Micro needle Technology an Overview

There are many routes by which the drugs can be delivered into the body. These routes include oral (drugs taken by mouth), injections, nasal (sprayed into nose), inhalation (breathed into the lungs), rectal (injection into the rectum), cutaneous (applied on the skin), and transdermal (delivery through the skin). Injections can be further divided into intravenous (injection into a vein), intramuscular (injection into a muscle), intrathecal (injection into the space around the spinal cord), and subcutaneous (injection beneath the skin). Each drug delivery route has specific advantages and disadvantages, and the route greatly impacts the therapeutic efficacy of the delivered drug inside the body. The oral route is the most common way to deliver drugs into the body. However, it should be noted that the popularity of oral drug administration is not because it is effective, but because it is convenient.

Compared to the majority of the other methods, oral drug administration is the simplest and the least expensive method and also often the safest method for most of the drugs. However, conventional oral drug delivery is not an ideal route for the delivery of many drugs, especially newly available protein- or peptide based drugs which are developed by using biotechnology. The orally administered drug is partially absorbed in the mouth and stomach, although most of the drug is absorbed from the small intestine. The drug passes through the liver before it is transported via the bloodstream to its target site. Most drugs are degraded in the gastrointestinal tract by digestive enzymes or eliminated by the liver. The most common alternative route to oral drug delivery is injection. Although injection would be an effective way to deliver large-molecule drugs into the body in large quantities, it has inherent problems, such as invasiveness (needles cause pain and tissue damage) and it is difficult to achieve a sustained, controlled release of the drug. In addition, this method is relatively expensive because medical professionals need to administer drugs in most cases.Recently, there have been many studies on new drug delivery methods using emerging micro- and nanotechnologies with goals of overcoming these limitations.

CONVENTIONAL NEEDLE-BASED ADMINISTRATION:

Constituting the standard method of parental administration, the use of a hypodermic needle is an efficient way of delivering a drug. For example, a bolus delivery of a drug (e.g. a vaccine), may be completed within a minute using disposables with essentially no cost. Despite the effectiveness, this administration method has some major drawbacks.

Firstly, ordinary needles are associated with pain which cause problems with acceptance, and therefore compliance. Secondly, the use of “sharps” raises concerns on device safety and safety for health care providers. This is of major concern especially in the developing countries, where unsafe injections account for a significant portion of transmission of hepatitis B and C viruses and human immunodeficiency virus (HIV). For hepatitis B, as much as 20% of the viral transmissions are estimated to be caused in this way. According to the World Health Organization (WHO), more than 1.3 million deaths and costs of US _535 million are attributed annually to unsafe injection practice. Thirdly and partly related to safety concerns, the use of “sharps” require trained personnel for administration and handling. Although patients can be trained in self-injections (as with diabetics).

Figure 1: A schematic diagram of a cross-section of human skin with a micro-needle array and a conventional needle.

HUMAN SKIN AND MICRO NEEDLES

Hypodermic syringes with a hollow pointed needle have been one of the most commonly used body fluid extraction, vaccination, and medication devices since their invention by C. Pravaz and A. Wood in the 1850s. While there have been many variations in materials and methods of providing safety, the hypodermic syringe design has changed very little since its first use. Conventional hypodermic needles create fear of injection-related pain among patients, and there has been increasing concern regarding the transmission of blood borne pathogens such as HIV (human immunodeficiency virus) and hepatitis to healthcare workers by accidental needle stick injuries.

Figure 2 shows a schematic diagram of a cross-section of human skin. Human skin is composed of three layers: epidermis, dermis, and subcutaneous tissue. The outermost layer of the epidermis is stratum corneum (10 to approximately 20μm thick), a layer of dead cells, which is a protective diffusion barrier layer preventing the loss of body fluids and blocking the entry of external materials into the body. Sensory fibers in the cutaneous nerves detect external stimuli such as temperature, pressure, and those causing pain, and generate signals that are relayed through a nerve pathway to the brain. Sensory fibers and blood vessels reach to the dermis layer in the skin. 

Fig.2 Cross-sectional illustration of human skin

The pain associated with an injection using a hypodermic syringe is due to the fact that the needle is large and penetrates deep into the skin with excessive contact with these sensory fibers. The smallest needle typically used for insulin injection for diabetes is a 31-gauge needle which is 254 μm in outer diameter.

