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IJRAR1903474 International Journal of Research and Analytical Reviews (IJRAR) www.ijrar.org 664

TRANSDERMAL DRUG DELIVERY SYSTEM –

MICRONEEDLES

K. Anusha and K.V Ratnamala

RBVRR Womens college of pharmacy, Osmania university, barkatpura, hyderabad, India

Corresponding author: K.V Ratnamala, Associate professor, RBVRR Women’s college of pharmacy, osmania university,

Hyderabad, India

Abstract:Transdermal drug delivery offers a number of advantages including improved

patient compliance, sustained release, avoidance of gastric irritation, as well as elimination

of pre-systemic first-pass effect. However, only few medications can be delivered through

the transdermal route in therapeutic amounts. Microneedles can be used to enhance

transdermal drug delivery. In this review different types of microneedles are described and

their methods of fabrication was highlighted. Microneedles can be fabricated in different

forms: hollow, solid, and dissolving. There are also hydrogel-forming microneedles, on

which a special attention was made. These are innovative microneedles which do not contain

drugs but imbibe interstitial fluid to form continuous conduits between dermal

microcirculation and an attached patch-type reservoir. Several microneedles approved by

regulatory authorities for clinical use are also examined.

Keywords: transdermal; microneedles; drug delivery; solid; hollow; dissolving

microneedles;

INTRODUCTION: Transdermal drug delivery involves the transport of drug across the

skin. Optimal physicochemical properties arerequired in drug candidates for delivery via

transdermal patches. Traditional transdermal patches can be divided into two categories –

reservoir-based and matrix-based – according to their physical structure. Transdermal drug

delivery offers advantages like patient compliance, avoidance of first pass metabolism, large

surface area of skin over which to deliver the drug, quick termination of dosing,

etc.[1]However, only a few drug products with optimum characteristics have been

successfully marketed to deliver a drug through the skin.[2] This is due to the resistance to

drug transport offered by the stratum corneum. The problem of poor drug transport can be

addressed by development of micron-sized needles, which deliver the drug painlessly across

the stratum corneum.[3]

Advantages of transdermal drug delivery system:

There are numerous advantages related with the use of transdermal system for the effective

delivery of drugs systemically. This includes improved patient compliance, avoids first pass

hepatic metabolism in comparison to oral drug delivery systems. this system reduces the

adverse effects associated with the drug caused due to overdose and is a convenient

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route and comprises of simple dosing, especially in case of transdermal patches that require

only once in a week application which helps in patient adherence to drug therapy. It also

avoids gastrointestinal absorption and enzymatic or pH related deactivation, avoids

gastrointestinal irritation and reduces fluctuations in plasma drug profile. Ease of therapy

termination and it co-ordinates controlled delivery of the drugs .It enhances the

bioavailability.[4]

Disadvantages of transdermal drug delivery system:

Despite of having the above discussed advantages, it also possessed some limitation such as

local irritation, erythema, itching, and local edema may be produced by the drug or other

excipients at the site of application especially in the patch formulation. Limited permeability

across the skin may limit the delivery of number of drugs. Systems containing small sized

molecules can only easily penetrate the skin. Various attempts have been made to overcome

these limitations.[4]

Mechanism of transdermal permeation:

Transdermal delivery of the systemically acting drugs to targeted tissues showed that the

drugs must possess some physicochemical properties which act by facilitating the systemic

absorption of drug across the skin and also enhance the drug uptake via capillary network

into the dermal papillary layer. The rate of permeation as depicted by dQ/dt, across the skin

layers can be expressed as[5]

dQ/dt = PS (Cd-Cr)

Where;

Cd & Cr = concentration of skin penetrate in donor and receptor phase respectively.

PS = Overall permeability coefficient of the skin.

PS = KSDSS/hS

Where;

KS = Partition Coefficient of the penetrant.

DSS = Apparent diffusivity of penetrant.

hS = Thickness of the skin.

