MICRONEEDLES BASED TRANSDERMAL DRUG DELIVERY

About Author:
Pooja Mittal
School of Pharmacy and Emerging Sciences,
Baddi University of Emerging Sciences and Technology,
Baddi H.P
pooja.mittal@baddiuniv.ac.in

Abstract:
The success of transdermal drug delivery has been severely limited by the inability of most drugs to enter the skin at therapeutically useful rates. Using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small molecular weight drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. Most drug delivery studies have emphasized solid microneedles, which have been shown to increase skin permeability to a broad range of molecules and nanoparticles in vitro. Microneedles inserted into the skin of human subjects were reported as painless. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. These results suggest that microneedles represent a promising technology to deliver therapeutic compounds into the skin for a range of possible applications.

REFERENCE ID: PHARMATUTOR-ART-1776

1. Introduction
When oral administration of drugs is not feasible due to poor drug absorption or enzymatic degradation in the gastrointestinal tract or liver, injection using a painful hypodermic needle is the most common alternative. An approach that is more appealing to patients, and offers the possibility of controlled release over time, is drug delivery across the skin using a patch(Bronaugh, R.L., Maibach, H.I.(1999, Touitou, E.(2002). 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. To increase skin permeability, a number of different approaches has been studied, ranging from chemical/ lipid enhancers (Barry, B., Williams, A.(2003, Cevc, G.(2004) to electric fields employing iontophoresis and electroporation to pressure waves generated by ultrasound or photoacoustic effects (Doukas, A. (2004, Mitragotri, S., Kost, J. (2004). 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. The size of disruptions generated by each of these methods is believed to be of nanometer dimensions, which is large enough to permit transport of small drugs and, in some cases, macromolecules, but probably small enough to prevent causing damage of clinical significance. An alternative approach involves creating larger transport pathways of microns dimensions using arrays of microscopic needles. These pathways are orders of magnitude bigger than molecular dimensions and, therefore, should readily permit transport of macromolecules, as well as possibly supramolecular complexes and microparticles. Despite their very large size relative to drug dimensions, on a clinical length scale they remain small. Although safety studies need to be performed, 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 (Champion, R.H. , Burton, J.L.et al (1998). Although the microneedles concept was proposed in the 1970s , it was not demonstrated experimentally until the 1990s when the microelectronics industry provided the microfabrication tools needed to make such small structures. Since the first studies of transdermal drug delivery in 1998 (Henry, S., McAllister, D. ,et al (1998), there has been rapidly increasing interest in the field, with most activity in the microfabrication community to develop novel needle fabrication technologies and the drug delivery industry to develop microneedles for pharmaceutical applications.

2. Transdermal drug delivery using microneedles
The overarching motivation for microneedles is that they can provide a minimally invasive means to transport molecules into the skin. Guided by this goal, a number of specific strategies have been employed to use microneedles for transdermal delivery. Most work has focused on making microscopic holes in the skin by inserting solid microneedles made of silicon or metal. The ‘‘poke with patch’’ approach uses microneedles to make holes and then apply a transdermal patch (or some prototype) to the skin surface. Transport can occur by diffusion or possibly iontophoresis if an electric field is applied. Another approach is ‘‘coat and poke,’’ where the needles are first coated with drug and then inserted into the skin. There is no drug reservoir on the skin surface; all the drug to be delivered is on the needle itself. A variation on this second approach is ‘‘dip and scrape,’’ where microneedles are first dipped into a drug solution and then scraped across the skin surface to leave behind drug within microabrasions created by the needles. Hollow microneedle designs and methods have also been studied using an approach more reminiscent of an injection than a patch. Following is a summary of the literature on the use of microneedles for transdermal delivery of drugs, proteins, genetic material, and vaccines. It emphasizes work that has been published and directly addresses drug delivery. This review does not include the dozens of conference abstracts from the microfabrication community that focus on novel needle fabrication technology without examining the performance of those needles to deliver drugs into skin. Similarly, it does not include the apparently extensive, unpublished work of companies developing microneedles for transdermal drug delivery.

