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A transdermal patch is a
medicated A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and rel ...
adhesive patch that is placed on the
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
to deliver a specific
dose Dose or Dosage may refer to: Music * ''Dose'' (Gov't Mule album), 1998 * ''Dose'' (Latin Playboys album) * ''Dosage'' (album), by the band Collective Soul * "Dose" (song), a 2018 song by Ciara * "Dose", song by Filter from the album '' Short ...
of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medication delivery (such as oral, topical, intravenous, or intramuscular) 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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
in December 1979. These patches administered
scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomit ...
for motion sickness. In order to overcome restriction from the skin, researchers have developed microneedle transdermal patches (MNPs), which consist of an array of microneedles, which allows a more versatile range of compounds or molecules to be passed through the skin without having to micronize the medication beforehand. MNPs offer the advantage of controlled release of medication and simple application without medical professional assistance required. With advanced MNPs technology, drug delivery can be specified for local usage, for example skin whitener MNPs that are applied to the face. Many types of MNPs have been developed to penetrate tissues other than skin, such as internal tissues of the mouth and digestive tract. These promote faster and more direct delivery of the molecule to the targeted area.


Applications

* The highest selling transdermal patch in the United States of America is the nicotine patch, which releases nicotine in controlled doses to help with cessation of
tobacco smoking Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is belie ...
. The first commercially available vapour patch to reduce smoking was approved in Europe in 2007. * Two
opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioi ...
medications used to provide round-the-clock relief for severe pain are often prescribed in patch form,
fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine ...
CII (marketed as Duragesic) and
buprenorphine Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal ...
CIII (marketed as BuTrans). * Hormonal patches: ** Estrogen patches are sometimes prescribed to treat menopausal symptoms (as well as post-menopausal osteoporosis) and to
transgender women A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...
as a type of
hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
. ** Contraceptive patches (marketed as Ortho Evra or Evra) and **
Testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...
CIII patches for both men (Androderm) and women (Intrinsa). * Nitroglycerin patches are sometimes prescribed for the treatment of
angina Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of obstruc ...
in lieu of sublingual pills. * Transdermal
scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomit ...
is commonly used as a treatment for motion sickness. * The anti-hypertensive drug
clonidine Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal ( alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, an ...
is available in transdermal patch form. *
Emsam Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
, a transdermal form of the MAOI
selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
, became the first transdermal delivery agent for an
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...
approved for use in the U.S. in March 2006. * Daytrana, the first
methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...
transdermal delivery system for the treatment of
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
(ADHD), was approved by the FDA in April 2006. *
Secuado Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder. It was chemically derived via altering the chemical structure of th ...
, a transdermal form of the
atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
asenapine, was approved by the FDA in October 2019. * Vitamin B12 may also be administered through a transdermal patch. Cyanocobalamin, a highly stable form of vitamin B12, is compatible with transdermal patching. *
5-Hydroxytryptophan 5-Hydroxytryptophan (5-HTP), also known as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. Uses 5-HTP is sold over the cou ...
(5-HTP) can also be administered through a transdermal patch, which was launched in the United Kingdom in early 2014. * Rivastigmine, an Alzheimer's treatment medication, was released in patch form in 2007 under the brand name Exelon. * In December 2019,
Robert S. Langer Robert Samuel Langer Jr. FREng (born August 29, 1948) is an American chemical engineer, scientist, entrepreneur, inventor and one of the twelve Institute Professors at the Massachusetts Institute of Technology. He was formerly the Germeshaus ...
and his team developed and patented a technique whereby transdermal patches could be used to label people with invisible ink in order to store medical information subcutaneously. This was presented as a boon to "developing nations" where lack of infrastructure means an absence of medical records. The technology uses a " quantum dot dye that is delivered along with a
vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. ...
". *
Caffeine patch A caffeine patch is a type of a transdermal patch designed to deliver caffeine to the body through the skin. The concept is similar to that of a nicotine patch. References Transdermal patches Caffeine {{medicine-stub ...
es, designed to deliver
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
to the body through the skin.


