Microneedles in Drug Delivery system

2010-11

1. Introduction
1.1 The concept of minimally invasive drug delivery A discussion of minimally invasive drug delivery must begin with a consideration of what invasive delivery means. Administration of drugs via needles and syringes has been with us for more than a hundred years. For example, the first all-glass syringe patent was licensed to Becton Dickinson & Co. in 1898. Metal cannula needles on piston syringes have become the most prevalent ethical device-based drug delivery modality in existence, with multiple billions being used each year in many health care applications. Conventional needles, whether on syringes or catheters, represent the preeminent invasive delivery mode in existence. They are, however, also the most efficient and cost effective device-based system for administering agents into the systemic circulation and are presently the general method for delivering polypeptide agents, which are otherwise proteolyzed by the oral route. The reason, as discovered more than a century ago, is that a thin, sharp sterile metal pipe is an ideal way to breach the stratum corneum and deliver agents past the skin barrier into the micro-vascularization of the dermis or lower tissues and thence into the systemic circulation. Despite this, conventional needle-based delivery suffers many well-recognized drawbacks, not the least of which is the negative psychosocial connotation of drug administration via needles. Other problems include the pain of administration; safety concerns over the possibility of transmission of blood-borne pathogens; the lack of compliance, the inability or dislike of patients to self-administer via needles; and the lack of ease of use, especially for younger or elderly patients. To address these needs, a number of new technologies have arisen or are in development, whose inventors intend to provide trans-epidermal drug delivery by circumventing the conventional needle and syringe.1 During recent years, transdermal drug delivery systems have shown a tremendous potential for their ever-increasing role in health care. This has been mainly attributed to the favourable properties of lack of first pass metabolism effects of liver, better patient compliance, steady release profile and lowered pill burden in transdermal system. However, the transdermal technology have limitations due to the inability of a large majority of drugs to cross the skin at the desired therapeutic rates because of the presence of a relatively impermeable thick outer stratum corneum layer. This barrier posed by human skin limits transdermal delivery only to lipophilic, low molecular weight potent

Chetan N. Chauhan

1

SSPC, Mehsana

Microneedles in Drug Delivery system

2010-11

drugs.2 Researchers are trying to overcome this hurdle of poor permeability by the following means: 1) Chemical Means: Chemical means include the prodrug approach and/or use of chemical penetration enhancers that can improve the lipophilicity, and the consequent bioavailability. Chemical approach increases the lipophilicity and therefore increase the permeability of drugs across skin, whereas the physical approaches disrupt the upper layers of skin (stratum corneum) and reduce the resistance to the passage of drugs by creating minute holes in the skin that are large enough for the passage of smaller drug molecules but probably small enough not to damage the skin. 2) Physical Means: Physical means of transdermal drug delivery comprises of iontophoresis, electroporation, and sonophoresis.

On the other hand hypodermic needles are effective at bolus delivery of drugs, but cause pain during insertion and are not ideally suited for delivery over extended periods. Transdermal patches address these shortcomings.

1.2 Mechanism of skin penetration

Chetan N. Chauhan

2

SSPC, Mehsana

Microneedles in Drug Delivery system

2010-11

The thickness of the stratum corneum is approximately 10 to 20 microns. Therefore the minimum distance breached by minimally invasive transdermal systems must be about 20 microns. During tissue damage, adenosine triphosphate (ATP) is released from damaged cells. ATP is a ubiquitous cellular energy storage compound, which when released extracellularly potentiates input nociceptors (pain receptors) via direct stimulation of neurons. The effect appears to provide a local signal for tissue destruction, which in turn stimulates remedial physiological responses such as inflammation, etc. Pain may also result from tissue distension caused by drug injection, skin damage (and ATP release), or direct damage to nerves. Researchers are approaching the challenge of pain reduction by several techniques that are linked by one unifying strategy: limiting the extent of mechanical insult to skin to the first 50 microns of tissue. The mechanical stress–strain relationships of skin complicate the practical manipulation of the stratum corneum, epidermis, and upper dermal layers. The mechanics of skin, and other soft tissue such as arteries, muscle, and ureter, do not display single-value relationships between stress and strain and are therefore classified as inelastic materials. When tissues in this group are held at constant strain, they display stress relaxation, and when held at constant stress they creep.2, 3 Historically this relationship has required uniaxial application of mechanical force to breach skin (as in needle penetration), and has made sensation-free clinical manipulation (containment, preparation, and breach) of skin tissue difficult. In general the new skin breach technologies described in this communication require either direct uniaxial application of mechanical energy or thermally/mechanically induced changes in the physical properties or structure of skin. They differ from classical approaches in that they attempt to target the epidermis and upper dermal layers devoid of nosiceptors while gaining access to the circulatory and immune systems via the dermal capillary bed and epidermis, respectively. If successful, these approaches may greatly reduce or eliminate the mechanical stimulation of pain responses during delivery.

1.3 Microneedles as a system for minimally invasive transdermal delivery

Chetan N. Chauhan

3

SSPC, Mehsana

Microneedles in Drug Delivery system

2010-11

The development of microneedles for transdermal drug delivery came about as an approach to enhance the poor permeability of the skin by creating microscale conduits for transporting across the stratum corneum. Microneedle technology has been developed as an advanced technique for penetration of large molecular weight and/or hydrophilic compounds. Micron scale needles assembled on a transdermal patch have been proposed as a hybrid between hypodermic needles and transdermal patches to overcome the individual limitations of both the injections as well as patches. Microneedles are so called because they are of micrometre (millionths of a metre) scale. Microneedle technique has been successfully used to deliver a variety of compounds including macromolecules and hydrophilic drugs into the skin. As microneedle system bypasses the stratum corneum barrier of the skin, permeability enhancement of two to four orders of magnitude has been observed for small molecules like calcein and also for the relatively larger compounds like proteins and nanoparticles. The technology that are long and robust enough to penetrate the layer of the stratum corneum but short enough to avoid stimulating the nerves has the potential to make the transdermal delivery of drugs more effective. Therefore, the main aim of the microneedle technology is to combine the efficacy of the hypodermic needle with the convenience of a transdermal patch.

Figure 1: Layers of the Human Skin

In modern medical applications, there is a need for very small hypodermic needles that are economical to fabricate. Currently, the smallest needles commercially available, 30 Chetan N. Chauhan 4 SSPC, Mehsana

One of the largest barriers to the commercialization of technology is the cost and effectiveness of producing the technology. This decreases the chance that a contaminated solution may be inadvertently injected. Chauhan 5 SSPC. In order to be minimally invasive. 29. Molded needles which do not sacrifice the mold wafers lead to an increased cost savings.Microneedles in Drug Delivery system 2010-11 gauge needles. Traditional machining methods make it unfeasible to create needles with a diameter less than 300 mm.5 Chetan N. since the mold may be used over and over. 31 Therefore as tip radii decreases the stress imposed at a constant force increases and allows lower forces to be used for needle insertion. with submicron tip radii. In addition. Internal features of the microneedle. Microneedles on the other hand can be any size and geometry since they are defined lithographically. Needles are also designed to be extremely sharp. the small size of the needles cause less compression of the tissue as needles are inserted which leads to less compression of pain receptors and a decrease in insertion discomfort. The stress on the skin is inversely proportional to the area over which the force is applied. The small size of the microneedles also decreases the chance that the needle will be inserted close to a pain receptor. may also be used to effectively filter any foreign matter including bacteria from the fluid being injected. such as in-line microfilters.3. Microneedles are designed to be high performance minimally invasive conduits. the needles are designed to be as small as possible. This allows the needles to be effectively inserted into the skin. which are defined as part of the needle during a lithography step. This leads to a high quality reproducible device that opens up a new option for drug delivery applications that has few cost and fabrication barriers to being employed in the marketplace. The decrease in tissue damage also decreases the likelihood of infection occurring at the site of insertion. have a 305 mm outer diameter with a wall thickness of 76 mm. Mehsana . Since microneedles are produced in a highly parallel batch process there is great potential that the individual cost per needle is lowered. through which drug solutions may pass into the body.