With the advances in technology, it is possible to make micro needles that are long enough to penetrate the epidermis, but short enough not to penetrate deep into the dermis layer and farther down in the subcutaneous tissue for minimally invasive transdermal drug delivery and body fluid sampling. Moreover, micro needles and micro needle arrays can be used as stand-alone devices as well as a part of more sophisticated smart biological detection and delivery systems in which micro needles are integrated with microfluidics and biosensors or microelectronics.Before micro needles find widespread use, the researchers must perfect the techniques for optimally inserting them into the skin, and complete the integration of micro needles into a full drug delivery system. The need to minimize variability in needle insertion is being addressed in part by development of an applicator device that would be part of the delivery system.

A painless"micro needle" that mimics the way a female mosquito sucks blood has been built by engineers in India and Japan.

ADVANTAGES OF MICRO NEEDLES

1. The major advantage of micro-needles over traditional needles is, when it is inserted into the skin it does bypass the stratum corneum, which is the outer 10-15 μm of the skin. Conventional needles which do pass this layer of skin may effectively transmit the drug but may lead to infection and pain. As for micro-needles 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 single water. This leads to high accuracy, good reproducibility, and a moderate fabrication cost.

3. Hollow like hypodermic needle; solid— increase permeability by poking holes in skin, rub drug over area, or coat needles with drug

4. Arrays of hollow needles could be used to continuously carry drugs into the body using simple diffusion or a pump system.

5. Hollow micro needles 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.

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 micro needles 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.

NEED FOR USING MICRO NEEDLES

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. 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 have been studied, ranging from chemical/lipid enhancers to electric fields employing iontophoresis and electroporation to pressure waves generated by ultrasound or photo acoustic effects. 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 are 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.

Transdermal drug delivery is a noninvasive, user-friendly delivery method for therapeutics. However, its clinical use has found limited application due to the remarkable barrier properties of the outermost layer of skin, the stratum corneum (SC). Physical and chemical methods have been developed to overcome this barrier and enhance the transdermal delivery of drugs. One of such techniques was the use of micro needles to temporarily compromise the skin barrier layer.

This method combines the advantages of conventional injection needles and transdermal patches while minimizing their disadvantages. As compared to hypodermic needle injection, micro needles can provide a minimally invasive means of painless delivery of therapeutic molecules through the skin barrier with precision and convenience. The micro needles seldom cause infection while they can allow drugs or nanoparticles to permeate through the skin. Increased micro needle-assisted transdermal delivery has been demonstrated for a variety of compounds. For instance, the flux of small compounds like calcein, diclofenac methyl nicotinate was increased by micro needle arrays. In addition, microneedles also have been tested to increase the flux of permeation for large compounds like fluorescein isothiocynate-labeled Dextran, bovine serum albumin, insulin and plasmid DNA and nano-spheres.

Micro-needles may create micro-conduits sufficiently large to deliver drug-loaded liposomes into the skin. The combination of elastic liposomes and micro needles may provide higher and more stable transdermal delivery rates of drugs without the constraints of traditional diffusion-based transdermal devices, such as molecular size and solubility. Though it could offer benefits mentioned above, the combined use of elastic liposomes and micro needle pre-treatment has received little attention.

MICRO NEEDLE PRODUCTION, GEOMETRY, AND APPLICATION TECHNOLOGY

Production of micro needles Numerous types of micro needles composed of various materials have been used for the (trans)dermal delivery of a broad range of compounds in a painless manner, a selection of which is shown in Fig. 3. The first produced micro needles for drug delivery were made from silicon wafers by photo-lithography and deep reactive ion etching. The used micro-fabrication technologies were initially developed for the production of integrated circuits and turned out to be very suitable for the highly-reproducible mass production of micro needles. Furthermore, these technologies enable the integration of, e.g., micro-sensors, micro-pumps, electrical circuits, and micro needles into one device. Another benefit of silicon micro needles is that they are usually much sharper than polymeric and metal micro needles. However, the production process for silicon micro needles requires expensive micro-fabrication processes and clean room processing. Another drawback of silicon needles is that they may break and stay behind in the skin due to the fragile nature of silicon

