Transdermal drug delivery system includes the delivery of drug via superficial lipophilic layer of the skin stratum corneum which is 10–15 μm thick. Stratum corneum obstructs the entry of antigens, bacteria; thus defining the skin barrier function which eventually suppresses the percutaneous penetration. Henceforth, the utmost challenge included a search for an alternative way which would surpass the repercussions provided by the skin barrier function of stratum corneum (Bhowmik et al., 2013). Various innovations, such as iontophoresis, electroporation, sonophoresis, magnetophoresis, and use of penetration enhancers have been proposed by different researchers which could help elevate the permeation and delivery of drug (Bhowmik et al., 2013). Out of all, the concept of using “microneedles”—micron-sized needles for the delivery and penetration of the drug is considered to be the most efficient method. The proof to this has been the experiments performed and subsequent results obtained by researchers and scientists (Bhowmik et al., 2013). A microneedle does not limit itself by improving only drug penetration. It has several other significant positive aspects (Wang et al., 2017). The drug delivery is specially preferred for pediatric application (Duarah et al., 2019) Thus, this review article focuses on microneedle drug delivery—its existence by overcoming the short comes of transdermal drug delivery system, types of microneedles used, different approaches for delivery, fabrication of microneedles, mechanism, materials, evaluation, and specific applications of microneedle drug delivery system.
Conventional mode of drug delivery
The delivery of the drugs plays a vital part in medicine and paramedical field. Normally, drug delivery system can be referred to as various ways, methods, and approaches for delivering the particular drug at proper site of action in order to obtain the highest amount of desired therapeutic effect. Normally, conventional modes of delivery include oral route, usage of carrier injections, or using novel approaches like transdermal drug delivery system for delivery of drug. With growing need for painless and less infectious prone way of drug delivery, microneedles are prone to fit the void for satisfying the requirement (Kaushik et al., 2001; Kshirsagar, 2000).
Transdermal drug delivery system
Transdermal drug delivery system (TDDS) is described as a novel drug delivery approach in which discrete and appropriate quantity of drug is delivered through the topmost layer of the skin which releases drug at a controlled rate for prolonged period of time into the systemic circulation. It can be described as a type of novel drug delivery approach which follows zero order drug release pattern (Kshirsagar, 2000).
The types of transdermal drug delivery include -
Membrane permeation controlled TDD system
In this type of transdermal drug delivery system, drug reservoir is in between backing layer and polymeric membrane. As shown in Figure 1(a), the drug reservoir area consists of the drug which is dispersed in the polymeric matrix solution to form a suspension like paste which is then delivered at a controlled rate through the rate controlling membrane which is non-porous or micro porous (Patel et al., 2012). Drugs like estradiol are delivered through membrane penetration (Chetkowski et al., 1986).
Matrix diffusion controlled transdermal drug delivery system
As shown in Figure 1(b), occlusive base plate, drug reservoir, polymeric membrane is present. The drug reservoir consists of the drug which is surrounded/coated with the matrix. Here, matrix could be any water-loving (hydrophilic) molecules or even lipophilic molecules. The dispersed form of drug and matrix forms a medicated disc like structure from which required amount of drug gets released at a controlled rate into the systemic circulation. The drug is in solution form in matrix and is backed by adhesive layer (Banerjee et al., 2014). Drugs like nitroglycerine can be delivered using this pathway (Rayment et al., 1985).
Reservoir gradient controlled transdermal drug delivery system
This type helps in dealing the issues related with non-zero release profile of the drug (Kesarwani et al., 2013). In this the drug and polymer matrix combined together in a reservoir could be converted in the form of a reservoir gradient along the diffusional pathway across the layer which leads to delivering a drug at a controlled rate as described in Figure 1(c). Glyceryl trinitrate is the drug which forms a deponit system for controlled delivery (Patel et al., 2012; Wiedersberg et al., 2014).
Microreservoir dissolution controlled transdermal drug delivery system
This type of drug delivery system is depicted in Figure 1(d) which has the combination of matrix and reservoir dispersion type of drug delivery system which includes two basic steps—Forming the drug reservoir which is done by suspending the drug in water soluble or aqueous solutions and then mixing/dispersing the suspension with lipophilic polymer by strong mechanical force which results in the formation of numerous microscopic reservoirs and finally the release of the drug at controlled rate (Patel et al., 2012).
|Figure 1. Types of transdermal drug delivery systems (a) Polymer membrane permeation TDDS (b) Polymer matrix diffusion TDDS (c) Drug reservoir gradient TDDS (d) Microreservoir dissolution TDDS explaining mechanism of different methods of drug delivery.|
[Click here to view]
Transdermal patches are widely used. Several transdermal patches available are for Pain relief, Patches for reducing hypertension, Vitamin B12 patches, Nicotine patches, etc. Trade name of certain transdermal products include Catapres-TTS®, Climara®, Climara pro®, Combipatch®, Duragesic®, Menostar®, Ortho Evra®, Oxytrol®, Transderm scop®, Vivelle®, Vivelle-Dot® (Wokovich et al., 2006). These transdermal products provide several benefits like it provides prolong effect with possibility of self-administration (Chaudhary et al., 2013), provides an alternative for patients who are unable to take oral medications, elimination of first past hepatic metabolism, avoid problems faced due to parenteral therapies, requires less dosage frequency (Allen and Ansel, 2013), visual confirmation while patch is applied, useful for trypanophobes (Raza et al., 2015), avoidance of enzymatic degradation, and gastrointestinal irritation. Also, it can be an alternative for the patients who are unable to take oral medications. Another advantage is that the drug release stops as soon as patch is removed. Despite of these ascendancies, there occur several stumbling blocks like unsuitableness for the drugs that irritate or sensitize skin and allowance for relative potent drugs only due to limitations related with skin permeability, problems related with non-adherence of a patch to skin, uneasiness while wearing a patch, change in barrier function of skin from site to site and person to person, the thickness of stratum corneum, poor solubility, allowance for only non-ionic, lipid and water-soluble molecules of particular molecular size, and shape limits the use of this type of drug delivery system. Hence, the more innovated type of drug delivery like microneedle drug delivery system can be employed to replace the setbacks offered by TDDS. Also, the transdermal drug delivery is unable to pass through stratum corneum which is the biggest limiting factor (Lampe et al., 1983; Ledger, 1992). The different transdermal systems currently available in the market, which could also be delivery with more effectiveness by microneedle drug delivery systems, are mentioned in Table 1.