Microneedles mechanically penetrate the skin barrier and allow the injection of any volume of fluid over time. Needles may also be used to transdermally sample body fluids for analysis. or chemical modifiers/enhancers all of which rely on decreasing the permeation barrier of the stratum corneum. Thus reduces the chances of pain. the outermost layer of the skin. Therefore. and a moderate fabrication cost Microneedles have a significant advantage over other approaches to transdermal drug delivery such as electroporation. Since drug is actively injected into a patient the dosage may be varied with time. Advantages & Disadvantages 2.1 Advantages The major advantage of microneedles over traditional needles is. but short enough not to puncture nerve endings. when it is inserted into the skin it does not pass the stratum corneum. This also allows complex drug delivery profiles. 4 The extreme miniaturization of fluidic devices enables portable devices for personalized medicine allowing continuous metabolite monitoring with drug delivery in response to Chetan N. As for microneedles they can be fabricated to be long enough to penetrate the stratum corneum. In addition. By fabricating these needles on a silicon substrate because of their small size. This allows precise localization of a high concentration drug solution in order to obtain effective absorption into the bloodstream or to stimulate particular clusters of cells in or near the skin. Microneedles have the ability to be precisely inserted to inject therapeutics any particular distance below the stratum corneum.Microneedles in Drug Delivery system 2010-11 2. Conventional needles which do pass this layer of skin may effectively transmit the drug but may lead to infection and pain. or injury. which occurs at a much faster rate than permeation of a solution across the skin. 5 In terms of processing there are also many advantages. infection. Chauhan 6 SSPC. ultrasonic delivery. by employing multiple needles or effective fluid control with mixing of solutions multiple drugs may be injected simultaneously specific to a patient’s personal needs. which is the outer 10-15 μm of the skin. Mehsana . The delivery is independent of the drug composition and concentration and merely relies on the subsequent drug absorption into the bloodstream. good reproducibility. thousands of needles can be fabricated on a single wafer. This leads to high accuracy. the drug delivery does not depend on transient delivery of therapeutics across the skin.

followed by a decay period as the drug is metabolized. the ability of microneedles to deliver therapeutics at a slow. controlled rate will make unnecessary the injection of a large bolus in the first place. Chauhan 7 SSPC. Mehsana . A bolus injection on the other hand leads to a rapid increase in blood concentration. Further. side effects associated with a high concentration bolus injection may be reduced. It allows patients more freedom in their treatment since they are no longer dependent on a facility to provide an outpatient service which often results in a bolus injection or a period of intravenous drug delivery while a patient is at the facility with little or no therapy between treatments. This has tremendous advantages over existing technologies. A bolus must be injected deeply into the tissue so it does not leak out the hole punched in the skin to deliver it. Microneedles make this form of therapeutic delivery unnecessary. It also allows a lower drug dosage to be injected over a longer period of time to maintain a constant blood concentration. By maintaining a constant blood concentration below toxic levels.Microneedles in Drug Delivery system 2010-11 metabolite levels. This time varying high concentration injection is often responsible for many side effects associated with a large number of therapeutics. often to toxic levels. Other advantages include: 8  Precise volumes of fluid moved rapidly and efficiently  Reduce the amount of drug used  Localize the delivery of potent compounds  Deliver otherwise insoluble or unstable therapeutic compounds  Reduce the chances of missing or erring a dose  Multiple injections can be avoided  Ability to administer the drug at the specific target site  Rapid onset of action  Possible self administration  Efficacy and safety comparable to approved injectable products  Improved patient compliance  Good stability Chetan N. This allows the delivery of therapeutics to a depth just below the stratum corneum and yet still above the nerve bed in the skin.

However. which may affect fluid delivery from the needles. surface modifications of silicon surfaces to reduce protein adsorption is an active area of research. Needles must be able to tolerate forces associated with insertion. with the migration of leukocytes to the injury site. constriction of capillaries may occur which may affect drug absorption. Namely. A silicon tip could be held rigid during Chetan N. Metal deposition also uses thin film processing techniques. polyethylene glycol (PEG).2 Current limitations of microneedles  Biological Response Future work needs to be performed to determine the biological response to microneedles.2  Breakage Versus Piercing Ability Due to the small size of microneedles.Microneedles in Drug Delivery system 2010-11  Cost effective 2. or plasma enhanced chemical vapor deposition (PECVD) of a Teflon-like fluoropolymer. Therefore. fibrous encapsulation is not expected because the needle is not inserted long enough for encapsulation to occur. Also. Metal and polymer needles on the other hand are not stiff so they can absorb larger stresses by plastically deforming. mechanical reinforcement may be required to keep the needle in place. Protein adsorption to the surface of the silicon will promote adhesion of leukocytes to the needles. However. intact removal and normal human movements if they are to be integrated into portable biomedical devices. During this time tissue edema may also occur. The first response to tissue distress from needle insertion is an inflammatory response at the insertion site. Since microneedles are designed for short term intradermal drug delivery. and therefore the metals are mechanically weaker than bulk hardened metals such as stainless steel. Some surface modifiers include: silicon carbide. Any of these coatings could be incorporated into needle fabrication to improve biocompatibility. materials such as silicon are strong and can easily pierce the skin but they are also brittle materials which fracture easily. strength and robustness are the major factors in determining the range of their applications. there is the chance that the body may try to extrude the needle by pushing it out over time. this ability also makes piercing the skin more difficult. A hybrid microneedle such as the parylene coated silicon needle appears to be most promising because it balances the advantages of each material. However. Mehsana . Chauhan 8 SSPC.

Chauhan 9 SSPC. This could consist of a microfabricated linear stepper motor or piezoelectric actuator.4 Chetan N. Another approach is to develop new polymer processing techniques which can be used to generate needles. but also have enough of the polymer in an amorphous phase to absorb mechanical stress. Piezoelectric actuators could also produce ultrasonic vibrations to decrease the amount of force required for insertion. Since the silicon tip is so much smaller than a whole needle it will experience smaller stresses and will be less likely to fracture. This could be accomplished by having a microfabricated insertion actuator to control the insertion force. In addition. Another way to take advantage of material limitations is to precisely control the stresses and forces the needle experiences. even if the tip does fracture it will be held together by the polymer coating. then it may be strong enough to allow needle insertion. Mehsana . If a semi-crystalline polymer is used.Microneedles in Drug Delivery system 2010-11 insertion and then released allowing the polymer tube to absorb the stress associated with movement. Both would allow precise positioning and direct insertion of the needles axially without any bending moment to deform or fracture the needles.

Pain relievers and Antibiotics Currently there are many medications. Mehsana . the needles have less chance of damaging tumors and causing the tumor to metastasize than larger needles.2 3. if cells are injected intravenously they are not always localized to tumors and the liver and spleen destroy a large majority of the cells. If the injection is directly into or around tumors (intralesionally). This is leading to a dramatic increase in antibiotic resistant bacteria strains. which must be injected at any one time. 2. By incorporating a longer treatment period with fewer side effects. they will be localized to attack the tumor. the patient may receive therapy over a longer period of time.2 Chemotherapy When a patient undergoes chemotherapy they often receive a fixed drug dosage in a session. which require several shots over a period of time. This more closely mimics the body’s natural regulation of sugar leading to fewer complications associated with the treatment. Analgesics such as Sufanta (Sufentanil Citrate). such as the Hepatitus B vaccine. it could shorten the overall number of treatments and recovery time to combat the disease.3 Vaccinations. Also. Quite often. Patients also take antibiotics until their symptoms subside but then do not finish their pills. There are also many cell based therapies which could be delivered continuously through a microneedle. Antitumor effector cells which attack melanomas have been extensively studied. Sublimaze (Fentanyl Citrate). By delivering the chemotherapeutic agents continuously through a microneedle. so a patient can receive continuous therapy. and Dilaudid (Hydromorphone) have doses of less than 3 Chetan N.Microneedles in Drug Delivery system 2010-11 3. Chauhan 10 SSPC. 9 3. people will receive the first or second shot but fail to return for subsequent shots. It could also lead to a lower dosage of the toxic drugs. The microneedles do very little tissue damage. Lowering chemotherapy dosages may lead to an overall lessening of the severity of side effects. However.1 Diabetes Microfluidic devices and sampling through a microneedle allows a feedback loop between a sensor which monitors the glucose levels in the body and a delivery module which can deliver insulin in a time varying fashion as needed. These cells have been shown to reduce the size of both solid and hematologic human tumors. Applications 3.