Adverse events

*In 2005, the FDA announced that they were investigating reports of death and other serious adverse events related to narcotic overdose in patients using Duragesic, the
fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine ...
transdermal patch for pain control. The Duragesic product label was subsequently updated to add safety information in June 2005. *In 2007, Shire and Noven Pharmaceuticals, manufacturers of the Daytrana ADHD patch, announced a voluntary recall of several lots of the patch due to problems with separating the patch from its protective release liner. Since then, no further problems with either the patch or its protective packaging have been reported. *In 2008, two manufacturers of the fentanyl patch, ALZA Pharmaceuticals (a division of major medical manufacturer Johnson & Johnson) and
Sandoz Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
, subsequently issued a recall of their versions of the patch due to a manufacturing defect that allowed the gel containing the medication to leak out of its pouch too quickly, which could result in overdose and death. As of March 2009, Sandoz—now manufactured by ALZA—no longer uses gel in its transdermal fentanyl patch; instead, Sandoz-branded fentanyl patches use a matrix/adhesive suspension (where the medication is blended with the adhesive instead of held in a separate pouch with a porous membrane), similar to other fentanyl patch manufacturers such as Mylan and Janssen.As stated on the packaging and labels of Sandoz-branded Fentanyl Transdermal System products, revised March 2009. *In 2009, the FDA announced a public health advisory warning of the risk of burns during MRI scans from transdermal drug patches with metallic backings. Patients should be advised to remove any medicated patch prior to an MRI scan and replace it with a new patch after the scan is complete. *In 2009, an article in ''Europace'' journal detailed stories of skin burns that occurred with transdermal patches that contain metal (usually as a backing material) caused by shock therapy from external as well as internal cardioverter defibrillators (ICD).Brown, MR: "Analgesic patches and defibrillators: a cautionary tale", ''Europace'',2009 Nov;11(11):1552-3


Components

The main components to a transdermal patch are: *Liner - Protects the patch during storage. The liner is removed prior to use. *Drug - Drug solution in direct contact with release liner *Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin *Membrane - Controls the release of the drug from the reservoir and multi-layer patches *Backing - Protects the patch from the outer environment *Permeation Enhancer - These are permeation promoters for drugs, which increase delivery of drug. *Matrix Filler - Provides bulk to the matrix, and some act as matrix stiffening agents. Other components include stabilizers (antioxidants), preservatives etc.


Types

There are five main types of transdermal patches.


Single-layer Drug-in-Adhesive

The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing. It is characterized by the inclusion of the drug directly within the skin-contacting adhesive placed onto the epidermis.


Multi-layer Drug-in-Adhesive

The multi-layer drug-in-adhesive patch is similar to the single-layer system; the multi-layer system is different, however, in that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). One of the layers is for immediate release of the drug, and the other layer is for controlled release of the drug from the reservoir. This patch also has a temporary liner-layer and a permanent backing. The drug release from this depends on membrane permeability and diffusion of drug molecules.


Reservoir

Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. The drug reservoir is totally encapsulated in a shallow compartment molded from a drug-impermeable metallic plastic laminate, with a rate-controlling membrane made of a polymer like vinyl acetate on one surface. This patch is also backed by the backing layer. In this type of system the rate of release is zero order.


Matrix

The matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer, partially overlaying it. Also known as a monolithic device.


Vapour Patch

In a vapour patch, the adhesive layer not only serves to adhere the various layers together but also to release vapour. Vapour patches release essential oils for up to 6 hours and are mainly used for decongestion. Other vapour patches on the market improve quality of sleep or aid in
smoking cessation Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often m ...
.


Microneedle patch

The microneedle patch (MNPs) is a type of transdermal patch that retains the advantages, but reduces the disadvantages, of basic transdermal patches. Embedding as many as 102-104 needles per square centimeter of patch, encapsulated or coated with intended drug, MNPs can easily pass skin tissue known as the
stratum corneum The stratum corneum (Latin for 'horny layer') is the outermost layer of the epidermis. The human stratum corneum comprises several levels of flattened corneocytes that are divided into two layers: the ''stratum disjunctum'' and ''stratum compac ...
that is roughly 20 μm in thickness, allowing up to the size macromolecule to pass. The development of MNPs is mainly because selective transdermal patch can deliver smaller size or micronized molecules such as nicotine and birth control that easily diffuse and penetrate the skin, but lack in delivering macro or large size molecules. The 100-1000 μm needles spread across the patch, making sure patients will not feel any discomfort from the patch. There are two types of needles used in MNPs, the first one is non-water-soluble needles made out of metal, ceramic, or polymer, and the second one is water-soluble needles made out of saccharides or soluble polymers. Other than skin patches, MNPs can also be engineered to deliver molecules in different tissues. Some that are under development include internal surfaces such as the mouth, vagina, gastrointestinal tract, and vascular wall; and external surfaces such as the skin, eyes, fingernails, anus, and scalp. This allows targeting a more specific area of wanted delivery, without having to solely rely on diffusion on blood flow like a normal transdermal patch.


