REVIEW ON MICRONEEDLE DRUG DELIVERY SYSTEM

www.wjpps.com │ Vol 9, Issue 11, 2020. │ ISO 9001:2015 Certified Journal │

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Patel et al. World Journal of Pharmacy and Pharmaceutical Sciences

REVIEW ON MICRONEEDLE DRUG DELIVERY SYSTEM

Smit Patel1*, Jitendra Patel

2 and Umesh Upadhayay

3

1Student

Sigma Institute of Pharmacy, Bakrol, Vadodara, Gujarat 390019, India.

2Associate Professor Sigma Institute of Pharmacy, Bakrol, Vadodara, Gujarat 390019, India.

3Principal

Sigma Institute of Pharmacy, Bakrol, Vadodara, Gujarat 390019, India.

ABSTRACT

Microneedle is the one of the best-targeted drug delivery system.

Microneedles has several types one of the micro syringes,

Microneedles patches, Admin Pen, derma roller etc. Microneedles

have been fabricated with a range of sizes, shapes and materials. Most

drug delivery studies have emphasized on solid microneedles, which

have been shown to increase skin permeability to a broad range of

molecules and nanoparticles in-vitro. In vivo studies have

demonstrated delivery of oligonucleotides, reduction of blood glucose

level by insulin and induction of immune responses from protein and

DNA vaccines.

KEYWORDS: Microneedle, Microneedle classification, Microneedle patches, Microneedle

pen & roller.

INTRODUCTION

The Microneedles drug delivery system is one of the impactful methods of the transdermal

drug delivery system. The transdermal drug delivery system (TDDS) is a deliver drug

substance via the skin. Specifically, the skin is one of the best targets for drug delivery

because in our body all organs are surrounds by the blood.[1]

The microneedle technology to

the increase delivery of high molecular weight drugs through the skin. It is the concept of the

combine the patches and hypodermic injections.[2]

The microneedle drug delivery system has

enhanced the popularity in the pharmaceutical industry in now days.[3]

This system is painless

and causes of this benefit it is the delivering drugs and vaccines through the membrane.[4]

The

microneedle size ranges from 1-100 microns in length and 1 micron in diameter. These are

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 11, 2643-2672 Review Article ISSN 2278 – 4357

*Corresponding Author

Smit Patel

Student Sigma Institute of

Pharmacy, Bakrol,

Vadodara, Gujarat 390019,

India.

Article Received on

22 Sept. 2020,

Revised on 12 October 2020,

Accepted on 02 Nov. 2020

DOI: 10.20959/wjpps202011-17776


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

being utilized to enhance transdermal delivery of small and large molecules.[5]

For the proper effect of the drug, it need to the cross barrier of the tissue. In this situation, the

barrier is the skin‟s outer membrane of the stratum corneum. It just 10µm-20µm in thickness.

Moreover, microneedle is easily passing this layer by the passively diffusing.[6]

Viable

epidermis pass located below the stratum corneum, 50 µm-100µm and dermis layer1mm-

2mm. below the epidermis located blood vessels, nerves, hair follicles and sweat glands.[7]

Figure 1: Cross section through human skin (A) intracellular, (B) hair follicles and

sweat glands, (C) Direct pathway through the SC and, (D) depicts the micron-sized

holes that can be created by MNs upon the skin.[8]

Microneedles required for constructing microneedles includes glass, silicone, metal such as

stainless steel, solid or coat of gold over nickel, palladium, cobalt and platinum and

biodegradable polymers. Microneedles designing as to minimize the pain and some specific

microneedles are also painless.[9]

Microneedles device is made by the arranging so many microneedles in array on the tiny

patch in order to sufficient drug on the patch for the therapeutic responses and this

hypodermic needle piercing into the upper layer of the skin (stratum corneum). Numerous

studies have found a marked increase in drug transport through the skin when using

microneedle arrays alone, in combination with other enhancers or even when including more

sophisticated devices such has micropumps.[10]


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According to the present invention of the microneedle drug delivery system used for delivery

of a solid or gel-type drug by forming a solid or gel-type drug. Layer on the top Surface of

capsule-disrupting micro-projections or on the bottom surface of the microneedles for

piercing the skin, and filling a solvent capable of dissolving the drug in the drug-containing

capsule .When the microneedle piercing to the skin and filling a solvent dissolve the drug into

the capsule. When the capsule disturbed that time solvent flow out from the capsule and gel

type drug contained into the drug layer so drug is dissolve in the body. Moreover, this time

microneedles tip protection film for preventing separation of drug.[11]

