A Review on Microneedles Based Drug Delivery Strategy

Skin is the largest organ in the human body. For several decades, it was only perceived as an “envelope” for the human body, aimed at separating the exterior from the interior. However, research has shown that the skin has multiple functions. Protection is one of them, but it is also involved in the immune system, thermal regulation, and even molecular synthesis. Skin can be used as a gateway for medical applications, for example, transdermal drug delivery, where the molecules released can be systemically absorbed into the bloodstream While the skin can act as a gateway for the absorption of therapeutic molecules, its effectiveness is hindered by the numerous layers it possesses. In a sense, this process goes against the very purpose of skin. Therefore, several strategies have been developed over the years to overcome this resistance. Micro-needles have attracted increasing interest in recent years in biomedical areas, such as drug delivery, biosensing, and fluid extraction. The tips of the micro-needles can penetrate the epidermis layer of skin to arrive at the top layer of the dermis that is above the blood capillaries. Thus, the micro-needles would not touch the nerve endings to further avoid bleeding and pain. Micro-needles are small, minimally invasive devices used in a variety of medical, cosmetic, and drug delivery applications. These needles are typically between 25 and 1000 micrometers in length—far smaller than conventional needles, making them virtually painless. They are designed to pierce the outermost layer of skin (the stratum corneum) without reaching deeper tissues, allowing for a more comfortable experience compared to traditional injections. Micro-needles work by creating micro-channels in the skin, enabling the delivery of therapeutic agents such as vaccines, insulin, or cosmetic products like serums and anti-aging treatments directly into the dermal layers. This technique can be more efficient and less painful than traditional methods, and it also improves the absorption of drugs that otherwise would not penetrate the skin effectively. Since the 2000s, there has been discoveries on new fabrication materials of MN(Micro- needles), like silicon, metal and polymer. Alongside with materials, a variety of MN types (solid, hollow, coated, hydrogel) has also been developed to possess different functions. The research on MN has led to improvements in different aspects, including instruments and techniques, yet adverse events are possible in MN users.

History of Micro needles: During 1905, Dr. Ernst Kromayer, a German dermatologist (skin doctor), preserved damaging, hyper active pigmentation, then other skin disorders by means of changed dimensions of power-driven dental burst (Dentist). The main part of poetry those discussions micro-needle usage be located in 1921 by Compartments anywhere she injected her needle hooked on the egg cell placing. In the 1960s, transporting medicines by inoculation inside the stratum corneum activated in the direction of is a magnet for concentration. After, the micro needle thought be located introduced in the 1970s though, this thought was non-established experimentally up to the 1990s. In 1979, the primary transdermic organization remained accepted used to distribute scopolamine (sedative, hypnotic drug) through put on a three days patch to remedy sign disorder. In 1994, a sequence surgical procedure remained performed through Orient Reich anywhere he injected a try-bevelled hypo dermal needle hooked on the skin to discharge rubbery components. This surgery targeted the coetaneous deficiencies placed below the skin which remained to blame designed for miserable scars and wrinkles. The primary micro needle for transdermic distribution remained suggested in 1998 then be located made-up since silicon crackers finished particle engraving then photo lithography. The study defined the usage of micro made-up micro needles designed for the reason of improve drug delivery crossways the membrane. These papers directed to wide-ranging investigate directed in the micro needle field. Different ingredients such as glass, ceramic, metallic, and polymer remained presented to manufacture micro needles. In 2004, a micro needle arrangement was used to penetrate holes interested in the skin for transdermic drug transfer, which led to some manufacture technique too material individual explore designed for the reason of TDD. Solid, coated, hollow, dissoluble, and hydro gel-creating MNs remain all dissimilar categories of MNs. additionally, a variety of manufacturing technique such as laser abstraction, photo lithography, micro-inoculation moulding etc. This discovery led in the direction of the primary information of a dissoluble micro needle actuality used for TDD in 2005. According in the direction of clinical Trials Gov. Website towards 43 clinical trials contain be finished by means of micro needles, through the primary micro needle clinical testing finished in 2007 (accessed on 30 June 2021, 5 p.m.). Freshly, additive manufactured approaches to production MN moulds be located established to supply inferior price solution for micro mould manufacturing. Information viewing the usage of commercially presented 3D printer to manufacture the MN leading mould accessible a novel phase in piece of equipment manufactures and potential for tradition constructed large volume manufacturing of MNs.

