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Pharmaceutical Manufacturing and Packing Sourcer

Microneedle Magic

Thakur R Raj Singh, Rita Majithiya, Rahamatullah Shaikh, Yusuf Kemal Demir and Ryan Donnelly of Queen’s University Belfast assess the extensive potential of microneedle technology in transdermal delivery

The human body’s largest organ, the skin, weighs five to six kilogrammes, accounts for an average of about 10 per cent of a person’s body weight and covers an average area of 1.7m2 (1). Over the past 25 years there has been increasing interest in transdermal drug delivery systems (TDDS) due to their potential advantages over conventional administration methods such as oral delivery and parenteral injections. Transdermal application avoids gastro-intestinal and first pass degradation, provides a patient-friendly approach and patches can also be formulated to deliver drugs in a controlled or continuous pattern. Over 35 transdermal products are currently approved for human use in the US and approximately 16 active ingredients have been approved for use globally, as shown in Table 1. Statistics reveal a market of $12.7 billion in the year 2005, which is expected to increase to $21.5 billion by the end of 2010 and to $31.5 billion in the year 2015 (2). In the early 1980s, the FDA approved the first transdermal patch, containing scopolamine for the prevention of motion sickness, as well as a patch system releasing nitroglycerin for the prevention of angina (1). Subsequently, patches containing clonidine, fentanyl, buprenorphine, levonorgestrel, lidocaine, norethisterone, estradiol, oxybutynin, testosterone and nicotine have all been approved (1,3). Transdermal products containing granisetron, human growth hormone, insulin, parathyroid hormone and rotigotine are currently undergoing clinical trials (1).


The exceptional barrier properties of the skin, primarily due to the outermost layer, the stratum corneum (SC), result in it being a challenging route for delivery of therapeutic agents. There are three principal ways in which a drug molecule can cross the intact SC: via skin appendages (shunt routes); through the intercellular lipid domains; or via a transcellular route (see Figure 1) (4). While drug substances may permeate the SC by a combination of these routes, the intercellular pathway is well-accepted as the predominant route taken in the vast majority of cases.


Only drugs with very specific physicochemical properties (a molecular weight of less than 500Da, adequate lipophilicity and a low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents, including peptides, DNA and small interfering RNA is problematic. Consequently, there has been a considerable effort in investigation and development of new strategies for maximising the amount of permeant crossing the skin barrier (see Figure 2) (5). Innovative approaches focus on altering the drug-vehicle interaction to enhance partitioning into the SC, or modifying the structure of the SC to make it less resistant to drug diffusion. In addition, energy-driven methods have also been employed to propel drugs across the skin.

Microneedles (MNs) have recently been widely investigated by various research groups. MNs consist of a plurality of microprojections, generally ranging from 25 to 2,000μm in height, made of different shapes and materials, and attached to a base support (see Figure 3A). MNs, when used to puncture skin, will bypass the SC, but due to their small size generally avoid contact with nerve fibres and blood vessels in the dermal layer and create transient aqueous transport pathways of micron dimensions to enhance transdermal permeability (see Figure 3B). These micropores are orders of magnitude larger than molecular dimensions, and therefore should readily permit pain- and blood-free delivery of both small and large molecular weight molecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide for fabrication of MNs. We have briefly outlined the main fabrication methods here.


The first MN devices were fabricated from silicon, but many other materials have also been used in MN fabrication, such as stainless steel, dextrin, glass, ceramic, maltose, galactose and various polymers. Over the past few years, investigators have used a multiplicity of methods in the manufacturing of a variety of MNs, such as conventional microelectronics fabrication technologies, including chemical isotropic etching, injection moulding, reactive ion etching, surface/bulk micromachining, polysilicon micromoulding, lithography-electroformingreplication and laser drilling.

Fabrication of Silicon Microneedles

Microfabrication technology, involving micro-machining or micro-electromechanical systems (MEMS), traditionally applied to produce microprocessors can be efficiently applied in the fabrication of MN arrays. Although these tools offer the potential for mass production of MNs, fabrication is often highly specialised and includes complex multi-step processes. MEMS technology utilises a number of tools and methodologies to create small three-dimensional (3D) structures, with dimensions ranging from sub-centimetre to sub-micrometre. The three basic techniques in MEMS technology are the application of a patterned mask on top of a film by photolithograpic imaging, deposition of thin films of material on a substrate and etching the films selectively to the mask (6).