Microneedle has proved that it is very worth it in the many fields in the pharmaceutical

industry. It is used in the cancer therapy, biomedical sensors and sample collection, and used

in the delivery of the vaccine in the human. It is continence the combination of the MN and

CS would be conductive to develop the novel patch with the function of smart drug delivery

for promoting would heal.[12]

Microneedles Pre-treatment of the skin with MN resulted in

increased transdermal flux of the beta-blockers as compared with the Passive delivery. The

flux values resulting from MNs pre-treatment are 6-fold to 10-fold higher than that of

corresponding Passive diffusion.[13]

We have demonstrated that these microneedles not only showed excellent adhesion when

applied to knuckles and ideal antibacterial activity but also performed well in drug-sustained

release and treatment for the osteoarthritis rat model. These results indicate that bio inspired

multifunctional microneedles will break through the limitation of traditional methods and be

ideal candidates for versatile transdermal drug delivery systems.[14]

Microneedle drug delivery technology

Microneedlling first used in the 1995 by Dr. Desmond Fernandez in Philadelphia to treat for

the wrinkles with help of the hypodermic needles. However, the first proof of the concept of

this technique emerged in 1998 by Henry et al.[15]

The microneedle ranges in size, shape and

microneedle range in size, shape, and function but are all used as an alternative to other

delivery methods like the conventional hypodermic needle or other injection apparatus.

Microneedle system can be apply on the patches, pen-shaped instruments, roller, stamps,

conventional syringes, or prefilled syringes since 1995. Microneedle technology first used in

the treatment of the acne, after used in the aesthetics products, also used in the delivery of the

specific drugs, vaccines, small-molecules drugs, so on.[16]


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Nowadays, transdermal drug delivery used for the patient compliance therapies. This therapy

also in the demand because there are many benefits from this technique as compare to the

conventional methods. Protein as a drug its major role in the treatment of the cancer,

vaccination, genetic disorders, inflammation, etc. but delivery of the protein through the

transdermal conventional methods it is difficult to pass through the stratum corneum. So

overcome to this problem used the microneedle system and it does easily penetrate through

the stratum corneum. Moreover, the use of microneedle likewise brings many benefits over

the cancer therapy and its easily controllability and applicability.[17]

Ranges of miniaturized needles are used to penetrate the skin layer. Since the needles are

short, they do not reach the nerve-rich regions of the lower parts of the skin. When the

microneedles are piercing into the skin. They are shorter penetrate and do not reach the

nerve- rich regional of the lower part of the skin.

By using batch-fabrication methods from the microelectronics industry, small-scale

microneedles can be mass-produced with high accuracy and reproducibility in an economical

manner.[18]

Excellent future of the Microneedle drug delivery system

Good efficacy and safety.

Painless drug delivery system.

Rapid onset of action.

Good stability.

Improve patient compliance.

Self-injectable.

Cost effective.[19]

Now days, biotechnology has produce many more potent drugs. There are so many methods

for the delivery these drugs into the body. However, there are such limitations.[20]

Like as oral

drug delivery for the DNA based, protein based and other therapeutic substance is generally

not possible to degradation of the drug by the gastrointestinal tract or elimination by the liver.

So used the anther technique by the injection, its direct to the blood stream or intramuscular

and subcutaneous injection. Nevertheless, this method has some limitation like pain, trauma

caused by the needle, need to expert for the drug delivery, and do not provide sustained

released drug delivery.


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To overthrow from this problem used the microneedle system. Which provide the sustained

release of the drug and it is design by such that way it decreases the size of the needles, also

reduce the pain and trauma from the needles.[21]

Microneedle drug delivery technique first fabricated by the Han et al. First, microneedles

were fabricating inclined UV lithography and electroforming with sharp tip and low force to

insert into the body. It is enough long to penetration to depth. It is also control the shape, side,

length and sharpness of the tip.[22]

Advantages of microneedles

Microneedles system useful for the sustained release of the drug delivery system.