This action will cause the microneedle to penetrate the skin and drain a very small volume of blood(less than 100 nanolitres) into the disposable. The needle could be used to breach blood vessel walls in order to inject precise dosages of drugs to the surrounding tissue. They may be used to inject clot-dissolving drugs directly into a coronary arteriosclerosis such as alteplase (a genetically engineered form of one of the body's own plasminogen activator proteins) or Streptokinase (a plasminogen activator produced by streptococcus bacteria)20 3.5 Blood glucose measurements Recent advancement involves the instrument in which a patient will load the cartridge into the electric monitor and simply press the monitor against the skin. Microneedle therapy is a way to rejuvenate the skin without destroying the epidermis. Chemical agents in the disposable react with the glucose in the blood to give a colour. By delivering these pain relievers continuously. and delivered as needed by the patient. 2 3. proteins or nanoparticles that would encapsulate a drug or demonstrate the ability to deliver a virus for vaccination. Mehsana . Delivery of all of these medications in a continuous fashion greatly simplifies the therapy. In addition. This leads to youthful looking skin. Chauhan 11 SSPC. The powder would be reconstituted with water. The blood glucose concentration will be measured either electrochemically or optically and the resultant value displayed on the monitor.6 Skin therapy Microneedle skin therapy is s till in testing development but it seems to show much promise. The only Chetan N. the drug could be kept in a lyophilized powder. insulin. The collagen strands that are destroyed create more collagen under the epidermis.Microneedles in Drug Delivery system 2010-11 ml per hour.4 Catheterized Instrumentation Microneedles may be placed on the end of a catheter for intervascular delivery. It is similar to laser treatment but with less damage. The use of hollow microneedles allows the delivery of medicine. a patient can obtain the benefits of the analgesic without being hindered by a intravenous drip.38 3. An assay of needles can be designed to puncture the skin and deliver the drug much like a nicotine patch for individuals who are trying to quit smoking. A patch device could be applied once a day or every few days and supply the patient with enough medication for a given time period. dosed. Microneedles penetrate the epidermis and break away old collagen strands.

non sun-sensitivity upon treatment. The needles used to penetrate the eye only go as deep as half a millimetre into the eye tissue. lower cost. 39  Cell manipulation.Microneedles in Drug Delivery system 2010-11 disadvantage of this method is that it causes blood oozing. they can be applied to the eye using only local anaesthetic.7 Eye Treatment Microneedles can be used to deliver drugs to the eye through a minimally invasive procedure. Other applications of microneedles include: 26. This means that the needles do not penetrate far enough to cause as much damage as traditional needles. This technique has the potential to revolutionise the way of treating common eye conditions such as glaucoma. 24. Chauhan 12 SSPC. Chetan N. which laser treatments do not. Mehsana . It does however have advantages such as: increased collagen.  Interconnection between microscopic and macroscopic fluidic systems. As a result.20 3. macular degeneration and diabetic retinopathy. no breaking of the epidermis. and ease of application.

28. With the goals of delivering genetic materials to cells. a photoresist is placed onto a silicon-dioxide coated wafer. These microneedles tend to have sharp tips and have good mechanical strength. They can be mass-produced at low cost.Microneedles in Drug Delivery system 2010-11 4. Classification – Types & Approaches Microneedles can be classified into various types as shown below: 4. 15. Using a spin casting method.1 Types of Microneedles: Figure 2: Classification of Microneedles 4. 41 Chetan N. These are of various types and as shown above. 27 In the early phase of microneedle development. 22 4. The photoresist is then removed and the wafer is anisotropically wet-etched in potassium hydroxide solution to create arrays of pyramidal probes. these microprobles are ten to hundreds of microns in height and have very sharp tips.1 Silicon Microprobes 18. pyramidal silicon microprobes were found. Chauhan 13 SSPC.1. The transferred pattern is then etched into the silicon dioxide masking layer. the wafer is then brought in contact with a photomask and is exposed to UV light. Mehsana .1 Solid Microneedles Solid microneedles are designed to create micron-size pores in the tissue. can be fabricated from various materials: 9. which act as direct pathways allowing drug molecules or particles to transport into the tissue.1.1.

The wafer is etched with an oxygen/fluorine plasma mixture to create the high aspect ratio silicon microneedles. The fabrication steps include depositing a chromium masking layer onto a silicon wafer. their unifying characteristics include being very sharp and usually had fairly simple fabrication schemes. The penetration of microneedles through the upper layer of skin (stratum corneum) created direct pathways for molecules that would not normally be able to diffuse through skin barrier due to size or water solubility. Chauhan 14 SSPC.2 Silicon microneedles Figure 3: Silicon Microneedles The simplest forms of the microneedles are solid spikes. 43  Silicon is abundant. and of high purity and perfection  Silicon processing is highly amenable to miniaturization  Photolithographic patterning allows for rapid evaluation of design ideas  Batch-fabrication results in high volume manufacturing at low unit cost  Silicon is also a biocompatible material (essential for blood testing) Henry et al. Besides being solid. (1998) conducted the first study to determine if silicon microneedles could be used to increase transdermal drug delivery.1. The study showed that the Chetan N. In addition.1. Kaushik et al. Mehsana . These needles were used to create micron-scale holes in the skin through which molecules can be more easily transported. Using a deep-reactive ion etching method. inexpensive.16.Microneedles in Drug Delivery system 2010-11 4. Silicon is preferred material for fabrication because it has the following characteristics. (2001) tested the pain level associating with the insertion of silicon microneedle arrays into human skin in vivo. patterning it using photolithography into dots with the size of the desired needle base. silicon microneedles were fabricated.

1. this comes at the cost of reduced sharpness at the tip of the microneedle due to low modulus and yield strength of the polymers. A solution of insulin was placed on top of the microneedle arrays and left in place for 4 h.2 Hollow Microneedles Skin permeability can be dramatically increased by the holes created from solid microneedles insertions. The resulting needle structures are bent out of the sheet. Chemically. In comparison to silicon counterparts. Rather than simply piercing the skin to create pathways for therapeutic molecules. biodegradable polymers allow additional functionality of the microneedles themselves. Mehsana . The fabrication of hollow microneedles that allow transport through the hollow shaft of the needle was based on this need. The needles can be in either single microneedles or multi-needle array form. the microneedles themselves become drug depots implanted in the skin.1. Unfortunately.2.  Minimize the cross-contamination of the deliverables and its surrounding.1.1. it is still necessary to have more controlled and reproducible transport pathways to delivery drugs into the tissue. Martanto et al (2004) used stainless steel solid microneedles to deliver insulin to diabetic hairless rats in vivo.1. Chetan N. is relatively inexpensive and can be fabricated with ease. stainless steel microneedles can be made by a laser-cutting technique.18. 34 4.  Deliver material in a convective transport fashion (for example. polymer microneedles offer the mechanical advantage of improved resistance to shear induced breakage. 4.3 Metal Microneedles Metal is considered a better alternative material for microneedles since it has good mechanical strength.Microneedles in Drug Delivery system 2010-11 microneedles caused an insignificant amount of pain compared to conventional hypodermic needle insertion. and no subjects reported any adverse reactions. The inclusion of a hollow lumen in a microneedle structure expands its capabilities dramatically and can offer the following advantages:  The ability to deliver larger molecules and particles. Chauhan 15 SSPC. pressure-driven flow) instead of passive diffusion. and electropolished. Needle arrays were inserted into the rat skin using a high-velocity injector. Solid. However. blood glucose level steadily decreased by as much as 80% compared to the control subject. 36 4. Over this time period.4 Polymer microneedles Polymers have also been used to form arrays of microneedles.

