Microneedle drug delivery

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Side comparison of microneedle (350mm in depth) to standard hollow-bore needle Microneedle array comparison with Hypodermic needle.jpg
Side comparison of microneedle (350μm in depth) to standard hollow-bore needle

Microneedles or Microneedle patches or Microarray patches are micron-scaled medical devices used to administer vaccines, drugs, and other therapeutic agents. [2] While microneedles were initially explored for transdermal drug delivery applications, their use has been extended for the intraocular, vaginal, transungual, cardiac, vascular, gastrointestinal, and intracochlear delivery of drugs. [3] [4] [5] Microneedles are constructed through various methods, usually involving photolithographic processes or micromolding. [6] These methods involve etching microscopic structure into resin or silicon in order to cast microneedles. Microneedles are made from a variety of material ranging from silicon, titanium, stainless steel, and polymers. [7] [1] Some microneedles are made of a drug to be delivered to the body but are shaped into a needle so they will penetrate the skin. The microneedles range in size, shape, and function but are all used as an alternative to other delivery methods like the conventional hypodermic needle or other injection apparatus.

Contents

Microneedles are usually applied through even single needle or small arrays. The arrays used are a collection of microneedles, ranging from only a few microneedles to several hundred, attached to an applicator, sometimes a patch or other solid stamping device. The arrays are applied to the skin of patients and are given time to allow for the effective administration of drugs. Microneedles are an easier method for physicians as they require less training to apply and because they are not as hazardous as other needles, making the administration of drugs to patients safer and less painful while also avoiding some of the drawbacks of using other forms of drug delivery, such as risk of infection, production of hazardous waste, or cost.

Background

Microneedles were first mentioned in a 1998 paper by the research group headed by Mark Prausnitz at the Georgia Institute of Technology that demonstrated that microneedles could penetrate the uppermost layer (stratum corneum) of the human skin and were therefore suitable for the transdermal delivery of therapeutic agents. [8] Subsequent research into microneedle drug delivery has explored the medical and cosmetic applications of this technology through its design. This early paper sought to explore the possibility of using microneedles in the future for vaccination. Since then researchers have studied microneedle delivery of insulin, vaccines, anti-inflammatories, and other pharmaceuticals. In dermatology, microneedles are used for scarring treatment with skin rollers.

The major goal of any microneedle design is to penetrate the skin's outermost layer, the stratum corneum (10-15μm). [9] Microneedles are long enough to cross the stratum corneum but not so long that they stimulate nerves which are located deeper in the tissues and therefore cause little to no pain. [8]

Research has shown that there is a limit on the type of drugs that can be delivered through intact skin. Only compounds with a relatively low molecular weight, like the common allergen nickel (130 Da), [10] can penetrate the skin. Compounds that weigh more than 500 Da cannot penetrate the skin. [9]

Types of microneedles

Since their conceptualization in 1998, several advances have been made in terms of the variety of types of microneedles that can be fabricated. The 5 main types of microneedles are solid, hollow, coated, dissolvable/dissolving, and hydrogel-forming. [2]

Solid

This type of array is designed as a two part system; the microneedle array is first applied to the skin to create microscopic wells just deep enough to penetrate the outermost layer of skin, and then the drug is applied via transdermal patch. Solid microneedles are already used by dermatologists in collagen induction therapy, a method which uses repeated puncturing of the skin with microneedles to induce the expression and deposition of the proteins collagen and elastin in the skin. [11]

Hollow

Hollow microneedles are similar to solid microneedles in material. They contain reservoirs that deliver the drug directly into the site. Since the delivery of the drug is dependent on the flow rate of the microneedle, there is a possibility that this type of array could become clogged by excessive swelling or flawed design. [9] This design also increases the likelihood of buckling under the pressure and therefore failing to deliver any drugs.

Coated

Just like solid microneedles, coated microneedles are usually designed from polymers or metals. In this method the drug is applied directly to the microneedle array instead of being applied through other patches or applicators. Coated microneedles are often covered in other surfactants or thickening agents to assure that the drug is delivered properly. [9] Some of the chemicals used on coated microneedles are known irritants. While there is risk of local inflammation to the area where the array was, the array can be removed immediately with no harm to the patient.

Dissolvable

In a more recent adaptation of the microneedle design, dissolvable microneedles encapsulate the drug in a nontoxic polymer which dissolves once inside the skin. [1] 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 microneedles and dissolved once in the body. [12]

Hydrogel-forming

In hydrogel-forming microneedles, medications are enclosed in a polymer. The microneedles can penetrate the stratum corneum and draw up interstitial fluid leading to polymer swelling. Drugs enter the skin from the swollen matrix.