Microneedle drug delivery system
The overarching response to microneedles is due to the concept of disrupting the stratum corneum layer of skin which can lead to smooth pathway for the entry of desired molecules. A microneedle drug delivery system can, thus, be explained as a Novel drug delivery system approach in which drug is delivered into the systemic circulation through the needles. The system in which micron-sized needles pierce the superficial layer of the skin and diffuses the drug across the epidermis layer which is then passed on into the blood capillary region for active absorption (Silpi et al., 2011) as microneedles are short and thin they help in avoiding the pain caused to patient (Shilpa et al., 2001). This could be achieved by Microfabrication technology (Bhushan and Caspers, 2017; Donnelly et al., 2010). With passing time, different materials, such as dextrin, stainless steel, ceramic, and maltose were utilized for preparing the microneedles (Donnelly et al., 2010). Few years later, pattern of permeability of drug to the skin via microneedles was studied which lead to a conclusion that permeability factor through microneedles could be elevated to three to four times as compared to that of TDDS. It was observed that the skin barrier function could be overcome by using micron-sized needles. Later, different materials through which microneedles could be fabricated were introduced. Hence, this lead to the inception of microneedles as a solution for more productive results in terms of bioavailability and permeation of drug. Scientists put down efforts using technology for proper optimization and geometrical measurements required for achieving accurate insertion in the skin of human which was major goal with respect to microneedle (Kong et al., 2011).
|Table 1. Overview of the different transdermal drugs in market, specific disease treated, type of transdermal mechanism used, main advantages, and side effects.|
[Click here to view]
|Figure 2. Mechanism of delivery of drugs by four types of Microneedles solid, coated, dissolving and hollow.|
[Click here to view]
TYPES OF MICRONEEDLES
These microneedles use the passive diffusion path (Larraneta et al., 2016). Solid microneedles follow two steps, as shown in Figure 2, in which the microchannels in the skin are first created by inserting the microneedle, followed by allowing the drug formulation to pass over the generated microchannels (Kaur et al., 2014). Solid silicon microneedles proved to be the most prominent approach because of their sufficient biocompatibility (Wei et al., 2010). The manufacture of such a type of microneedle involves the use of various materials, such as polymers (Park et al., 2006), stainless steel metal (Martanto et al., 2004), biodegradable polymers (Park et al., 2005), and silicon (Li et al., 2010), for which silicon is the most important material to be used. Food and Drug Administration must approve these materials before fabrication starts on the basis of biocompatibility and safety (Kotzar et al., 2002). For proper production, various methods are used. One possibility is the use of thermal oxidation and lithography, wherein silicon on insulator wafer and oxide layer is processed to form a silicon oxide layer by thermal oxidation and lithography to obtain the first layer. The second layer (parylene coated) is deposited thereon to protect and isolate the chip. Furthermore, the microneedle electrode assembly is emancipated by separating the silicon oxide layer. Thus, the silicon array is obtained by modifying the parylene layer, which was previously under the silicon oxide layer, as a carrier layer of the solid silicon microneedle obtained by simply depositing the parylene layer to impart adhesives and strength to the microneedle (Wang et al., 2012). The main precision that emanates from a solid silicon microneedle is the rare occurrence of inflammatory or infectious conditions (Vicente-Perez et al., 2017). However, the high silicon cost is causing a setback in the use of silicon as the material for solid microneedles (Yue et al., 2009). Thus, a solid microneedle can also use other materials, such as parylene (Johnson and Wise, 2010), polyimide (Seo et al., 2004), nickel (Wang et al., 2007), titanium (Fofonoff et al., 2002), Polymethyl methacrylate, and polyvinyl (Matteucci et al., 2009).
These type include coating of the drug on the solid microneedle before inserting it into the skin (Gill and Prausnitsz, 2007a). The coated microneedle is inserted into the skin where the drug gets dispersed into the systemic circulation. This system is utilized to deliver complex and macro molecules, including Deoxyribonucleic acid, drugs, like desmopressin, parathyroid hormone, and vaccines (Gill and Prausnitsz, 2007b, Quinn et al., 2014), peptides (Cormier et al., 2004), proteins (Matriano et al., 2002). Different methods like micro dip-coating for vaccine delivery (Koutsonanos et al., 2009) are used for fabricating microneedles onto which a drug solution can be coated to obtain a drug-coated microneedle ready for administration. Other method for developing coating microneedle include fabrication via laser cutting in which stainless steel material is used and according to the required acreage the sheet is cut by allowing infrared rays to pass through it. The obtained cutout is then cleaned by using proper cleanser. Furthermore, the electro polishing is required which is done by using copper plate which acts as a cathode and microneedles to be obtained would act as anode. The procedure requires continuous vibration in order to avoid the unwanted air bubbles. Microneedles are then cleansed using the de-ionized water followed by hot water which are then allowed to dry and the stored at optimum temperature. A coating solution is then prepared of the drug to be coated and microneedle is then coated using dip-coating technique. Coated microneedle is specifically used in treating enuresis, diabetes insipidus, hemophilia A, Willebrand’s disease and certain trauma induced diseases (Gill and Prausnitz, 2007a).
