Microneedles : A Revolution of Transdermal Drug Delivery
Optimization of drug delivery through human skin is important in modern therapy. With the limitations of oral drug delivery and the pain and needle phobias associated with traditional injections, drug delivery research has focused on the transdermal delivery route.
This review considers various studies related to microneedles for transdermal drug deliveries. A formidable barrier to transdermal drug delivery is the stratum corneum, the superficial layer of the skin. In the last 10 years, microneedles were proposed as a mechanical tool to pierce through the stratum corneum, in order to create drug delivery channels without stimulating underlying pain nerves. Since then, the field of microneedles has rapidly evolved to spawn a plethora of potential transdermal applications. Using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. To address practical applications of microneedles, the ratio of microneedle fracture force to skin insertion force (i.e. margin of safety) was found to be optimal for needles with small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported as painless. Together, these results suggest that microneedles represent a promising technology to deliver therapeutic compounds into the skin for a range of possible applications.
If we analyze the history of human suffering, we observe that diseases and compulsions imposed by diseased states are considered to be a greater enemy to mankind rather than the death. Naturally, the ultimate aim of every therapy is to restore the normalcy of life, but ironically sometimes, the requirements of treatment are such that the normal rhythm of life is disturbed. Most drugs are administered in the form of pills or injections, but these methods of delivery are not always optimal. Medication taken orally must not only be absorbed successfully out of the intestine into the bloodstream, but also survive the harsh and enzyme-rich environments of the gastrointestinal tract and first pass through the liver. Drugs that cannot be taken as pills are usually administered by injection, which introduces the problems of pain, possible infection, and expertise required to carry out an injection. Both routes of delivery have added limitations as bolus delivery methods, where the full dose of drug is introduced into the body at once. An approach that is more appealing to patients and offers the possibility of controlled release over time using transdermal drug delivery.
Clinical benefits, industry interest and regulatory precedence had predicted a strong market for transdermal drug products due to limitation of conventional drug deliveries.1, 2 However, transdermal delivery is severely limited by the inability of the large majority of drugs to cross skin at therapeutic rates due to the great barrier imposed by skin’s outer stratum corneum layer. Recently researchers focusing on overcoming problems associated with the barrier properties of the skin, reducing skin irritation rates and improving the aesthetics associated with passive patch systems.
To increase skin permeability, a number of different approaches has been studied, ranging from chemical/ lipid enhancers 3,4 to electric fields employing iontophoresis and electroporation 5,6 to pressure waves generated by ultrasound or photoacoustic effects 7,8. Although the mechanisms are all different, these methods share the common goal to disrupt stratum corneum structure in order to create ‘‘holes’’ big enough for molecules to pass through.
A new approach to transdermal drug delivery that acts as a bridge between the user-friendliness of patches and the broad effectiveness of hypodermic needles has recently received attention. By using needles of microns dimensions, termed microneedles, skin can be pierced to effectively deliver drugs, but do so in a minimally invasive and painless manner that lends itself to self-administration and slow delivery over time. It is proposed that micron-scale holes in the skin are likely to be safe, given that they are smaller than holes made by hypodermic needles or minor skin abrasions encountered in daily life.
Microneedles: A Novel Approach to Transdermal Drug Delivery
A microstructured transdermal system also called microneedle consists of an array of microstructured projections coated with a drug or vaccine that is applied to the skin to provide intradermal delivery of active agents, which otherwise would not cross the stratum corneum. The mechanism for delivery, however, is not based on diffusion as it is in other trandsermal drug delivery products. Instead, it is based on the temporary mechanical disruption of the skin and the placement of the drug or vaccine within the epidermis, where it can more readily reach its site of action
Microneedles are somewhat like traditional needles, but are fabricated on the micro scale. They are generally one micron in diameter and range from 1-100 microns in length. Microneedles have been fabricated with various materials such as: metals, silicon, silicon dioxide, polymers, glass and other materials. It is smaller the hypodermic needle, the less it hurts when it pierces skin and offer several advantages when compared to conventional needle technologies. The major advantage of microneedles over traditional needles is, when it is inserted into the skin it does not pass the stratum corneum, which is the outer 10-15 μm of the skin.9 Conventional needles which do pass this layer of skin may effectively transmit the drug but may lead to infection and pain. As for microneedles they can be fabricated to be long enough to penetrate the stratum corneum, but short enough not to puncture nerve endings. Thus reduces the chances of pain, infection, or injury.