It is main advantage of microneedles over the normal needles, when normal needles

inserted into the skin, needles pass stratum corneum layer(which is the outer layer 10-

20μm of the skin) for the drug delivery it is effective but it cause the pain and some

infection and injury related to the Skin. However, when microneedle insert into the skin it

does not pass the stratum corneum layer. Therefore, this needle reduces the chances of

pain, infection, or any injury.[23]

Microneedles system has a rapid one set of action on the delivery site.

Very small microneedle could provide highly targeted drug administration to the

individual cells.

Immunization programs in developing countries, or mass vaccination or administration of

antidotes in bioterrorism incidents, could be applied with minimal medical training.[24]

Hollow like microneedle, solid increase permeability by inserting into the holes in skin,

rub drug over the area, or coating needles with drug.[25]

Microneedles fabricating by the silicone substrate because of that small size, thousands of

needles can be fabricated on the single patch. This lead to the high accuracy, good

reproducibility and low costing of fabrication.[26]

Array of hollow needles could be used to continue carry drugs into the body and used

pump for the diffusion of drug.[27]

Hollow microneedles could be used the remove body fluid such as blood glucose

measurements and then supply micro litre volumes of insulin or other drug as required.

• Avoidance of „first-pass‟ metabolism of drugs and providing a large surface area and ease

of accessibility for drug administration.

• Peak plasma levels of drugs are reduced, leading to decreased side effects.


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• Reduction of fluctuations in plasma levels of drugs.

• Utilization of drug candidates with short half-life and low therapeutic index.[28]

Disadvantages of microneedles

The drug and other excipient may produce local irritation, itching, and oedema, which is

present in the patch.

Limited permeability across through the skin may limit the delivery of number of

drugs.[29]

Microneedles are used in various instruments like as conventional syringes, microneedles

patches, pen-shaped instruments, rollers, stamps, or prefilled syringes since 1995, first time

microneedles were used for the treatment of the acne scars.[30]

Micro syringes used for the treatment for the conventional drug delivery system. When

microneedles patches used in the treatment for the alopecia and transdermal disease. And

roller were used for the cosmetic products improve the skin appearance.

Classification of microneedle

The most common material used for micro fabrication on the needles by the silicone. These

microneedles have extremely sharp tips that facilated easily piercing of the membrane.[19]

Microneedle can be divided into four categories like solid, coated, hollow, polymer.

1) Hollow microneedles

- Hollow microneedles presented by the McAllister et al. in 1999 and 150μm long hollow

microneedles and micro tubes could be fabricated.[18]

Figure 2: Hollow microneedle “poke and flow” approach.[31]


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- Hollow microneedles system has been most successful in terms of commercialization. It

is used for the one time used injection of the drugs. However, if the needles attached to

the skin for a long period, congestion is a possible problem that to be stunned, and access

blood.[32]

- Hollow microneedles are like regular hypodermic needles but shorter in length. In this

type, liquid formulation of the drug is infused through bores in the microneedles. This

advance is more evocative of an injection than a patch.[19]

- Hollow microneedles contain a hollow bore in the centre of the needle hollow

microneedles can also be used for the large drug contained.

- Hollow microneedles can be penetrate into the viable epidermis to dermis avoiding the

stratum corneum

- Silicon microneedles of 300 μm in height, with 130 μm outer diameter and 110 μm inner

diameter at the tip

- These are very expensive to prepare and require expensive micro fabrication techniques.

- Hollow microneedles use especially for the vaccines, proteins likes as high molecular

weight compounds.[29]

- Hollow microneedles more valuable method for its controlled drug release feature.

- It is less used due to its practical problems.

- Most studies on hollow microneedles were of in experimental performance.[33]

2) Solid microneedles

Figure 3: Solid microneedle “poke with patch” approach.[31]

- Solid microneedles are the first type of the microneedles drug delivery. The Diazon et al

developed it in 1993.


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- The microneedles were successful inserted into the skin and its dissolve at 0, 60, 120 and

180 s after the inserted.

- Solid microneedles fabricated from silicon, metal and polymer.

- Fabricated solid microneedles with rectangular cup shaped tip are 200 μm in height.

- The cup shaped tips have dimensions of 60 × 60 μm (length × breadth) with a depth of 60

μm.

- The cup is filled with the drug using the novel drug coating methods.

- Solid microneedles is passed out by the passive diffusion for drug deliver by creating

micro channels to enhance skin permeability followed by the application of a drug-loaded

patch on the channels.

