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International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 5.13***

Pharmaceutical Sciences REVIEW ARTICLE……!!!

ADVANCES IN MICRONEEDLES BASED TRANSDERMAL DRUG

DELIVERY

Nitin Saini1*, Anshul Bajaj

2

1Department of Pharmaceutics, M.M. College of Pharmacy, M.M. University, Mullana-Ambala

2 Department of Pharmaceutics, Manav Bharti University, Solan, Himachal Pradesh

KEYWORDS:

Microneedles, TDDS,

Dermis Layer, Degradable

Microneedle ,

Methodology.

For Correspondence:

Nitin Saini *

Address:

M.Pharmacy

(Pharmaceutics), M.M.

College of Pharmacy,

M.M. University,

Mullana-Ambala

(Haryana)

Email-

[email protected]

ABSTRACT

One of the thrust areas in drug delivery research is

transdermal drug delivery systems (TDDS) due to their

characteristic advantages over oral and parenteral drug

delivery systems. To overcome the skin‟s barrier properties

that block transdermal delivery of most drugs, arrays of

microscopic needles have been microfabricated primarily

out of silicon or metal. Microneedles are thin and short and

do not penetrate the nerves in dermis layer thereby avoids

causing pain. Advances in microneedle research led to

development of dissolvable/degradable and hollow

microneedles to deliver drugs at a higher dose and to

engineer drug release. This review article discusses the

recent advances in the development of microneedles,

different types of microneedles, methodology, their

application in different drug delivery to the skin and the

combination of microneedles with other technologies.



INTRODUCTION:

Microneedles can be defined as solid or hollow cannula with an approximate length of 50–900 µm and an

external diameter of not more than 300 µm. Microneedle concept employs an array of micron-scale

needles that is inserted into the skin sufficiently far that it can deliver drug into the body, but not so far that

it hits nerves and thereby avoids causing pain. An array of microneedles should be long enough to deliver

drug into the epidermis and dermis, which ultimately leads to uptake by capillaries for systemic delivery.

This is similar to conventional transdermal patch delivery, except the rate limiting barrier of the stratum

corneum is circumvented by the pathways created by microneedles.

Small microneedles can also be painless if designed with an understanding of skin anatomy. Microneedles

can be fabricated within a patch for transdermal drug delivery. The use of microneedles in increasing skin

permeability has been proposed and shown to dramatically increase transdermal delivery, especially for

macromolecules. When oral administration of drugs is not feasible due to poor drug absorption or

enzymatic degradation in the gastrointestinal tract or liver, injection using a hypodermic needle is painful,

microneedles is the most common alternative in such cases. This approach is more appealing to patients,

and offers the possibility of controlled release over time.(1,2)

Advantages & disadvantages associated with microneedles

Microneedles with a patch-like structure, has all the favourable properties of a traditional transdermal

patch, i.e. continuous release, ease-of-use, unobstructiveness and painlessness. Microneedles are thin and

short and do not penetrate the nerves in dermis layer. Hence painless application is possible by this

approach but dosage accuracy is less as compared to hypodermic needles.

Unlike the standard patch, a microneedle-based patch enables delivery of virtually any macromolecular

drug (including insulin and vaccine). It would not only offer a discreet and patient-friendly drug

administration system, but also an efficient and possibly safe way to administer drugs with minimum

involvement from health-care professionals. But careful use of the device may be needed to avoid particles

„bouncing off‟ the skin surface. If the device is not held vertically, the dose may escape or can penetrate the

skin to differing degrees.

The rate of drug delivery can be controlled more effectively by this system as compared with drug delivery

via the stratum corneum. Rapid drug delivery can be achieved by coupling the microneedles with an

electrically controlled micropump. Microneedles are also used to target the specific skin area and also for

enhanced drug efficacy which results in dose reduction. But sometimes the tip of the microneedle may

break off and remain within the skin on removal of the patch. First pass metabolism is avoided by



microneedle approach. Decreased microbial penetration as compared with a hypodermic needle, the

microneedle punctures only the epidermis. (3-6)

RECENT ADVANCES IN MICRONEEDLES

Kim et al, 2010 prepared solid metal microneedles coated with influenza virus-like particle (VLP) vaccine

and used for intradermal immunization. They used trehalose in the coating formulation to increase vaccine

stability during coating by maintaining hemagglutination activity. Mice vaccinated with stabilized

microneedles developed strong antibody responses comparable to conventional intramuscular vaccination

and were fully protected against subsequent viral challenge. Whereas, coating microneedles with a coating

solution lacking trehalose led to only partial protection against lethal viral challenge. Their results show

that microneedles coated with trehalose-stabilized VLP vaccine can be a promising tool for improving

influenza vaccination.