Various types of needles have been fabricated as well, for example: solid (straight, bent, filtered), and hollow. Solid microneedles could eventually be used with drug patches to increase diffusion rates; solid-increase permeability by poking holes in skin, rub drug over area, or coat needles with drug.9
Hollow needles could eventually be used with drug patches and timed pumps to deliver drugs at specific times. Arrays of hollow needles could be used to continuously carry drugs into the body using simple diffusion or a pump system. Hollow microneedles could also be used to remove fluid from the body for analysis – such as blood glucose measurements – and to then supply microliter volumes of insulin or other drug as required.10
The hollow needle designs include tapered and beveled tips, and could eventually be used to deliver microliter quantities of drugs to very specific locations. The researchers demonstrated that an array of 400 microneedles can be used to pierce human skin delivering drug macromolecules. Very small microneedles could provide highly targeted drug administration to individual cells. These are capable of very accurate dosing, complex release patterns, local delivery and biological drug stability enhancement by storing in a micro volume that can be precisely controlled.11
Current Research in Microneedles Technology
The first microneedle arrays reported in the literature were etched into a silicon wafer and developed for intracellular delivery in vitro by Hashmi et al.12. These needles were inserted into cells and nematodes to increase molecular uptake and gene transfection. Henry et al.13 conducted the first study to determine if microneedles could be used to increase transdermal drug delivery. An array of solid Microneedles was embedded in cadaver skin, which caused skin permeability to a small model compound.
In a follow-up study, McAllister et al.14 studied permeability of cadaver skin to a range of different compounds and found that insulin, bovine serum albumin, and latex nanoparticles as large as 100 nm in diameter could cross the skin after treatment withmicroneedles. Mathematical modeling of the data indicated that transport of these compounds was by simple diffusion.
Extending in vitro findings to the in vivo environment, Lin et al.15 used microneedles either alone or in combination with iontophoresis to deliver 20-mer phosphorothioated oligodeoxynucleotides across the skin of hairless guinea pigs. A related study further demonstrated microneedle- enhanced delivery of desmopressin and human growth hormone using a similar approach 16.
Using solid microneedles of a different design, Martanto et al. 17 delivered insulin to diabetic hairless rats in vivo. Microneedle arrays were inserted into the skin using a high-velocity injector and shown by microscopy to embed fully within the skin. Matriano et al.18 examined the use of Microneedles to deliver ovalbumin as a model protein antigen coated onto the needle surface. Microneedles were prepared with a dry-film coating of antigen and then inserted into the skin of hairless guinea pigs in vivo using a high-velocity injector. Mikszta et al.19 studied delivery of naked plasmid DNA into skin using microneedles. The arrays were dipped into a solution of DNA and scraped multiple times across the skin of mice in vivo to create microabrasions.
A variety of hollow microneedles have been fabricated, but only limited work has been published on their possible use to deliver compounds into skin. McAllister et al.14 used single glass Microneedles inserted into the skin of diabetic hairless rats in vivo to deliver insulin during a 30-min infusion. In related studies, Stoeber and Liepmann 20 demonstrated injection into chicken thigh in vitro using microneedle arrays. Chen and Wise 21 used microneedles to inject chemical stimuli into brain tissue in vivo. Smart and Subramanian 22 used single microneedles to extract nanoliter quantities of blood from the skin to measure glucose levels.
Kaushik et al. 23 carried out a small trial to determine if microneedles are perceived as painless by human subjects. Microneedle arrays were inserted into the skin of 12 subjects and compared to pressing a flat surface against the skin (negative control) and inserting a 26-gauge hypodermic needle into the skin surface (positive control). Subjects were unable to distinguish between the painless sensation of the flat surface and that caused by microneedles. All subjects found the sensation caused by the hypodermic needle to be much more painful. Other studies have also reported that microneedles were applied to human subjects in a painless manner 19,22.
Several new and interesting microneedle concepts have been recently proposed which may find great utility in the future. For example, biodegradable polymer microneedles have recently been fabricated and characterized. The advantage of polymer needles is that they may be produced much more inexpensively (compared to silicon) and they should not pose a problem if they break in the skin since they are biodegradable 24. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach.
Gill et al (2007) have been studied on coating of Microneedle. A novel micron-scale dip-coating process and a GRAS coating formulation were designed to reliably produce uniform coatings on both individual and arrays of microneedles. This process was used to coat compounds including calcein, vitamin B, bovine serum albumin and plasmid DNA. Modified vaccinia virus and microparticles of 1 to 20 μm diameter were also coated. In conclusion, this study presents a simple, versatile, and controllable method to coat microneedles with proteins, DNA, viruses and microparticles for rapid delivery into the skin.25
Recently Lee et al (2008) has studied on dissolving microneedles for transdermal drug delivery. This study presents a design that encapsulates molecules within microneedles that dissolve within the skin for bolus or sustained delivery and leave behind no biohazardous sharp medical waste.26
A review of the literature shows that microneedles can be fabricated by a number of different methods to yield a variety of needle sizes, shapes and materials. It could be very good technique to increase diffusion rates of drug macromolecules. Very small microneedles could provide highly targeted drug administration to individual cells. These are capable of very accurate dosing, complex release patterns, local delivery and biological drug stability enhancement by storing in a micro volume that can be precisely controlled.These studies suggest that microneedles may provide a powerful new approach to transdermal drug delivery.