Skin anatomy and transdermal drug delivery systems:

Skin can be divided into three regions:(1)the outer most cellular layer, epidermis, which

contains stratum corneum, (2) the middle layer, dermis, and (3) the inner most layer,

hypodermis (Figure 1). The epidermis layer is 150 200 mm thick and is made up of viable

cells without a vascular network.This layer obtains its nutritional needs by passive diffusion

through interstitial fluid.The outermost layer of the epidermis (10–20 mm) consists of dead

cells, known as the stratum corneum, which act as a rigorous barrier.The dermis, an

integrated fibro-elastic structure, provides mechanical strength to the skin. This layer

contains an extensive nervous and vascular network. The pain associated with parenteral

drug delivery is due to possible damage to the nerves endings within the dermis. For drug




delivery across the skin, the challenge is to cross the intact stratum corneum layer without

causing damage to nerves endings. Only a fewpotent drug molecules having high

lipophilicity and small molecular weight (500Da) can be administered directly through

passive diffusion.Various chemical and physical approaches have been employed to improve

drug penetration across the skin.Chemical approaches include the use of penetration

enhancers, like surfactants, fatty acids/esters and solvents to dissolve the stratum corneum

lipid or to increase the solubility of drugs. Physical approaches, like electroporation,

iontophoresis, magnetophoresis and sonophoresis, have been found suitable to create

pathways for only a few drugs across the skin.[6][7]

Figure 1 Skin structure showing three major regions: epidermis, dermis and hypodermis(with their thickness)[6]

The before mentioned approaches are associated with certain bottlenecks: chemical

approaches are often associated with higher skin irritation and are applicable only to small

molecules while physical methods typically require a device with a power supply which

adds to the cost and complexity. Research is focused in the development of transdermal drug

delivery systems for existing molecules to improve the pharmacokinetic and

pharmacodynamic profiles. Each of such developed TDDS suffers with one or other type of

demerits. and comparative efficacy of such delivery systems in terms of increase in drug

transport, sustained drug release, pain sensation and complexity.The search for an




inexpensive and reliable mode of administering the drug safely to the epidermal layer

without damaging the nerve cells, and minimising chances of microbial penetration, led to

the development of microneedles.

MICRONEEDLES:

Microneedles are recently developed systems for drug delivery which is similar likely to

traditional needles but the difference is thse are fabricated on the micron scale.these are

defined as micro-scale needles, arranged on a transdermal patch.microneedles currently

beingutilized to enhance transdermal delivery of small and large molecules.[8]

Microneedles can also be defined as solid orhollow cannula with an approximate length of

50–900 mm and an external diameter of not more than 300mm. Microneedles can be

fabricated within a patch for transdermal drug delivery. Patches containing microneedles

have been evaluated in the delivery of drugs, bio-pharmaceuticals, vaccines, etc. A quick

response can be observed due to disruption of stratum corneum by microneedles. Although

microneedles were first proposed in 1976, the technology needed to make needles of micron

dimensions was not widely available until 2000s. Using the low-cost mass production tools

of the microelectronics industry, needles have been fabricated out of silicon, metals and

other materials. Microneedles have been designed to penetrate through the epidermis up to a

depth of 70–200 mm. Microneedles are thin and short and do not penetrate the dermis layer

with its nerves; hence painless application is possible. Microneedlesare more capable of

enhancing the transport of drug across the skin as compared with other transdermal delivery

methods.[9]

Advantages of microneedles:

The advantages of microneedles are: (1) large molecules can be administered, (2) painless

administration of the active pharmaceutical ingredient, (3) first-pass metabolism is avoided,

(4) faster healing at injection site than with a hypodermic needle,(5) no fear of needle, (6)

ease of administration,(7) decreased microbial penetration as compared with a hypodermic

needle, the microneedle punctures only the epidermis, (8) specific skin area can be targeted

for desired drug delivery, (9) enhanced drug efficacy may result in dose reduction, (10) good

tolerability without long-term oedema or erythema.[10]

Disadvantages of microneedles:The disadvantages of microneedles are: (1) dosage

accuracy may be less than with hypodermic needles, (2) careful use of the device may be

needed to avoid particles ‘bouncing off’ theskin surface; if the device is not held vertically,

the dose may escape or can penetrate the skin to differing degrees, (3) the thickness of the

stratum corneum and other skin layers varies between individuals and so penetration depth

of particles could vary too, (4) the external environment, like hydration of the skin, could

affect delivery, (5) repetitive injection may collapse the veins. [10]




Types of microneedles:

Microneedles can be broadly divided into three categories: solid, degradable /dissolvable and

hollow. Selection of the material for constitution of the microneedle should be based on

criteria such as gentle fabrication without damage to sensitive bio-molecules, sufficient

mechanical strength for insertion into skin and controlled or rapid drug release as per the

requirement. Microneedles have been produced using glass, silicon and metals. The use of

polymers to constitute microneedles has also been explored; skin.