Micro needles produced from silicon wafers have been developed with multiple geometries and can be divided into two major groups: in-plane and out-of-plane micro-needles. In-plane micro needles are formed in parallel with the machined surface of the silicon wafer, enabling the production of needles with various lengths over a large range. In-plane production techniques are state-of-the-art techniques, including surface micro-machining and a variety of etching methods. Furthermore, they offer flexibility regarding needle design and shape, and are beneficial for the integration of micro needles with biosensors and micro-pumps. Out-of plane micro-needles are formed perpendicular to the silicon wafer and are more easily produced in arrays than in-plane micro needles. Furthermore, out-of-plane micro needles have the major advantage of arranging the single micro needles of an array in such a way that the drug can be delivered over a larger surface area of the skin. However, out-of-plane hollow micro needles are more difficult to integrate with lab-on-a-chip technologies than in-plane hollow micro needles. More recently, other micro needle production processes have been introduced for the generation of cheaper and biocompatible micro needles, including metal, polymer and sugar-based micro needles. Solid metal micro needles can be produced by laser cutting them out of sheet metal and subsequently bending them out-of-plane .

Furthermore, solid micro needle arrays with a length of 300 μm have been made from the tip of 30 G needles, molded in a plastic back plate and stainless steel 34 G hollow micro needles have been developed for insulin delivery. Hollow metal micro needles are often made from metal tubing by laser machining, electro-chemical etching or by electrode discharge machining. Another technology to produce metal micro-needles is laser patterning. This is a technique whereby liquid particles, containing the micro needle material of interest, are deposited on a substrate in order to produce an out-of-plane 3- dimensional structure. Laser patterning may be a versatile method to create micro needles from a broad range of materials. Polymeric micro needles could have important benefits over micro needles made of other materials, because polymers are inexpensive, can be biocompatible, and they are amenable to mass production. Furthermore, because of their visco-elastic properties polymeric micro needles may be less sensitive to shear-induced breakage, and drugs may be incorporated into biodegradable polymeric micro needles for controlled drug delivery. Furthermore, polymeric micro needles are extremely suited for the development of an all-in one drug delivery system, whereby the micro needle is the drug delivery device as well as the drug formulation.

MICRO NEEDLE GEOMETRY

Several factors may prevent micro-needles from penetrating the skin. In particular, the elastic nature of skin can prevent micro needles from penetration by folding around the needles during micro-needle application, especially in case of blunt and short micro needles. Due to the robustness of the skin, micro needle insertion forces may exceed the ultimate tensile forces of the micro needle and thereby damage the micro needles, especially for longer micro needles and micro needles made of relatively weak materials. Therefore, micro needle geometry is crucial for efficient micro-needle-based (trans) dermal drug delivery, because it influences the strength of the micro needles, their ability to pierce the skin, the drug flow (through hollow micro needles), and therefore the rate of drug delivery. Various different micro needle shapes have been developed, ranging from cylindrical, rectangular, pyramidal, conical, and octagonal, to quadrangular, with different needle lengths and widths. The sharpness of the micro needle tip is a very important factor for skin penetration, as sharper micro-needles have higher potential for sufficiently penetrating the skin at a certain insertion force, i.e., larger tip diameters need higher insertion forces .

For hollow micro needles it is important that a sufficient and constant flow rate is generated for delivering drugs into the skin, without affecting the micro needle strength. The main factor affecting the flow rate is the compression of the dense dermal tissue at the needle tip during insertion. Therefore, the shape of the tip is of great importance for the flow rate, e.g., the flow from a blunt-tip micro needle supports less flow than a bevel-tip micro needle, because a blunt-tip micro needle compresses the skin more extensively and thereby has an increased risk of clogging. Hence, it could be beneficial to have very sharp micro needles with the bore of the micro-needle off centered or on the side of the micro needle. Increasing the micro needle bore may increase the flow rate, however, these results in decreased micro needle strength and a reduction in sharpness. A way to increase the micro needle strength is by applying a metal coating on the micro needles, which however, may decrease their sharpness.

For both hollow and solid micro needles, a low density of micro needle arrays may be beneficial for piercing the skin because they can pull the skin tied between the needles. Conversely, very dense micro needle arrays may be less efficient in piercing the skin because they can cause a ‘bed of nails’ effect. Therefore, designing micro needles involves making compromises and using micro needle insertion devices, as described below.

