intracutaneous Macroflux delivery of a

45-kDa protein antigen provided a better vaccine response than an equivalent dose

delivered by intramuscular or subcutaneous injection in preclinical studies.4 In addition,

Macroflux transdermal technology provided system-controlled and sustained delivery of

an antisense oligodeoxy- nucleotide, 7 kDa, achieving delivery of 15 mg over a 24-hour

period from a 2cm2 patch.

Figure 9: Component of Macroflux

ALZA has entered into partnerships to explore development of products utilizing

Macroflux transdermal technology. Preclinical work is ongoing to explore the feasibility

of using the Macroflux patch technology to deliver this peptide. Additional partnering

programs are in place including a second collaboration with Theratechnologies for an

undisclosed endocrinology product.

In summary, the Macroflux patch incorporates a drug-coated titanium micro-projection

array that offers marked advantages over other transdermal delivery systems for efficient

delivery of peptides, proteins, and other therapeutic macromolecules. Dose delivery is



controlled by the patch size and drug loading on the microprojections. The system is

minimally invasive and well tolerated. It is convenient for users and provides controlled,

consistent dosing. Drug-coated Macroflux microprojections penetrate the skin and deliver

drug into the epidermal layer for rapid dissolution and absorption that yields high drug

utilization and bioavailability. In preclinical studies, approximately 85% of drug present

on the Macroflux array patch was delivered in less than 5 minutes patch-wearing time.

For biopharmaceuticals, the Macroflux pharmacokinetic delivery profile and

bioavailability may be equivalent to subcutaneous injection. The Macroflux patch is a

developing technology that may provide expanded drug delivery opportunities for

therapeutic peptides, proteins, and vaccines.25

6.2 h- Patch

With clearance from the US Food and Drug Administration (FDA), Valeritas' h-Patch

basal bolus insulin delivery system is poised to help Type 2 diabetes patients improve

their compliance and glycemic control with their prescribed therapy regimen.

This disposable, waterproof device is as small as a ChapStick tube and as easy to apply

as a Band-Aid bandage, making it an attractive alternative to other insulin delivery

methods such as catheter-based electronic pump systems or injections. Morever, the h-

Patch is easy, safe and convenient.

Patients simply peel the protective liner from the adhesive backing, apply the device to a

part of the body where it can be easily reached (such as the abdomen, arm or thigh), and

push the start button, which painlessly inserts the micro-needle and begins the basal flow

of insulin. When a meal-time bolus is needed, the wearer simply presses the bolus button

on the h-Patch system, which can easily be done through his or her clothing. No need to

access the device directly. The user will hear a click to indicate that the bolus has been

delivered.

When the h-Patch system is removed, the micro-needle retracts, locks in place, and

cannot be redeployed, making device disposal as easy as removing and discarding a

bandage as well as eliminating the need for sharps disposal. The h-Patch system is

designed to easily be replaced every 24 hours, allowing patients to rotate site placement

and minimize the risk for local infection.48



Figure 10: Application of h-Patch

6.3 Micro Trans

Valeritas microneedle array patch (Micro trans) technology enables drug delivery or

interstitial fluid sensing at the epidermis or dermis, without limitations of drug size,

structure, charge, or the patient's skin characteristics. Arrays penetrate only the shallow

layers of the skin, avoiding close proximity to pain receptors, making the system

extremely comfortable for the patient to wear.

Valeritas' Microneedle Array technology consists of multiple small, hollow or solid

needles fabricated on a single surface. Microneedles can be constructed of metal or

biodegradable polymers. The length, diameter, wall thickness, and shapes can be

manufactured to a variety of specifications. Valeritas' proprietary manufacturing

processes ensure that these arrays can be fabricated at very low cost. 47

Applications Include:

Delivery of large proteins, fragile antibodies, and hormones.

Delivery of small molecules, particularly those with difficulty diffusing through skin

layers.

Delivery of vaccines, both conventional and DNA-based.

Fluid sensing of glucose, hormones, blood gases, and therapeutic drug levels.



Key Features:

Simple for patient to use, and fully disposable.

Unique manufacturing techniques result in very low cost.

Accurate, reliable delivery of drug to epidermis or dermis, circumventing the stratum

corneum.

Passive or active drug delivery profiles.

Can be used with Valeritas' e-Patch device to deliver a wide range of drug volumes

under various extended or time-release profiles

Figure 11: Micro-Trans



7. Future Trends

Integration of solid microneedles with transdermal patch provides a minimal invasive

method to increase the skin permeability of drugs, including the macromolecules such as

proteins. Till date, microneedles made up of silicon, metal, glass and plastics have been

utilized for transdermal delivery.

However, with rapid advancement in technology, microneedles composed of

biodegradable and biocompatible materials have been explored. For instance, fabrication

of dissolving microneedles using polysaccharide biomaterials have been utilized for

controlled drug delivery.2 Microneedle approach of drug delivery is currently being

evaluated for a number of drugs, but extensive studies would be required to foster the

application of these delivery modes in the clinical set up. However, some of the future

directions are discussed below:

7.1 Improved Microneedle Research

There are many aspects of the microneedle field which require future research. The most

important is to balance microneedle robustness with needle deformation in response to

imposed stresses. Needles must be able to tolerate forces associated with insertion, intact

removal and normal human movements if they are to be integrated into portable

biomedical devices. Materials such as silicon can easily pierce the skin but they are also

brittle materials which fracture easily. Metal and polymer needles are not stiff so they can

absorb larger stresses by deforming. However, this ability also makes piercing the skin

more difficult.