10.2. and a larger circular mask was patterned on the front side and underetched to create the tapering effect of the microneedle. 18 Chetan N. Chauhan 16 SSPC. Silicon nitride was then deposited. As expected these benefits come at the cost of increased complexity. Figure 4: Hollow Microneedles 4. After both silicon dioxide and silicon nitride layers were removed. The fabrication steps include coating silicon dioxide on a silicon wafer. symmetrical and asymmetrical needle structures can be achieved by adjusting the relative position of the isotropic and anisotropic etching axis.Microneedles in Drug Delivery system 2010-11 A variety of hollow microneedles has been fabricated and has demonstrated success in transdermal drug delivery.1. The hollow silicon structures have been created in three-dimensional arrays out of the substrate plane. Mehsana .1 Silicon hollow microneedles The most logical technique for the inclusion of a lumen in the silicon spikes presented is the addition of an etching step to form a fluidic channel using standard photolithography and isotropic-anisotropic etching combination. patterning the backside of the wafer and etching through the wafer stopping on the upper oxide layer to define the needle lumen.

The results indicated an up to 70% drop in blood glucose level over a 5-h period after the insulin was administered. 21 4. beveled-tip microneedles. Martanto et al. Coupling with an insertion apparatus. The study reported that partial retraction of the needle within the tissue increased delivery flow rate 10-fold compared to that without retraction. A thin coating of metal was then electrodeposited onto the molds to produce the desired microneedles. Mehsana .1. Infusion rates could also be increased at a greater insertion depth. Using single. 18. (2006) examined the effect of different experimental parameters on microinfusion through hollow glass microneedles into human skin in vitro. Tapered hollow needle was fabricated either by obtaining a mold from a silicon master or laser drilling tapered holes into polymer sheets. glass microneedles can be quickly produced with different geometric parameters for small-laboratory use.e.2. a larger infusion pressure.2. The needles had a tip radius of 60 μm and were inserted into the tissue of a depth of 500-800 μm. the insertion depth of the needle into the tissue can be controlled precisely. Thin glass capillaries were placed within a micropipette puller. 21 Chetan N. 44 McAllister et al.2 Metal hollow microneedles Hollow metal microneedles can be creating using laser micromachining (Davis 2003). a beveled-tip instead of a blunt tip and the addition of hyaluronidase enzyme. followed by electrodeposition of a thin metal coating onto the mold. Chauhan 17 SSPC. that is not tapered) are fabricated using molds with cylindrical holes created either by reactive ion etching (RIE) through silicon wafers or lithographically defining holes in SU-8 photoresist polymer.Microneedles in Drug Delivery system 2010-11 4. Microneedles with straight walls (i. which allowed ease of needle insertion into the tissue. and could have either a blunt or a beveled tip. having a larger drug loading dose and permitting visualization of the deliverables.3 Glass hollow microneedles Hollow. These needles are physically capable of insertion into the tissue without breaking. 40.1. (2003) used single glass microneedles inserted into the skin of diabetic hairless rats in vivo to deliver insulin during a 30-min infusion period.

The lengths of these needles were ranging from 150 μm to 2 mm. 37 Microneedles made out of maltose mixed with ascorbate were developed for transdermal delivery of drugs. and finally producing replicate microneedles by melting biodegradable polymer formulations (i.3 Other types of microneedles Besides solid and hollow microneedles. poly-lactic acid.5 Transport can occur via diffusion or possibly iontophoresis if an electric field is applied. various other types of microneedles were fabricated using different materials such as biodegradable polymers. Because of their biocompatible nature with the tissue. One major reason for loss of biosensor activity is through the settling of large molecular weight compounds onto the sensor and affecting senor signal stability. A microdialysis microneedle is fabricated that is capable of excluding large MW compounds 19 4. The tests showed the sugar-based microneedles spontaneously dissolved and released ascorbate into epidermis and dermis of human skin. A clinical experiment was performed to test the biosafety and basic tolerance of these microneedles. or poly-lactic-co-glycolic acid. Unlike solid and hollow microneedles. creating inverse structures from the master molds. These include: 4.1. The resulting microneedles can be loaded with molecules. DNA or proteins. PLGA) into the molds. Insulin delivery using poke and patch approach: Chetan N.e. microneedles can also be used as a biosensor. No dermatological problems were reported.2 Delivery Strategies A number of delivery strategies have been employed to use the microneedles for transdermal drug delivery. 30. polymer microneedles themselves serve as the drug implants after insertion into the tissue.Microneedles in Drug Delivery system 2010-11 4. PLA. polysilicon and sugar with additional functionalities. Chauhan 18 SSPC. These needles were fabricated by initially making master structures using lithography-based methods. biodegradable polymer microneedles were developed. drugs.2.1 Poke and patch approach This method uses microneedles to make holes and to apply a transdermal patch to the skin surface. Mehsana . Aside from being a drug delivery tool.

2. 5. 20 4. A solution of insulin was placed on the top of the microneedle array and left in place for 4 hours. Microneedle arrays were inserted into the skin using a high velocity injector and shown by embed fully within the skin.2. Insulin placed on the skin surface without microneedles did not have any significant effects. 20 4. the entire drug to be delivered is on the needle itself. There is no drug reservoir on the skin surface. Over this time period blood glucose levels steadily decreased by as much as 80%. Mehsana .5 Protein vaccine delivery using coat and poke method Examination of microneedles to deliver ovalbumin as model protein was done using coat and poke method. Chetan N.2 Coat and poke Another approach is coat and poke where the needles are first coated with the drug and then inserted into the skin.3 Biodegradable microneedles It involves injecting the drug through the needle with a hollow bore. Antigen release from the needle surface was found to occur quickly where upto 20mg could be released in five sec. This approach is more reminiscent of an injection than a patch. A variation on this method is the dip and scrape where microneedles are first dipped into the drug solution and then scrapped across the skin surface to leave behind the drug within micro abrasions created by microneedles. Chauhan 19 SSPC.Microneedles in Drug Delivery system 2010-11 Insulin was delivered to diabetic hairless rat’s in-vivo.

chemical and vibration sensors. which is the photoactive ingredient Chetan N. the field of MEMS became distinct division from microelectronics and commercial products became available.  The resist layer is then selectively exposed to radiation such as ultraviolet light. Microfabrication MEM is an acronym for Microelectromechanical systems. Mehsana . These gained popularity in the 1960’s in the microelectronics industry when sensors were integrated with the electronic circuits. microactuators for read/write heads and all-optical switches that reflect light beams to the appropriate output port. pacemakers and games. Photo resist materials consist of three components:  A matrix material (also known as resin).  A layer of photo resist (PR) material is first spin-coated on the surface of the wafer. exposing the corresponding areas of the underlying layer. Chauhan 20 SSPC.  Depending on the resist type.  After exposure. mask. vehicle control. the lithography process generally consists of the following steps. 45 Simply put. or x-rays. light reflectors and switches as well as accelerometers for airbags.13. with the exposed areas defined by the exposure tool.1 General fabrication of microneedles The various patterns used in depositing layers and doping regions on the substrate are defined by a process called lithography. 35 5. of them selective The areas with no resist material left on top are then subjected to additive or subtractive processes. the PR layer is subjected to development which destroys unwanted areas of the PR layer. They are used to make pressure. Slowly. electrons. allowing the deposition or removal of material on the substrate. or computer data. temperature. the development stage may destroy either the exposed or unexposed areas. These are systems that have either mechanical or electric devices typically containing sub millimeter feature sizes. which provides body for the photo resist  The inhibitor (also referred to as sensitizer). The technology is also used to make inkjet print heads.Microneedles in Drug Delivery system 2010-11 5.

masking a region for removal and stripping away the On a fundamental level these processes include deposition of the materials (additive). which keeps the resist liquid until it is applied to the substrate. depositing the material and removing material the mask.Microneedles in Drug Delivery system 2010-11  The solvent. Mehsana .1 Etching Processes Definition of Etch: A category of lithographic processes that remove material from selected areas of a die.1. Most lithography based MEMS fabrication processes are either additive or subtractive. In general the following processes are used in the block building processes. Examples are nitride etch and oxide etch Figure 5: Outline of etching process Chetan N. Chauhan 21 SSPC. These are described below: 5. for deposition. etching of the materials (subtractive) thus enabling the process of patterning.  Patterning and masking a region for deposition.  Depositing a material.