MNPs Drug Delivery

As mentioned earlier, MNPs deliver more efficient delivery compared to topical or oral intake. In drug delivery study, researchers want to gain faster
peak concentrations Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pharm ...
(Cmax) in MNPs compared to other methods. Study shows that MNPs reach peak concentration as fast as 20 minutes (tmax), while oral intake reaches peak concentration in one hour. Furthermore, the Cmax from MNPs is higher up to six times, compared to oral intake. Making the delivery fast and the body gets the most concentration of intended drugs. This value is only matched with direct injection, but with skin trauma and people with needle phobia, MNPs might be an alternative to reach roughly the same time and concentration. In order to get more direct local delivery, MNPs can be used in different tissues other than the skin. In Table 1, there are at least five internal surfaces that MNPs have been studied for its delivery and four other external surfaces other than the skin.


Types of Microneedle

There are many types of microneedle that are distinguished by the shape and other characteristics. The types include: Dissolvable MNPs, solid non-soluble MNPs, and hollow MNPs. Different MNPs may be chosen depending on the situation and the drug properties.


Soluble or Dissolvable MNPs

One of the types of MNPs are water-soluble needles made out of soluble polymers or saccharide. However, dissolvable needles cannot efficiently deliver drugs to the dermal layer. Drug maximum concentration cannot be carried out to the skin, as the needles will dissolve beforehand. Fortunately, researchers have developed a water-insoluble backing layer, making the needle last longer in the human body environment. This design enables efficient delivery of more than 90% of the drug within 5 minutes of application of MNPs to the skin.


Non-soluble or Undissolvable MNPs

Other than dissolvable MNPs, needles can also be made out of metal or ceramic that will not dissolve in the body environment. These coated drug needles can deliver consistent concentration of drugs without the needles dissolving in the body. This kind of MNPs has better performance, but compared to the soluble MNPs, metal or ceramic MNPs are the older version of MNPs. Even if the patches are small, the metal or ceramic MNPs may cause several waste issues. Recycling the metal and ceramic are very hard, as the quantity is very small to overcome the cost to recycle. That is why researchers try to develop the dissolvable MNPs with similar characteristic and performance of drug delivery in non-soluble MNPs.


Hollow MNPs

Among all of the MNPs, hollow needles allow a bigger amount of delivery up to 200μL. The mechanism mimics the operation of a hypodermic, but the fabrication is hard and complex. The hollow needles introduce a potential failure if the insertion is improper. That is why, among the others, hollow MNPs are the least popular because of the complex manufacturing and applying process.


Advantages

# The MNPs may puncture the skin surface, enabling rapid onset of drug bypassing directly into the dermal capillaries. # Painfree. # Can be localized to provide direct access to the intended tissues. # Less dependent on skilled medical workers, as MNPs can be administered safely by the patient itself. # Some drugs have poor solubility in water, with MNPs insoluble drugs and compounds can be directly "injected" to the dermal layer. Further enhancing the transdermal delivery of insoluble drugs. # Better safety compared to needle and syringe method (needlestick). Less waste, eliminate pathogen transmission, and injuries. At least 300,000 needlestick related injuries occurred in the US annually, with disposal contribute to almost half of the injuries.


