
A transdermal patch is a
medicated adhesive
Adhesive, also known as glue, cement, mucilage, or paste, is any non-metallic substance applied to one or both surfaces of two separate items that binds them together and resists their separation.
The use of adhesives offers certain advantage ...
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 animal coverings, such as the arthropod exoskeleton, have different ...
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 (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 List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
in December 1979. These patches administered
scopolamine for
motion sickness
Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include ...
.
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 is the
nicotine patch
A nicotine patch is a transdermal patch that releases nicotine into the body through the skin. It is used in nicotine replacement therapy (NRT), a process for smoking cessation. Endorsed and approved by the U.S. Food and Drug Administration, it ...
, which releases
nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
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 released from the mouth, as is generally done with pipes and cigars. The practice is believed to hav ...
. The first commercially available vapour patch to reduce smoking was approved in Europe in 2007.
* Two
opioid
Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
medications used to provide round-the-clock relief for severe pain are often prescribed in patch form,
fentanyl
Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...
CII (marketed as
Duragesic) and
buprenorphine CIII (marketed as
BuTrans).
* Hormonal patches:
**
Estrogen patches are sometimes prescribed to treat
menopausal symptoms (as well as post-menopausal
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk.
It is the most common reason f ...
) and to
transgender women 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. Effects of menopause can include symptoms such ...
.
**
Contraceptive patch
A contraceptive patch, also known as "the patch", is a transdermal patch applied to the skin that releases synthetic oestrogen and progestogen hormones to prevent pregnancy. They have been shown to be as effective as the combined oral contra ...
es (marketed as
Ortho Evra or
Evra) and
**
Testosterone
Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
CIII patches for both men (Androderm) and women (Intrinsa).
*
Nitroglycerin
Nitroglycerin (NG) (alternative spelling nitroglycerine), also known as trinitroglycerol (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless or pale yellow, oily, explosive liquid most commonly produced by ...
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 parti ...
in lieu of
sublingual pills.
* Transdermal
scopolamine is commonly used as a treatment for
motion sickness
Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include ...
.
* The anti-hypertensive drug
clonidine is available in transdermal patch form.
*
Emsam, a transdermal form of the
MAOI selegiline
Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...
, became the first transdermal delivery agent for an
antidepressant
Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.
Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
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 a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
transdermal delivery system for the treatment of
attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...
(ADHD), was approved by the FDA in April 2006.
*
Secuado, a transdermal form of the
atypical antipsychotic asenapine, was approved by the FDA in October 2019.
*
5-Hydroxytryptophan (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 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 Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifi ...
".
[
* Caffeine patches, designed to deliver ]caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
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
The term narcotic (, from ancient Greek ναρκῶ ''narkō'', "I make numb") originally referred medically to any psychoactive compound with numbing or paralyzing properties. In the United States, it has since become associated with opiates ...
overdose
A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014. in patients using Duragesic, the fentanyl
Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...
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
Johnson & Johnson (J&J) is an American multinational pharmaceutical, biotechnology, and medical technologies corporation headquartered in New Brunswick, New Jersey, and publicly traded on the New York Stock Exchange. Its common stock is a c ...
) and Sandoz, 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
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
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:
*Release liner
A release liner or ''release paper'', also called a ''backing liner'', is a paper or plastic-based film sheet (usually applied during the manufacturing process) used to prevent a sticky surface from prematurely adhering. It is coated on one or bo ...
– 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
* Penetration 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
Vinyl acetate is an organic compound with the Chemical formula, formula CH3CO2CH=CH2. This colorless liquid is the precursor to polyvinyl acetate, ethylene-vinyl acetate copolymers, polyvinyl alcohol, and other important industrial polymers.
Prod ...
on one surface. This patch is also backed by the backing layer. In this type of system the rate of release is zero order. Reservoir patches should not be cut (with the exception of hyoscine hyrdobromide 1.5mg patch according to the British National Formulary for Children).
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. The release rate is determined by the physical properties of the matrix. Also known as a monolithic device. Limited research indicates that it may be possible to cut some matrix patches to provide lower doses, provided the cut part not immediately used is stored at cool temperatures.
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 Addiction, addictive and can cause Substance dependence, dependence. As a resu ...
.
Microneedle patch
The microneedle patch (MNPs) is a type of transdermal patch which retains the advantages, but reduces the disadvantages of basic transdermal patches. Embedding as many as 102-104 needles per square centimetre of patch, encapsulated or coated with intended drug, MNPs can easily pass skin tissue known as the stratum corneum
The stratum corneum (Latin language, Latin for 'horny layer') is the outermost layer of the epidermis (skin), epidermis. Consisting of dead tissue, it protects underlying tissue from infection, dehydration, chemicals and mechanical stress. It is ...
which is roughly 20 μm in thickness, allowing up to the size of macromolecule
A macromolecule is a "molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass." Polymers are physi ...
to pass. MNPs were developed mainly because transdermal patch can deliver smaller size or micronized molecules such as nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
and birth control
Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...
which 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 people 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
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
, and the second one is water-soluble needles made out of saccharide
A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' m ...
s or soluble polymers.
MNPs can also be engineered to deliver molecules into other tissues. Some that as of 2018 have been 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.
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) 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.
# Pain-free.
# 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 themself.
# 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, 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 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
MNPs may cause skin irritation on people with sensitive skin. Majority of studies show that MNPs do not irritate the skin.
Especially for hollow MNPs, the not so stiff needles may cause unnecessary puncture of the skin outer layer, and 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 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 assura ...
combined with a drug 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
The 10th US-Japan Symposium on Drug Delivery Systems
Using Skin Patch Medicines Safely
{{DEFAULTSORT:Transdermal Patch
Routes of administration
Drug delivery devices
Dosage forms