Fabrication of Metal and Other Types of Microneedles

Although silicon is attractive as a common microeletronics substrate with extensive processing experience for more than 30 years, it is relatively expensive and requires cleanroom processing. In contrast, metal and glass MNs have been found to be equally effective in skin penetration and can be produced at a much lower cost than silicon ones. Various metals, such as stainless steel, titanium, palladium, palladium-cobalt alloys and nickel have all been used as structural materials for MN fabrication (7). A number of approaches have been investigated for fabricating metal MNs, such as electroplating (palladium), photochemical etching (titanium) and laser cutting (stainless steel).

Fabrication of Polymeric Microneedles

Most MNs described in the literature to date have been made of silicon or metal by MEMS technology. Silicon MNs, being brittle, may break and remain within the skin during the application. Silicon is not a biocompatible material, and therefore, the safety of silicon MN should be demonstrated. Many metals are cheaper, stronger and known to be biocompatible, but there are concerns about the immunoinflammatory response of soft tissue around stainless steel and titanium implants. On the other hand, polymeric MNs are gaining importance due to a variety of properties, such as biocompatibility, biodegradability, strength, toughness and optical clarity. In addition, polymeric MN fabrication is considerably more cost-effective when compared to that of typical MEMS processes. To accurately produce the micron-scale dimensions of polymer MNs, a variety of mouldbased techniques such as casting, hot embossing, injection moulding and investment moulding have been investigated. Additionally, deep x-ray lithography, UV excimer laser and the two-photon polymerisation technique are used to create hollow MNs. Polymeric materials which have been efficiently fabricated into MNs include poly(methylmetha-acrylate) (PMMA), poly-L-lactic acid (PLA), poly-glycolic acid (PGA), poly-lacticco- glycolic acid (PLGA), cyclic-olefin copolymer, poly(vinyl pyrrolidone), poly(methylvinylether-comaleic andhydride) and sodium carboxymethyl cellulose (see Figure 3A, page 27). Sugars have also been used to fabricate MNs.

The four basic methods of transdermal drug delivery mediated by MNs are depicted in Figure 4. Various types of molecules have been delivered both in vitro and in vivo using MNs, including cascade blue, insulin, sulforhodamine, bovine serum albumin, ribolavin, curcumin, ovalbumin, fluorescein, pilocarpine, radiolabelled mannitol, carboxyfluroescein, nicardipine hydrochloride, desmopressin, pDNA, lidocaine and parathyroid hormone.


A significant number of pharma and medical device companies are now at the phase of preclinical or clinical studies associated with novel MN devices. A smaller number of firms have already entered the market with their patented MN-based devices. A currently marketed MN product called the ‘Microneedle Therapy System’, or MTS-Roller, contains MNs on a plurality of discs stacked upon one another. The integrated MN roller is rolled over the skin surface to stimulate the production of skin’s natural collagen in treating aged skin. Drug-loaded patches can also be applied after using the MTS-Roller to create pores in the SC (9,10). Another MN applicator, MicroCor from Cornium International Inc, has two nearly concentric portions – a solid disc and an annulus surrounding it. The MNs are present on the inner portion of the applicator and the outer portion is placed on the skin and pressed down so the MNs puncture the skin surface (11). Becton Dickinson and Company (BD) have patented MN devices primarily for vaccine delivery (12,13). Sanofi-Aventis received marketing authorisation from the European Commission for the first intradermal (ID) influenza vaccine Intanza or IDflu, using the innovative BD Soluvia microinjection system (14). Independently, BD conducted clinical trials with BD Soluvia, and demonstrated that the system is barely perceptible, safe, easy to use, and showed reproducible injections (15,16). Zosano Pharma has patented a microprojections device called Macroflux (17,18) and have finished Phase II clinical trials using Macroflux to deliver parathyroid hormone (hPTH 1-34, teraparatide) for treatment of severe osteoporosis in post-menopausal women. Presently, Macroflux is at the preclinical stage for a number of other therapeutic molecules (19). Furthermore, several other companies and research centres are also actively involved in research and development of novel MN devices.


Protein and peptide therapeutics are set to revolutionise healthcare over the coming decades. However, at present, their large sizes and susceptibility to gastro-intestinal degradation mean they must be given by injection. A solution to the problems posed by needle-based injections, such as cost, need for trained personnel and risk of infection, is development of minimally invasive microporation-based devices. Advances in this field, particularly with the recent advent of microneedle arrays made from polymeric materials will realise the development of new and better devices, which will be cost-effective, smaller, pain-free and easy to use. Currently several companies and universities are actively involved in the fabrication of the microporation devices, while some companies have demonstrated clinical efficacy of these devices – whereas most are still at the development stage. Extensive clinical studies are now necessary to illustrate consistent delivery of macromolecular drugs in particular and to show that creation of pores in biological membranes is safe and reversible. MN applicator design will undoubtedly be vital if MN-based drug delivery systems are to gain widespread clinical and patient acceptance, since these devices must be able to be reproducibly applied to consistent depths in every patient every time. MN applicators should be available at a relatively low cost, be reusable, and be easily handled by all patients. MN-based drug delivery is still in at a relatively early stage but it shows much promise.