Choi et al, 2013 introduced novel method for the fabrication of biodegradable microneedles with ultra

sharp tip ends. They developed spatially discrete thermal drawing method, which provides the enhanced

control of microneedle shapes by spatially controlling the temperature of drawn polymer as well as

drawing steps and speeds. They utilize the surface energy of heated polymer to form ultra-sharp tip ends.

They investigated the effect of such temperature control, drawing speed, and drawing steps in thermal

drawing process on the final shape of microneedles using biodegradable polymers. XRD analysis was

performed to analyze the effect of thermal cycle on the biodegradable polymer. Load–displacement

measurement also showed the dependency of mechanical strengths of microneedles on the microneedle

shapes. Ex vivo vascular tissue insertion and drug delivery demonstrated microneedle insertion to tunica

media layer of canine aorta and drug distribution in the tissue layer.

Chaudhria et al, 2011 prepared hollow circular cross sectioned microneedles involving one lithography

step. The average failure force for each microneedle was measured experimentally. They measured

insertion force in agar gel, which serves as a reliable human skin equivalent in terms of its visco-elastic

properties was obtained. The safety factor, ratio of failure force to insertion force was computed to be

almost 600. Therefore, the fabricated microneedles are sufficiently strong to be inserted into the stratum

corneum. The fabrication process was enhanced to incorporate sharpening of the tips of the microneedles

as well as mounting them on a platform such that the bores of the needles are continuous through the bore

of the platform on which they are mounted.

Gill and Prausnitz developed coated microneedles to deliver proteins and DNA into the skin in a

minimally invasive manner. They fabricated microneedles from stainless steel sheets as single



microneedles or arrays of microneedles. They designed novel micron-scale dip-coating process and a

GRAS coating formulation, to reliably produce uniform coatings on both individual and arrays of

microneedles. calcein, vitamin B, bovine serum albumin and plasmid DNA are coated by this process.

Modified vaccinia virus and microparticles of 1 to 20 μm diameter were also coated. Coatings could be

localized just to the needle shafts and formulated to dissolve within 20 s in porcine cadaver skin.

Histological examination validated that microneedle coatings were delivered into the skin and did not wipe

off during insertion. This study presents a simple, versatile, and controllable method to coat microneedles

with proteins, DNA, viruses and microparticles for rapid delivery into the skin.

NEED FOR USING MICRONEEDLES (10-12)

When oral administration of drugs is not feasible due to poor drug absorption or enzymatic degradation in

the gastrointestinal tract or liver, injection using a painful hypodermic needle is the most common

alternative. An approach that is more appealing to patients, and offers the possibility of controlled release

over time, is drug delivery across the skin using a patch. However, transdermal delivery is severely limited

by the inability of the large majority of drugs to cross skin at therapeutic rates due to the great barrier

imposed by skin's outer stratum corneum layer. To increase skin permeability, a number of different

approaches have been studied, ranging from chemical/lipid enhancers to electric fields employing

iontophoresis and electroporation to pressure waves generated by ultrasound or photoacoustic effects.

Although the mechanisms are all different, these methods share the common goal to disrupt stratum

corneum structure in order to create “holes” big enough for molecules to pass through. The size of

disruptions generated by each of these methods is believed to be of nanometer dimension, which is large

enough to permit transport of small drugs and, in some cases, macromolecules, but probably small enough

to prevent causing damage of clinical significance. An alternative approach involves creating larger

transport pathways of microns dimensions using arrays of microscopic needles. These pathways are orders

of magnitude bigger than molecular dimensions and, therefore, should readily permit transport of

macromolecules, as well as possibly supramolecular complexes and microparticles. Despite their very large

size relative to drug dimensions, on a clinical length scale they remain small. Although safety studies need

to be performed, it is proposed that micron-scale holes in the skin are likely to be safe, given that they are

smaller than holes made by hypodermic needles or minor skin abrasions encountered in daily life.