These type of microneedles include usage of the biocompatible polymers like poly vinyl alcohol (Chu et al., 2010), carboxymethyl cellulose (Guo et al., 2013), or sugars (Miyano et al., 2005) which on insertion into the skin releases the drug and dissolves into the systemic circulation due to which a controlled release is obtained. The needle or the coating on the needle dissolves itself to release drug (Lee et al., 2008; 2011; Matriano et al., 2002). The main advantage is low cost of polymers and usage of water-soluble materials. But, one of the major downsides is deposition of polymers into the skin. These are prepared by lithographic approach (Moga et al., 2013) or a two-layered approach in which two plates are used. Drug and polymer are mixed and the solution formed is allowed to pass into the holes of the array. The push and pull movement is enforced onto the two plates placed parallel to each other. The polymeric solution is allowed to pass into plate below and the top plate is removed at the end after the dissolving microneedle have been fabricated as the polymeric solution gets solidified resulting in conical shaped microneedles which can be mostly used in administering influenza vaccine (Roxhed and Griss, 2008; Sullivan et al., 2008). Recently, Wu et al. (2016) prepared sinomenin loaded dissolving microneedles using a specialized fabrication technique using biocompatible polymers. (Wu et al., 2008).
These microneedles are the one which allows the passage of the drug through the hollow bore channel present in the needle. The needle is inserted into the skin and the drug is allowed to pass through the bore which diffuses into the systemic circulation (Kurz et al., 2009). It is made up of various materials, such as silicon, metals (Chandrasekaran and Frazier, 2003; Roxhed and Griss, 2008; Roxhed et al., 2008), glass (Wang et al., 2006), and polymers (Sammoura et al., 2007). The main obstacle of hollow microneedle is the problem of clogging of the bore which leads to resistance to flow (Gardeniers et al., 2003). It can be manufactured by using lithographic technique which ultimately helps in intradermal drug delivery (Laurent et al., 2007). For fabrication, a silicon wafer is used onto which the photoresist layer is spinned and the deep molds are formed after the ultraviolet rays are allowed to pass through the molds. By wet etching process, the KOH solution is used due to which silicon wafer gets etched and the required microneedles are obtained by cutting silicon wafer into a microneedle array (Torin et al., 2011). Hollow microneedles are utilized in extraction of the blood sample by least amount of invasion. It helps to replace traditional technique of utilizing hypodermic needle (Li et al., 2013). The mechanism of various microneedles is described in Figure 2.
Each and every microneedle whether it is solid or drug coated follow certain common steps in mechanism. Microneedles when inserted leads to mechanical disruption of the skin creating pore, and then, the drug coated on the needle is dispersed in the systemic circulation. Microneedles firstly disrupt the stratum corneum region of the skin. Stratum corneum includes skin barrier function (Bouwstra and Ponec, 2006) and microneedle helps to eradicate the problem of skin barrier function of stratum corneum. Hence, microneedles create a pathway for drug to directly get delivered into the blood rich region bypassing the stratum corneum which is not the case in transdermal drug delivery system. To give the desired outcome, it follows poke and patch, coat and poke, poke and release, poke and flow approach as discussed in Table 2. It depends on the fabrication of a microneedle which can be in-plane or out-plane. In-plane microneedles are parallel to the surface and out-plane microneedles are perpendicular to the surface as shown in Figure 3 (Van der Maaden et al., 2012).
Clinical Trials on Microneedle Patch
In order to understand the working and advantages of microneedle patches over the hypodermic needle or any other drug delivery system like transdermal drug delivery, Arya et al. (2017) worked for many years to develop a technology based on microneedle and finally designed a technique for delivery by recommending use of the microneedle patch. Arya et al. (2017) worked at Georgia Tech and Emory University who designed microneedle patch and manufactured them at Global Centre for Medical Innovation at Atlanta. Individuals between the age group of 18 to 57 were chosen as the participants for the clinical trials. Seven males and seven females were considered for each category of the test. The test was divided into several parts (Arya et al., 2017).
The effectiveness of microneedle patches: The study was conducted on four groups including the people with traditional flu shot as first group, microneedle patch (vaccine) as second group, placebo patch without drug as third group, and people who administered the patch using the instructional video as fourth group. The results obtained were quiet interesting as it was observed that the patch worked similar to the traditional flu shot. The drug bioavailability was monitored and it was same to that of first group. Hence, the patches were approved for further studies. (Arya et al., 2017).
Skin toxicity studies: The skin scoring scale was utilized in which the site at which the patches applied was evaluated on the factors, such as pain, tenderness, erythema, and swelling. Pain was evaluated on the basis of after effects, i.e., the effect after the patch is removed. Similarly, tenderness was defined on the basis of touch on the skin by the evaluator after the patch is administered and the appropriate results were obtained. (Arya et al., 2017).
For the evaluation through skin staining and microscopy, 1% gentian violet solution was used to stain the skin. After the insertion of microneedle, it was immediately removed off and the amount of stained skin was observed with the help of microscope and the punctures that microneedle made was counted, i.e., the stained part. Skin staining is calculating the microneedles that penetrated into the skin. The efficiency of microneedles was checked, i.e., microneedles that actually delivered the drug and dissolved after administration. The results obtained were satisfying as it was observed that almost 95% of the microneedles penetrated in the skin, i.e., punctured the skin layer and delivered almost 70%–80% of the drug after penetration (Arya et al., 2017).
|Table 2. Overview of different approaches used in delivery of drug via microneedles, description and type of microneedle that follow different approach. |
[Click here to view]
To evaluate the microneedle patches based on user surveys, participants had to answer short questions based on patches. The pain during administration, the confidence, and preference of a conventional patch or a microneedle patch were evaluated. As a result, the evaluators found that 86% were confident in applying the patch and that the majority of participants experienced no pain. In addition, it was observed that the participants preferred more microneedle patches compared to conventional injections because the patches did not cause pain and were easy to handle and use (Arya et al., 2017).
The advancement in microneedle drug delivery can be judged from the success of these microneedles in delivering drug into systemic circulation. Few of these successful systems are listed in Table 3.
Applications of Microneedle Drug Delivery System
The some of the important applications of microneedle drug delivery along with the successful product are listed in Table 4.