  1. Thomas BJ and Finnin BC, The transdermal revolution, Drug Discov Today 9: pp697-703, 2004
  2. Kumar R and Anil P, Modified Transdermal Technologies: Breaking the Barriers of Drug Permeation via the Skin, Tropical Journal of Pharmaceutical Research 6:1, pp633-644, 2007
  3. BNF No53, British National Formulary, London: BMJ Publishing Group Ltd 2007
  4. Skin care forum (SCF) _e/skinpenetration37_e.htm, accessed 1 October 2009
  5. Barry BW, Novel mechanisms and devices to enable successful transdermal drug delivery, Eur J Pharm Sci 14: pp101-114, 2001
  6. Banks D, in Microengineering, MEMS, and Interfacing: A Practical Guide, Boca Raton, CRC, Taylor and Francis, pp21-72, 2006
  7. Saluja S, Naeli K, Badkar A and Banga A, Optimization of fabrication of in-plane titanium microneedles, CRS, 18-22 July, 2009
  8. Arora A, Prausnitz MR and Mitragotri S, Micro-scale devices for transdermal drug delivery, Int J Pharmaceu 364: pp227-236, 2008
  9. Lee J and Hong S: US2008016735A1, 2008
  10. Lee J and Hong S: US20080161747A1, 2008
  11. Trautman JC, Worsham W, Bayramov DF, Bowers DF, Klemm SR and Singh P, US2008000824, 2008
  12. Avrahami Z: US20046711435, 2004
  13. Avrahami Z, Yossi G and Ze’ev S: US20036597946, 2003 
  14. Avrahami Z and Ze’ev S: US20036611706, 2003
  15. Avrahami Z and Ze’ev S: US20046708060, 2004
  16. TransPharma Medical Ltd /, accessed 27 February 2009
  17. Levin G, Meir S and Dorit D: US20050287217, 2005
  18. Levin G and Dorit D: US20050260252, 2005 
  19. Levin G, Hagit S and Sergey R: US20070270732, 2007

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Dr Thakur R Raj Singh is Lecturer in Pharmaceutics at the School of Pharmacy, Queens’s University Belfast. He obtained his doctorate in Drug Delivery in November 2009 and worked as a Research Assistant until July 2010 at School of Pharmacy, Queens University Belfast. He also obtained his MSc in Pharmaceutical Sciences in August 2006 from the University of Science Malaysia, Penang. He has a BSc in Pharmacy from Jawaharlal Nehru Technological University, India. His major research interests are microneedle-based transdermal drug delivery and regenerative medicine, and he has published over 14 articles.

Dr Rita Majithiya is a BBSRC Post-doctoral Research Fellow in the School of Pharmacy, Queen’s University Belfast. Her research is focused on transdermal drug delivery systems and particularly investigations of safety of novel microneedle arrays. Rita obtained her MPharm and PhD in Pharmaceutical Technology from The MS University of Baroda, Vadodara, India.

Rahamatullah Shaikh is currently pursuing a PhD on the design and evaluation of a novel topical photosensitiser delivery system in the School of Pharmacy, Queen’s University Belfast. His research interests include buccoadhesive drug delivery systems, investigation and development of controlled release matrix tablet formulations and bioanalytical method development and validation in biological matrices.

Yusuf Kemal Demir is an MPhil student in the School of Pharmacy, Queen’s University Belfast. Prior to joining Queen’s, Yusuf was a Research and Teaching Assistant at the Faculty of Pharmacy, Marmara University, Istanbul, Turkey. Yusuf’s research interests are in the physical characterisation of polymeric microneedle arrays and in intradermal vaccine delivery.

Dr Ryan Donnelly is Senior Lecturer in Pharmaceutics at the School of Pharmacy, Queen’s University Belfast. His research interests are centred on transdermal and topical drug delivery, with a particular emphasis on design and characterisation of novel microneedle-based drug delivery systems. He has authored approximately 200 peerreviewed publications, and is funded by BBSRC, EPSRC and the pharmaceutical industry. He is involved in editorial for various industry journals, and has received an Innovation Leader Award from the NHS Research & Development Office.

Thakur R Raj Singh
Rita Majithiya
Rahamatullah Shaikh
Yusuf Kemal Demir
Ryan Donnelly
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