Transdermal drug delivery is a non invasive, user-friendly delivery method for therapeutics. However, its

clinical use has found limited application due to the remarkable barrier properties of the outermost layer of

skin, the stratum corneum (SC). Physical and chemical methods have been developed to overcome this



barrier and enhance the transdermal delivery of drugs. One of such techniques was the use of microneedles

to temporarily compromise the skin barrier layer. This method combines the advantages of conventional

injection needles and transdermal patches while minimizing their disadvantages. As compared to

hypodermic needle injection, microneedles can provide a minimally invasive means of painless delivery of

therapeutic molecules through the skin barrier with precision and convenience. The microneedles seldom

cause infection while they can allow drugs or nanoparticles to permeate through the skin. Increased

microneedle-assisted transdermal delivery has been demonstrated for a variety of compounds. For instance,

the flux of small compounds like calcein, diclofenac methyl nicotinate was increased by microneedle

arrays. In addition, microneedles also have been tested to increase the flux of permeation for large

compounds like fluorescein isothiocynate-labeled Dextran, bovine serum albumin, insulin and plasmid

DNA and nanospheres. Microneedles may create microconduits sufficiently large to deliver drug-loaded

liposomes into the skin. The combination of elastic liposomes and microneedles may provide higher and

more stable transdermal delivery rates of drugs without the constraints of traditional diffusion-based

transdermal devices, such as molecular size and solubility. Though it could offer benefits mentioned above,

the combined use of elastic liposomes and microneedle pretreatment has received little attention.

MECHANISM OF ACTION (13)

In microneedle devices, a small area (the size of a traditional transdermal patch) is covered by hundreds of

microneedles that pierce only the stratum corneum (the uppermost 50 μm of the skin), thus allowing the

drug to bypass this important barrier. The tiny needles are constructed in arrays to deliver sufficient amount

of drug to the patient for the desired therapeutic response. It is based on the temporary mechanical

disruption of the skin and the placement of the drug or vaccine within the epidermis, where it can more

readily reach its site of action. The drug, in the form of biomolecules, is encapsulated within the

microneedles, which are then inserted into the skin in the same way a drug like nitroglycerine is released

into the bloodstream from a patch. The biodegradable microneedles dissolve within minutes, releasing the

trapped cargo at the intended delivery site. They do not need to be removed and no dangerous or bio

hazardous substance is left behind on the skin.

FABRICATION OF MICRONEEDLES (14-25)

Microneedles have been fabricated out of numerous materials, including metal, polymer, glass and ceramic,

and in a variety of shapes and sizes, as needed for different applications. Most microneedle fabrication

methods are based on the conventional microfabrication techniques of adding, removing, and copying

microstructures utilizing photolithographic processes, silicon etching, laser cutting, metal electroplating,



metal electropolishing and micromolding. In general, microneedles can be categorized as solid

microneedles for tissue pretreatment, drug-coated microneedles, dissolving microneedles, and hollow

microneedles.

Solid microneedles

The fabrication of solid microneedles has focused on providing sufficient mechanical strength through

choice of microneedle material and geometry and reducing the force needed to insert microneedles into

tissue by increasing tip sharpness. Solid microneedles have been fabricated out of various materials,

including silicon; non-degradable polymers such as photolithographic epoxy, a copolymer of

methylvinylether and maleic anhydride (PMVE/MA), polycarbonate and polymethylmethacrylate

(PMMA), biodegradable polymers such as poly-lactic-co-glycolic acid (PLGA), polyglycolic acid (PGA)

and polylactic acid (PLA), watersoluble compounds including maltose; metals including stainless steel,

titanium, tantalum and nickel and ceramics.

Coated microneedles (28)

Solid microneedles can be used not only as piercing structures, but also as vehicles to carry and deposit

drug within the skin or other tissue. This can be done by coating microneedles with a drug in a formulation

suitable for coating and subsequent dissolution. In this way, the desired dose of the drug is delivered into

tissue quickly upon insertion of the microneedles. The drug dose that can be administered this way is

limited to the amount that can be coated onto the tip and shaft of the microneedles, which is typically less

than 1 mg for small microneedle arrays.