Table 1 List of materials used for preparation of microneedles.[1]

Metals

Synthetic polymers

Natural polymers

Biodegradable Non-biodegradable

Silicon Stainless steel Titanium19

Mesoporous silicon

Polylactic acid (PLA) Polyglycolic acid (PGA)

Polylactide-co-glycolic

acid(PLGA)

Polycarbonate

Polyvinylpyrrolidone (PVP)

Polyvinyl acetate

Alginic acid

GantrezAN-139, a copolymer

ofmethylvinyletherand

maleicanhydride (PMVE/MA)

Carbopol 971 P-NF18

Polyetherimid

Thermoplastic

starch, Carboxy –

methylcellulose

Amylopectin

Dextran,galactose

chondroitinsulfate

Maltose




Figure 2: Types of microneedles used for transdermal drug delivery. (a) Solid microneedles ionically etched from silicon wafer, (b) solid microneedles laser cut from stainless steel, (c) solid microneedles acid etched from titanium sheet, (d) solid microneedles chemically etched from silicon wafers and (e) hollow microneedles formed by electro deposition of metal on to a polymer. [1]

solid microneedles:

Solid micro needles are defined as the arrays of projections that are employed for creating

holes in stratum corneum and are applied before the application of a drug and then removed

afterwards. These can essentially create micron scale holes in the skin, through which drug

molecules can easily enters.[8]

These can be used by inserting the needles into the skin for specified time period. The micro

channels developed by the insertion of micro needles promote the drug transport in to the

viable epidermis. Solid micro needles can be prepared by coating with the drug and then

inserted into the skin. After removal of the micro needle containing device, drug will remain

deposited within the skin membranes.

Erodible microneedles when inserted into the skin, dissolves and the drug can easily be

loaded into the soluble needles. These microneedles can pierce through the superficial skin

layers then followed by the delivery of drugs. It also suffers from some limitations such as in

solid microneedle arrays, the drug delivered cannot easily flow via the holes present in the

skin because it remains plugged by the Microneedles. An application of a thick layer of drug

formulation was not found to be the desirable because it reduces the sharpness of the

microneedles and therefore made insertion more difficult and painful.[11]




2.Hollow microneedles:

Hollow microneedles contain a hollow bore in the centre of the needle. When inserted into

the skin, the hollow bore present bypasses the stratum corneum layer of the skin and

produces a direct channel into the other lower layers of the epidermis. These microneedles

are mainly employed to inject the drug solutions directly into the skin.[12] These are very

expensive to prepare and require expensive micro fabrication techniques. These micro

needles contains hollow bore which offers possibility of transporting drugs through the

interior of well defined needles by diffusion or for more rapid rates of delivery by pressure

driven flow.

3.Dissolvable microneedles:

Rapid-dissolving sugars and polysaccharides have also been explored to prepare dissolvable

microneedles. Carbohydrates have addressed many disadvantages of metal microneedles and

provide rapid drug delivery. Microneedles of dextrin can be prepared without any special

fabrication equipment. However, processing problems such as caramelization and

difficulties in handling of molten sugar can be observed. Moreover, sugar microneedles are

hygroscopic. The material should have a high Young’s modulus so that sufficient

mechanical strength can be provided. Microneedles made up of Gantrez AN-139, a

mucoadhesive polymer, were able to withstand higher compression than microneedles

formed using poly vinyl alcohol (PVA), alginic acid and Carbopol 971.[13]