Types of Micro-needles: There are 5 types of micro needles

1. Solid Micro needles
2. Hollow Micro needles
3. Coated Micro needles
4. Dissolving Micro needles
5. Hydrogel-Forming micro needles

Solid Micro needles:

Design: Solid MN are the first type of MN fabricated and are the most commonly used. Hard solid MN shave sharp tips that pierce through and form pores on the stratum corneum. A drug patch will then be applied to the skin for drug to be absorbed slowly and passively through numerous micropores. Solid micro-needles are made from materials like silicon, metal, or polymers. They simply puncture the skin to create micro- channels through which drugs, vaccines, or cosmetic agents can be administered.

Function: These micro needles are primarily used to enhance skin permeability. Once inserted, they allow for the passive diffusion of drugs or act as carriers for the active substances.

Applications: Solid micro needles are used in drug delivery (e.g., insulin delivery for diabetes) or cosmetic treatments (e.g., enhancing the penetration of anti-aging serum.

1. Hollow Micro needles:

Design: Hollow MN are designed with a hole at the tip and a hollow capacity that store drugs.Upon MN insertion, stored drug is directly injected into the dermis and this effectively facilitates the absorption of either large-molecular or large-dosage drug. Yet, a portion of the drug can be leaked or clogged and it may hinders the overall drug administration. These micron needles have a hollow core, similar to traditional hypodermic needles, allowing them to inject liquid substances into the skin.

Function: The hollow micro needles act as channels through which drugs, vaccines, or other treatments can be injected directly into the skin layers. They are used for vaccination, insulin delivery, or local anesthetic injections.

Applications: Hollow micro needles are especially useful in medical treatments, such as vaccine delivery and other parenteral drug delivery applications.

Coated Micro-needles:

Design: Coated MN are fabricated by coating drug solution over solid MN and the thickness of the drug layer can be adjusted depending on the amount of drug to be administered. A benefit of coated MN is that less amount of drug is needed as compared to other drug administration route. This is because the layer of drug will quickly dissolve and delivered into the systemic circulation directly across the skin. Coated micro needles are often covered in other surfactants or thickening agents to assure that the drug is delivered properly. These micro needles are coated with a thin layer of the active drug or vaccine. The coating is designed to dissolve once the micro needles are inserted into the skin, releasing the therapeutic substance.

Function: Coated micro needles allow for the delivery of solid formulations in a more controlled and localized manner. The micro needle tip dissolves, releasing the coating into the skin, where it can be absorbed.

Applications: This type is often used in cosmetic treatments, such as anti-aging therapies, and in vaccinations.

Dissolving Micro needles: Dissolving MN are mostly composed of water-soluble drugs that enable the dissolution of MN tips when inserted into skin. This is a one-step approach which does not require the removal of MN and is convenient for long-term therapy. However, incomplete insertion and delay dissolution is observed with the use of dissolving MN. This polymer would allow the drug to be delivered into the skin and could be broken down once inside the body. Pharmaceutical companies and researchers have begun to study and implement polymers such as Fibroin, a silk-based protein that can be molded into structures like micro-needles and dissolved once in the body.

Hydrogel-forming Micro needles: The primary material for the fabrication of hydrogel- forming micro needles (HFMs) is hydrophilic polymer that encloses drugs. This material draws water from interstitial fluid in the stratum corneum and results in polymer swelling and release of drug. Besides, the hydrophilic features of HFMs allow readily uptake of interstitial fluid that could be used for disease diagnosis.

Material Used in micro needles:

Silicon: Silicon micro-needles are popular due to their sharpness and precision in penetrating the skin. They are often used in solid micro-needles. MNs made of metals like stainless steel, titanium, and aluminum, are non-toxic and possess strong mechanical properties to penetrate the skin without breakage.