Dissolving microneedles

Polymer microneedles have been developed to completely dissolve in the skin and thereby leave behind no

biohazardous sharps waste after use. These microneedles are typically made solely of safe, inert, water-

soluble materials, such as polymers and sugars that will dissolve in the skin after insertion. While

dissolving microneedles can be used as a skin pretreatment to increase permeability, drugs are often

encapsulated inside the microneedle for release into the skin similarly to coated microneedles.

Hollow microneedles

Hollow microneedles provide a defined conduit for drug delivery into the skin or other tissue. Similar to

hypodermic injection, hollow microneedles enable pressure-driven flow of a liquid formulation. Pressure,

and thereby flow rate, can be modulated for a rapid bolus injection, a slow infusion or a timevarying

delivery rate. The liquid formulationmay simplify use of existing injectable formulations for delivery using

microneedles, but misses the opportunity of solid microneedle delivery methods to administer dry-state



drug formulations without reconstitution to improve drug stability and the patient convenience of a patch-

based delivery method. Hollow microneedles have also been used as a conduit for drug diffusion into the

skin from a non-pressurized drug reservoir.

Fig 1: Methods of drug delivery to the skin using microneedles (MN). Microneedles are

first applied to the skin (A) and then used for drug delivery (B)

METHODOLGY FOR DRUG DELIVERY (13)

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

These includes

1. Poke with patch approach

It involves piercing an array of solid microneedles into the skin followed by application of the drug patch at

the treated site. Transport of drug across skin can occur by diffusion or possibly by iontophoresis if an

electric field is applied eg: Insulin Delivery.

2. Coat and poke approach

In this approach needles are first coated with the drug and then inserted into the skin for drug release by

dissolution. The entire drug to be delivered is coated on the needle itself eg: Protein vaccine delivery.

3. Biodegradable microneedles

It involves encapsulating the drug within the biodegradable, polymeric microneedles, followed by the

insertion into the skin for a controlled drug release.

4. Hollow microneedles

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

(suggestive) of an injection than a patch eg: Insulin Delivery.



5. Dip and scrape

Dip and scrape approach, where microneedles are first dipped into a drug solution and then scraped across

the skin surface to leave behind the drug within the microabrasions created by the needles. The arrays were

dipped into a solution of drug and scraped multiple times across the skin of mice in vivo to create

microabrasions. Unlike microneedles used previously, this study used blunt-tipped microneedles measuring

50–200 μm in length over a 1 cm2 area eg: DNA Vaccine Delivery.

Fig 2: Approaches for drug delivery by different designs of microneedles: (a) „poke and patch‟ using solid

microneedles, (b) „coat and poke‟ using coated solid microneedles, (c) „poke and release‟ using polymeric

microneedles, (d) „poke and flow‟ using hollow microneedles. (29)

SILENT FEATURES OF MICRONEEDLE DRUG DELIVERY TECHNOLOGY (27)

Rapid onset of action

Painless drug delivery system

Possible self-administration



Efficacy and safety comparable to approved injectable products

Improved patient compliance

Good stability

Cost effective

Valuable source of intellectual property

Applications of microneedle technology in a follow up study, Mc-Allister et al found a change in the

permeability ofcadaver skin to insulin, latex nanoparticles and bovine serumalbumin after treatment with

microneedles, Microneedle technology has been developed as a platformtechnology for delivery of high

molecular weight andhydrophilic compounds through the skin. The firstever study of transdermal drug

delivery by microarray technology was conducted by Henry et al who demonstrated an increase in the

permeability of skin to a model compound calcein using microarray technology. In a follow up study, Mc-

Allister et al found a change in the permeability ofcadaver skin to insulin, latex nanoparticles and bovine

serum albumin after treatment with microneedles, and unleashed the mechanism of transport as simple

diffusion.

APPLICATIONS OF MICRONEEDLE TECHNOLOGY (13, 27)

Microneedle technology has been developed as a platform technology for delivery of high molecular

weight and hydrophilic compounds through the skin. The first ever study of transdermal drug delivery by

microarray technology was conducted by Henry et al who demonstrated an increase in the permeability of

skin to a model compound calcein using microarray technology. In a follow up study, Mc- Allister et al

found a change in the permeability of cadaver skin to insulin, latex nanoparticles and bovine serum

albumin after treatment with microneedles, and unleashed the mechanism of transport as simple diffusion.

