Microneedles In Transdermal Drug Delivery

Presented by: Samiksha Sawant

M.Pharm(IP), 3rd Sem

Need for microneedles

From child to elder everyone hates needles and “ PAIN” caused by them. Various systems are adopted to avoid needles. Among them is the “Microneedle mediated transdermal drug delivery system “

Need for an ideal TDDSThere is a need for an ideal TDDS that:

Maintains skin permeability only for desired time period

Can create sustained/bolus delivery profiles

Can deliver drug quickly with minimal discomfort

Has responsive pharmacokinetics and pharmacodynamics

Causes minimal pain and irritation

Simple, inexpensive, and self-administrable.

Quick look at skin’s anatomy...

How it combines the benefits of hypodermic needle injections and transdermal patches ..?

Need for microneedles

First generation TDDS: Eg-Transdermal patches

Second generation TDDS: Eg-Chemical enhancers, iontophoresis, sonophoresis

Third generation TDDS: Eg: Thermal ablation, electroporation, microderma

abrasion, “MICRONEEDLES”

Microneedles...

• The concept of microneedles was first proposed in the 1970s

• Combines the benefits of hypodermic needle injections and transdermal patches

• Microneedles are typically hundreds of microns long, 1 to 50 μm wide at the tip, and approximately 50 - 300 μm at the base.

• They can be solid/hollow and can be fabricated as single needles or multi-needle arrays

Advantages of microneedles• Large molecules can be administered• Painless administration of the active pharmaceutical ingredient• First-pass metabolism is avoided• Faster healing at injection site than with a hypodermic needle,• No fear of needle • Ease of administration• Decreased microbial penetration as compared with a hypodermic

needle,the microneedle punctures only the epidermis• Specific skin area can be targeted for desired drug delivery

enhanced drug efficacy may result in dose reduction• Good tolerability without long-term oedema or erythema • Rapid drug delivery can be achieved by coupling the microneedles

with other technologies

Disadvantages of microneedles• Careful use of the device may be needed to

avoid particles ‘bouncing off’ the skin surface• The thickness of the stratum corneum and

other skin layers varies between individuals and so penetration depth of particles could vary too

• The external environment, like hydrationof the skin, could affect delivery

• Repetitive injectionmay collapse the veins• The tip of the microneedle may break off and

remain within the skin on removal of the patch,

Types of microneedlesFABRICATION

In-plane microneedlesMicroneedles are parallel to the

substrate surface

Out of plane microneedlesThe microneedles protrude out

of the substrate surface

Types of microneedlesBased on drug delivery

Solid microneedles

• Solid microneedles create holes in SC and are applied before application of medicine and removed there after

• Or the drug may be coated onto the needle• Increase the permeability by pocking the holes in skin, rub drug

over area or coat needle with drug.• They are fabricated in 750-1000μm in length Materials used: Silicon: Fabrication by microneedle is costly. Silicon is brittle and

may break in the skin.

Metal: They have good mechanical strength, cost is low Eg: stainless steel, titanium, nickel, iron.

Dissolving microneedles

It involves encapsulating the

drug within the biodegradable,polymeric microneedles,

followed by the insertion into the

skin for drug release.

Polymers used: PLA, PGA, PLGA,

PVP, Polycarbonate

Hollow microneedles

Lumen diameter 30μm and height

250μm.

Carry drug continuously into the

body by diffusion

Large amount of drug are delivered

Remove fluid from the body for

analysis

Fabrication of microneedles

Microneedles are cut from stainless steel sheets using an infrared laser.

The desired microneedle shape and dimensions are first drafted in AutoCAD software.

Using this design laser energy is used to cut the microneedles.

A cutting speed of 2 mm/s and air purge at a constant pressure of 140 kPa is used.

Microneedles are either prepared as in-plane needles or as out of the plane microneedles

Laser cutting

MEMS technology• The three basic techniques in MEMS technology are deposition of

thin films of material on a substrate, patterning and etching

Methodology for Drug delivery

Poke and patch approach Coat and poke approach

Poke and release approach

Poke and flow approach

Dip and scrap approachHere 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.

Characteristics of microneedles• Ruggedness: Must be able to withstand the insertion

force without being fractured• Penetration: Must penetrate the drug to required depth

in the tissues. • Dimensions: Lenght: 100-900microns; Base widht:50-300microns Tip diameter: 1-50microns• Shape:

• Margin of safety: It is defined the margin of safety as the ratio between the force required for piercing the stratum corneum and the force at which microneedles broke.