Microneedles for vaccine delivery
The increase in awareness among people regarding vaccination has led scientists to find new approaches for the delivery of vaccine. The recent one being microneedle drug delivery in which the antigen is directly introduced in the dermis. Thus, immune response can be achieved and vaccination therapy can be completed. This activity is carried out mostly by using dissolving type of microneedles. Various tecniques and devices like “mantoux” or “soluvia microinjection system” can be used to perform this process. According to the studies, mantoux tecique is difficult to perform as it requires professional person, whereas soluvia technique is commonly used and that too for the delivery of influenza vaccines, such as trivalent or quadrivalent or influenza type A or B (Pettis and Harvey, 2012; Van Damme et al., 2009; Vankerckhoven and Van, 2010).
|Table 3. List of few microneedle drug delivery systems successful in clinical trials that can be used to deliver drug into systemic circulation. |
[Click here to view]
|Table 4. List of marketed products used in specific treatment. |
[Click here to view]
Microneedles for insulin delivery
Many research studies were carried out for insulin delivery by various scientists, such as Martanto et al. (2004) and Henry et al. (1998), and they found that the insulin delivered through microneedle drug delivery was appropriate and it produced proper biological effect and maintained the blood glucose level. Also, bioavailability of insulin was found to be proper as insulin was introduced into the body by coating it on the microneedle which pierced the stratum corneum layer which led to the delivery of insulin. The first approach for insulin delivery was done by using 10-IU standardized insulin lispro which showed good absorption rate (Pettis and Harvey, 2012). Borosilicate glass microneedles were used (Gupta et al., 2009; 2011).
Microneedles for delivery of parathyroid hormone
It is used for the delivery of the parathyroid hormone, i.e., teriparatide. Drug-coated type of microneedles is used in it which delivers the drug after it is inserted in the skin, i.e., the drug coated gets dissolved after insertion. The delivery of parathyroid hormone through microneedle is not yet approved. But, it has undergone phase 1 and 2 studies which concluded that the drug delivered via microneedles reached three times earlier to the maximum concentration as compared to that delivered via traditional route (Pettis and Harvey, 2012). Parathyroid patches have also been prepared (Daddona et al., 2011).
Microneedles for delivery of Lidocaine and other anesthetics
The type of microneedles used here were solid and hollow microneedles. The anesthetic drug was delivered to the various participants selected for study and criteria, i.e., pain and numbness obtained were evaluated. The results showed that the pain was less as compared to that of traditional needle and numbness obtained was as effective as that of the conventional way of approaching numbness to particular part. Thus, it was concluded that microneedles were more effective than hypodermic needle in producing more numbness and less of pain which consequently worked for the betterment of patient (Pettis and Harvey, 2012). Solid-based microneedle has been formulated for delivery of lidocaine for patients to be anesthetized (Zhang et al., 2012).
Microneedles for cosmetic purpose (Dermaabrasion)
Microneedles are used for decreasing the scars, wrinkles, etc from the skin. This is achieved by puncturing the skin multiple times through microneedles, earlier which was done through hypodermic needle. The pores, thus, created through microneedles resulted in the increase of collagen growth and breaking or disruption of old collagen which caused damaged to the skin. This led to decreasing the wrinkles, also helped in treating acne. The special instrument made for this is Dermaroller®. It is 12 cm long and consists of 192 miniature needles arranged in 24 circular arrays. The length of which is 0.5 to 3 mm and diameter of which is 0.1 to 0.25 mm. These needles can be adjusted according to the depth, skin layer in which one wants the insertion (Fabbrocini et al., 2009; Nair and Arora, 2014; Pettis and Harvey, 2012).
Microneedles for naltrexone
Microneedle patches were used to treat opioid-dependent patients as well as alcohol addict treatment. When patches were administered, it was found that the optimum plasma level was obtained within 2 hours after administration and the effect prolonged till 72 hours. Thus microneedles coated with naltrexone, thus delivered drug into the systemic circulation which helped block the opioid effect (Pettis and Harvey, 2012; Stinchcomb et al., 2008).
Microneedles for acne scar treatment (Dermaroller)
For acne scar treatment, microneedles are used. The area with acne scar is treated with anesthetic agent and the Dermaroller is used and allowed to move in vertical and horizontal direction. The saline pads are used for treating the bleeding which could be controlled. The process takes 20 minutes for getting completed. Also, home care derma rollers are used for delivering anti-ageing products (Dogra et al., 2014).
Microneedles for glucose monitoring
Microneedles are used indirectly for glucose monitoring. Previously, devices, namely, “Cygnus glucowatch” were used more for monitoring the glucose levels in the body (Tierney et al., 2001). Using silicon microneedles gave proper precision, appropriate needle penetration which helped extracting interstitial fluid with minimum pain which helped monitor blood glucose level. (Koschinsky and Heinemann, 2001) Commercially available glucose monitoring/sensing device is Kumetrix® which is made up of silicon microneedle (Smart and Subramanian, 2000).
Microneedle patch for iron deficiency anemia
Success in modulating microneedle patches to replace the oldest approach of using iron supplement and parenteral approaches for treating iron deficit human was achieved by using micro molding technique which helped treat anemia in patients without any gastric side effect. Rapidly dissolving type of microneedles loaded with ferric pyrophosphate which could help treat Iron deficiency anemia efficiently was formulated. On carrying out in vivo and in vitro studies, satisfying results were obtained (Maurya et al., 2018).
Microneedles for transdermal protein delivery
Microneedle mask devices have been prepared using continuous liquid interface production technique coated on polyethylene glycol base for appropriate delivery of proteins like serum albumin and ovalbumin. To avoid damage to the encapsulated protein which can eventually result in immunogenicity due to exposure to free radical polymerization procedure used to produce Continuous Liquid Interface Production-based microneedles during fabrication. The way out to this was coating microneedles after fabrication process is over. The successful delivery has been noted in studies carried out on mice for 72 hours in which sustained retention of protein was observed (Caudill et al., 2018).