Application


MNPs as Vaccine Delivery Platform

MNPs vaccination might be an alternative from direct injection. Able to deliver bigger molecules than transdermal patch, MNPs can also deliver bioactive molecules with different physical sizes. Meaning that inactive virus or pathogen can be introduced in the body without discomfort or skin irritation from conventional injection. Possibly it can also reduce the cost of storage that usually needs to be transported in a particular temperature and condition. Stated in cdc.gov website,
Mark Prausnitz 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 E ...
, co-developer of the microneedle, says "A major advantage of the microneedle patch would be the ease of delivery." The MNPs are small and thin compared to bottles of vial, making it possible to transport in massive quantities in a single trip. Medical waste such as syringes and dirty needles are also eliminated, reducing the possibility of pathogen transmission of blood-borne disease in rural areas. In a study, measles coated MNPs might be resistant to higher temperature compared to vial transport. Higher temperature resistance is a safe bet in low income countries, where there is no such luxury for refrigeration. Furthermore, the delivery of the vaccine is controlled by the MNPs. Less requiring highly trained medical workers in developing countries to apply the vaccine. However, the study in MNPs measles vaccine is still under development, but opening possibilities in the future for other types of vaccines


MNPs to Reduce Obesity

Obesity is one of the most popular topics in developed countries nowadays. Researchers have tried to reduce obesity rate using certain drugs, one in particular known as browning compound. In order to target a certain group of fat tissue, MNPs is utilized and shows that the patch can deliver browning nano particles to a certain group of fat tissue. By doing so, the drug's side effects can be reduced as MNPs are localized. The result shows that in mice experiments in a four weeks period, the white fat of the mice shrunk. Furthermore, an improved metabolism in the mice also signifies that the experiment to reduce obesity using MNPs might be worth testing in the future. If the research has been proved successful, MNPs treatment might be a great choice, as direct injection obesity drugs need medical professional assistance. While here, MNPs can be done by the patient without special skills.


MNPs for Cosmetic and Skin Care

Skin treatment including face whitening agent and dark eye circles serum can also incorporated in MNPs. Its localized property enhance skin whitening delivery to the face area. Even a very specific spot like dark eye circles. By measuring the melanin (dark or black pigment found on the skin) index, subjects that are treated with whitening agents coated in MNPs show lower melanin index, compared to the whitening essence (topical) group. The treatment lasts for eight weeks, and the result shows MNPs might be a promising cosmetic vector because MNPs does not introduce skin irritation and can be engineered to localize or specific parts of the body.


Safety

Micro Needle Patch (MNPs) might be another choice of safety compared to direct injection using candlestick. Not only safety in handling, MNPs also promote better disposal and prevent pathogen transmission. Under extraordinary circumstances, MNPs may cause complication mentioned below.


Skin Irritation

Under rare circumstances, MNPs may cause skin irritation on people with sensitive skin. Majority of studies show that MNPs do not irritate the skin, but does not close the possibility for sensitive skin group of people.


Improper Application

Especially for hollow MNPs, the not so stiff needles may cause unnecessary puncture to the skin outer layer. Thus may cause trauma to the skin and restricting the performance and flow of the drugs to the body.


Future Development

Because most of MNPs applications are still under development, it is important to note the long effect of the efficiency of the drug deliveries. Furthermore, more research is needed to get information of what molecule can be delivered using MNPs. Disposal is also an important topic, as the small plastic backing may contribute to water pollution remembering the compact size can be easily carried away by wind and water without proper disposal.


Regulatory aspects

A transdermal patch is classified by the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
as a ''combination product'', consisting of a
medical device A medical device is any device intended to be used for medical purposes. Significant potential for hazards are inherent when using a device for medical purposes and thus medical devices must be proved safe and effective with reasonable assur ...
combined with a
drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...
or biological product that the device is designed to deliver. Prior to sale in the United States, any transdermal patch product must apply for and receive approval from the Food and Drug Administration, demonstrating safety and efficacy for its intended use.


See also

* IOMAI


References


Further reading

* Ita K. Chapter 1 - Transcutaneous drug administration. In: Ita K, editor. Transdermal Drug Delivery: Academic Press; 2020. p. 1-7.


External links


PlastoPharmaThe 10th US-Japan Symposium on Drug Delivery Systems

ProSolus Pharmaceuticals - Transdermal development and manufacturingUsing Skin Patch Medicines Safely
{{DEFAULTSORT:Transdermal Patch Routes of administration Drug delivery devices Dosage forms