Hemp extract pain patches (aka CBD pain patches) are really taking off in the market these days, quickly eclipsing other topical applications by leaps and bounds. But some have been surprised at how long that took. It makes sense when you think about it, though. Transdermal patches have been previously unfamiliar to the common consumer, and unless you’ve used one, maybe to stop smoking or for post-surgical pain, you probably walked right by the hemp extract pain patches at your local market or drug store, totally unaware of their benefits.
Today, transdermal patches like CBD pain patches are the outcome of many years of research and development in skin science technology and trial and error in the drug delivery field. But their use can be traced back all the way through to ancient history in some form or another.
Ancient History of Topical Skin Applications
The human skin is simply amazing. The largest organ in the human body, it covers an area of up to 2 square meters, has the ability to renew and regenerate itself naturally every few weeks, and is our waterproof barrier, yet it can emit water and other liquids as well as absorb them. Topical therapies–bandaged, rubbed, or applied to the skin, have likely been used since the origin of human evolution. We have written records of such practices as far back as on the clay tablets used by the Sumerians.
Anthropologists believe that a liquefied ochre-rich mixture, made some 100 000 years ago and found at the Blombos Cave in South Africa, may have been used for decoration and skin protection. Ancient Egyptians used oils, fats, and scents like bitter almonds and rosemary for cosmetic and dermatologic products, and early proof of the skin’s ability to absorb what we apply to it, slowly poisoned themselves with lead-based pigments.
The well-known Papyrus Ebers (1550 BC) is thought to be the best pharmaceutical record from ancient times. It not only contains many recipes for treating skin conditions, but also poultices for such ailments as the weakness of the male member, topical application of frankincense to expel pain in the head, and a product applied to the belly of a woman or a man to expel pains caused by tapeworm, and other remedies that serve as some of our earliest examples of the first transdermal delivery of drugs for systemic effects.
A millennium and a half later, a Greek physician named Galen (AD 129–199), often considered the father of pharmacy for his introduction of herbal drugs into dosage forms, compiled his teachings into a tomb known as the Gaelenic Pharmacy. Within it appears one of his most famous formulas: Gaelen’s Cerate, a cold cream with a composition relatively similar to the one still used today.
In Asia, medicated plasters, widely considered true predecessors to the modern transdermal patch, can be traced all the way back to around 2000 BC. These emplastra were composed of multiple herbal drugs dispersed into an adhesive natural gum rubber base applied to a fabric or paper backing. This was in contrast to the simpler Western style, which usually contained only a single ingredient, such as the nicotine one during the time of Paracelus (1493 – 1541).
The idea of drugs being able to pass through the skin barrier appears in the work of Ibn Sina (AD 980–1037), a Persian physician best known as Avicenna within the Western World. He suggested drugs applied to the skin can affect the tissue and local joints, but also remote areas, suggesting systemic effects. One of his treatments for sciatica pain was a plaster-like formula in which sulphur was mixed with tar and applied to the skin with a piece of paper employed as backing to keep the formulation in place. Other transdermal forerunners include a syphilis treatment in the late 15th century made of purified mercury, lard, and suet.
The Industrial Revolution and a Phase of ‘Non-Belief’
The Industrial Revolution saw a jump in transdermal science, much as it did in most all other areas of scientific inquiry. Acceptance of the transdermal properties of certain medications met advances in plaster (patch) innovations, and the modern era of transdermal products approached infancy. It was not, however, without its significant ups and downs.
The 1800’s in The West seemed to suggest a rise in transdermal use, with the German Pharmacopoeia 1872, listing 28 Emplastra formulae. These included adhesive products meant to produce systemic effects (like Emplastrum aromaticum, which contained peppermint and other aromatic oils targeted for the treatment of the stomach), as well as early pain patches [AC2] [AC3] containing belladonna (for T.B., and tumors) or opium (for stomach movement and pain). Some of these, like the Belladonna Plaster, are well-known for having made their way into the US pharmacopeia as well.