Drug Delivery through Microneedles

In an earlier phase of research on microneedles, an array of solid microneedles was pierced

through the skin to circumvent the barrier effect of the stratum corneum. The needles were

made up of silicon wafers and a medicated patch was applied to the treated skin surface there

after. This approach is known as ‘poke and patch’ (Figure 4a). This technique was also tried

to extract the interstitial fluid to measure the glucose level by non-invasive

method.[14]Subsequent research in microneedle technology focused on development of solid

microneedles coated with drug solution using a dip coating method. The skin was pierced

before the release of the drug (Figure4b).A limited amount of drug could be coated over the

microneedles (only about 1 mg) and extensive optimization was required for uniform coating

in this ‘coat and poke’ approach. Further research resulted in the development of a‘poke and

release’ approach (Figure 4c).

Microneedles were made from polymers and polysaccharides that either slowly dissolved or

degraded after administration. The advantage of the ‘poke and release’ approach was that the

drug release could be modulated as per the requirement using a variety of available polymers

and polysaccharides. The administration of a large amount of drug was still not feasible with

dissolvable or degradable microneedles like other physical approaches, which led to Hollow

microneedles. This approach was known as ‘poke and flow’ (Figure 4d), where after




piercing the skin, drug was allowed to flow through hollow microneedles from the reservoir

in the patch.[15]

Hollow microneedle arrays with a drug reservoir. Upon the application of external pressure

on the reservoir, the microneedle system penetrates into the skin, followed by the release of

the drug solution into the skin. Thus a large amount of drug can be administered by

fabrication of hollow microneedles. Generally the pore is kept alongside walls rather than at

the centre for easy insertion of the microneedle as well as to prevent blockage of channel.

The design of the microneedle is critical for achieving successful drug delivery such that the

microneedle neither breaks nor causes pain or irritation. All of the above-mentioned

approaches can be employed to deliver drugs either systemically or at a restricted site (local

action).

Fig.3(a): Structure of microneedles 3(b): (Insertion into skin)




Figure

4:Approaches for drug delivery by different designs of microneedles: (a) ‘poke and patch’ using solid microneedles,

(b) ‘coat and poke’ usingcoated solid microneedles, (c) ‘poke and release’ using polymeric microneedles, (d) ‘poke

and flow’ using hollow microneedles.[16]




Fabrication of Microneedles

MNs have been fabricated with a wide range of designs (different sizes and shapes) and

different types (solid, hollow, sharp, or flat). The two The two basic designs are: in- plane

and out-of-plane However, a combination of both in-plane and out-of-plane designs has also

been reported. In in-plane designs, the MNs are parallel to the fabrication surface; whereas

in out-of-plane designs, the MNs are perpendicular to the fabrication surface.

Microneedles can be fabricated employing micro electromechanical systems (MEMS). The

basic process can be divided in to three parts: deposition, patterning and etching.

Deposition refers to the formation of thin films with a thickness anywhere between a

few nanometers to about 100 micrometers.

Patterning is the transfer of a pattern onto the film. Lithography is used to transfer a

pattern into a photosensitive material by selective exposure to a radiation source such

as light. This process can involve photolithography, electron beam lithography, ion

beam lithography or X-ray lithography. Diamond patterning is also an option for

lithography.[1]

Etching is a process of using strong acid or mordant to cut into the unprotected parts

of a material’s surface to create a design in it and can be divided into two categories:

wet etching or dry etching. The selection of any of the abovementioned methods

largely depends on the material of construction and the type of microneedle.Wet

etching is a material removal process that uses liquid chemicals or etchants to remove

materials from a wafer. The specific patterns are defined by masks on the wafer.

Materials that are not protected by the masks areetched away by liquid chemicals.

These masks are deposited and patterned on the wafers in a prior fabrication step

using lithography.in dry etching, plasmas or etchant gasses remove the substrate

material. The reaction that takes place can be done utilizing high kinetic energy of

particle beams, chemical reaction or a combination of both.[17]

fabricated biodegradable polymeric microneedles are prepared by using micro molding

technique. In this process, moulds or microarray of SU-8 epoxy photo resist were initially

made in different shapes, like bevelled-tip, chisel-tip and tapered-cone, using different

techniques. biodegradable polymer pellets were put on the master structures of different

shapes and placed under vacuum at high temperature. Polymeric melt was pulled into the

mould by application of vacuum, followed by freezing for separation of the master

structure from the mould.[18]

Micro fabrication of biodegradable polymers under normal atmospheric conditions.