3D printed Microneedles
Such types are mostly used for delivery of insulin. The cone shaped polymeric microneedles have been obtained via stereo lithography technique using a biocompatible resin. To prevent rapid degradation and maintain stability of insulin, it is coated on microneedle by using inject print technique in which insulin solution is printed on each microneedle by keeping them at 45oC and repeating the process for 92 times in which 10 dots of 2 droplets are longitudinally dispensed (Pere et al., 2018).
Microneedles for subcutaneous tumor
A fast dissolving microneedle patch has been fabricated using sodium hyaluronate on to which 5-aminolevulinic acid is coated to the tips of microneedle. This led to maximum drug utilization and avoidance of drug residue. Also, it helped overcome problems related with hydrophilicity and zwitterion nature of aminolevulinic acid. Hence, by using photodynamic therapy and sodium hyaluronate-based microneedles a dissolving microneedle of aminolevulinic acid proves to be best for treating subcutaneous tumor (Zhao et al., 2018).
The strategy of delivering drug via microneedle has resulted in several patents which are listed in Table 5. Different mechanisms for different types of microneedle were reported.
Adachi et al. (2007) developed microneedle device which helps permeate layers of skin for painless delivery of drug. Tomono (2008) utilized chitosan which is a biodegradable material for fabricating a microneedle. Lee et al. (2011) came up with an idea of developing a hermetically sealed bottom of which the microneedle array is attached at the opening of the setup of a container in which capsule kept releases drug at desired time periods.
|Table 5. The patents on Microneedle system. |
[Click here to view]
Birchall et al. (2012) developed a system in which indicator material and therapeutic agent is coated on microneedle and the arrangements are such that drug to be delivered is delivered first and once the drug is delivered the indicator indicates the success of the drug delivered. The therapeutic agent is toward the tip and the indicator material is underneath for appropriate delivery. Herman et al. (2013) developed a system used for treating various urinary tract diseases using microneedles for drug delivery of various treatment fluids.
Levin et al. (2013) developed device that includes a syringe connected with a barrel, a plunger, and a hollow microneedle adapter. The injections, thus obtained contain microneedle adapter which are used to deliver the fluids to intradermal area. Levin, thus, devised this technique which also helps in dose sparing as it has been proven that delivering via intradermal routes produces the same efficacy as that of the doses not given in intradermal space. Vaccines are also given through this route (Levin et al., 2014).
Shaari et al. (2013) developed nasal delivery device in which in certain embodiments, the nasal delivery device comprises a substrate for administration of a composition to the nasal and/or sinus mucosa, wherein the substrate is non-absorbent and comprises one or more microneedles. In some embodiments, the nasal delivery device comprises a reservoir comprising one or more therapeutic agents, wherein the reservoir is in fluid communication with one or more microneedles.
Uhland and Peeters (2015) developed device for intraluminal delivery in which disrupted mucosal region helped in delivering of the drug through microneedles. The drug from the housing is dispensed in the disrupted mucosal region which is obtained via microneedles.
Cannehan and Cachemaille (2016) lead to the development of system having independent lumen connected with elongated body, head, and sharp tip with distal opening in perpendicular direction with respect to lumen used to deliver drug via stratum corneum into systemic circulation.
Gharib et al. (2016) developed system using one or more needle(s) or micro-needle arrays in which description related with shift of fluid volume from a first expansion member position to a second expansion member position drives delivery of the fluid, which can be a drug or drug solution, through the needle(s) or micro-needle arrays.
Cheng and Huang (2017) developed embeddable microneedle patch in which when the embeddable micro-needle patch for transdermal drug delivery is attached to the skin for a predetermined time, the biodegradable carrier is separated from the supporting shafts and embedded into the skin, and the biodegradable carrier swells and then degrade, so as to release the drugs, which are encapsulated in the biodegradable carrier, at a rate of 1%˜99% loaded drug per day into the skin.
Birchall and Coulman (2017) developed microneedle device for treating skin improvement or repair comprising: a plurality of microneedles attached to or integral with a supporting base member and arranged in at least one circular pattern on same wherein said microneedles are hollow and have a bore size of between 60 and 150 μm diameter. Hence, subsequent growth can be observed in the field of microneedle drug delivery system.
Thus, this review article included the basics of transdermal drug delivery system as well as microneedle drug delivery system. Through this, one can understand that in the coming years, the importance of microneedle drug delivery is going to increase due to the advantages that it offers. It can replace the conventional methods of drug delivery most probably the transdermal approach. The biggest advantage that it offers is the painless treatment. Furthermore, the efficiency of increasing the penetration through the skin which is one of the biggest hurdles in transdermal drug delivery system has increased the scope of microneedle drug delivery system in the coming years. Also, there is no limitation of using only potent drugs for microneedle drug delivery system. Furthermore, patient compliance, possibility of self-administration, bioavailability, accuracy, precision, less chances of bacterial infections, and many other advantages leads to conclusion that the microneedle drug delivery system can definitely be used for betterment of people and eventually for good public health. Thus, microneedle drug delivery system obtained from the basis of transdermal drug delivery system can be used for better.
The manuscript is conceptualized and data acquisition done by Dr. Surendra Agrawal and Ms. Suchi Gandhi; Ms. Pravina and Dr. Saraswathy critically reviewed the content and revised it.
CONFLICT OF INTERESTS
The authors of this manuscript do not have any conflict of interest.
TDDS: Transdermal drug delivery system,
NDDS: Novel drug delivery system.