But by 1883, a second edition featured only 11, including Leukoplast®, which was invented in 1882 and is still used today. It is unclear exactly what brought this shift in thinking away from transdermal innovations, but in 1877, one review still suggested that intact human skin was totally impermeable to all substances, even though several cases of systemic poisoning after external application of belladonna were reported in the British Medical Journal in the 1860–1870s. It would be almost a hundred years before the torch of transdermal inquiry would be picked back up.
The Modern Era and the Transdermal Patches Boom
By the early 20th century, it once again became widely accepted that the skin was relatively permeable. This understanding was, in part, due to several incidences of poisoning that occurred in the early part of the century. In the early 1900’s France, there were reports of poisoning in children after topical application of nitrobenzene or aniline dyes in dyed clothing or shoes. Another case of a young man who died from the systemic absorption of phenol over a large body surface after the accidental spillage of a bottle of phenol over himself further emphasized the consequences of exposure, or indeed, overexposure to drugs that come in contact with the skin.
Various transdermal experiments in vivo (on live subjects) throughout the first half of the century and beyond proved topical absorption by measuring the drug levels in blood and urine. The first report of clinically managing a systemic condition with topical application was the work of a gynecologist named Berhard Zondek. In the 1950s this German-born Israeli found that an external disinfectant called chloroxylenol (still used in soaps today) could be an effective treatment for urogenital infections when a 30% lanolin ointment was applied.
But for transdermal technologies to advance past the ointments and plasters of the historic past, advances were needed in the ability to maximize and control the rate of absorption over time. This came, in part, with the work of Dale Wurster in 1961. By adding a diffusion cell to a bandage with a drug on it, Wurster discovered that he could modify the amount of absorption when he varied the diffusion area of the cell, combined with changing the level of hydration in the skin. That primitive diffusion cell would become the forerunner of what was to come and can now be looked back at as the first prototype of the transdermal patch of today.
From there, advances were made in the development of adhesive transdermal delivery methods until cadaver experiments produced solid enough results to warrant the culling together of a list of ideal drug candidates with promising enough transdermal properties for the next phase, considered the “transdermal boom.” To be thought of as ideal for transdermal application, even to this day, molecule size is key—it has to be small enough to fit through the curtain of the skin’s layers of cells easily. Scopolamine, nitroglycerin, estradiol, and fentanyl all emerged as early candidates.
What followed was a progression of first and second-generation transdermal drug delivery systems (TDDs, or patches) for these drugs and a few others, from the 1970s to the 1990s, each having proved effective in their own right. The very first was a scopolamine [AC4] patch used for motion sickness, best placed behind the ear. Invented in 1961by biotechnology innovator Alejandro Zaffaroni via his company, Alza, the patch was developed and tested on Alza employees in a particularly rough part of the San Francisco Bay known as the Potato Patch. But the application actually harkened all the way back to the ancients’ Papyrus Ebers, where Powder of Hyoscyamus (scopolamine’s parent plant) appeared as a topical treatment for abdominal discomfort.
In the latter half of the 20th and the first part of the 21st century, administering medications via transdermal patches has proven to have many benefits over oral and other conventional methods. Transdermal delivery ensures patient compliance for one thing: no more forgotten doses. Too, bioavailable absorption through the skin can be far better and more controlled than oral methods. This improved bioavailability is because transdermals avoid something called first-pass metabolism, which happens when the amount of a drug absorbed is drastically reduced when taken orally because part of it is lost during the process of absorption through the liver and gut wall, thus administering a less than therapeutic (subtherapeutic) dose[AC5].
The World of Transdermal Patches and CBD
Like topical treatments themselves, treating with the cannabis plant has been around since the ancients, with the first record of use in medicine dating back to Chinese Emperor Shennong, of 2700 BCE. CBD (cannabidiol), a compound in the plant without the psychoactive effects of marijuana, is an ideal candidate for transdermal application for many reasons.