More research is needed to develop needles which balance the stiffness required for

insertion with the ability to deform to absorb stress associated with movement. Research

should include hybrid needle designs which incorporate silicon tips with polymer lumens,

or “knuckled” silicon designs with polymer coatings. Thus, the silicon could be used as a

stiff material for piercing the skin and the polymer coating would hold the needle

together and absorb stress.18

7.2 Improved Microdialysis Microneedles

Future work should focus on determining how larger biological molecules such as serum

proteins permeate a microdialysis membrane to allow optimization of the design. This



will allow a balance between mass transfer rates and filtering effectiveness of a

membrane.18, 20



8. Conclusion

Microneedles are needle-like structures which are fabricated on substrates like silicon.

Other materials include: metals, silicon dioxide, polymers, and glass. With the use of

photolithography and various etching methods, it will give the profile of these needles.

Various shapes can also be fabricated to have structures that are straight, bent, filtered

and hollow. Microneedles are applied in the medical field for such applications as: a

blood glucose measurement device, transdermal delivery device, and skin therapy.

Although microneedles will not fully replace the traditional needles, they do, however

posses certain capabilities that traditional needles do not.



9. References

1. James A Down, Noel G Harvey; Transdermal Drug Delivery; Marcel Dekker Inc.

2. Mark R Praunitz ; Microfabricated Microneedles and Transdermal drug Delivery

Technology; Modified Release Drug Delivery Technology; Marcel Dekker Inc.;513-

522

3. Kenneth A Walters; Drug Delivery:Topical and Transdermal Routes;Encyclopedia of

Pharmaceutical Technology- Third Edition;1319

4. Jing Ji, Francis E.H Tay et al; Microfabricated Silicon Microneedle array for

Transdermal Drug Delivery ; Journal of Physics: Conference series34(2000)1127-

1131

5. Pushpat Bora,Lokesh Kumar, Arvind Bansal;Microneedle Technology for Advanced

drug Delivery-Evolving Vistas;Department of Pharmaceutical Technology;NIPER

6. E.R Parker,M.P Rao, K.L Turner; Mechanical & Environmental

Engineering;University of California;USA

7. Jeffery David Zahu; Microfabricated Microneedles & minimally invasive drug

delivery sampling & Analysis;University of California

8. Microneedles: A new Alternative to Hypodermic syringes; MNT

network(www.mntnetwork.com)

9. Nicolle Wilke;Micromachined Silicon and Polymer MicroneedleArrays for cancer

therapy & drug delivery

10. Phil Green, Franklin lakes;Delivery of Macromolecules using Microneedles;BD-

NJ,USA

11. Hurat Karabiyukoglu;New Frontiers in Transdermal Drug Delivery System;Drug

Delivery Report Spring Summer;2007

12. Ritesh Kumar, Anil Philip;Modified Transdermal Technology:Breaking the barriers

of Drug Permeation via Skin; March 2007;6(1);633-644

13. Firas Sammoura , Jeo Jon Kong et al ; Polymeric microneedle for using

microinjection using Microinjection mould Technology ; Microsyst Technology

(2007)13;517,522

14. Microneedle Therapy System ; Prof. Kim Beom Jaon



15. Fabrication of Silicon micronedles for Biomedical Applications ; Summary of work

done for BOC Bursary; Application 2006

16. Medical Diagnoistics Technologies based on Bio MEMS; Jianwei Mo; Director of

Electronic research; Kumetrix Inc.

17. Boris Stuber; Microneedles for Drug delivery and Biosensing ; Department of

Mechanical Engineering; University of British Columbia ; Canada

18. Shaun Paul Davis ; Hollow Microneedles &Molecule transport across the skin ;

Georgia institute of Technology 2003

19. Ninghao Jiang ; Ocular Drug Delivery using Micronedles; Georgia institute of

Technology 2003

20. Pharma Bioworld; July 2008;6(12)

21. Oddvar Sorasen;Microsystems in Biomedical Engineering; Department of

Informatics; 2004

22. Bangtao Chen, Jiashen Wei, Francis E.H. Tay, Yee Ting Wong , Ciprian Iliescu;

Silicon microneedles array with biodegradable tips for Transdermal drug delivery;

DTIP ; April 2007

23. A. K. Paul, A. K. Dimri and R. P. Bajpai; Plasma etching processes for the realization

of micromechanical structures for MEMS ; J. Indian Inst. Sci., Nov.-Dec. 2001, 81

669-674.

24. Royal pharmaceutical Society of Great Britan; News Release; Microscopic Needles

could Revolutionise eye Treatment

25 James A. Matriano, Michel Cormier, Juanita Johnson, Wendy A. Young, Margaret

Buttery, Kofi Nyam, Peter E. Daddona ; Macroflux_ Microprojection Array Patch

Technology: A New and Efficient Approach for Intracutaneous Immunization;

Pharmaceutical Research, Vol. 19, No. 1, January 2002

26. Timothy Olsen, Drug Delivery to the Suprachoroidal Space Shows Promise; Retina

Today ; April 2007

27. www.ivos.org

28. www.cmoset.com

29. www.etd.gatech.edu

30. www.tyndall.ie


http://www.tyndall.ie/


31. www.me.berkeley.edu

32. www.engr.ucsb.edu

33. www.anesthesia-analgesia.org

34. www.nicolle-wilke.de

35. www.nanocentral.eu

36. www.aapspharmaceutica.com

37. www.imre.a-star.edu.sg

38. www.clinicalresolution.com

39. www.retinatoday.com

40. www.ibn.a-star.edu

41. www.nicolle-wilke.de

42. www.iop.org

43. www.wipo.int

44. www.cacshq.org

45. www.wikipedia.com

46. www.siliconvalley.com

47. www.drugdeliverytech.com

48. www.valeritas.com


Documents

Micro Needles in Drug Deliveryf