Microneedles in Drug Delivery system 2010-11 There are two basic categories of etching processes:  Wet etching  Dry etching.1. the material is sputtered or dissolved using reactive ions or a vapor phase etchant. Table 1: Comparison of Dry and Wet etching processes 5. usually in specific patterns defined by photoresist masks on the wafer. Materials not covered by these masks are 'etched away' by the chemicals while those covered by the masks are left almost intact. In the former. the material is dissolved when immersed in a chemical solution. In general. In the latter. Chetan N.14. a wet etching process involves one or more chemical reactions that consume the original reactants and produce new species. however.1.1 Wet Etching Wet Etching is an etching process that utilizes liquid chemicals or etchants to remove materials from the wafer.15 A simple wet etching process may just consist of dissolution of the material to be removed in a liquid solvent. Chauhan 22 SSPC. without changing the chemical nature of the dissolved material. Mehsana . A basic wet etching process may be broken down into three basic steps:  Diffusion of the etchant to the surface for removal.

with dimensions and angles being extremely accurate.Microneedles in Drug Delivery system 2010-11  Reaction between the etchant and the material being removed. will have different etching rates depending on the crystallographic orientation of the substrate. a good selectivity can often be obtained. Long and narrow holes in a mask will produce v-shaped grooves in the silicon. vertical only) is said to be 'completely anisotropic'.  Diffusion of the reaction byproducts from the reacted surface Due to the chemical nature of this etching process. Mehsana .. Therefore. The surface of these grooves can be atomically smooth if the etch is carried out correctly. i..7° walls. Chauhan 23 SSPC.g. etching a rectangular hole in a (100)-Si wafer will result in a pyramid shaped etch pit with 54. An etching process that is not isotropic is referred to as 'anisotropic. Wet etching is generally isotropic. it proceeds in all directions at the same rate. Lateral etch ratio (RL) = Horizontal etch rate Vertical etch rate Isotropic Etching: RL = 1 Anisotropic Etching: 0<RL<1 Directional Etching: RL=0 Chetan N. where etching progresses at the same speed in all directions.' An etching process that proceeds in only one direction (e. where Si <111> planes etch approximately 100 times slower than other planes (crystallographic orientations). instead of a hole with curved sidewalls as it would be the case for isotropic etching. This is known as anisotropic etching and one of the most common examples is the etching of silicon in KOH (potassium hydroxide). which means that the etching rate of the target material is considerably higher than that of the mask material if selected carefully. Some single crystal materials.e. such as silicon.

Microneedles in Drug Delivery system 2010-11 Figure 6: Illustration of Isotropic. the etched film is said to have 'undercut' the mask. When an isotropic etchant eats away a portion of the material under the mask. and so on until the material is consumed. Chauhan 24 SSPC.Anisotropic and directional etching Reduction-oxidation (redox) reactions are commonly encountered in wafer fab wet etching processes. i. Mehsana . which is then dissolved. in order to create the desired feature on the wafer. The amount of 'undercutting' is a measure of an etching parameter known as the 'bias. an oxide of the material to be etched is first formed.e. leading to the formation of new oxide.. Thus. Smaller RL results in smaller bias. which is again dissolved.' Bias is defined as the difference between the lateral dimensions of the etched image and the masked image or simply it is the difference in the lateral dimensions between the features on the mask and the actually etched pattern. Chetan N. the mask used in etching must compensate for whatever bias an etchant is known to produce.

wet etching has its own disadvantages. but the mask and the substrate (the surface under the material being etched) as well. Selectivity.  High throughput. is measured as the ratio between the different etch rates of the etchant for different materials.  Higher safety risks due to the direct chemical exposure of the personnel.  Problems related to incomplete or non-uniform etching.e.Microneedles in Drug Delivery system 2010-11 Another important consideration in any etching process is the 'selectivity' of the etchant. and  Excellent selectivity in most cases with respect to both mask and substrate materials Automated wet etching systems add even more advantages:  Greater ease of use. The 'selectivity' of an etchant refers to its ability to remove only the material intended for etching. Mehsana . it has found widespread use because of its following advantages:  Low cost.  Problems related to the resist's loss of adhesion to the substrate.  High cost of etchants in some cases. An etchant not only attacks the material being removed. Despite the resolution limitations of wet etching. These include the following:  Limited resolution.. its etching rate for the film being etched must be much higher than its etching rates for both the mask and the substrate. Of course. Chauhan 25 SSPC. Thus. i.  Problems related to the formation of bubbles which inhibit the etching process where they are present. S. and  Better efficiency in the use of etchants.  High reliability. while leaving the mask and substrate materials intact.  Higher reproducibility. a good etchant needs to have a high selectivity value with respect to both the mask (Sfm) and the substrate (Sfs). Chetan N. like any process.

be wet-etched using a variety of HF solutions. 5. which in turn is dissolved away by the HF. Silicon dioxide may. The over-all reaction is as follows: Si + HNO3 + 6 HF H2SiF6 + HNO2 + H2 + H2O. by exposing the material to a bombardment of ions (usually a plasma of reactive gases such as fluorocarbons. Again.2 Dry Etching Dry Etching is an etching process that does not utilize any liquid chemicals or etchants to remove materials from the wafer. The nitric acid consumes the silicon surface to form a layer of silicon dioxide. chlorine. generating only volatile by products in the process.1. Dry etching may be accomplished by any of the following:  Through chemical reactions that consume the material. boron trichloride. oxygen. sometimes with addition of nitrogen. and water. as mentioned above. using chemically reactive gases or plasma (plasma etching)23  Physical removal of the material.Microneedles in Drug Delivery system 2010-11 Silicon (single-crystal or poly-crystalline) may be wet-etched using a mixture of nitric acid (HNO3) and hydrofluoric acid (HF).1. acetic acid. as more Al2O3 is formed simultaneously to keep the cycle going. the nitric acid consumes some of the aluminum material to form an aluminum oxide layer. Water-diluted HF with some buffering agents such as ammonium fluoride (NH4F) is a commonly used SiO2 etchant formulation Wet etching of aluminum and aluminum alloy layers may be achieved using slightly heated (35-45 deg C) solutions of phosphoric acid. (Reactive ion etching) Dry etching refers to the removal of material. Mehsana . usually by momentum transfer (physical sputtering and ion beam milling)  A combination of both physical removal and chemical reactions. argon. The main purpose of developing dry etching is to achieve anisotropic etching. This oxide layer is then dissolved by the phosphoric acid and water. typically a masked pattern of semiconductor material. Chauhan 26 SSPC. Chetan N. nitric acid. The over-all reaction for this is: SiO2 + 6 HF  H2 + SiF6 + 2 H2O. helium and other gases) that dislodge portions of the material from the exposed surface.

and  Diffusion of the desorbed byproducts into the bulk of the gas.  Desorption of the byproducts from the surface. Mehsana .  High selectivity against etching the material under the layer being etched. The reactive species used in dry chemical etching must be selected so that the following criteria are met:  High selectivity against etching the mask material over the layer being etched. basically consists of the following steps:  Generation of reactive species in a plasma.  Adsorption of these species on the surface. forming volatile byproducts. Chauhan 27 SSPC.Microneedles in Drug Delivery system 2010-11 Figure 7: Illustration of dry etching Plasma etching. a purely chemical dry etching technique.  Occurrence of chemical reactions between the species and the material being etched.  Diffusion of these species to the surface of the material being etched. Chetan N.