In addition to the fact that the molecule size is ideal for skin transmission, CBD is a perfect medicine for skin application for other reasons as well. This is because it works by stimulating receptors in the body that are part of our endocannabinoid system (ECS), responsible for regulating functions like pain, mood, and sleep. Our skin actually contains a good deal of those receptors, allowing the medication to get right to work once applied. Too, hemp extract works best when consistent dosage is allowed to build up in the bloodstream over time—something transdermal application makes easy. Finally, the low oral bioavailability of cannabinoids due to significant first-pass metabolism has led to considerable exploration into other methods of administration like the transdermal route, with great success.
With new advances every year, the latest in hemp extract patch technology allows for multiple days of care and high rates of absorption. There are three variations of hemp extract and transdermal patches, Reservoir, Matrix, and patches with an active adhesive:
The transdermal research of the 20th century advanced the desire for a way to deliver consistent dosage via topical applications. But early accidents with spillage unintentional transfer spurred on the search for safer and more controlled delivery systems. In one well-known case, a man who was using nitroglycerin on his penis to treat erectile dysfunction, caused headaches in his spouse after intercourse.
The work that Zaffroni did in the 1960s on that very first motion-sickness patch, with a drug reservoir surrounded by an adhesive and a microporous membrane that could control the delivery, laid the groundwork for the reservoir patch used today. A patent was filed in 1971 and the advancement was prized for its ability to precisely control the amount of drug delivered to the bloodstream, as well as because it minimized side effects on the central nervous system like drowsiness and confusion.
The primary concept behind reservoir patches is the reservoir of the drug that is to be administered and some membrane or means to control the amount of the drug transferred from this reservoir through the skin.
In the 1980s, several of Alza’s competitors furthered development on the matrix concept for patches in an effort to get around the intellectual property challenges posed by Alza’s patents. Over time, these products became the dominant method of delivery in the patch market. This preference in the marketplace was due to the fact that matrix patches can be made thinner and more flexible, so they can be more comfortable and better adhering. Also, they were less expensive to manufacture.
Any patch without a liquid reservoir may be considered a matrix patch. When an active is suspended in a matrix (a well-mixed composite of one or more drugs) within the patch without a distinct reservoir, it can be delivered steadily. Delivery can be at a constant rate over multiple days because as the drug is released and absorbed, the substance dissolves back in the adhesive and compensates for what was released.
Active in Adhesive Patches
Essentially a newer generation matrix patch, active adhesive patches[AC6], or Drug in Adhesive (DIA) patches, have the active ingredient incorporated into a pressure-sensitive adhesive (PSA). Including the drug in the adhesive polymer not only solves for the stickiness aspect of patch design but also holds the drug and controls the rate of drug delivery. The idea for the DIA patch is said to have come from the concept of the bubble jet printer where the ink was printed on the surface of paper or other materials. At some point, someone realized that a composite of an active suspended in an could be loaded onto the patch backing in the same way.
In terms of design, DIA patches are the simplest and most state-of-the-art, but formulation can be extremely tricky. Once the proper formula is figured out, the patches are easy to make, so those with effective rates of diffusion can become highly prized in the marketplace.
The Future: A Second Boom?
Topical administration of drugs has been used to successfully treat human ailments since the rise of early civilization. As developments in transdermal patches have advanced, current work begins to try to push the limited number of active molecules available for transdermal applications. Today, there is a move towards increasing that number by using minimally invasive technologies such as iontophoresis and microneedles to enhance delivery for drugs with a previously lower potential for flux.
There are certainly continued uses for these technologies. Transdermal patches solve many needs in the health and wellness market today including consistency of accurate dosage, reduction of side effects, and ease of use. With the rise in popularity of over-the-counter patches like CBD pain patches and sleep patches not far behind, a second-wave transdermal boom is projected by many. As consumers become more and more aware of these benefits, the ability for over-the-counter patches to move into becoming staples in the medicine cabinets of homes across the country and beyond.