Polymers:  Polymer is also regarded as a promising material for MN due to its good biocompatibility and low toxicity. Biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA) and polyvinyl alcohol (PVA), are frequently used for dissolving micro-needles, allowing them to degrade after drug release.

Metals: Stainless steel and titanium are commonly used for hollow micro-needles due to their strength and durability.

Ceramic: Due to their superior chemical properties and compression resistance, ceramic materials such as alumina have been used to fabricate a MN. However, alumina possesses a lower tensile strength compared to other materials. Calcium sulphate dehydrate and calcium phosphate dehydrate are additional types of ceramics utilized in the fabrication of MNs. A study conducted by Bystrova et al. showed that MNs fabricated from alumina fractured upon manual application to the skin.

ADVANTAGES AND DISADVANTAGES

Application of Micro-needles:

1. 1. Drug Delivery: The first application of MN for drug delivery was by using a solid silicon MN in 1998. A dissolvable MN patch was used to deliver human growth hormone for transdermal delivery to hairless rat skin. A dissolvable caffeine loaded MN patch was able to control the weight of obese mice and work as an anti-obesity treatment plan. A coated MN patch was used to deliver salmon calcitonin. Furthermore, MNs have been used for transdermal permeation for several drugs such as ibuprofen, ketoprofen, and paracetamol. Other drugs administrated via microneedles include L- Ascorbic acid, riboflavin, aspirin, docetaxel, pilocarpine, lidocaine, hydrochloride, ketoprofen, and glycerol.

Vaccine Delivery: A dissolvable MN is a common type of MN used for vaccine delivery purposes. The dissolvable MNs were used to replace hypodermic injection needles that were typically used to administer vaccines. Unlike other types of MN, the dissolvable MNs are biocompatible, robust, scalable, and do not generate biohazardous waste. Dissolvable MNs were used to deliver vaccines for malaria, diphtheria, influenza, Hepatitis B, HIV, and polio . Even though dissolvable MNs are most frequently used for vaccine delivery, coated MNs arrays have also been successfully used for vaccination purposes

1. 2. Diseases Diagnosis: Disease diagnosis and therapeutic efficacy can be monitored via several established bioassays that sample body fluids to assess and monitor health conditions. The current methods induce pain, require specialised techniques, tailored equipment, and professional medical personnel However, microneedle technology offers bioassays solution with painless experience and simple implementation. A hollow MN has the ability to diagnose several diseases such as cancer diabetes and Alzheimer’s disease. Patient health monitoring is another application of the MNs. For example, a hollow glass MN may be used to investigate the glucose level.
   3. Cosmetic Application: MNs have widely been used in cosmetic applications such as skin treatment and hair growth Kim et al. developed a hyaluronic acid-based dissolvable MN patch for the intradermal delivery of ascorbic acid and retinyl retinoate. Kumar et al. showed an enhancement of local delivery of eflornithine (used to reduce facial hirsutism) in vitro and in vivo using a solid MN. Further, MN technology was able to treat two patients suffering from alopecia areata disease. These patients experienced hair growth after treatment. Effective clinical trials have been conducted in atrophic facial scarring atrophic acne scars and hypertrophic burn scars using a MN. Microneedles are considered as an effective treatment for cosmetic applications related to aging, skin lesions, vulgaris, and wrinkles With an increasing demand of cosmetic products, microneedles (patches and rollers) have a high potential in the future

Micro-needle Fabrication method

There exist numerous techniques for fabricating micro needles. This section outlines the predominant methods employed not just for crafting micro needles themselves, but also for producing molds tailored to micro needle fabrication. Indeed, micro needles can be manufactured either directly or via a mold, particularly when aiming for cost-effective large-scale production.