Polylactic acid microneedles were blocked because of formation of hydrolysed intermediate

products of polylactic acid. This intermediate product was not formed under vacuum laser

micro fabrication of needles. Hence application of vacuum during the laser micro fabrication

process was suggested.




Laser micromachining technology for preparation of microneedle moulds of silicon.[18] An

aqueous polymeric blend was filled in the moulds to fabricate microneedles. Polymeric

microneedles can also be fabricated using casting, injection moulding and hot embossing. a

robust Gas-jet coating method to achieve uniform coating of a range of immune therapeutics,

like antigens, DNA and proteins, on microneedles.[19]

Characteristics of microneedles

The characteristics of micro needles include

Ruggedness:

Micro needles developed must be capable of insertion deep into the skin without breaking.

They should be manufactured by taking optimum size and if they are too long, upper portion

of micro needles may not have enough rigidity and could undergo breakage before

penetration. They must be able to withstand the insertion force without delaminating, or

fracture.[5]

Controlled drug release:

The micro needles should deliver the controlled amount of drug at a definite and

predetermined rate.[5]

Penetration:

The micro needles should be able to penetrate the drug to the required depth in the tissues of

the body. Painless insertions of micro needles into the skin can be accomplished by gentle

pushing, using approximately 10 Newton forces.[5]

Evaluation of microneedles:

Functional capacity test:

The functional capacity of micro-fluidic lumens using a custom fluidic test set up.The test

setup consisted of a syringe pump system with a dye-filled syringe, a polymer tube and

microneedle array. This syringe pump system was used to examine the formation of the

microneedle lumens by allowing dye to flow from the syringe to the microneedle orifice.

Microscopic inspection of the microneedle tips and the base plate during the microfluidic

characterization can be used to detect cracks in the base plate and passage continuity.[20]

Measurement of insertion force intohuman skin:

A displacement–force test station was used To measure the force applied to a needle,

position and skin resistance during the sequence of the needle’s translation, deflection of

tissue around the needle and observation of needle insertion was extremely difficult. The

electrical resistance of skin’s outermost layer, the stratum corneum, is much greater than

deeper tissues, therefore the resistance of the skin drops dramatically as soon as a needle

penetrates.[21]




Margin of safety:

The margin of safety as the ratio between the force required for piercing the stratum

corneum and the force at which microneedles broke. They hypothesized that if the ratio is <1

then microneedle array can be used in biomedical application. They checked margin of

safety for silicon microneedles using computerized apparatus. For compressive failure force

measurement, Enduratec station was used in which microneedles were placed between

punch and load cell. An appropriate margin of safety was found for sample silicon

microneedle arrays.[22]

Measurement of fracture force:

The force required for mechanical fracture of a microneedle was tested an axial load test

station that drove the microneedle against a flat block of aluminium at a rate of 0.01 mm/s

until a preset displacement of 500 mm was reached. Microneedles were attached to the

testing surface using adhesive tape around the base of the needle. Microneedle fracture was

observed through an attached microscope to evaluate the mode of failure. The force and

displacement data were used to quantitatively determine the fracture force.[23]

In-Vitro study of Microneedles:

In vitro evaluation microneedles are accomplished by using various mediums like agarose

gel and methanol to insert the microneedles. In vitro tests are used to determine the

characteristics of new test device or compound. The main key objectives of the in vitro

testing of microneedles involves optimization of the microneedles, finding out the

penetration force and bending force, evaluation of strength of microneedle, determination of

the dissolution rate of coating material and the estimation of the efficiency of drug delivery.

Various methods employed for conducting in vitro studies are as follows[24]

Method 1

In vitro methods tested the delivery efficacy of the microneedles. In this test, the

microneedles are integrated with Paradimethylsiloxane (PDMS) biochip and black ink is

injected by the microneedles into the petridish, which contains methanol. The right

triangular microneedles with 8.5 and 15 tip taper angles and isosceles triangular

microneedles with 9.5 and 30 tip taper angles have been used for this purpose .