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 S. Hashmi, P. Ling, G. Hashmi, M. Reed, R. Gaugler, W. Trimmer, Genetic transformation of nematodes using arrays of micromechanical piercing structures, BioTechniques 19(1995) 766–770.
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 D.V. McAllister, P.M. Wang, S.P. Davis, J.-H. Park, M.G. Allen, M.R. Prausnitz, Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: novel fabrication methods and transport studies, submitted for publication.
 W. Lin, M. Cormier, A. Samiee, A. Griffin, B. Johnson, C. Teng, G.E. Hardee, P. Daddona, Transdermal delivery of antisense oligonucleotides with microprojection patch (Macroflux) technology, Pharm. Res. 18 (2001) 1789– 1793.
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 W. Martanto, S. Davis, N. Holiday, J. Wang, H. Gill, M. Prausnitz, Transdermal delivery of insulin using Microneedles in vivo, Proceedings of International Symposium on Controlled Release Bioactive Material, No. 666, 2003.
 J.A. Matriano, M. Cormier, J. Johnson, W.A. Young, M. Buttery, K. Nyam, P.E. Daddona, Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization, Pharm. Res. 19 (2002) 63– 70.
 J.A. Mikszta, J.B. Alarcon, J.M. Brittingham, D.E. Sutter, R.J. Pettis, N.G. Harvey, Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery, Nat. Med. 8 (2002) 415–419.
 B. Stoeber, D. Liepmann, Fluid injection through out-of-plane microneedles, Proceedings of the International IEEE-EMBS Special Topic Conference on Microtechnologies in Medicine and Biology, No. 34, 2000.
 J. Chen, K.D. Wise, A multichannel neural probe for selective chemical delivery at the cellular level, IEEE Trans. Biomed. Eng. 44 (1997) 760– 769.
 W.H. Smart, K. Subramanian, The use of silicon microfabrication technology in painless blood glucose monitoring, Diabetes Technol. Ther. 2 (2000) 549– 559.
 S. Kaushik, A.H. Hord, D.D. Denson, D.V. McAllister, S. Smitra, M.G. Allen, M.R. Prausnitz, Lack of pain associated with microfabricated microneedles, Anesth. Analg. 92 (2001) 502–504.
 J.H. Park, M.G. Allen, M.R. Prausnitz, J. Control. Release 104 (2005) 51–66.
 Jeong W. Lee, Jung-Hwan Park, Mark R. Prausnitz, Dissolving microneedles for transdermal drug delivery. Biomaterials 29 (2008) 2113-2124
 Harvinder S. Gill, Mark R. Prausnitz, Coated microneedles for transdermal delivery. Journal of Controlled Release 117 (2007) 227–237
Ashish Jain is presently working as Assistant professor in the department of Pharmaceutics and Pharmaceutical Technology at Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India. He has worked on iontophoretic drug delivery system during his post graduation (M.Pharm) and has got international publications of this work. He further focuses his research activity in the other novel drug deliver system.
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Mr. Vinod Dhote is a final year B.Pharma student of Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India. He has completed his project on microneedle during his graduation. He is now focusing on other novel drug deliver system.
Mr. Hemant Dhongade is presently working as Assistant professor in the department of Pharmacogonosy at Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India. He has worked on Antihyperlipidemic activity of herbal drugs during his post graduation (M.Pharm) and was awarded the first prize for same work. He further focuses his research activity in characterization and standardization of herbal medicines.
Mr. Sandip Sumbhate is presently working as Assistant professor in the department of Pharmaceutical chemistry at Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India. He has worked on colorimetric estimation of sertaralin and estimazole in their tablet dosage forms during his post graduation (M.Pharm). He further focuses his research activity in analysis of drugs in tablet dosage form.
Dr. Satish Nayak is currently working as Principal in Bansal College of Pharmacy, Kokta, Aanand Nagar, Bhopal-462021, M.P., India. He earned his Ph.D in pharmacogonosy. Dr. Satish Nayak has 15 years of academic and research experience. He has more than 25 national and international research papers to his credit.