2.1. Solid microneedles
Solid microneedles can be used to create micronscale holes in the skin through which molecules can more easily transport. The first microneedle arrays reported in the literature were etched into a silicon wafer and developed for intracellular delivery in vitro by Hashmi, S., Ling, P. ,et al ,(1995). These needles were inserted into cells and nematodes to increase molecular uptake and gene transfection. Shortly after this work was published, microneedles were developed for transdermal delivery applications, which have been shown to insert into skin and thereby deliver a variety of different compounds in vitro and in vivo.

2.2. Hollow microneedles
In contrast to the solid microneedles discussed above, microneedles containing a hollow bore offer the possibility of transporting drugs through the interior of well-defined needles by diffusion or, for more rapid rates of delivery, by pressure-driven flow. A variety of hollow microneedles have been fabricated, but only limited work has been published on their possible use to deliver compounds into skin. Smart and Subramanian,(2001) used single microneedles to extract nanoliter quantities of blood from the skin to measure glucose levels.

3. Mechanics of microneedle insertion into skin
Most studies of microneedles have addressed methods of fabrication and assessed drug delivery capabilities. Only microneedles with the correct geometry and physical properties are able to insert into skin. Some needle designs require only insertion by hand, whereas others benefit from high-velocity insertion, as mentioned above. When the force required for insertion is too large, needles can break or bend before insertion occurs. These issues have been explicitly addressed by Davis et al. who measured the force required for fracture, the force required for insertion, and their ratio (termed the margin of safety) as a function of needle geometry and physical properties.

4. Lack of pain caused by microneedles
Microneedles are of interest primarily because they offer the promise of painless drug delivery. Because the skin’s stratum corneum barrier has no nerves, skin anatomy provides the opportunity to pierce needles across the stratum corneum without stimulating nerves. In current practice, there is no evidence of microneedles penetrating just 10–20 Am across stratum corneum without entering the viable epidermis, where nerves are found. Instead, microneedles are inserted at least into the epidermis and sometimes into the superficial dermis, as discussed above. Nevertheless, microneedles are still reported as painless, probably because their small size reduces the odds of encountering a nerve or of stimulating it to produce a painful sensation.

Kaushik et al.(2001), 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 (Mikszta, J.A., Alarcon, J.B. et al ,(2002). Stoeber, B., Liepmann, D.(2000),. Chen, J. , Wise, K.D. (1997)., Smart, W.H., Subramanian, K.(2000).

5. FABRICATION OF MICRONEEDLE DEVICES
The stratum corneum is the outermost layer of the skin (epidermis) which serves as an effective material permeation barrier. Beneath this lies the viable epidermal layer that s devoid of blood vessels and contains very few nerve endings. The next layer is highly vascularized dermis that consists of blood vessels, nerves, lymph vessels, dendritic cells, hair follicles, collagen, and sweat glands. Underlying the dermal layer, is the fatty subcutaneous layer, with fat cells, blood vessels and connective tissue(GBS Banker CT Rodes (1979). In order to deliver drug or skin cosmetic components to all the layers or to a certain skin layer, the microneedles are preferably fabricated to have an upper end diameter of 5-40 µm and an effective length of 1000-2000 µm (Park JH, Allen MG,et al.(2005). The method for fabricating biodegradable solid microneedles comprises following main steps:
1. Coating the surface of a substrate with a viscous material for forming biodegradable solid microneedles.
2. Bringing the surface of a frame having pillar patterns formed thereon, into contact with the surface of the coated viscous material
3. Drawing the coated viscous material using the frame, while solidifying the viscous material
4. Cutting the drawn material at a given position thereof, thus obtaining biodegradable solid microneedles (Lin L, Pisano AP.(1999).

Various materials, such as hydrogel, maltose, drugs for the treatment for skin diseases, cosmetic components, water-soluble materials and polymeric proteins, may be used to form the biodegradable solid microneedles. Microneedles manufactured by the silicon etching technology and micro-mechanical system manufacturing (MEMS) technique are tiny and very thin (even thinner than human hair), which do not penetrate deep enough into the skin to reach up to the nerve endings and therefore there is no perception of pain during the microneedles insertion into the skin.