If the ratio is <1 then microneedle array can be used in biomedical application.

• Effect of the Length of microneedle on pain: The designing of microneedles can be such so as to minimize the

pain. Increment in needle length(i.e., 500-1500 microns) increases the pain.An increase in number of microneedles from 5- 50 also increases the pain

• Transepidermal water loss: It is determined using diffusion cell, intact animal skin and probes

that measure TEWL befoe and after application of microneedles• Biological safety test: Extract chemicals from microneedles by immersing them in

physiological saline and apply on intact human skin

Patents on microneedles

A majority of patent application

are focussed on design and

delivery through hollow

microneedles

This is because of merit of

administration of higher

amount of drug

Patent US 8696637 B2:Transdermal patch containing microneedles

• A transdermal patch that can easily deliver a controlled volume of a fluidic drug compound to skin is provided.

• The patch contains a microneedle assembly that is configured to be placed in fluid communication with a drug delivery assembly.

• The microneedle assembly contains a support and a plurality of microneedles that extend outwardly from the support.

• The microneedles are formed with one or more channels of a certain dimension such that passive capillary flow drives a flow of the drug compound. The drug delivery assembly contains a reservoir for the drug compound that is in fluid communication with a rate control membrane that helps control a flow rate of the drug

• A release member is also positioned adjacent to the microneedle and drug delivery assemblies.

• Prior to use, the release member acts as a barrier to the flow of the drug • When it is desired to release the drug compound, the patch can simply be

activated by at least partially separating the release member from the drug delivery and microneedle assemblies

1 2

3 4

A Patchless Dissolving Microneedle Delivery System • DMN patch efficacy reduces due to variation in skin elasticity,

chemicals in patch can cause skin irritation, diificulty in adhering etc.

• In needleless injection systems, injection depth is difficult to control

• Microlancer combines advantages of both DMN patches and needlesless jet injectors

Application of microneedles

Microneedles

Cellular deliveryCan be used to

deliver membrane impermeable

molecules into the cells

Local deliveryTargeted delivery help reduce side effects, minimize

the dose and helps deliver drug to

locations difficult to treat

Systemic delivery

Helps overoming limitations of conventional

injections

Application of microneedles

Microneedles are used in delivering:Immunobiologicals: Microneedles have an edge over the other methods due to lack of pain.Eg: influenza vaccine, hepatitis B vaccine,flavivirus vaccine etc

Biopharmaceuticals: Insulin, heparin, and growth hormones, parathyroid hormone, human growth hormone, desmopressin can be delivered by microneedles

Drugs: Diclofenac, lidocaine, naltrexone, doxetaxel etc can be administered via microneedles

Phlebotomy: Phlebotomy is the withdrawal

of blood for diagnostic purpose.

Painless hollow microneedle-based micro

sampling can be used for

estimation of blood

components

It can be used to obtain precise blood samples

from the capillaries, which are situated at a distance of 500–2000microns in the dermis layer beneath the skin.

Hollow microneedles can be used to withdraw fluid from tissue or which can be subsequently analysed to

check the status of diseases like

cancer, diabetes etc

Cosmetics: Only minor fractions (maximum 0.3%) of the active substance present in a cream, gel/lotion can penetrate deeply into the skin.

The microneedle based products contain numerous very fine needles that penetrate the skin up to a depth of 0.2–0.3 mm to pierce the epidermis, creating a micro-channel effect

Majority of cosmetic products lending themselves to microneedle technology are for non-surgical and nonablative treatment of skin conditions

Eg for treating ageing(wrinkles, lax skin), scarring (acne, surgical), photodamage,hyperpigmentation (age/brown spots), alopecia etc.

MicroCor Macroflux

Microjet MTS Roller

For diagnostic purpose:• Nevisense is a diagostic handheld device

developed by SciBase, a Swedish medtech company for early detection of malignant melanoma

• It is based on a technology called Electrical Impedance Spectroscopy (EIS), which uses the varying electrical properties of human tissue to categorize cellular structures and thereby detect malignancies.

• The device has electrodes with microneedles to pass the electrical signal into the skin

• The device is held on the lesion and harmless electrical signal is applied through the skin lesion using an innovative electrode-microneedle system on the tip of the Nevisense probe

• A reference measurement is performed at first, on healthy skin close to the lesion.