Method 2

In this method, the diluted form of Rhodamine B dye is injected through the microneedles

into the 1% agarose gel to evaluate the penetration and flow of the solution after penetrating

into the 1% agarose gel.

Method 3

Inserting microneedles into the porcine cadaver skin and pig cadaver skin for 10s to 20 s and

5 minutes respectively are evaluated by this method. This method is used to test the delivery

efficacy, dissolution rate of the coated material, which is coated on the microneedle tip,

coated with vitaminB, calcein orsulforhodamine.




In Vivo Testing of microneedles:

To conduct the in vivo pre-clinical study, generally mice, rabbits, guinea pigs, mouse and

monkey etc are used. The main motive of the in-vivo testing is the determination of safety as

well toxicity of the tested compound. The key objectives behind in vivo testing of the

microneedles includes to perform skin toxicity test, determination of penetration force in

different skin, mechanical stability, bending breakage force, to perform various non-clinical

safety study and pharmacological study, determination of various parameters like

immunogenicity, genotoxicity, skin sensitization and allerginisation, study, developmental

toxicity, acute and chronic dermal toxicity, carcinogenicity.[24]

Method 1

This in vivo method involves testing of microneedles by pricking the microneedles into vein

of the tail of hairless mice. It is used for the determination of the penetration force of the

microneedle into the skin .

Method 2

This method of in vivo testing of the microneedles, Rhodamine B isinjected into tail of

laboratory mouse-tail and anaesthetized for the determination of penetration force and

bending breakage force.

Method 3

This method has been performed for the evaluation of vaccine delivery via microneedles.

Ovalbumin is used in this method, as a model protein antigen and administered into hairless

guinea pig by using solid metal microneedles at the rate of 20 μg ovalbumin in 5sup to 80

μg.

Method 4

In this method rabbits have been used to evaluate the vaccine delivery. The anthrax vaccine

containing recombinant protective antigen (rPA) of Bacillus anthracis has been administered

in the rabbits via solid and hollow microneedles .

Applications of Microneedles

Skin is suitable for gene and oligonucleotide delivery because it is well characterized at the

cellular as well as the molecular level. The microneedle delivery system can be used for

treatment of various genetic diseases related to skin, various types of malignancies and

infectious diseases, and for immunization. Microneedle delivery of gene is better than a

microinjection technique because many cells can be treated at once. Thus microneedles can

be used to deliver bioactive agents systematically as well as locally. Research could focus on

antiviral, antidiabetic, genetic, oncological, anti-osteoporosis, vaccine, dermatological, etc.,

areas for bioavailability improvement by developing microneedle-based transdermal drug

delivery systems.




Immunobiologicals:

Conventionally immuno-biologicals are administered through a needle via the subcutaneous,

intramuscular or intradermal route for prevention of infectious diseases.

However the conventional vaccination procedure suffers from drawbacks like needle phobia

and the pain associated with insertion of needle into the skin. Research has focused on

development of needle-free vaccination like liquid jet injectors, powder injectors, thermal

ablation and microneedles. Microneedles have an edge over the other methods due to lack of

pain, self administration and quick delivery of vaccine.[25]Combination vaccination is one of

the ways to reduce the number of injections to be administered; ‘DPT’ is a well known

example, used to prevent infection of diphtheria, pertussis and tetanus. However to develop

such a formulation is a challenge as the physical, chemical and biological interactions

between the vaccine components may have a detrimental effect on vaccine safety or

efficacy. Physical and chemical interaction as well as adverse effect on the biological

activity of each component was not observed by researchers. Conventional liquid vaccines

require cold conditions during transportation and tend to have a short shelf life. The stability

of vaccines at high temperature as well as maintenance of antigenicity.[26]

High purity subunit vaccines are safer than live attenuated or whole inactivated vaccines.

The use of pure vaccines results in decreased immunogenicity. studies have been carried out

to achieve effective immunization of vaccines via microneedle delivery along with adjuvant.