chemical reactions can attack in the horizontal direction and consume a portion of the material covered by the mask..  They should also allow a safe. dislodging these atoms in the process. Reactive ion etching is one such process that involves both physical and chemical means to remove material. most etching techniques that employ purely chemical means to remove the material (whether through wet or dry etching) do not exhibit high anisotropy. then dry etching techniques that employ physical removal of material must be considered. Unfortunately. One such technique is physical sputtering. the substrate is placed inside a reactor in which several gases are introduced. A good balance between isotropy and selectivity may be achieved by employing both physical sputtering and chemical means in the same dry etching process. 19  Reactive ion etching (RIE) Reactive ion etching (RIE). which involves purely physical removal of material by bombarding it with highly energetic but chemically inert species or ions.  Excellent etching uniformity. and automation-ready etching process. Such bombardment with energetic ions dislodges atoms from the material (just like purely physical sputtering). These energetic ions collide with atoms of the material as they hit the material's surface. This is because chemical reactions can and do occur in all directions. physical sputtering has never become popular as a dry etching technique for wafer fabrication. Thus. is sometimes referred to as reactive sputter etching (RSE). i. Chauhan 28 SSPC. such a purely physical process is also non-selective. Targeting the layer to be etched with incident ions that are perpendicular to its surface will ensure that only the material not covered by the mask will be removed. consists of bombarding the material to be etched with highly energetic chemically reactive ions. in effect achieving material removal by sputtering. breaking the Chetan N.Microneedles in Drug Delivery system 2010-11  High etch rate for the material being removed. Mehsana . since the mask is also directly hit by the bombarding species.18. a phenomenon known as 'undercutting. clean. it also attacks the mask layer covering the material being etched. Plasma is struck in the gas mixture using an RF power source. Unfortunately. In reactive ion etching (RIE).e. For this reason.' If maximum anisotropy is of utmost concern.

forming another gaseous material. Mehsana . gas flow rate and the type of reactant gas or their combinations used. Chauhan 29 SSPC. In the 1st Variation.45  Deep reactive ion etching (DRIE) A special subclass of RIE which continues to grow rapidly in popularity is deep RIE (DRIE). the etch cycle is as follows: (i) SF6 isotropic etch. Chetan N. The degree of anisotropy and selectivity depends on a larger number of parameters such as etch. In this process. In the 2nd variation. By changing the balance it is possible to influence the anisotropy of the etching. If the ions have high enough energy. steps (i) and (iii) are combined. There is also a physical part which is similar in nature to the sputtering deposition process. This is known as the chemical part of reactive ion etching. (ii) C4F8 passivation. selectivity is a chemical phenomenon that occurs on the surface to be etched due to the chemical reaction of the active radicals and the neutral species present in the plasma thereby producing loosely bound compound. (iii) SF6 anisoptropic etch for floor cleaning. where two different gas compositions are alternated in the reactor. radio frequency (RF) power. since there are many parameters to adjust.9–12 Anisotropy is attributed to ionic bombardment which is basically a physical phenomenon. It is a very complex task to develop dry etch processes that balance chemical and physical etching. The ions are accelerated towards. the surface of the material being etched. This compound is then pumped away from the etched surface due to physical bombardment of energetic ions present in the plasma. On the other hand. they can knock atoms out of the material to be etched without a chemical reaction. named after the German company Robert Bosch which filed the original patent. RIE is a chemical-physical etching process capable of providing highly anisotropic etch profiles with good selectivity. Currently there are two variations of the DRIE. and react at. since the chemical part is isotropic and the physical part highly anisotropic the combination can form sidewalls that have shapes from rounded to vertical. pressure. The primary technology is based on the so-called "Bosch process". Plasma etching process was optimized for photo-resist removal using oxygen plasma and the etching end point was determined by in-situ monitoring of the emission spectral lines of different species present in the plasma. etch depths of hundreds of micrometres can be achieved with almost vertical sidewalls.Microneedles in Drug Delivery system 2010-11 gas molecules into ions.

Ti Tungsten Refractory Silicides TiN. The C4F8 creates a polymer on the surface of the substrate. and etch rates are 3-4 times higher than wet etching. Mehsana . CCl4+Cl2.1. In addition to sputter-removal. SF6.it achieves the required anisotropy (by means of sputter-removal) and the required selectivity (through chemical reactions). As a result. etching aspect ratios of 50 to 1 can be achieved. but only on the horizontal surfaces and not the sidewalls. Cu. the bombarding ions used in RIE were chosen so that they will chemically react with the material being bombarded to produce highly volatile reaction byproducts that can simply be pumped out of the system. Chauhan 30 SSPC. BCl3+Cl2 Fluorinated Gases Fluorinated plus Chlorinated Gases (w/ or w/o oxygen) Same as Al Etch Table 2: Examples of Gases Used in the RIE of Common Wafer Materials 5.Microneedles in Drug Delivery system 2010-11 Both variations operate similarly. The polymer is immediately sputtered away by the physical part of the etching. etc. The process can easily be used to etch completely through a silicon substrate. TiC Examples of Gases Used in the RIE CF4. Al doped with Si. Cl2.2 Deposition processes Chetan N. BCl3. (w/ or w/o oxygen) CCl4. CCl3F.19 Material to be Etched Polysilicon Al. and the second gas composition (SF6 and O2) etches the substrate. it builds up on the sidewalls and protects them from etching. This is the reason why RIE is widely used in wafer fabrication . Since the polymer only dissolves very slowly in the chemical part of the etching. Table 1 presents some examples of the process gases usually employed in the reactive ion etching of common wafer materials.

However in general it refers to the deposition of the organic or inorganic substances by reactions driven externally by applying potential (electroplating) or by in situ potential generated by chemical reactions (electrode-less or electrode plating) 5. Another area of interest with regard to electroless plating is the ability to plate onto insulating surfaces since the necessicity of the substrate serving as an electrode is obviated. Electroless plating of nickel used sodium hypophosphate as the reducing agent. nickel chloride.2. The Chemical Vapor Deposition Process is a very intricate process which takes place in several steps. Physical Vapour Deposition (PVD) and Chemical Vapour Deposition (CVD).1. Metal microneedles are formed by the deposition of nickel into molds. Chetan N. and boric acid and the reaction governing the deposition is: Ni 2+ + 2e.1 Electrodeposition It is the deposition of the material initiated and propogated by an electrochemical reaction. This includes electroplating nickel to form microneedle itself and electroless plating of seed layer to polymer molds.2. Mehsana . An external power supplies the electrons to reduce the nickel species. 5. The bath is a solution of nickel sulfate.1. Ni0 The anode is typically nickel foil which is dissolved from its ground state to replenish the ionic species consumed in the bath. Chauhan 31 SSPC.2 Specific Processes used in the Fabrication of Microneedles. 5. The part is immersed in an electrolyte bath and an external power source supply electrons for the reduction to occur. Sputter deposition. 5. The anode can serve as both a electrode for carrying the current as well as a source for replenishing the ions in the electrolyte bath. The first practical electroplating bath was created in 1843.Microneedles in Drug Delivery system 2010-11 Commonly used deposition processes are: Electrodeposition.2.1. However a chemical reducing agent is present in the solution instead of electricity. Most commonly the term is used to identify the deposition of various metals on to a substrate via electroplating.2 Electroplating The general principle guiding electroplating is the reduction of a metal species onto a desired part.3 Elecroless plating It occurs in a manner similar to electroplating as described above.