Advantages

There are many advantages to the use of microneedles, the most prominent being the improved comfort of patients. Needle phobia can affect both adults and children, and sometimes can lead to fainting. The benefit of microneedle arrays is that they reduce anxiety that patients have when confronted with a hypodermic needle. In addition to improving psychological and emotional comfort, microneedles have been shown to be substantially less painful than conventional injections. [9] Some studies recorded children's views on blood sampling with microneedles and found patients were more willing when prompted with a less painful procedure than traditional sampling with needles. Microneedles are beneficial to physicians as well, since they produce less hazardous waste than needles and are generally easier to use. Microneedles are also less expensive than needles as they require less material and the material used is cheaper than the materials in hypodermic needles.

Microneedles present a new opportunity for home and community-based healthcare. One of the biggest drawbacks of traditional needles is the hazardous waste that they produce, making disposal a serious concern for doctors and hospitals. For patients who require regular administration of medication at home, disposal can become an environmental concern is needles are placed in the trash. Dissolvable or swelling microneedles would provide those who are limited in their ability to seek hospital care with the ability to safely administer drugs in the comfort of their homes, although disposal of solid or hollow microneedles could still pose a needle-stick or blood borne pathogen infection risk. [1]

Another benefit of microneedles is their lower rates of microbial invasion into delivery sites. [1] [9] Traditional injection methods can leave puncture wounds for up to 48 hours post-treatment. This leaves a large window of opportunity for harmful bacteria to enter into the skin. Microneedles only damage the skin to a depth of 10-15μm, making it difficult for bacteria to enter the bloodstream and giving the body a smaller wound to repair. [6] Further research is required to determine the types of bacteria able to breach the shallow puncture site of microneedles.

Disadvantages

There are some concerns about how physicians can be sure that all of the drug or vaccine has entered the skin when microneedles are applied. Hollow and coated microneedles both possess the risk that the drug will not properly enter the skin and will not be effective. Both of these types of microneedles can leak [13] [9] onto a person's skin either by damage of the microneedle or incorrect application by the physician. This is why it is essential that physicians are trained how to properly apply the arrays.

Another concern is that incorrectly applied arrays could leave foreign material in the body. Although there is a lower risk of infection associated with microneedles, the arrays are more fragile than a typical hypodermic needle due to their small size and thus have a chance of breaking off and remaining in the skin. Some of the material used to construct the microneedles, such as titanium, cannot be absorbed by the body and any fragments of the needles would cause irritation.

There is a limited amount of literature available on the subject of microneedle drug delivery, as current research is still exploring how to make effective needles.

Related Research Articles

<span class="mw-page-title-main">Hypodermic needle</span> Device to inject substances into the circulatory system

A hypodermic needle, one of a category of medical tools which enter the skin, called sharps, is a very thin, hollow tube with one sharp tip. It is commonly used with a syringe, a hand-operated device with a plunger, to inject substances into the body or extract fluids from the body. Large-bore hypodermic intervention is especially useful in catastrophic blood loss or treating shock.

<span class="mw-page-title-main">Route of administration</span> Path by which a drug, fluid, poison, or other substance is taken into the body

A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.

Iontophoresis is a process of transdermal drug delivery by use of a voltage gradient on the skin. Molecules are transported across the stratum corneum by electrophoresis and electroosmosis and the electric field can also increase the permeability of the skin. These phenomena, directly and indirectly, constitute active transport of matter due to an applied electric current. The transport is measured in units of chemical flux, commonly μmol/(cm2*hour). Iontophoresis has experimental, therapeutic and diagnostic applications.

<span class="mw-page-title-main">Transdermal patch</span> Adhesive patch used to deliver medication through the skin

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medication delivery is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered by this method. The first commercially available prescription patch was approved by the U.S. Food and Drug Administration in December 1979. These patches administered scopolamine for motion sickness.

<span class="mw-page-title-main">Topical medication</span> Medication applied to body surfaces

A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including creams, foams, gels, lotions, and ointments. Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be inhalational, such as asthma medications, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of a tooth. The word topical derives from Greek τοπικόςtopikos, "of a place".

<span class="mw-page-title-main">Jet injector</span> Needle-free medical injection syringe

A jet injector is a type of medical injecting syringe device used for a method of drug delivery known as jet injection, in which a narrow, high-pressure stream of liquid penetrates the outermost layer of the skin to deliver medication to targeted underlying tissues of the epidermis or dermis, fat, or muscle.

<span class="mw-page-title-main">Drug delivery</span> Methods for delivering drugs to target sites

Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance. Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices. There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes. Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.

Sonophoresis is a method that utilizes ultrasound to enhance the delivery of topical medications through the stratum corneum, to the epidermis and dermis. Sonophoresis allows for the enhancement of the permeability of the skin along with other modalities, such as iontophoresis, to deliver drugs with lesser side effects. Currently, sonophoresis is used widely in transdermal drug delivery, but has potential applications in other sectors of drug delivery, such as the delivery of drugs to the eye and brain.