Oligonucleotide delivery

Lin and coworkers extended the in vitro findings of microarray drug delivery to in vivo environment. An

oligonucleotide, 20- merphosphorothioated oligodeoxy nucleotide was delivered across the skin of hairless

guinea pig either alone or in combination with iontophoresis. Lin and coworkers used solid microneedles

etched from stainless steel or titanium sheet prepared with the poke with patch approach. This delivery

system increased the absorption of the molecules relative to the intact skin. Iontophoresis combined with

microneedles was able to increase the transdermal flux by 100 fold compared to the iontophoresis alone.

DNA vaccine delivery

The cells of Langerhans present in the skin serve as the first level of immune defense of the body to the

pathogens invading from the environment. These cells locate the antigens from the pathogens and present



them to T lymphocytes, which in turn stimulate the production of antibodies. Mikszta et al reported the

delivery of a DNA vaccine using microneedle technology prepared with the dip and scrape approach. The

arrays were dipped into a solution of DNA and scrapped multiple times across the skin of mice in vivo.

Expression of luciferase reporter gene was increased by 2800 fold using microenhancer arrays. In addition,

microneedle delivery induced immune responses were stronger and less variable compared to that induced

by the hypodermic injections. Similar results were obtained by researchers at Beckett- Dickinson™ in an

animal study for antibody response to HepB naked plasmid DNA vaccine 3. This approach has a potential

to lower the doses and the number of boosters needed for immunization.

Desmopressin delivery

M. Cormier et al (Alza Corporation, USA) examined the use of microneedles to deliver desmopressin, a

potent peptide hormone used in the treatment of nocturnal enuresis in young children, as well as for the

treatment of diabetes insipidus and haemophilia A. Microneedles were coated by an aqueous film coating

of desmopressin acetate on titanium microneedles of length 200 μm, a maximal width of 170 μm and a

thickness of 35 μm. Microneedle patch was inserted into the skin with the help of an impact applicator. A

target dose of 20 μg of desmopressin was delivered to hairless guinea pig from 2 cm2 microneedle array

within 15 minutes.

Insulin delivery

Insulin is one of the most challenging drug of all times for the drug delivery technologists. Martano et al10,

used microarrays for the delivery of insulin to diabetic hairless rats. Solid microneedles of stainless steel

having 1mm length and tip width of 75 μm were inserted into the rat skin and delivered insulin using poke

with patch approach. Over a period of 4 hours, blood glucose level steadily decreased by as much as 80%

with the decrease in glucose level being dependent on the insulin concentration.

Porphyrin Precursor 5-Aminolevulinic Acid (ALA) Delivery

Photodynamic therapy of deep or nodular skin tumours is currently limited by the poor tissue penetration of

the porphyrin precursor 5- aminolevulinic acid (ALA). Ryan F. Donnelly and co workers have shown that,

in vivo experiments using nude mice showed that microneedle puncture could reduce application time and

ALA dose required to induce high levels of the photosensitiser protoporphyrin IX in skin. This clearly has

implications for clinical practice, as shorter application times would mean improved patient and clinician

convenience and also that more patients could be treated in the same session.



COMBINATION OF MICRONEEDLES WITH OTHER TECHNOLOGIES (3, 28)

Application of physical methods such as iontophoresis, sonophoresis and electroporation have been

explored in conjunction with microneedles to provide enhanced drug delivery and better control of delivery

of drug across the skin.

Combination of iontophoresis and microneedles (28)

In iontophoresis a small electrical current is used for transportation of drug across the stratum corneum of

the skin. The main advantage of using iontophoresis along with microneedles is to control delivery of drug

by controlling the current. The current may be turned on and off by the patient, and can deliver small drug

molecules and biomolecules having a molecular weight up to a few thousand Daltons. Chen et al. 2009

studied the administration of insulin unilamellar nanovesicles through microneedles along with

iontophoresis. The positive zeta-potential and small diameter of the nanovesicles enhanced the penetration

of insulin with the help of iontophoresis and microneedles. Lin et al. investigated the delivery of antisense

oligonucleotide (ODN) by using Macroflux microprojection patch technology. They used hairless guinea-

pigs for comparative transdermal delivery of ODN via passive diffusion, Macroflux patch and Integrated

Macroflux patch with iontophoresis. They found an increase in the concentration of ODN from the stratum

corneum to the dermis in the following order: Integrated Macroflux patch with iontophoresis > Macroflux

patch > passive diffusion. Macroflux patch technology was found capable of delivering a therapeutically

relevant amount of ODN into and through the skin.

