Microneedles : The option for painless delivery

Geeta M Patel

Transdermal drug delivery is limited by the extraordinary barrier properties of the stratum corneum, the outer 10-15 mm of skin. Conventional needles inserted across this barrier and into deeper tissue effectively deliver drug, but can lead to infection and cause pain, thereby reducing patient compliance.

The biomedical industry seeks to replace stainless steel hypodermic injection needles with needles that have smaller diameter and sharper tips, to minimize pain and tissue damage. Since the dawn of microelectronic processing, electronic devices have been fabricated to smaller and smaller scales on a silicon substrate. As technology improves and smaller devices are created with more robust processes, the complexity of these devices will increase. In the meantime, non-implantable devices, such as the microneedles, are proving to be useful and worthwhile. This paper will discuss what microneedles are, the advantages of microneedles and processing applications.

Introduction

For over 150 years, syringes and hypodermic needles have been utilized to deliver drugs into patients.¹ Because of the transport barriers that exist in other delivery routes; injection is still a prominent method for drug delivery today. Currently, the smallest needles that are commercially available for injections are 30 gauge for conventional syringes and 31 gauge for pen injectors, which are utilized mainly for insulin delivery. The 30 and 31 gauge needles have outer diameters of 305 and 254 um, respectively.² Microfabrication has been utilized to create microneedles, which are orders of magnitude smaller in diameter, capable of localized and painless delivery of drugs into cells or tissues. Research into the application of microneedles for gene and drug delivery has been divided into three broad areas: cellular delivery, local delivery and systemic delivery.³

Until very recently, the only drugs that could permeate transdermally were those possessing a very narrow and specific combination of physicochemical properties. However, rapid advances in bioengineering have led to the emergence of various new "active" enhancement technologies designed to transiently circumvent the barrier function of the stratum corneum. These novel systems, using iontophoresis, sonophoresis, electroporation, or microneedles arrays, will greatly expand the range of drugs that can be delivered transdermally. Crucially, the delivery of macromolecules will become possible and the transdermal flux of other molecules could be enhanced by several orders of magnitude.⁴

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. An example of microneedles, which was fabricated by creating micron-sized holes on a silicon substrate and by using a KOH solution to create the needle shape, is shown in Figure 1 and Figure 2. Various types of needles have been fabricated as well, for example: straight, bent, filtered, and hollow. 

Figure 1: Array of silicon microneedles ⁵

Figure 2 – Photomicrograph of a 20 x 20 array of solid microneedles resting on a human finger to give a sense of its small size ⁶

Advantages of Microneedles

1. 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.⁵ 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.
2.  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.⁷
3. Hollow like hypodermic needle; solid—increase permeability by poking holes in skin, rub drug over area, or coat needles with drug .⁸
4. Arrays of hollow needles could be used to continuously carry drugs into the body using simple diffusion or a pump system.⁹
5. Hollow microneedles could 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 .⁹
6. Immunization programs in developing countries, or mass vaccination or administration of antidotes in bioterrorism incidents, could be applied with minimal medical training.
7. Very small microneedles could provide highly targeted drug administration to individual cells.
8. 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.¹⁰

In general terms, make needles that:

•   Go into skin easily
•   Deliver drugs effectively
•   Don’t hurt
•   Are biocompatible

The needles need to:

•   Withstand typical handling
•    Deliver controlled amount of drug at specific rate
•    Deliver to precise depth in body
•   Withstand insertion without buckling, fracture, or delamination ¹¹

Materials

Needles have been made from:

•   Glass
•   Silicon
•   Metal—stainless steel, solid or coat of gold over Ni, Pd or Pd-Co, and Pt
•   Biodegradable polymers, if a tip snaps off while inserted, it will easily biodegrade

Microneedle fabrication

The needle fabrication process involved four steps. First, arrays of microneedles made of SU-8 epoxy photo resist were fabricated by patterning SU-8 onto glass substrates and defining needle shape by lithography. Then, the tips of the needles were sharpened using reactive ion etching. The next step involved laser drilling holes through the microneedles and base substrate oriented off-center, but parallel to the Microneedle axis. This created holes that serve as the micro fluidic needle bores for injection or infusion, which terminate in side-opening holes along the needle shaft below the needle tip. Finally, the needle arrays were coated with nickel by electroplating to increase their mechanical strength.¹²