- Solid microneedles can be fabricated by the polymer. It prepared from the biopolymers

film extracted from the fish scales of tilapia.[34]

- Solid microneedles piercing an array of solid microneedles into the membrane followed

by application of the drug patch at the treat site. Transport of drug transversely skin can

occur by diffusion or ionotophoresis if an electrical field is applied.[35]

- Solid microneedles can be used to create holes in the skin through which is more easily

transport of the drug.

- These microneedles were inserted into tissue it enhance molecular uptake and gene

transfection. After that developed for the transdermal delivery application, which is

inserted into the skin and it deliver in vitro and in vivo.[36]

3) Coated microneedles

- This type of the needle is coated with the drug substances. Then inserted into the skin for

the dissolution. Entire drug is the dissolve by itself.

- Coated needles method used the dip and rub approach for the delivered of the drug

substance. Where a microneedle are first dipped into a drug solution and then enter the

drug into the skin and after drug is apply then its leave within the micro abrasions twisted

by the needles.[19]


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Figure 4: Coated microneedle “coat and poke” approach.[31]

- A plethora of methods has been used in the literature to prepare coated microneedles

advantages of hydrogel-forming microneedles are that they can be fabricated in a wide

range of patch sizes and geometries, can be easily sterilized, resist hole closure while in

place and are removed completely intact from the skin.[37]

- Coated polymer is stick on the microneedles. Because of their structural and storages

advantages and delivery of such microneedles is diffusion through the skin.[38]

4) Polymers

- Microneedles are made of the polymers. Polymers that can be dissolving, non-dissolving

or hydrogel- forming.[29]

Dissolving microneedles

- This type of microneedles is encapsulation with the drugs, this type microneedles are

insertion into the skin for controlled drug release.[19]

- Dissolving microneedles have to many of advantages. These include the one-step

application process, which is convenient for patients.

- Dissolving microneedles are fabricated based on the “poke and release” principle. They

aremade from polysaccharides or other polymers. These microneedles release

encapsulated drug into the skin following application and dissolution.

- Micro moulding is the preferred fabrication method for making dissolving microneedles.

- Certain drugs and vaccines are thermo labile so moulds are sometimes filled with

solutions of drugs and excipients and then dried under minor situations.

- The manufacture process involves pouring the polymer solution into female molds, filling

the micro cavities of the mould under vacuum or pressure, drying under ambient


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conditions, centrifugation or pressure. Master structures for microneedles supporting

arrays, and Chen et al. using proprietary electro-discharge-machining technology created

pressing tools. Each master structure consisted of 64 (8×8) microstructures.[39]

- Maltose has been tried for formation of biodegradable microneedles.[40]

Hydrogel – Forming microneedles

- Hydrogel-forming microneedle systems are relatively novel and were first developed by

Donnelly et al., in 2012. As with dissolving microneedle systems, mechanical strength

and physical stability are the main concerns associated with this system.

- Hydrogel-forming microneedles require materials that are strong enough for insertion into

the skin followed by rapid swelling and release of the drug after mixing with interstitial

fluids.

- Unlike dissolving microneedles, hydrogel-forming microneedle systems do not leave

microneedles in the skin, which represents a significant advantage.

- Another advantage is that dose limitation is less of a problem for these microneedles

compared to dissolving.

- Coated microneedles because hydrogel-forming microneedle systems use a drug

reservoir. So it is the also used as sustained release delivery.[16]

Figure 5: Hydrogel microneedle “poke and release” approach.[31]


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Figure 6: Different types of microneedle (1) Solid MNs; (2) coated MNs; (3) dissolving

MNs; (4) hollow MNs and (5) hydrogel forming MNs.[15]

Recent patent of microneedles

Microneedle application is an emerging technique for transdermal drug delivery and the large

number of patent applications filed reflects this. The majority of these patent applications are

focused around design of, and delivery through, hollow microneedles since a higher amount

of drug can be delivered from such microneedles as compared with other microneedles. Many

of the patents based on hollow microneedle technology are also because of its major merit of

administration of a larger volume compared with other microneedles. So hollow microneedle

have more patent than the other microneedles.[41]

Figure 7: Division of patents filed based on type of microneedles.[42]


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Different types of microneedles design variable