Table 2 Applications of microneedles[5]:

Active

constituent/product

Delivery

approach

Description

Immunobiologicals

Biopharmaceuticals

Drugs

Influenza vaccine

Hepatitis B vaccine

Human IgG

Tetanus toxoin

Ovalbumin

Flavivirus vaccine

L-Carnitine

Recombinant human

growthHormone and

desmopression.

Albumin

Low molecularweight

heparin,

calcein,erythropoietin

Insulin

Calcein and bovine

serum albumin

L-Ascorbic acid

Galanthamine

Aspirin

Docetaxel

Pilocarpin,.

Riboflavine

Coat and poke

Poke and release

Poke and release

Poke and release

Coat and poke

Poke and flow

Poke and patcth

Poke and release

poke and flow

Poke and release

Poke and patch

poke and release

poke and release

Poke andpatch

Poke and patch

Poke and patch

Coat and poke

Coat and poke

Adjuvant increases cellular

immunogenicity, safety and self life.

Antigenicity was maintained at high

temperature.

Transportation ofmacromolecules

through skin was enhanced.

Due to enhanced immunogenicity dose

can be reduced by four time.

Antigenicity was increased.

Vaccination was safer and well

tolerated.

Bioavailability of L-carnitine was

increased and controlled

delivery could be achieved.

Absorption, bioavailability and stability

were increased

MEMS syringe were used to successfully

delivery of macromolecules.

Bioavailability and stability were increased

bioavailability and rapid onset of action.

controlled release in skin for hours to

month

Faster hair growth due to 10.54 fold

increased in penetration.

Enhanced drug delivery.

Polymeric microneedle rollers were

fabricated.

Administration in form of liposomes

increases the bioavailability and reduces

lag-time...Rapid and extensive pupil

constriction with higher bioavailability

Studied various parameters of coating of

riboflavin on Microneedles




Bioactive macromolecules(biopharmaceuticals): Insulin, heparin, and growth hormones are not administered orally due to proteolytic

degradation and hindered absorption. The majority of commercially available

biopharmaceuticals are administered via the parenteral route and hence a suitable non

invasive route is desirable. administered macromolecules with varying molecular weight

across human dermatomed skin using microneedles. They revealed that microneedle arrays

enhanced the transport across dermatomed human skin both low and high molecular weight

compounds[26]

Parathyroid hormone is used in the treatment of advanced osteoporosis in men and post-

menopausal women. Forteo (a once-daily subcutaneous injection of human parathyroid

hormone) is the only US-approved anabolic therapy for the treatment of osteoporosis. The

use of Forteo is limited due to the requirement of product refrigeration a parathyroid

hormone coated microneedle patch system that is now under phase-3 clinical trial. These

patches show an ideal plasma profile, indicative of efficient parathyroid hormone therapy in

osteoporosis using microneedles.

Dissolving microneedles can be developed for rapid release as well as controlled release of

molecules. Microneedles prepared with water-soluble polysaccharides dissolve within a

minute in the body. self-dissolving microneedles for rapid delivery of low-molecular-weight

heparin using dextrose, dextran and chondroitinsulfate. matrix dissolving microneedles by

encapsulation using amylopectin/carboxy methyl cellulose polymers. They found that the

microneedles dissolved in a minute followed by bolus delivery of bio-therapeutics and

proteins due to micro encapsulation. Likewise, formation of microneedles of calcein, insulin,

erythropoietin and l-carnitine showed good bioavailability and stability

Drugs:

Very few drug molecules possess the necessary physicochemical properties to cross the skin

barrier and even if the drug can cross the barrier, drug delivery rate via the transdermal route

is very low. Physico-chemical properties like hydrophilic-lipophilic balance, solubility,

molecular weight, etc., govern the transport of a drug through the skin and also the rate of

transportation. Highly hydrophilic drug formulations like PEGylated naltrexone or

hydrophobic formulations of drugs like ketoprofen, show a many-fold increase in area under

the curve (AUC) and maximum drug concentration as compared with conventional cream or

gel formulations Microfabrication technology can be used in the delivery of drugs for the

treatment of restenosis and late thrombosis. Various medical devices, such as stents, embolic

grafts, stent grafts, catheters, etc., of micron size can be used as minimally invasive surgical

treatments. Drugs like riboflavin, galanthamine, aspirin, etc. have also been evaluated for

administration through microneedles.[27]