Applications of Microneedles

1 Blood Glucose Measurements

As stated previously microneedles can be fabricated to only penetrate the 10-15 μm of the skin. This means there is no pain when taking blood samples for glucose measuring devices. There is a huge market in glucose testers due to diabetic patients and hospitals. Kumetrixs is an example of a company that fabricates such a device. The micro-needle is penetrating to the skin and draws a very small volume of blood (less than 100 nanoliters) into the disposable. Chemical reagents in the disposable react with the glucose in the blood to produce a color. The blood-glucose concentration will be measured either electrochemically or optically, and the resultant value displayed on the monitor.¹³

2 Transdermal Drug Delivery

The conventional transdermal drug delivery limits the applicability to small drug molecules because the stratum corneum does not have any nerves. Since microneedles that are long enough and robust enough to penetrate across this layer, but short enough to not stimulate the nerves in the deeper tissue, have the potential to make transdermal delivery a painless and much more viable option .³ With the use of hollow microneedles it allows the delivery of medicines, insulin, proteins, or nanoparticles that would encapsulate a drug or demonstrate the ability to deliver a virus for vaccinations .¹⁴ An array of needles ranging from 300-400 needles can be designed to puncture the skin and deliver the drug.

3 Molecular and cell biology

Microneedles have been applied for the delivery of membrane impermeable molecules into cells. For application in molecular cell biology, methods for the delivery of peptides, proteins, oligonucleotides, DNA and other probes that alter or assay cell function is desired. Arrays of microneedles were fabricated and utilized to deliver DNA into plant and mammalian cells, as a method for transforming cells.

4 Target drug delivery

Additionally, microneedles have been utilized to target drug delivery to a specific region or tissue in the body, thus avoiding detrimental effects that can result from administering certain drugs systemically. This targeting can reduce side effects, minimize the dose of an expensive drug, and/or provide a means of delivery to a location that is difficult to treat.¹⁵ For instance, a multichannel silicon microneedle has been microfabricated to deliver bioactive compounds into neural tissue while simultaneously monitoring and stimulating the neurons in vivo.¹⁶ In addition, microneedles have been used to penetrate vessel walls of normal and atherosclerotic rabbit arteries in vitro demonstrating potential use for targeted delivery of antirestenosis drugs.¹⁷

5 Future Applications - Microneedle Skin Therapy

Microneedle skin therapy is still in testing development, but it seems to show much promise. Microneedle therapy is a way to rejuvenate the skin without destroying the epidermis. It is similar to laser treatments but with less damage. Companies like the Clinical Resolution Lab utilize treatments using microrollers .¹⁸ Microneedles penetrate the epidermis and break away old collagen strands. The collegen strands that are destroyed create more collagen under the epidermis. This leads to youthful looking skin. The only disadvantage of this method is that it causes blood oozing, which laser treatments do not. It does however have advantages such as: increased collagen, non sun-sensitivity upon treatment, no breaking of the epidermis, lower cost, and ease of application

Conclusion

Many people, particularly children, are ‘needle-phobes’. In addition, there are several patients, such as diabetics who are dependant on multiple injections on a daily basis. Many other disease conditions also require the delivery of therapeutic agents to the skin, while the outbreak of a pandemic would necessitate mass vaccinations. A solution to the problems posed by needle-based injections is the development of microneedles. This technology will help realise the development of new and improved devices, which will be smaller, cheaper, pain-free and more convenient with a wide range of biomedical and other applications. The future of drug delivery is assured to be significantly influenced by microfabrication technologies. These microfabricated drug delivery devices can enable efficient drug delivery that was unattainable with conventional drug delivery techniques, resulting in the enhancement of the therapeutic activity of a drug.

References

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    http://www.kumetrix.com/http/kumetrix.com/technology.html
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About Authors:

Patel Geeta M is presently working as Lecturer in the department of Pharmaceutics and Pharmaceutical Technology at S. K. Patel college of Pharmaceutical education and research, Kherva, Ganpat University, Mehsana, India. She worked on floating drug delivery system during her post graduation. She has 11 publications in different journals. She further focuses her research activity in the novel drug deliver system.
Corresponding Author: E-mail – geekhappy2002@yahoo.co.in

Patel Hitesh R is presently working as Lecturer in the department of Pharmaceutics and Pharmaceutical Technology at S. K. Patel college of Pharmaceutical education and research, Kherva, Ganpat University, Mehsana, India. he worked on oral mucosal drug delivery system during his post graduation. He has 4 publications in different journals. He further focuses her research activity in the same.

Dr. Madhabhai Patel is currently Principal of Kalol institute of Pharmacy, Kalol India. He earned his PhD in Pharmaceutics and Pharmaceutical technology. Dr. Madhabhai Patel has 25 years of academic and research experience.He has 40 national and intentional research papers to his credit. He is an approved PhD guide at Hemchandrachayra North Gujarat University, Patan, and Ganpat University,Kherva, India.