There are eight design variables to be manipulated and enhanced. The variables involved are

the shape of microneedle, the material used, and the array of the needles, microneedle base,

lumen base, and height of microneedle, height of lumen and height of the drug

container/reservoir. These variables are manipulated to achieve the required microneedle

specification as shown in Table 2. Figure 2 shows four types of microneedles shape involved

in this study, which are: a) canonical; b) pyramidal; c) hexagonal; and d) octagonal

Figure 8: Four Types of Microneedles Shape: (a) Canonical, (b) Pyramidal, (c)

Hexagonal, and (d) Octagonal.[43]

Despite the eight design variables to be optimized, there are two constant Variables in this

study. The constant variables are the pressure applied at the tip of microneedle and the size of

the microneedle array base. In this study, the pressure is set to 3.18 MPa because according

to, human skin offers resistance of 3.18 MPa during microneedle penetration. Hence, to

overcome This skin resistance, the microneedle must withstand the load more than 3.18 MPa.

As for the size of the microneedle array base, it is set to 5000 μm × 5000 μm × 50 μm.[44]

Microneedle patches (MNPs)

Microneedles patches made of the so many tiny needles are stuck on the one patch are called

as a microneedles patches. Microneedles patches have been fabricating to penetrate into the

stratum corneum with the micro-scale pores that are large enough to enable drugs, and small

molecules. When the apply the patches on the skin do not rub the patch. In addition, leave for

at least two hours, although it is best to leave it overnight for the better result.[45]

Microneedles are combined with drugs and make patch-like structure, a system can be

realized which essentially has all the favourable properties of a traditional transdermal patch,

either is continuous release, ease-of-use, unobtrusiveness and painlessness.


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Different the standard patch, a microneedle-based patch allows delivery of almost any

macromolecular drug including insulin and vaccine. Such a patch 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. And

over the 500 companies are start the start-up of the microneedle related transdermal drug

delivery system.[18]

Microneedles patches have so many advantages like it is avoid pain, irritation, and needle

phobia when the penetrate into the skin layer. Usually contain range of area approximately 1

cm2. Microneedles length generally between the 100-1000 μm.

Microneedles is made of two type of the substances.

[1] Non-water soluble material. [2] Water soluble material.

1) Non-water soluble material is made of the metal, polymer, or ceramic and some type

coated with drug formulation. These types of material not easily dissolve into the skin.

2) Water soluble material made of the saccharides or soluble polymers and encapsulated

with soluble material drugs.

Advatages of microneedle patches

Microneedle patches had big advantages is they avoid the first pass metabolism by the

targeted delivery to the dermal capillaries. Therefore, this is rapid onset of drug delivery

action.

Its grate advantages is that its self-administration therapy. This therapy not need expert

for the applying patches.

MNPs for cosmetics by this time been commercialized so many products sold for the

improving skin appearance. Moreover, many companies all around the world. The many

cosmetic MNPs presented commercially show that MNPs can be widely accepted in

many countries and cultures, and self-administered repeatedly in a home setting.

Even, Prepared MNPs for the onset action of migraine, they administration zolmitriptan

and its currently reached under the phase 3 clinical trials, it is give the peak drug

concentration and its six time higher on set action compared to the oral doses forms.

This method is most effective than the other transdermal drug delivery system.[46]


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Figure 9: Microneedle patch (MNP) for transdermal drug delivery. (A) Representative

MNP. (B) Magnified view of microneedles. (C) Image showing skin histology after

puncture with a microneedle.[45]

This method is most effective for the treatment of alopecia (In the alopecia patient suffering

from the hair follicle problem). Studied the result of microneedle pre-treatment of the skin of

the scalp on hair growth in human subjects by comparing minoxidil treatment with or without

microneedling.

The microneedle treated group showed a expressively quicker speed of hair growth,

suggesting that microneedle pre-treatment improved the permeation of minoxidil drug

through the skin to the hair follicle, though the effect of microneedles on the drug transport

Process was not directly measured.[47]

We have established that these microneedles not only presented admirable adhesion when

applied to knuckles and perfect antibacterial activity but also accomplished good in drug-

sustained release and treatment for the osteoarthritis rat model.

These results indicate that bio inspired multifunctional microneedles will break through the

limitation of traditional methods and be ideal candidates for useful transdermal drug delivery

systems.