 MICRO  NEEDLE APPLICATION DEVICES

For medical application reproducible piercing is crucial, which demands the use of an applicator, even in the case of sharp micro needle arrays. However, the importance of using micro needle applicators has been underestimated for a long time. Applicators for micro needles should meet certain requirements to be suitable for clinical use. Since micro needles are developed for decreasing patient discomfort and eliminating pain sensation, the applicator itself should not induce any pain. Furthermore, the use of an applicator should lead to a more effective, reproducible and depth controlled penetration of micro-needles into the skin, without increasing the risk of micro needle fracture. Several micro needle application devices have been developed, for example an applicator based upon the reduction of insertion forces by a hand-operated rotary application for single hollow micro-needles, which drills individual micro-needles into the skin to a predetermined depth. Furthermore, a hand-held micro needle applicator was developed to apply micro needles in a single rolling motion from an angle of 45° to 135° with the skin and vibration-based micro needle insertion devices have been used to reduce the insertion forces. Partial retraction of hollow micro needles is beneficial for the flow rate, because this leads to less clogging at the tip opening. However, most application devices are based upon impact insertion,which mainly reduce the insertion forces by circumventing the skin's elasticity. These impact-insertion devices range from simple hand-held applicators, by which micro needles are either manually punched into the skin or via a mechanically-driven applicator, to more sophisticated electrically-driven micro needle applicators. The latter are preferable for multiple use (e.g. repeated dose, multiple patients) because the easily adjustable forces are more stable over time than manually or spring-induced forces.

However, for a single administration a mechanically-driven applicator may be beneficial from an economic point of view. In conclusion, there is no universal applicator for micro needles and therefore the requirement of the applicator is dependent on the geometry, sharpness and density of the relevant micro needle and the intended use.

MECHANISM OF ACTION

                                                    Fig.4 Delivery site for micro-needle technology

The mechanism for delivery 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.

The drug, in the form of biomolecules, is encapsulated within the micro needles, which are then inserted into the skin in the same way a drug like nitroglycerin is released into the bloodstream from a patch. The needles dissolve within minutes, releasing the trapped cargo at the intended delivery site. They do not need to be removed and no dangerous or bio-hazardous substance is left behind on the skin, as the needles are made of a biodegradable substance.

In micro needle devices, a small area (the size of a traditional transdermal patch) is covered by hundreds of micro needles that pierce only the stratum corneum (the uppermost 50 μm of the skin), thus allowing the drug to bypass this important barrier. The tiny needles are constructed in arrays to deliver sufficient amount of drug to the patient for the desired therapeutic response .The mechanism of action depends on the micro needle design and is summarized in Fig.5. All types of microneedles are typically fabricated as an array of up to hundreds of micro needles over a base substrate. Solid micro needles can either be pressed on to the skin or scraped on the skin for creating microscopic holes, thereby increasing skin permeability by up to four orders of magnitude. This is followed by application of drugs or immune-biological from a patch. Residual holes after micro needle removal measure microns in size and have a life time of more than a day when kept under occlusion, but less than 2 hours, when left uncovered. The second strategy is to have immune-biological in a dry coating onto solid micro needles. This coating can dissolve within 1 minute after insertion into skin, after which the micro needles can be withdrawn and discarded. As an alternative for using insoluble metal or polymer micro needles, complete micro needles have been fabricated out of biodegradable or water-soluble polymers. Model drugs have been encapsulated within PLGA micro needles for controlled release over hours to months and, more recently, water-soluble carboxymethyl-cellulose, polyvinyl-pyrrolidone and maltose for rapid release within minutes. The final approach consists of using hollow micro needles to puncture the skin followed by infusion of liquid formulation through the needle bores in a manner similar to hypodermic injection.

Fig 5: Mechanism of Action

(a) Solid micro needles for permeability of skin via formation of micron sized holes across stratum corneum. The needle patch is withdrawn followed by application of drug-containing patch.

(b) Solid micro needles coated with dry drugs or vaccine for rapid dissolution in the skin.

(c) Polymeric micro needles with encapsulated drug or vaccine for rapid or controlled release in the skin.

(d) Hollow micro needles for injection of drug solution.