Skin absorption is a route by which substances can enter the body through the skin. Along with inhalation, ingestion and injection, dermal absorption is a route of exposure for toxic substances and route of administration for medication. Absorption of substances through the skin depends on a number of factors, the most important of which are concentration, duration of contact, solubility of medication, and physical condition of the skin and part of the body exposed.

<span class="mw-page-title-main">Human skin</span> Outer covering of the body

The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to most of the other mammals' skin, and it is very similar to pig skin. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin, hairy and glabrous skin (hairless). The adjective cutaneous literally means "of the skin".

Medicine in Star Trek refers to the medical technologies, procedures and conditions as seen in the Star Trek fictional universe.

<span class="mw-page-title-main">Transdermal</span>

Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect.

<span class="mw-page-title-main">Phonophoresis</span>

Phonophoresis, also known as sonophoresis, is the method of using ultrasound waves to increase skin permeability in order to improve the effectiveness of transdermal drug delivery. This method intersects drug delivery and ultrasound therapy. Phonophoresis is able to achieve specific and efficient delivery of drugs that are delivered through the skin and ensure that the drug reaches the targeted area in the tissue environment. By assisting transdermal drug delivery, phonophoresis can help patients experience painless, minimal risk, and effective treatment.

<span class="mw-page-title-main">Intradermal injection</span> Medical injection into the dermis

Intradermal injection, often abbreviated ID, is a shallow or superficial injection of a substance into the dermis, which is located between the epidermis and the hypodermis. For certain substances, administration via an ID route can result in a faster systemic uptake compared with subcutaneous injections, leading to a stronger immune response to vaccinations, immunology and novel cancer treatments, and faster drug uptake. Additionally, since administration is closer to the surface of the skin, the body's reaction to substances is more easily visible. However, due to complexity of the procedure compared to subcutaneous injection and intramuscular injection, administration via ID is relatively rare, and is only used for tuberculosis and allergy tests, Monkeypox vaccination, and certain therapies.

IOMAI was a Biotech company founded in 1997 by Gregory Glenn M.D. of the Walter Reed Army Institute of Research and Dean Lewis, a World Bank employee. The company was the first to develop the concept of transcutaneous immunization, delivery of vaccines to the skin using a patch or similar method. This provided a means to stimulate robust immune responses safely as the skin patch-based immunization targeted Langerhans cells in the skin. The patch technology underwent extensive evaluation in the context of a traveler's diarrhea vaccine which entered Phase 3 pivotal trials in 2009. IOMAI was acquired by Intercell in 2008 and the technology was the subject of a development license to GSK in 2009. Dr. Glenn pioneered needle free delivery to the skin and spawned general interest in skin-targeting vaccine technologies, including intradermal delivery and the use of the heat labile toxin as an adjuvant and the adjuvant patch.

<span class="mw-page-title-main">Joseph Kost</span> Chemical engineering researcher

Joseph Kost is an Israeli academic, currently holder of The Abraham and Bessie Zacks Chair in Biomedical Engineering and the past Dean of the Faculty of Engineering Sciences at the Ben-Gurion University of the Negev.

<span class="mw-page-title-main">Smart insulin patch</span> Wearable medical device

A smart insulin patch, also known as a glucose-responsive insulin patch, is a type of wearable medical device for diabetes treatment. It is a transdermal patch comprising glucose-sensitive microneedle-array loaded with insulin for blood glucose regulation. Once applied on the skin, the microneedles penetrate under the skin and can sense blood sugar levels. If glucose levels go up, it can promote the release of insulin, which is transported through the regional lymph and capillary vessels for glucose regulation.

<span class="mw-page-title-main">Topical cream formulation</span>

Topical cream formulation is an emulsion semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and volatiles and/or less than 50 per cent of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external skin application. In a topical cream formulation, ingredients are dissolved or dispersed in either a water-in-oil (W/O) emulsion or an oil-in-water (O/W) emulsion. The topical cream formulation has a higher content of oily substance than gel, but a lower content of oily ingredient than ointment. Therefore, the viscosity of topical cream formulation lies between gel and ointment. The pharmacological effect of the topical cream formulation is confined to the skin surface or within the skin. Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. Topical cream formulation is used for a wide range of diseases and conditions, including atopic dermatitis (eczema), psoriasis, skin infection, acne, and wart. Excipients found in a topical cream formulation include thickeners, emulsifying agents, preservatives, antioxidants, and buffer agents. Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of active substances, and homogenization of the product mixture.