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Figure 10: Diagram and digital images of the bio inspired multifunctional MNs

adhering to the knuckle of the thumb when the knuckle is bent to 90°. The thickness of

the MNs was 2 mm. The scale bar is 1.5 cm.[48]

Advance drug delivery system

1. Admin pen

Admin patch microneedle array if refined microneedle technology. Adminpen was developed

for the novel drug delivery system. In this technique, inject the microneedle array based pen-

injector that is painless and conveniently inject standardise drug into the skin. While enter the

medicine into the body this technology enhanced the efficacy, safety, and patient compliance.

This system is painless and instantaneously forms hundreds of small microspores through the

stratum corneum and epidermis. When the microneedle array is removed from the skin, the

microspores simply collapse, and the skin barrier is quickly restored

This device very economical and produce the large scale using the high volume low cost

process. Admin pen can inject the various vaccines like as a HIV, cancer, smallpox and give

hormone and insulin injection from this method. This technique similarly beneficial for the

cosmetic preparations. The technology cans delivery pharmaceutical drugs in 10 to 60

seconds versus the 1 to 2 hours. These transdermal patches are used for the small molecules

under 500 Daltons.

Figure 11: Microneedle- based adminpentm pen-injector device.


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The human skin has three separate layers: the outer layer (stratum corneum), having a

reported thickness of between 10 to 30 microns; the viable epidermis, containing sentinel

cells of the immune system; and the dermis, within which are capillaries and various trauma-

sensing receptors. The aqueous channels formed by the microneedles in the stratum corneum

using the AdminPatch system have a depth of about 100 to 1000 microns, enough to extend

through the viable epidermis into the dermis to reach blood vessels but shallow enough to

avoid most pain receptors. AdminMed has completed studies that show that while the

AdminPen microneedle devices are kept applied on the skin, the microspores formed by

microneedles allows injection of drug or any other liquid from an attached syringe into the

underlying skin.

Figure12: Adminpentm connected to a regular syringe filled with blue dye.

Advantages

Adminpen technology enhanced the patient compliance and this technique is painless

system as a compare to the other drug delivery system.

Admin pen can inject the various vaccines like as a HIV, cancer, smallpox and give

hormone and insulin injection from this method.

This technique compatible with the standard syringes and its precise modest system for

the using.

This pen tip is don‟t harm to the skin. And not produce the any hazardous side effects.

Admin pen technique attractive for the pharma companies because of the there low cost

and high speed manufacturing process.

Admin pen uniformly inserted into flexible skin.[49]


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2. Derma pen and derma roller

Microneedling is an effective and valuable procedure that can be used to tighten, regenerate

and refresh the aged skin in natural way. This modality has proved it, can reverse the physical

as well as histopathological signs of aging, taken into account the easiness of its application

and free risk procedure with no lost time. This innovative technique of microneedling is very

revolutionary and considered a great breakthrough in microchanneling for beautification of

the skin, eluding pain and no lost time.

Ageing of the skin is a multifactorial incident, which circulates of the increasing effects of

chronic exposure to sun UV radiation, degradation and decline of elastin fibres, noticeable

collagen reduction incurring wrinkle progress, as well as development and profound digging

out.[50]

Figure 13: Derma pen.

Figure14: Derma roller.


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It can be carried out by a simple relatively cheap method.

1) Derma pen an advanced automated electrical calibrated microneedling

2) Device derma roller or a slightly costly

3) Expensive comparatively the fractional controlled microtunneling laser.

Both tools are however simple to work, as they are remarkable hand held medical devices

which naturally increase the levels of collagen and elastin in the treated skin.

Application

It assists in minimizing the appearance of spots and surgical marks, post-burn mark, Post-

traumatic scar, hypertrophic scars, varicella marks.

Diminishing fine lines and wrinkles, uneven skin tone and pigmentation, minimize pores,

reduce sebum production, reducing skin imperfections and tightening the skin and

increasing firmness, minimizing stretch marks, and improving skin texture and increasing

blood supply to the skin along with hydration.

Microneedling also support in removing the scales and sebum residue around the hair

infundibulum.

The skin comprises a barrier to penetration of exogenous substances to the body, skin

and the hair.