Methods of fabrication are as follows:

1. MEMS (Micro-electromechanical systems)
2. Micro molding
3. Laser ablation
4. Injection moulding
5. Lithography

1. Micro-electromechanical systems : MEMS methods can be used to manufacture hollow and solid micro needles, as well as molds for dissolving micro needles, directly from an appropriate material substrate .The fabrication process for micro needles, along with molds using this technique, involves a meticulously controlled three-step process—deposition, patterning, and etching of materials In this way, complex three-dimensional structures emerge as a result of variations in etchant selectivity among different materials. The first step consists of forming a film with a thickness ranging from a few nanometers to 100 µm on a substrate through chemical or physical vapour deposition

In this way, the film can be formed through the chemical reaction on the substrate surface (chemical vapour deposition process) or by atoms transferred directly from the source to the substrate through the gas phase (physical vapor deposition process). Subsequently, during the second stage of the process, named patterning, a two dimensional master pattern of the desired material is transferred from the initial photomask to the substrate coated with photosensitive material. Typically, a silicon wafer serves as the substrate, and the transfer process is conducted using a radiation source in one of the lithography techniques (photolithography, ion beam lithography, or X-ray lithography. The most common type of lithography used is photolithography, which is activated by ultraviolet light and an X-ray onto diverse photosensitive polymers, including SU-8 [, poly (methyl methacrylate) (PMMA), polyethylene glycol diacrylate (PEGDA) and chitosan lactate.

Micro-Molding:

The micro-molding process consists of making replicates of the master mold. The mold is casted with a solution containing a polymer and active pharmaceutical substances. Micro-molding is considered a cost-effective method and is used for mass production Micro-molding is commonly used with polymer material for MN fabrication [. The PDMS has several advantages in micro-molding techniques such as low cost, ease of use, low surface energy, and thermal stability. The limitations associated with this technique are difficulties associated with controlling the depth of penetration, drug load capacity, and mechanical behavior of the polymer.

3. Laser ablation: Laser ablation incorporates the use of a focused optical light beam in eliminating material from a substrate to create MN arrays. Lasers have been used to process different materials ranging from micro- and nano-scale for several applications Various laser types have been studied for the manufacture of MN arrays. These include CO2, UV excimer and femtosecond laser machine. The laser ablation method is considered an effective and fast method for MNs fabrication. The laser beam takes 10 to 100 nanoseconds to approach the burn point in the material sheet. Laser could also be used to shape any metal. This method is associated with thermal effects at the cutting surface that result in the alteration of MN structure and mechanical properties. This might lead to undesirable effects in MNs such as cracking, or fatigue resistance. The laser ablation method is a non-contact process and subjects low heat loads to the substrate. However, the cost of the laser is higher compared to other types of equipment. The laser ablation method is not suited for large scale manufacturing.

Injection moulding: Injection molding is another MN fabrication method. The process of fabricating MNs using injection molding and the hot embossing technique Lhernould et al. used poly carbonate (PC) material to fabricate a 4 × 4 hollow polymer MN array. The MNs were shown to withstand high force and were used for multiple insertions without blunting the needle. Another study used a micro-injection molding process to fabricate a solid MN. These needles could deliver hydrophilic-high molecular weight molecules. Sammoura et al. fabricated a polymeric MN by molding plastic material.

The needles were used to successfully penetrate a fresh chicken leg and beef liver and ~0.04 µL of liquid was drawn from these tissues. The proposed method allows the mass production of MNs at low cost. Micro-injection molding also offers high repeatability, accurate dosing, and high injection flow rates when separating the plasticization and polymer melt injection. The limitation of applying injection molding technique is controlling the small shot size due to the common size of screw which is approximately 15–150 mm and higher initial cost of the equipment.

Lithography: The lithography technique is used to transfer the master pattern of the geometric shapes onto a surface of a substrate. Photolithography is primarily used for pattern transfer due to its wide applicability in the field of microelectronics. Other techniques such as microelectronic and micro machining use lithography as the first step in fabricating a MN. Lithography requires precise processing of the photoresist. This technique contributes to approximately 30–35% of costs for manufacturing integrated circuits. Lithography possesses the ability to create products from a variety of materials such as glass, metal, ceramics, and plastics It also produces precise geometries and smooth vertical sidewalls. However, this technique requires an advanced facility (cleanroom) and extended production time.