Amodwala S, Kumar P, Thakkar HP. Statistically optimized fast dissolving microneedle transdermal patch of meloxicam: a patient friendly approach to manage arthritis. Eur J Pharm Sci, 2017; 104:114–23. CrossRef
Arya J, Henry S, Kalluri H, McAllister DV, Pewin WP, Prausnitz MR. Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects. Biomaterials, 2017; 128:1–7. CrossRef
Bal S, Kruithof AC, Liebl H, Tomerius M, Bouwstra J, Lademann J, Meinke M. In vivo visualization of microneedle conduits in human skin using laser scanning microscopy. Laser Phys Lett, 2010; 7(3):242–6. CrossRef
Banerjee S, Chattopadhyay P, Ghosh A, Datta P, Veer V. Aspect of adhesives in transdermal drug delivery systems. Int J Adhes Adhes, 2014; 50:70–84. CrossRef
Bhushan B, Caspers M. An overview of additive manufacturing (3D printing) for microfabrication. Microsyst Technol, 2017; 23(4):1117–24. CrossRef
Birchall JC, Coulman SA, Allender CJ, Brain KR, inventors; Cardiff University College Consultants Ltd, assignee. Monitoring system for microneedle drug delivery. United States patent application US 12/809,667, 2012 May 17.
Bouwstra JA, Ponec M. The skin barrier in healthy and diseased state. Biochim Biophys Acta (BBA)-Biomembranes, 2006; 1758(12):2080–95. CrossRef
Caudill CL, Perry JL, Tian S, Luft JC, DeSimone JM. Spatially controlled coating of continuous liquid Interface production microneedles for transdermal protein delivery. J Control Release, 2018; 284:122–32. CrossRef
Chandrasekaran S, Frazier AB. Characterization of surface micromachined metallic microneedles. J Microelectromech Syst, 2003; 12(3):289–95. CrossRef
Chaudhary H, Rohilla A, Rathee P, Kumar V. Optimization and formulation design of carbopol loaded Piroxicam gel using novel penetration enhancers. Int J Biol Macromol, 2013; 55:246–53. CrossRef
Cheng MC, Huang SF, inventors; National Cheng Kung University, assignee. Embeddable micro-needle patch for transdermal drug delivery and method of manufacturing the same. United States patent US 9,675,789, 2017 Jun 13.
Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biologic effects of transdermal estradiol. N Engl J Med, 1986; 314(25):1615–20. CrossRef
Chu LY, Choi SO, Prausnitz MR. Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: bubble and pedestal microneedle designs. J Pharma Sci, 2010; 99(10):4228–38. CrossRef
Clissold SP, Heel RC. Transdermal hyoscine (scopolamine). Drugs, 1985; 29(3):189–207. CrossRef
Cormier M, Johnson B, Ameri M, Nyam K, Libiran L, Zhang DD, Daddona P. Transdermal delivery of desmopressin using a coated microneedle array patch system. J Control Release, 2004; 97(3):503–11. CrossRef
Daddona PE, Matriano JA, Mandema J, Maa YF. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharma Res, 2011; 28(1):159–65. CrossRef
Dogra S, Yadav S, Sarangal R. Microneedling for acne scars in A sian skin type: an effective low cost treatment modality. J Cosmetic Dermatol, 2014; 13(3):180–7. CrossRef
Donnelly RF, Singh TR, Woolfson AD. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Delivery, 2010; 17(4):187–207. CrossRef
Duarah S, Sharma M, Wen J. Recent advances in microneedle-based drug delivery: Special emphasis on its use in paediatric population. Eur J Pharm Biopharm, 2019; 136:48–69. CrossRef
Fabbrocini G, Fardella N, Monfrecola A, Proietti I, Innocenzi D. Acne scarring treatment using skin needling. Clin Exp Dermatol Exp Dermatol, 2009; 34(8):874–9. CrossRef
Fofonoff T, Wiseman C, Dyer R, Malasek J, Burgert J, Martel S, Hunter I, Hatsopoulos N, Donoghue J. Mechanical assembly of a microelectrode array for use in a wireless intracortical recording device. In Microtechnologies in Medicine & Biology 2nd Annual International IEEE-EMB Special Topic Conference, IEEE, pp 269–272, 2002.
Gardeniers HJ, Luttge R, Berenschot EJ, De Boer MJ, Yeshurun SY, Hefetz M, van't Oever R, van den Berg A. Silicon micromachined hollow microneedles for transdermal liquid transport. J Microelectromech Syst, 2003; 12(6):855–62. CrossRef
Gill HS, Prausnitz MR. Coated microneedles for transdermal delivery. J Control Release, 2007a; 117(2):227–37. CrossRef
Gill HS, Prausnitz MR. Coating formulations for microneedles. Pharma Res, 2007b; 24(7):1369–80. CrossRef
Guo C, Zhou L, Lv J. Effects of expandable graphite and modified ammonium polyphosphate on the flame-retardant and mechanical properties of wood flour-polypropylene composites. Polym Polym Compos, 2013; 21(7):449–56. CrossRef
Gupta J, Felner EI, Prausnitz MR. Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. Diabetes Technol Ther, 2009; 11(6):329–37. CrossRef
Gupta J, Felner EI, Prausnitz MR. Rapid pharmacokinetics of intradermal insulin administered using microneedles in type 1 diabetes subjects. Diabetes Technol Ther, 2011; 13(4):451–6. CrossRef
Henry S, McAllister DV, Allen MG, Prausnitz MR. Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharma Sci, 1998; 87(8):922–5. CrossRef
Johnson AC, Wise KD. A robust batch-fabricated high-density cochlear electrode array. InMicro Electro Mechanical Systems (MEMS), 2010 IEEE 23rd International Conference, 2010 Jan 24, IEEE, pp 1007–10. CrossRef
Kaur M, Ita KB, Popova IE, Parikh SJ, Bair DA. Microneedle-assisted delivery of verapamil hydrochloride and amlodipine besylate. Eur J Pharma Biopharma, 2014; 86(2):284–91. CrossRef
Kaushik S, Hord AH, Denson DD, McAllister DV, Smitra S, Allen MG, Prausnitz MR. Lack of pain associated with microfabricated microneedles. Anesth Analg, 2001; 92(2):502–4. CrossRef
Kearney MC, Caffarel-Salvador E, Fallows SJ, McCarthy HO, Donnelly RF. Microneedle-mediated delivery of donepezil: potential for improved treatment options in Alzheimer’s disease. Eur J Pharma Biopharma, 2016; 103:43–50. CrossRef