In fact, they do provide advanced skin needling, which stimulates the skin to self-

regenerate and self-repair naturally and safely, promoting a smoother, brighter, radiant,

healthier younger-looking skin. These treatments are recommended in every month for

get the desirable results.[51-52]

All measurements were performed in a temperature-controlled room at 21 ± 1°C. All

participants were in a semi-supine position in a bed for at least 10 minutes before the

measurements started. All measurements were done on the forearms which were disinfected

with a skin cleaner (Klorhexidin 5 mg/ml, Fresenius Kabi AB, Uppsala, Sweden) before the

experiments. Stainless steel microneedles arrays wereused in all experiments. This

experiment devided into the two rows and need 8 microneedles. And used the 300 μm, 500

μm and 750 μm lengths.[53]


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Table 1: Different types of microneedles products in the world.[54]

Fabrication of microneedle

For the making polymer microneedles for controlled-release, delivery involved fabricating

structures using the micro electrical system (MEMS) techniques. There are uses the mould

for the make microneedle shape, and used the biodegradable polymer for the making

microneedles. There are two different geometries of the microneedle structure fabricated by

the SU-8 epoxy using lithography-based methods.

Representative bevelled-tip microneedles are shown in Fig. A and have a base radius of 50

mm, a tip radius of 5 mm, and a height of 600 mm. The needles are positioned in a 20 _ 6

arrays with centre-to-centre spacing between needles of 400 and 1400 mm. The needle height

was controlled by the thickness of SU-8 photoresist casting and etching parameters. The tip

sharpness was controlled by the etching parameters.


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Figure 15: Microscopy images of microneedles. (A) bevel-tip microneedles and (B)

tapered-cone microneedles used as master structures (imaged by SEM). (C) bevel-tip

and (D) tapered-cone microneedles made of PLGA and encapsulating calcein within

their tips. Using a double-encapsulation method produced microneedles that

encapsulate micro particles that, in turn, encapsulate calcein. (E) Cutting off the tip of a

PLGA microneedle reveals the PLA micro particles within (imaged by SEM). (F) A

complete 20*10 array of PLGA microneedles is shown.[55]

Fabrication of Inorganic Material MNs Since the first solid MNs made of silicon by reactive

ion etching was reported, the techniques to fabricate the silicon MNs have been developed for

years. This type of method use that the ceramic slurry was filled into the cavities of moulds,

and then the ceramic MNs were formed when the ceramic materials were dried. This method

required the clean room and this method is very expensive method.

Glass MNs are usually manufactured by pulling of glass rods using pipette puller. For

example, pipette puller to fabricate the glass MNs based on borosilicate glass capillary tubes.

The MNs with fine gradually tapered shape by pulling of borosilicate glass rods using a

micropipette puller. The MNs were cut into different finial length by platinum wire. After

that, the tips were fire polished until smooth and then the MNs were bent into a cantilever by


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the micro forge. Micromolding process to fabricate BCMN-G. BCMN-G indicates bio

ceramic microneedle with gelatine substrate.[35]

Figure 16: Fabrication of microneedles.[57]

Microneedle use for treatment of diabetes mellitus

Normally we can classify into two types. (1) Insulin dependent diabetes, type 1 and (2)

Diabetes mellitus, type 2 diabetes. In the first type of diabetes treated by the giving insulin

and type 2 diabetes are treated by the metformin, sulfonylurea, etc.

(1) Insulin dependent diabetes

Insulin is one of the most challenging drug of all times for the drug delivery technology.

Insulin dependent diabetes first MNs developed by the Martanto et al. (2004) used MN arrays

(7 × 15) for transdermal delivery of insulin in diabetic rat models.

During and after MN treatment, an insulin solution (100 or 500 U/ml) was placed in contact

with skin for 4 hours.[45]

blood glucose level steadily decreased by as much as 80% with the

decrease in glucose level being dependent on the insulin concentration.[58]

These MNs is suitable for transdermal delivery of drugs with a relatively high degree of

water solubility, for example, metformin HCl. The primary objectives of this work included

formulating a well formed lyophilised drug reservoir using biocompatible materials with a

high drug loading of metformin HCl, rapidly dissolving in aqueous fluid and yielding high

drug recovery. This MN type and shows that hydrogel-forming MNs have considerable

promise for commercial success.


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MNs should have sufficient mechanical strength and demonstrate consistent insertion

properties to achieve successful application of MN array into the dermatomed porcine skin in

vitro and rat skin in vivo.[59]

(2) Diabetes mellitus

This type of the diabetes is used microneedle patches for the treatment. Drugs are available to

treat type-II diabetes such as sulfonylurea, metformin, alpha-glycosidase inhibitor.