• This procedure is repeated on the lesion to be examined and then the two results are compared

Conclusion

Transdermal drug delivery system is an emerging area

for systemic as well as local delivery of macromolecules.

The biggest drawback of TDDS is

poor permeability through stratum

corneum and it can be overcome by

using microneedles.

Researchers focused their attention on development of

different types of microneedles for

delivery of proteins, peptides,

immunobiological, drugs , cosmetics as well as for biofluidic

analysis.

Microneedles provides devices that are smaller

improved, cheaper painfree convenient

and method of delivering

therapuetics

Brand name Manufactured by Applications

Vaxmat TheraJect Inc., USA Dissolvable microneedle, can deliver 100microgram drug

Microtrans Valeritas Inc., USA Can deliver drug irrespective of its size, structure, charge

Nanoject Debiotech, Switzerland For intradermal drug delivery and fluid diagnotics

Janisyns Janisys, Ireland Helps delivering multiple drugs via one patch

BD Soluvia Becton Dickinson, USA Intradermal delivery of drugs and vaccines

Onvax Becton Dickinson, USA Delivery of vaccines

MicronJet NanoPass Inc, Israel Delivery of drugs, protiens, vacccines

Macroflux Zosano Pharma Inc., USA Delivery of peptides and vaccines

MicroCor Corium International Inc., USA Delivery of protiens, peptides and vaccines

MTS 3 M Corp., USA Delivery of drugs, monoclonal antibodies

AdminPen AdminMed, USA Delivery of liquid pharma formulations and cosmetics

References • Review article on “Microneedles: An Innovative Approach To

Transdermal Delivery” by Nida Akhtar, International Journal of Pharmacy and Pharmaceutical Sciences, Vol 6, Issue 4, 2014, 18-25

• Review article on “Microneedle: An Advanced Technique in Transdermal Drug Delivery system” by S.More, T.Ghadge, S.Dhole, Asian Journal of Research in Pharmaceutical Sciences, Vol 3, Issue 3, 2013, 141-148

• Review article on “Microneedles – An Advanced Drug Delivery System” by Gul S, Khan MN, Khalid F, International Journal of Pharmaceutical Research and Bio-science, Vol 3, Issue 4, 2014, 299-304

• An article on “Microneedle applications in improving skin appearance” by Maelosa T.C. McCrudden, Experimental Dermatology, Vol 24, Issue 8, , 561–566, 2015

References • Article on “A Patchless Dissolving Microneedle Delivery System Enabling

Rapid and Efficient Transdermal Drug Delivery” by Shayan F. Lahiji, Manita Dangol & Hyungil Jung, Scientific Reports, 2015,

• A patent on “Transdermal Patch containing Microneedles” by Russel F. Ross, United States Patent, Patent no. US 8696637 B2, Date: 15/4/2014

• Microneedles used in Nevisense product, published on 25/5/15 () http://www.businesswire.com/news/home/20150524005053/en/SciBase-Receives-Patent-Approval-Electrodes-Micro-Needles#.Vh-EQXqqqko), visited on 24/9/15

• Review article on “Microneedles: An Emerging Transdermal Drug Delivery System” by Bariya SH, Gohel MC, Mehta TA, Sharma OP, Journal of Pharmacy and Pharmacology, Vol 64, Issue 1, 2012, 11-29

• Microneedles: Applications and Devices, Encyclopedia of Microfluidics and Nanofluidics, 2014 (http://link.springer.com/referenceworkentry/10.1007/978-3-642-27758-0_993-2), visited on 27/9/15

References • Review paper on “ Microneedle Technology: A New Drug Delivery

System” by Nahida Tabassum, Aasim Sofi, Tahir Khuroo, International Journal of Reseach in Pharmaceutical and Biomedical Sciences, Vol 2, Issue 1, 2011

• Review article on “Microneedles: Promising Technique for Transdermal Drug Delivery” by Kumar Vaidya, Priyanka Kulkarni, Rajvaibhav Raut, International Journal of Pharma and Biosciences, Vol 2, Issue 1, 2011

• Review article on “Microneedles for Transdermal Drug Delivery” by Mark Prausnitz, Advance Drug Delivery Reviews, Vol 56, Issue 5, 2010, 581-587

• An article on “A scalable fabrication process of microneedles” by Sixing Yng, Yan Feng , Lijun Zhang, International Journal of Nanomedicine, Vol 7, 1415-1422, 2012

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