2 Laser Micro Machining Three-dimensional arrays of hollow and solid microneedles have been fabricated using laser micromachining techniques. In general. The mechanical stability and insertion characteristics of hollow microneedles were tested. the metal structures serve as the mould for the polymeric parts. Galvanoforming and Abforming. electroplating and molding. and titanium. the process includes the following procedure:  To form a mould using lithography  Electroplate into this mould to form a metallic structure  To remove the mould and reveal a completed structure. Mold materials included polyimide.18. Where lithography offers batch fabrication. Mehsana . 19 5. Chauhan 32 SSPC.Microneedles in Drug Delivery system 2010-11 5. polyethylene terephthalate. dry step is often reason enough to adopt laser fabrication technique. In the past this was accomplished using polymethyl methacrylate and X-ray lithography but later this technique was later broadened to include many other types of lithography and mould materials.2. While standard lithography offers patterning in the lateral dimension. Ultraviolet (UV) and infrared (IR) laser machining was used to create molds for electrodeposition of metals. This translates into lithography. The force necessary for insertion was found to vary linearly with the interfacial area of the microneedle. laser ablation requires each feature to be patterned individually.  If the desired parts are polymeric. The primary disadvantage of laser patterning is the serial nature of the process.19 Chetan N.2. IR laser machining was also used to cut solid needle designs directly from stainless steel. the LIGA process offers projection in the vertical direction. The ability to crete three dimensional structures of similar quality in a single .1 LIGA LIGA is a german acronym that stands for Lithographic.

the current state of development is largely focused on developing scaleable microfabrication processes and efficacious architectures for the microdevice. Integration of the microdevice in a larger system that will be handled by the practitioner and connection to a fluidic system and reservoir for solution or dry-powder-based formulations is not a trivial undertaking.3 Packaging of Microneedle-Based Drug Delivery Systems Handling by patients or healthcare workers in the macroscopic world is an inherent challenge confronting microdevices that perform biomechanical functions directly on tissue. Mehsana . This is especially true of hollow highaspect-ratio parts like microneedles. Chauhan 33 SSPC.Microneedles in Drug Delivery system 2010-11 5. It is not unreasonable to assume that device package as a whole “enables” the use of the microdevice.2 Chetan N.1. and that the entire drug delivery package will need to be developed for testing well in advance of clinical trials. However. Although advances in surface-smoothing and coatings technologies are likely to improve device robustness. it is likely that the packaging of the microdevice will play a most important role in the development of procedures for their use. The current state of microfabrication technology allows the construction of precise architectures with the limitation of physical fragility.

reproducible manner that optimizes bioavailability and efficacy without significant discomfort for the patient. The array has an area of up to 8 cm2 and contains as many as 300 micro projections per cm2 with individual micro projection lengths of <200 µm.1 Macroflux technology Macroflux transdermal patch technology has been developed to deliver biopharmaceutical drugs in a controlled.Microneedles in Drug Delivery system 2010-11 6. Chauhan 34 SSPC. Drug is absorbed by the micro capillaries for systemic distribution. The maximal adhesive patch size is 10 cm2. The rate of absorption is promoted by the high local drug concentration around the micro projections and the large surface area provided by the patch array. the drug-coated micro projections penetrate through the skin's barrier layer into the epidermis. Chetan N. many commercial technologies have come into the market including the Macroflux technology. When the patch is applied to the skin. Mehsana . h-patch. Macroflux technology incorporates a titanium micro projection array affixed to a polymeric adhesive back. Micro-Trans and many more (as shown in the table) Table 3: Commercial Microneedle technologies 6. Commercial Microneedle Technology A decade after the first microneedles were reported. A coating process is used to apply drug to the tip of each micro projection in the array.

This reusable. potent biopharmaceuticals. The patch-application system is easy to use. it self-actuates to release the patch with the correct force and timing (in milliseconds). only a small percentage of drug is actually delivered from the patch reservoir into the skin. Chauhan 35 SSPC. In the current environment of cost containment and disposal risks. In order to maximize the efficiency of drug incorporation into the patch and to ensure the precision of drug transport to the skin. requiring no special training. a coating process has been developed that applies the drug formulation just on the tips of the Macroflux microprojections. this is undesirable. Figure 8: Figure illustrating ease of application of Macroflux  Efficient Tip Coating Process With many traditional patch technologies. When the applicator is pressed onto the skin. spring-loaded applicator ensures reproducible patch application and uniform penetration of Macroflux microprojections through the stratum corneum layer. particularly for the more expensive.Microneedles in Drug Delivery system 2010-11 Following are the salient features of Macroflux:  Systemic Approach The Macroflux patch and application system are shown in Figure below. Chetan N. Mehsana .

time to maximum plasma drug concentration (Tmax) of hGH occurred sooner with hGH coated on Macroflux patches than with subcutaneous injection.4 In addition. Chauhan 36 SSPC. and bioavailability was similar Scientists at ALZA have also demonstrated that intracutaneous Macroflux delivery of a 45kDa protein antigen provided a better vaccine response than an equivalent dose delivered by intramuscular or subcutaneous injection in preclinical studies. Drug-coated Macroflux microprojections penetrate the skin and deliver Chetan N. Mehsana .Microneedles in Drug Delivery system 2010-11  Rapid Delivery & High Bioavailability Macroflux patches can provide rapid and efficient delivery of therapeutic agents. The system is minimally invasive and well tolerated. proteins. Additional partnering programs are in place including a second collaboration with Theratechnologies for an undisclosed endocrinology product. Dose delivery is controlled by the patch size and drug loading on the microprojections. Figure 9: Component of Macroflux ALZA has entered into partnerships to explore development of products utilizing Macroflux transdermal technology. Preclinical work is ongoing to explore the feasibility of using the Macroflux patch technology to deliver this peptide. It is convenient for users and provides controlled. and other therapeutic macromolecules. In the HGP model. Macroflux transdermal technology provided system-controlled and sustained delivery of an antisense oligodeoxy. In summary. 7 kDa. achieving delivery of 15 mg over a 24-hour period from a 2cm2 patch.nucleotide. consistent dosing. the Macroflux patch incorporates a drug-coated titanium micro-projection array that offers marked advantages over other transdermal delivery systems for efficient delivery of peptides.

making device disposal as easy as removing and discarding a bandage as well as eliminating the need for sharps disposal. Mehsana . The user will hear a click to indicate that the bolus has been delivered. No need to access the device directly.Microneedles in Drug Delivery system 2010-11 drug into the epidermal layer for rapid dissolution and absorption that yields high drug utilization and bioavailability.Patch With clearance from the US Food and Drug Administration (FDA). The h-Patch system is designed to easily be replaced every 24 hours. and vaccines. The Macroflux patch is a developing technology that may provide expanded drug delivery opportunities for therapeutic peptides. which painlessly inserts the micro-needle and begins the basal flow of insulin. which can easily be done through his or her clothing. safe and convenient. making it an attractive alternative to other insulin delivery methods such as catheter-based electronic pump systems or injections. Patients simply peel the protective liner from the adhesive backing.25 6. apply the device to a part of the body where it can be easily reached (such as the abdomen. the h-Patch is easy. For biopharmaceuticals. waterproof device is as small as a ChapStick tube and as easy to apply as a Band-Aid bandage. allowing patients to rotate site placement and minimize the risk for local infection. Chauhan 37 SSPC. and push the start button. arm or thigh). and cannot be redeployed. the wearer simply presses the bolus button on the h-Patch system. the micro-needle retracts. Valeritas' h-Patch basal bolus insulin delivery system is poised to help Type 2 diabetes patients improve their compliance and glycemic control with their prescribed therapy regimen. When the h-Patch system is removed. In preclinical studies. Morever.2 h. the Macroflux pharmacokinetic delivery profile and bioavailability may be equivalent to subcutaneous injection. This disposable. When a meal-time bolus is needed.48 Chetan N. approximately 85% of drug present on the Macroflux array patch was delivered in less than 5 minutes patch-wearing time. locks in place. proteins.

hollow or solid needles fabricated on a single surface.3 Micro Trans Valeritas microneedle array patch (Micro trans) technology enables drug delivery or interstitial fluid sensing at the epidermis or dermis. wall thickness. 47 Applications Include:   Delivery of large proteins. fragile antibodies. blood gases. Microneedles can be constructed of metal or biodegradable polymers. diameter. The length. both conventional and DNA-based. avoiding close proximity to pain receptors. Chauhan 38 SSPC. Mehsana .Microneedles in Drug Delivery system 2010-11 Figure 10: Application of h-Patch 6. Delivery of small molecules. making the system extremely comfortable for the patient to wear.   Chetan N. Delivery of vaccines. particularly those with difficulty diffusing through skin layers. Valeritas' proprietary manufacturing processes ensure that these arrays can be fabricated at very low cost. and therapeutic drug levels. Fluid sensing of glucose. without limitations of drug size. and hormones. Valeritas' Microneedle Array technology consists of multiple small. or the patient's skin characteristics. Arrays penetrate only the shallow layers of the skin. charge. hormones. and shapes can be manufactured to a variety of specifications. structure.