6. POTENTIAL OF MICRONEEDLE TECHNOLOGY
Fabricating microneedles in a variety of shapes, sizes and materials allows delivering large molecules with significant therapeutic interest such as insulin, proteins produced by the biotechnology industry, and nano particles that could encapsulate a drug or demonstrate the ability to deliver a virus for vaccinations.

Microneedles may prove useful for immunization programs in developing countries or for the mass vaccination or administration of antidotes in bioterrorism incidents because persons with minimal medical training could apply them.
Very small microneedles could provide highly targeted drug administration to individual cells.
By fabricating these needles on a silicon substrate because of their small size, thousands of needles can be fabricated on a single wafer. This leads to high accuracy, good reproducibility, and a moderate fabrication cost.
Microneedles 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 (Zachary Hilt J, Nicholas A. P.(2003).
Hollow microneedles could be used to remove fluids from the body for analysis such as blood glucose measurements and to supply micro liter volumes of insulin or other drug as required.

7. Conclusion
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. Solid microneedles have been shown to increase transdermal delivery by ‘‘poke with patch,’’ ‘‘coat and poke,’’ and ‘‘dip and scrape’’ methods, and hollow microneedles have been shown to microinject into skin. Therapeutic responses have been achieved in vivo following delivery of proteins, DNA and vaccines. Proper needle design can assure insertion into the skin that prevents needle fracture or patient pain. These studies suggest that microneedles may provide a powerful new approach to transdermal drug delivery.

REFERENCES
1.Barry, B., Williams, A.(2003) Penetration enhancers, Adv. Drug Deliv. Rev. 56( 603–618).
2.Bronaugh, R.L., Maibach, H.I.(1999). Percutaneous Absorption: Drugs –Cosmetics-Mechanisms-Methodology, Marcel Dekker, New York.
3.Cevc, G.(2004) Lipid vesicles and other colloids as drug carriers on the skin, Adv. Drug Deliv. Rev. 56 ,675– 711.
4.Champion, R.H. , Burton, J.L.et al (1998). Textbook of Dermatology, Blackwell Science, London.
5.Davis, S. , Landis, B. ,et al .Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force, submitted for publication.
6.Doukas, A. (2004). Transdermal delivery with a pressure wave, Adv. Drug Deliv. Rev. 56 ,559–579.
7.GBS Banker CT Rodes (1979), “Modern Pharmacist”, 2nd edition Vol. 40, Marcel Dekker, New York, 263-273, 283,286-287,299-311.
8.Hashmi, S., Ling, P. ,et al ,(1995).Genetic transformation of nematodes using arrays of micromechanical piercing structures, BioTechniques 19 ,766–770.
9.Henry, S., McAllister, D. ,et al (1998).Microfabricated microneedles: a novel method to increase transdermal drug delivery, J. Pharm. Sci. 87, 922– 925.
10.Kaushik, S. , Hord, A.H. ,et al (2001).Lack of pain associated with microfabricated microneedles, Anesth. Analg. 92 ,502–504.
11.Lin L, Pisano AP.(1999). Silicon processed microneedles. IEEE J Micromech Syst. 8(1):78 84.
12.Mikszta, J.A., Alarcon, J.B. et al ,(2002).Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery, Nat. Med. 8 , 415–419.
13.Mitragotri, S., Kost, J. (2004).Low-frequency sonophoresis: a review, Adv. Drug Deliv. Rev. 56 ,589–601.
14.Park JH, Allen MG,et al.(2005). Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release ,104(1):51-66.
15.Smart, W.H., Subramanian, K.(2000). The use of silicon microfabrication technology in painless blood glucose monitoring, Diabetes Technol. Ther. 2 , 549– 559.
16.Touitou, E.(2002) Drug delivery across the skin, Expert Opin. Biol. Ther. 2 723– 733.
17.Zachary Hilt J, Nicholas A. P.(2003). Microfabricated drug delivery devices. Int J Pharmaceutics. 306:15-23.