Combination of sonophoresis and microneedles

Sonophoresis uses ultrasound (frequency, 20 kHz to 10 MHz; intensity, up to 3 W/cm2) for enhancing

transportation of drugs by forming cavitation and change in the lipid arrangement of the stratum corneum.

Drug permeation can be controlled by controlling the frequency of the ultrasound. As the sound frequency

increases from 20 kHz to 1 MHz, skin perturbation increases 1000 fold. Chen et al. found that an increase

in the rate and extent of delivery of calcein (623 Da) and bovine serum albumin (66.430 kDa) could be

achieved by using a combination of sonophoresis and microneedles.

Combination of electroporation and microneedles

Electroporation causes localized perturbation by forming aqueous pathways in the lipid bilayer of skin

using highvoltage short-duration current. A trans-membrane potential up to 1 kV for 10 ms to 500 ms was

used for in-vitro electroporation of stratum corneum. Longer pulse width and higher voltage was required

to increase skin perturbation. This technique was also used for permeation enhancement of larger

molecules having molecular weight up to several kiloDaltons. Furthermore, each microneedle behaved as a



microelectrode for electroporation, which eradicated the need for electrodes. Electroporation can be used in

concert with chemotherapy (electrochemotherapy) for effective tumour treatment. Wilke et al. designed a

silicon microneedle electrode array with integrated temperature and fluidic system for drug delivery

specifically to tumour cells.

Combination of vibratory actuation and microneedles

Penetration of a microneedle into the skin requires precise control of insertion force, which should not

exceed the fracture force of the microneedle.A satisfactory balance between structure rigidity and

miniaturization should be kept in mind. Yang and Zahn studied the effect of vibratory actuation on

microneedle insertion force and found there to be a reduction in insertion force by greater than 70%.

Vibration caused tissue damage via fluid cavitation and thermal damage due to frictional interaction, which

reduced microneedle insertion force. This combination helped in the preparation of microneedles using

metals and polymers with low value of Young‟s Modulus.

Pocketed and grooved microneedles

Microneedles with modified surface can be used for the targeting of drugs to a specific depth in the skin

and to load a greater amount of drug onto the microneedles. The protective coat, or second drug coat can

also be applied on same microneedles after filling the first part in the pockets. Gill and Prausnitz made

pocketed microneedles by fabricating microneedles with one or more holes cut through the centre. They

worked on parameters like controlled coating of pockets, their filling capacity, possibility of multi-layered

coating and targeting drug to specific depths in the skin. Grooved microneedles were prepared by Han et al.

for improvement of antigen delivery. They prepared 3D polymeric microneedles having groove-embedded

shafts, sharp tips and a large base and determined drug loading capability. A higher antibody response was

observed with more antigen being loaded in comparison with smooth microneedles.

Combination of micro-pumps and microneedles

Micro-pumps, when associated with microneedles, provide precise delivery of drug. Pumps control flow

rate and pressure for delivery of concentrated drug solution as per specifications.

Conclusion

Microfabricated microneedles have been demonstrated as powerful tools for the delivery of drugs and other

molecules to cells, target regions and systemically. These microneedles have facilitated drug delivery,

which was impossible with traditional delivery methods. For example, the capability of utilizing these

microneedles for transdermally delivering macromolecules, such as proteins, with no pain was described.

This is a key example of the enhancement that microfabrication can bring to the field of advanced drug



delivery. In addition, micropumps and microvalves have been demonstrated as viable microfluidic

elements that are critical for the development of drug delivery microdevices. These microfabricated

components and future improved models will enable the creation of novel microdevices that can be tailored

to give any drug delivery profile desired. In addition, the implantable microdevices that were described

show promise. These are capable of very accurate dosing, complex release patterns, local delivery and

biological drug stability enhancement by storing in a microvolume that can be precisely controlled. These

microfabricated drug delivery devices can enable efficient drug delivery that was unattainable with

conventional drug delivery techniques, resulting in the enhancement of the therapeutic activity of a drug.

The future of drug delivery is assured to be significantly influenced by microfabrication technologies.

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