Topical drug delivery (TDD) is a route of drug administration that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like eczema. The formulation of topical drugs can be classified into corticosteroids, antibiotics, antiseptics, and anti-fungal. The mechanism of topical delivery includes the diffusion and metabolism of drugs in the skin. Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like ointments and potions were used on the skin. The delivery of topical drugs needs to pass through multiple skin layers and undergo pharmacokinetics, hence factor like dermal diseases minimize the bioavailability of the topical drugs. The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like liposomes and nanotechnologies are used to enhance the absorption of topical drugs. On the other hand, physical agents, like micro-needles is other approach for enhancement ofabsorption. Besides using carriers, other factors such as pH, lipophilicity, and drug molecule size govern the effectiveness of topical formulation.

<span class="mw-page-title-main">Mark Prausnitz</span>

Mark Robert Prausnitz is an American chemical engineer, currently Regents’ Professor and J. Erskine Love, Jr. Chair in Chemical & Biomolecular Engineering at the Georgia Institute of Technology, He also serves as Adjunct Professor of Biomedical Engineering at Emory University and Adjunct Professor of Chemical & Biomolecular Engineering at the Korea Advanced Institute of Science and Technology. He is known for pioneering microneedle technology for minimally invasive drug and vaccine administration, which has found applications in transdermal, ocular, oral, and sustained release delivery systems.

References

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  2. 1 2 Dharadhar S, Majumdar A, Dhoble S, Patravale V (February 2019). "Microneedles for transdermal drug delivery: a systematic review". Drug Development and Industrial Pharmacy. 45 (2): 188–201. doi:10.1080/03639045.2018.1539497. PMID   30348022. S2CID   53039251.
  3. ↑ Panda A, Matadh VA, Suresh S, Shivakumar HN, Murthy SN (January 2022). "Non-dermal applications of microneedle drug delivery systems". Drug Delivery and Translational Research. 12 (1): 67–78. doi:10.1007/s13346-021-00922-9. PMID   33629222. S2CID   232047454.
  4. ↑ Thakur RR, Tekko IA, Al-Shammari F, Ali AA, McCarthy H, Donnelly RF (December 2016). "Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery". Drug Delivery and Translational Research. 6 (6): 800–815. doi: 10.1007/s13346-016-0332-9 . PMC   5097091 . PMID   27709355.
  5. ↑ Peppi M, Marie A, Belline C, Borenstein JT (April 2018). "Intracochlear drug delivery systems: a novel approach whose time has come". Expert Opinion on Drug Delivery. 15 (4): 319–324. doi: 10.1080/17425247.2018.1444026 . PMID   29480039.
  6. 1 2 Kim YC, Park JH, Prausnitz MR (November 2012). "Microneedles for drug and vaccine delivery". Advanced Drug Delivery Reviews. 64 (14): 1547–1568. doi:10.1016/j.addr.2012.04.005. PMC   3419303 . PMID   22575858.
  7. ↑ Park JH, Allen MG, Prausnitz MR (May 2005). "Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery". Journal of Controlled Release. 104 (1): 51–66. doi:10.1016/j.jconrel.2005.02.002. PMID   15866334.
  8. 1 2 Henry S, McAllister DV, Allen MG, Prausnitz MR (August 1998). "Microfabricated microneedles: a novel approach to transdermal drug delivery". Journal of Pharmaceutical Sciences. 87 (8): 922–925. doi:10.1021/js980042+. PMID   9687334. S2CID   14917073.
  9. 1 2 3 4 5 6 7 Jeong HR, Lee HS, Choi IJ, Park JH (January 2017). "Considerations in the use of microneedles: pain, convenience, anxiety and safety". Journal of Drug Targeting. 25 (1): 29–40. doi:10.1080/1061186x.2016.1200589. PMID   27282644. S2CID   44629532.
  10. ↑ Bos JD, Meinardi MM (June 2000). "The 500 Dalton rule for the skin penetration of chemical compounds and drugs". Experimental Dermatology. 9 (3): 165–169. doi: 10.1034/j.1600-0625.2000.009003165.x . PMID   10839713.
  11. ↑ McCrudden MT, McAlister E, Courtenay AJ, González-Vázquez P, Singh TR, Donnelly RF (August 2015). "Microneedle applications in improving skin appearance". Experimental Dermatology. 24 (8): 561–566. doi: 10.1111/exd.12723 . PMID   25865925.
  12. ↑ Mottaghitalab F, Farokhi M, Shokrgozar MA, Atyabi F, Hosseinkhani H (May 2015). "Silk fibroin nanoparticle as a novel drug delivery system". Journal of Controlled Release. 206: 161–176. doi:10.1016/j.jconrel.2015.03.020. PMID   25797561.
  13. ↑ Rzhevskiy AS, Singh TR, Donnelly RF, Anissimov YG (January 2018). "Microneedles as the technique of drug delivery enhancement in diverse organs and tissues". Journal of Controlled Release. 270: 184–202. doi:10.1016/j.jconrel.2017.11.048. hdl: 10072/376324 . PMID   29203415. S2CID   205883540.

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