Figure 17: Preparation of single layer dissolving micro-needle.

Figure 18: Mechanism of action of metformin & glipizide through double-layered

microneedle.[60]


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Microneedle vaccination

Most vaccines, such as polio, diphtheria, tetanus or pertussis, are administered in the first

year after birth and during childhood. Vaccination using a conventional needle system often

poses challenges for both parents and medical due to needle phobia and pain.

MNs can have a major positive impact on childhood vaccination as already demonstrated by

the positive perception from parents, children and medical staff.[61]

Children‟s skin is thinner

compared with adult skin and may require new and deeper studies on the pharmacodynamics

of transdermal drug dissolution. However, some studies have reported no deference in skin

thickness depending on age, gender or body mass index in children below 5 years old; and

although they found variable thicknesses in diverse areas of the body, these were found to

have no clinical relevance.

It is considered that children‟s top layer of skin can be disrupted with a needle height of

around 300 mm and a diameter of less than 100 mm. In terms of dosage, a lower dosage

requirement in paediatrics is expected, which may make it easier to achieve therapeutic doses

through MN patches. These parameters have to be addressed by designing suitable

microneedle architectures to target children of different age groups infants, children and

adolescents.[62]

MNA delivery has the potential to accelerate the process of vaccine production and to

significantly reduce cost by considerably reducing the required vaccine doses. The stability

studies with our MNA SARS-CoV-2 vaccines are currently in progress. However; there is

evidence in the literature that vaccine components including proteins are typically stabilized

by integration into the MNA polymer matrix, and retain their conformational structures, as

evidenced by maintenance of antibody binding function MNAs described here are designed

to be applied without the need for an applicator or any specialized equipment, supporting the

potential for self-administration. Combining emerging biotechnology methods with

bioengineering advances in vaccine delivery strategies, it may now be possible to rapidly

produce clinically translatable vaccines against novel pathogens for human testing and

subsequent global distribution in time to significantly impact the spread of disease.[63]

Clinical study of microneedle

There are a lot of studies of the microneedle transdermal drug delivery. And this delivery

used in both ex vivo and vitro. There is only few success studies report on the human. The


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first reported human study was carried out by Kaushik et al. [64] consisting of 12 human

volunteers between the ages of 18-40 years to demonstrate the application of MN is a

painless procedure. The MN used in this experiment was 150 μm long with a base diameter

of 80 μm and tip radius of 1 μm. In this study used the pointed tip fir the microneedles.

First clinical trial of microneedle transdermal delivery on the human carried out by

Wermeling et al. they used 5 × 10 microneedle arrays with a height of 620 μm and a width of

160 μm was used in this study. And take the naltrexone compound as a sample. A blood

sample carried out from the upper arm over a period of time of 72 hr. and in the end this

volunteer do not shown sign of redness, edema. MN technology fabricated with

biocompatible material is safe, painless and offers exciting opportunities for transdermal

delivery compared to hypodermic needles.[65]

CONCLUSION

Microneedles also in the form of patch or syringe have been observed as a possible

transporter for the effective transdermal delivery for the delivery of numerous

macromolecular drugs. Various research reports studied confirmed that microneedles are

ought to be the prominent carriers for enhancing the permeation deep into the systemic

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

microneedles plays important role in innovation and design of controlled drug delivery for

various drugs. 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.

Future perspectives

Microneedles can be considered emerging devices in the field of drug delivery compared

with current other techniques. Microneedle is used for the vaccination in future. In fact, MNs

have achieved excellent results, especially in the cosmetic field, undergoing rapid growth in

the last decade. For example, the Raphas Company and many more currently sell

Microneedle patches around the world for cosmetic purposes. Moreover, multicompartmental

and novel smart materials, such as hydrogel MNs, can provide a designed drug release which,

in the case of bio responsive MNs, is even more advanced and effective. Starting from these

new proposals and developing progressively innovative technologies, microneedles could

represent a significant improvement in the fields of drug administration and delivery, disease


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treatment, and cosmetic applications. of course, on an engineering level, the complexity of

the system needs to be justified by the final application, always respecting the market price

expectations. So we can say that microneedle technology is future of the drug delivery

approach.

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