Kim JG, Sohn SK, Kim DH, Baek JH, Chae YS, Bae NY, Kim SY, Lee KB. Effectiveness of transdermal fentanyl patch for treatment of acute pain due to oral mucositis in patients receiving stem cell transplantation. In Transplantation proceedings (Vol. 37, No. 10, pp 4488–4491), 2005 Dec 1, Elsevier. CrossRef
Kong XQ, Zhou P, Wu CW. Numerical simulation of microneedles' insertion into skin. Computer methods in biomechanics and biomedical engineering, 2011; 14(9):827–35. CrossRef
Koschinsky T, Heinemann L. Sensors for glucose monitoring: technical and clinical aspects. Diabetes/Metab Res Rev, 2001; 17(2):113–23. CrossRef
Kotzar G, Freas M, Abel P, Fleischman A, Roy S, Zorman C, Moran JM, Melzak J. Evaluation of MEMS materials of construction for implantable medical devices. Biomaterials, 2002; 23(13):2737–50. CrossRef
Koutsonanos DG, del Pilar Martin M, Zarnitsyn VG, Sullivan SP, Compans RW, Prausnitz MR, Skountzou I. Transdermal influenza immunization with vaccine-coated microneedle arrays. PLoS One, 2009; 4(3):e4773. CrossRef
Kurz A, Farlow M, Lefevre G. Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer’s disease: a review. Int J Clin Pract, 2009; 63(5):799–805. CrossRef
Larraneta E, Lutton RE, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Mater Sci Eng R: Rep, 2016; 104:1–32. CrossRef
Laurent A, Mistretta F, Bottigioli D, Dahel K, Goujon C, Nicolas JF, Hennino A, Laurent PE. Echographic measurement of skin thickness in adults by high frequency ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines. Vaccine, 2007; 25(34):6423–30. CrossRef
Ledger PW. Skin biological issues in electrically enhanced transdermal delivery. Adv Drug Deliv Rev, 1992; 9(2–3):289–307. CrossRef
Lee JW, Choi SO, Felner EI, Prausnitz MR. Dissolving microneedle patch for transdermal delivery of human growth hormone. Small, 2011; 7(4):531–9. CrossRef
Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials, 2008; 29(13):2113–24. CrossRef
Levin Y, Kochba E, Kenney R. Clinical evaluation of a novel microneedle device for intradermal delivery of an influenza vaccine: are all delivery methods the same?. Vaccine, 2014; 32(34):4249–52. CrossRef
Li CG, Lee CY, Lee K, Jung H. An optimized hollow microneedle for minimally invasive blood extraction. Biomed Microdevices, 2013; 15(1):17–25. CrossRef
Martanto W, Davis SP, Holiday NR, Wang J, Gill HS, Prausnitz MR. Transdermal delivery of insulin using microneedles in vivo. Pharma Res, 2004; 21(6):947–52. CrossRef
Matriano JA, Cormier M, Johnson J, Young WA, Buttery M, Nyam K, Daddona PE. Macroflux® microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharma Res, 2002; 19(1):63–70. CrossRef
Matteucci M, Fanetti MA, Casella M, Gramatica F, Gavioli L, Tormen M, Grenci G, De Angelis F, Di Fabrizio EN. Poly vinyl alcohol re-usable masters for microneedle replication. Microelectron Eng, 2009; 86(4–6):752–6. CrossRef
Maurya A, Nanjappa SH, Honnavar S, Salwa M, Murthy SN. Rapidly dissolving microneedle patches for transdermal iron replenishment therapy. J Pharm Sci, 2018; 107(6):1642–7. CrossRef
McGrath MG, Vrdoljak A, O’Mahony C, Oliveira JC, Moore AC, Crean AM. Determination of parameters for successful spray coating of silicon microneedle arrays. Int J Pharm, 2011; 415(1–2):140–9. CrossRef
Miyano T, Tobinaga Y, Kanno T, Matsuzaki Y, Takeda H, Wakui M, Hanada K. Sugar micro needles as transdermic drug delivery system. Biomed Microdevices, 2005; 7(3):185–8. CrossRef
Moffatt K, Wang Y, Singh TR, Donnelly RF. Microneedles for enhanced transdermal and intraocular drug delivery. Curr Opin Pharmacol, 2017; 36:14–21. CrossRef
Moga KA, Bickford LR, Geil RD, Dunn SS, Pandya AA, Wang Y, Fain JH, Archuleta CF, O'Neill AT, DeSimone JM. Rapidly–dissolvable microneedle patches via a highly scalable and reproducible soft lithography approach. Adv Mater, 2013; 25(36):5060–6. CrossRef
Park JH, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release, 2005; 104(1):51–66. CrossRef
Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharma Res, 2006; 23(5):1008–19. CrossRef
Patel D, Chaudhary SA, Parmar B, Bhura N. Transdermal drug delivery system: a review. Pharma Innov, 2012; 1(4):66–75. CrossRef
Pere CP, Economidou SN, Lall G, Ziraud C, Boateng JS, Alexander BD, Lamprou DA, Douroumis D. 3D printed microneedles for insulin skin delivery. Int J Pharm, 2018; 544(2):425–32. CrossRef
Pettis RJ, Harvey AJ. Microneedle delivery: clinical studies and emerging medical applications. Ther Deliv, 2012; 3(3):357–71. CrossRef
Quinn HL, Kearney MC, Courtenay AJ, McCrudden MT, Donnelly RF. The role of microneedles for drug and vaccine delivery. Expert Opin Drug Deliv, 2014; 11(11):1769–80. CrossRef
Rayment CM, Kaul AF, Garfield JM. Comparative acceptance of three transdermal nitroglycerin placebo patches. Am J Hosp Pharm, 1985; 42:1362–5. CrossRef
Roxhed N, Griss P. Membrane-sealed hollow microneedles and related administration schemes for transdermal drug delivery. Biomed Microdevices, 2008; 10(2):271–9. CrossRef
Roxhed N, Samel B, Nordquist L, Griss P, Stemme G. Painless drug delivery through microneedle-based transdermal patches featuring active infusion. IEEE Transact Biomed Eng, 2008; 55(3):1063–71. CrossRef
Sammoura F, Kang J, Heo YM, Jung T, Lin L. Polymeric microneedle fabrication using a microinjection molding technique. Microsyst Technol, 2007; 13(5–6):517–22. CrossRef
Seo JM, Kim SJ, Chung H, Kim ET, Yu HG, Yu YS. Biocompatibility of polyimide microelectrode array for retinal stimulation. Mater Sci Eng C, 2004; 24(1–2):185–9. CrossRef
Smart WH, Subramanian K. The use of silicon microfabrication technology in painless blood glucose monitoring. Diabetes Technol Ther, 2000; 2(4):549–59. CrossRef
Stinchcomb A, Banks S, Pinninti R, inventors; University of Kentucky Research Foundation, assignee. Transdermal delivery of naltrexone hydrochloride, naltrexol hydrochloride, and bis (hydroxy-methyl) propionyl-3-0 ester naltrexone using microneedles. United States patent application US 11/812,249, 2008 Jan 10.
Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater, 2008; 20(5):933–8. CrossRef
Tierney MJ, Tamada JA, Potts RO, Jovanovic L, Garg S, Cygnus Research Team. Clinical evaluation of the GlucoWatch® biographer: a continual, non-invasive glucose monitor for patients with diabetes. Biosens Bioelectron, 2001; 16(9–12):621–9. CrossRef
Torin Huzil J, Sivaloganathan S, Kohandel M, Foldvari M. Drug delivery through the skin: molecular simulations of barrier lipids to design more effective noninvasive dermal and transdermal delivery systems for small molecules, biologics, and cosmetics. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2011; 3(5):449–62. CrossRef
Utian WH. Transdermal estradiol overall safety profile. Am J Obstet Gynecol, 1987; 156(5):1335–8. CrossRef
Van Damme P, Oosterhuis-Kafeja F, Van der Wielen M, Almagor Y, Sharon O, Levin Y. Safety and efficacy of a novel microneedle device for dose sparing intradermal influenza vaccination in healthy adults. Vaccine, 2009; 27(3):454–9. CrossRef
Van der Maaden K, Jiskoot W, Bouwstra J. Microneedle technologies for (trans) dermal drug and vaccine delivery. J Control Release, 2012; 161(2):645–55. CrossRef
Vankerckhoven V, Van Damme P. Clinical studies assessing immunogenicity and safety of intradermally administered influenza vaccines. Expert Opin Drug Deliv, 2010; 7(9):1109–25. CrossRef
Vicente-Perez EM, Larrañeta E, McCrudden MT, Kissenpfennig A, Hegarty S, McCarthy HO, Donnelly RF. Repeat application of microneedles does not alter skin appearance or barrier function and causes no measurable disturbance of serum biomarkers of infection, inflammation or immunity in mice in vivo. Eur J Pharm Biopharm, 2017; 117:400–7. CrossRef
Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman the testosterone gel study group N. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab, 2000; 85(8):2839–53. CrossRef
Wang PM, Cornwell M, Hill J, Prausnitz MR. Precise microinjection into skin using hollow microneedles. J Invest Dermatol, 2006; 126(5):1080–7. CrossRef
Wang R, Zhao W, Wang W, Li Z. A flexible microneedle electrode array with solid silicon needles. J Microelectromech Syst, 2012; 21(5):1084–9. CrossRef
Wang T, Yang W, Huang H, Fu C. A novel fabrication method of flexible micro electrode array for neural recording. InMicro Electro Mechanical Systems, 2007. MEMS. IEEE 20th International Conference, 2007 Jan 21, IEEE, pp 295–300. CrossRef
Wang M, Hu L, Xu C. Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing. Lab Chip, 2017; 17(8):1373–87. CrossRef
Wei-Ze L, Mei-Rong H, Jian-Ping Z, Yong-Qiang Z, Bao-Hua H, Ting L, Yong Z. Super-short solid silicon microneedles for transdermal drug delivery applications. Int J Pharm, 2010; 389(1–2):122–9. CrossRef
Wiedersberg S, Guy RH. Transdermal drug delivery: 30+ years of war and still fighting! J Control Release, 2014; 190:150–6. CrossRef
Wiwanitkit V. Intradermal trivalent influenza vaccination in nursing home older adults. J Am Med Dir Assoc, 2014; 15(10):773. CrossRef
Wokovich AM, Prodduturi S, Doub WH, Hussain AS, Buhse LF. Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute. Eur J Pharm Biopharm, 2006; 64(1):1–8. CrossRef
Wu X, Chen Y, Gui S, Wu X, Chen L, Cao Y, Yin D, Ma P. Sinomenine hydrochloride-loaded dissolving microneedles enhanced its absorption in rabbits. Pharm Dev Technol, 2016; 21(7):787–93. CrossRef
Wu Y, Qiu Y, Zhang S, Qin G, Gao Y. Microneedle-based drug delivery: studies on delivery parameters and biocompatibility. Biomed Microdevices, 2008; 10(5):601–10. CrossRef
Yue R, Wang Y, Liu L, inventors; Tsinghua University, assignee. 3d solid or hollow silicon microneedle and microknife with"-" shape structure. United States patent application US 12/296,672, 2009 Apr 9.
Zhang Y, Brown K, Siebenaler K, Determan A, Dohmeier D, Hansen K. Development of lidocaine-coated microneedle product for rapid, safe, and prolonged local analgesic action. Pharm Res, 2012; 29(1):170–7. CrossRef
Zhao X, Li X, Zhang P, Du J, Wang Y. Tip-loaded fast-dissolving microneedle patches for photodynamic therapy of subcutaneous tumor. J Control Release, 2018; 286:201–9. CrossRef