Cosmetic products:

Generally, only minor fractions (maximum 0.3%) of the active substance present in a cream,

gel or lotion can penetrate deeply into the skin. This means that the majority of an active




ingredient, about 99.7%, is wasted. Derma rollers and stamps are available on the market for

treatment of skin problems as well as to improve looks. Clinical Resolution Laboratory

markets MTS Dermaroller, a cosmetic aid possessing needles that penetrate the skin up to a

depth of 0.2–0.3mm.The product contains 200 very fine stainless-steel needles to pierce the

epidermis, creating a micro-channel effect. Clinical studies from various countries have

proven that therapeutic Serum absorption is increased by as much as 1000 times when

applied using the MTS Dermaroller.The majority of cosmetic products lending themselves to

microneedle technology are for non-surgical and non-ablative treatment of skin conditions

such as ageing(wrinkles, lax skin), scarring (acne, surgical), photo damage, Hyper

pigmentation (age/brown spots) and hair loss (alopecia).The process facilitates and

stimulates skin’s natural repair without causing permanent epidermal damage.[28]

Advances in Drug Delivery by Microneedles

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:

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. studied the administration of

insulin unilamellar nanovesicles through microneedles along with iontophoresis.The positive

zeta-potential and small diameter of the nano vesicles enhanced the penetration of insulin

with the help of iontophoresis and microneedle 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.[29]

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 ª1 MHz, skin perturbation

increases 1000 fold. 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.[30]

Combination of electroporation and microneedles:

Electroporation causes localized perturbation by forming aqueous pathways in the lipid

bilayer of skin using high voltage 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. a silicon

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

specifically to tumour cells of microneedles. On the basis of their experiment, it can be

concluded that to administer higher dose or to increase permeability, it might be better to

increase the number of microneedles in spite of increasing length of microneedles. the safety

of microneedles and reported that drug could be delivered without adverse reactions and

pain using microneedles.[31]

Conclusions

Transdermal drug delivery has historically been limited to only those compounds that

possess the appropriate physicochemical properties, which allow for movement across the

SC and into the viable epidermis. The advancing nature of research into MN delivery

systems shows continual improvement in transdermal delivery of therapeutics, which would

otherwise never passively cross the sc. Various research reports studied confirmed that

microneedles are the prominent carriers for enhancing the permeation deep into the systemic

circulation and providing a painless, effective and safe route for the drug delivery. These

painless systems are slowly gaining importance and would qualify to be one of the important

devices for controlled drug release in future. Thus, it was concluded that, these systems

represented it to be an efficient and superior carriers as compared to other needle based

formulation for the transdermal delivery.

Table 3: Commercial status of microneedle-based transdermal products[1][32]

Brand name Manufactured by Applications Vaxmat Theraject Inc., USA It is dissolvable microneedles and can deliver

hundreds of microorganisms of drug rapidly

through the stratum corneum into the

epidermal tissue.

Micro- trans Valeritasinc.,USA It can deliver the drug into dermis without

limitations of drugsize,structure,charge or the

patient skin characteristics.




Nanoject Debiotech,Switzerland Useful for intradermal and hypodermic drug

delivery and for interstitial fluid diagnostics,

Janisys Janisys, Irland Actively delivers drugs from transdermal

patches and multiple drugs can be administerd

via one patch.

Onvax Becton Dikinson, USA It is a skin micro abrader having plastic

microneedles for disruption of stratum

corneum for the delivery of vaccines .

Micronjet Nanoopass Inc.,Israel It can be used withany standard syringe for

painless delivery of drugs,protein and

vaccines approved for this delivery route.

Macroflux ZosanopharmaInc,USA Metallic microneedles for the delivery of

peptides and vaccines.

Microcor Corium International

Inc.,USA

It can be used to deliver small as well as large

molecules like proteins,peptides,and vaccine,

Adminpen Adminmed, USA Liquid pharmaceutical formulation or

cosmetics can be conveniently injected in to

the skin.

Nanocare Nanopass Inc., Israel It is a small hand-held device for rejuvenation

of skin and to boosts the cosmetic effect of

topical applications.

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