Passive or active drug delivery profiles. Mehsana . and fully disposable. Can be used with Valeritas' e-Patch device to deliver a wide range of drug volumes under various extended or time-release profiles   Figure 11: Micro-Trans Chetan N. Accurate.Microneedles in Drug Delivery system 2010-11 Key Features:    Simple for patient to use. Unique manufacturing techniques result in very low cost. circumventing the stratum corneum. reliable delivery of drug to epidermis or dermis. Chauhan 39 SSPC.

18 7. Research should include hybrid needle designs which incorporate silicon tips with polymer lumens. Mehsana . microneedles made up of silicon. fabrication of dissolving microneedles using polysaccharide biomaterials have been utilized for controlled drug delivery.Microneedles in Drug Delivery system 2010-11 7. Metal and polymer needles are not stiff so they can absorb larger stresses by deforming. Thus. Future Trends Integration of solid microneedles with transdermal patch provides a minimal invasive method to increase the skin permeability of drugs. Needles must be able to tolerate forces associated with insertion.18. with rapid advancement in technology. More research is needed to develop needles which balance the stiffness required for insertion with the ability to deform to absorb stress associated with movement. Till date. metal. the silicon could be used as a stiff material for piercing the skin and the polymer coating would hold the needle together and absorb stress.2 Improved Microdialysis Microneedles Future work should focus on determining how larger biological molecules such as serum proteins permeate a microdialysis membrane to allow optimization of the design. For instance. However. this ability also makes piercing the skin more difficult.2 Microneedle approach of drug delivery is currently being evaluated for a number of drugs. 20 Chetan N. However.1 Improved Microneedle Research There are many aspects of the microneedle field which require future research. Materials such as silicon can easily pierce the skin but they are also brittle materials which fracture easily. glass and plastics have been utilized for transdermal delivery. including the macromolecules such as proteins. However. intact removal and normal human movements if they are to be integrated into portable biomedical devices. Chauhan 40 SSPC. This will allow a balance between mass transfer rates and filtering effectiveness of a membrane. The most important is to balance microneedle robustness with needle deformation in response to imposed stresses. but extensive studies would be required to foster the application of these delivery modes in the clinical set up. or “knuckled” silicon designs with polymer coatings. microneedles composed of biodegradable and biocompatible materials have been explored. some of the future directions are discussed below: 7.

Mehsana . Chetan N. polymers. filtered and hollow. they do. and skin therapy. bent. Although microneedles will not fully replace the traditional needles. it will give the profile of these needles. and glass. transdermal delivery device. Other materials include: metals. Microneedles are applied in the medical field for such applications as: a blood glucose measurement device.Microneedles in Drug Delivery system 2010-11 8. Various shapes can also be fabricated to have structures that are straight. however posses certain capabilities that traditional needles do not. With the use of photolithography and various etching methods. silicon dioxide. Conclusion Microneedles are needle-like structures which are fabricated on substrates like silicon. Chauhan 41 SSPC.

Modified Release Drug Delivery Technology. Mehsana . Mark R Praunitz . E.BDNJ. Mechanical & Environmental Engineering.USA 11. Jeo Jon Kong et al .Third Edition. References 1. Francis E.L Turner.2007 12. Application 2006 Chetan N.633-644 13.University of California 8. MNT network(www.Delivery of Macromolecules using Microneedles. Transdermal Drug Delivery.Encyclopedia of Pharmaceutical Technology. Jing Ji. Microfabricated Microneedles & minimally invasive drug delivery sampling & Analysis.513522 3.. Phil Green. Chauhan 42 SSPC. Anil Philip. Kenneth A Walters.NIPER 6. March 2007. Polymeric microneedle for using microinjection using Microinjection mould Technology . Drug Delivery:Topical and Transdermal Routes.Lokesh Kumar.H Tay et al.Department of Pharmaceutical Technology. Firas Sammoura .517. Ritesh Kumar. Microfabricated Silicon Microneedle array for Transdermal Drug Delivery .USA 7. Noel G Harvey.Micromachined Silicon and Polymer MicroneedleArrays for cancer therapy & drug delivery 10. Arvind Bansal. Microsyst Technology (2007)13.Microneedles in Drug Delivery system 2010-11 9.1319 4. Microneedles: A new Alternative to Hypodermic syringes.University of California. Nicolle Wilke.mntnetwork.Modified Transdermal Technology:Breaking the barriers of Drug Permeation via Skin. Prof. Fabrication of Silicon micronedles for Biomedical Applications . K.P Rao.Drug Delivery Report Spring Summer.Microneedle Technology for Advanced drug Delivery-Evolving Vistas. Jeffery David Zahu.522 14.M. Hurat Karabiyukoglu. Summary of work done for BOC Bursary. Journal of Physics: Conference series34(2000)1127-1131 5.New Frontiers in Transdermal Drug Delivery System.6(1). Pushpat Bora.R Parker. Microfabricated Microneedles and Transdermal drug Delivery Technology. Marcel Dekker Inc. Kim Beom Jaon 15. Franklin lakes. Microneedle Therapy System . Marcel Dekker Inc. James A Down.com) 9. 2.

April 2007 27. 19. University of British Columbia . Canada 18. 2004 22. www. K. Department of Informatics. Margaret Buttery.H. Microneedles for Drug delivery and Biosensing .ie 31. Ocular Drug Delivery using Micronedles. Indian Inst.org 28. Silicon microneedles array with biodegradable tips for Transdermal drug delivery. July 2008. Kofi Nyam. Hollow Microneedles &Molecule transport across the skin . News Release. Pharmaceutical Research. Kumetrix Inc. April 2007 23. Georgia institute of Technology 2003 19.6(12) 21. Medical Diagnoistics Technologies based on Bio MEMS.edu 30. 2001. Francis E. P. www. Oddvar Sorasen. Georgia institute of Technology 2003 20. Wendy A. Retina Today .me. Ciprian Iliescu. www. www. 1.Microneedles in Drug Delivery system 2010-11 16.engr. Mehsana . Department of Mechanical Engineering. Jiashen Wei. Bangtao Chen. J.tyndall. A. Yee Ting Wong . No.ucsb. Chauhan 43 SSPC. Young. Tay. Michel Cormier. Shaun Paul Davis . Timothy Olsen. Bajpai.edu Chetan N.berkeley. 24.ivos. www. Plasma etching processes for the realization of micromechanical structures for MEMS . Director of Electronic research. Boris Stuber. Jianwei Mo.com 29. January 2002 26. Juanita Johnson. Ninghao Jiang . 17. www.cmoset.Microsystems in Biomedical Engineering.edu 32. Pharma Bioworld. Drug Delivery to the Suprachoroidal Space Shows Promise. Microscopic Needles could Revolutionise eye Treatment 25 James A. Daddona . Macroflux_ Microprojection Array Patch Technology: A New and Efficient Approach for Intracutaneous Immunization. Matriano.. A.etd. Peter E. DTIP . Vol. Paul.gatech. 81 669-674. K. Sci. Nov.-Dec. Royal pharmaceutical Society of Great Britan. Dimri and R.

com 40. www. www.int 44.a-star.cacshq.edu 41.eu 36.de 35.org 43. www.siliconvalley.imre. www.wipo. www.aapspharmaceutica.edu.ibn.a-star.valeritas.com 48.sg 38. www. Chauhan 44 SSPC.Microneedles in Drug Delivery system 2010-11 33. www.nicolle-wilke.com 39.com 46. www.nanocentral. www. www.com Chetan N.nicolle-wilke.com 47.com 37.org 34. www. www.org 45.anesthesia-analgesia. www.iop.de 42.wikipedia. www.clinicalresolution.retinatoday. www. Mehsana . www.drugdeliverytech.

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