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Pharmaceutical Technology Europe
A new generation of drug delivery devices is being developed. Smart skin patches, it is claimed, will provider a safer and more user-friendly method of taking medication. This article highlights some recent developments in the field and analyses some of the many benefits the patches will provide to patients.
Today's drugs are mainly supplied in pots or blister packs. Cosmetics and other skin treatments are usually supplied as ointments in pots or tubes, or as pots of powder. Many delivery systems act indirectly — for example, tablets take a drug to the bloodstream via the digestive system and painkillers may be required to travel through the body to find the site of the pain. This can mean that inflated doses may be required and unwanted side-effects could occur in more locations than with a direct system.
Smart skin patches are one of the new delivery systems for drugs and cosmetics that address these and several other problems associated with traditional methods, such as
Demographic trends will make these challenges greater. For example, the percentage of the European population that will be 'dependent elderly' will rise from 20% to 30% by 2015. Figure 1 gives the dependent elderly as a percentage of the population from 1970-2050. The UK National Institute for the Blind estimates that 20% of people in the UK are currently sight impaired — a situation that will worsen with an increase in the elderly. A study in
Archives of Ophthalmology
found that nearly half of Americans older than 65 develop at least one of three chronic eye diseases, and the number of elderly is increasing rapidly. Even today, 100 million Americans are thought to have difficulty reading the instructions on medicines, reasons for which include poor printing, illiteracy, dyslexia and sight impairment. It is not prudent to let such people control the nature and timing of their medication if it can be avoided.
Traditional delivery systems for drugs and cosmetics rely heavily on humans administering the correct dosage at the right time, or in response to a subjective appraisal of need. Humans are notoriously bad at performing all these tasks.
The sick are even less reliable than the fit. Yet, since the time of Socrates more than 2000 years ago, it has been recognized that non-compliance with medication instructions can have severe effects. Newsweek has reported that if AIDS drugs are taken at the wrong time or in the wrong quantity for 5% of the time, then the chances of suppressing the virus are reduced by 50%. As that can mean that the patient dies 10-20 years earlier than would otherwise be the case, there is much at stake here.
Figure 1 Dependent elderly as a percentage of the population 1970-2050.
It is not a problem that is confined to drugs. Skin care treatments that are incorrectly applied may be ineffective or, at the other extreme, they may cause adverse events, such as cancer. Skin care is an enormous market, having been worth $31 billion in 2001, and is predicted to grow by 24.6% through 2006, according to Power Paper (Einat, Israel). Here, the interest is in vitalizers that have rejuvenation effects and enhancers that boost delivery of the ointment through the skin. Figure 2 shows the level of non-compliance for various medical treatments. It averages 50% overall afflications.
Drug trials are also imperilled by non-compliance. One may even be deciding whether to launch a new drug based on 50% corrupt data; that is, knowing that 50% of patients do not administer the drug correctly, but not knowing who they are. Add this to the fact that many drugs are only effective on one in three patients because of genetic and other differences, and one can be peering through a fog in assessing new formulations.
It can be distressing for unwell people to have to attempt to fulfil complicated instructions to prepare and administer a formulation, sometimes to a part of their body that they cannot see or easily reach. Most distressing for sufferers of severe forms of Parkinson's disease and diabetes is the need to inject themselves, deliberately causing pain — they may be shaking and may inadvertently inject at the wrong location, causing injury.
Figure 2 Level of non-compliance for different medical treatments.
An increasing number of these patients are required to be attached with a needle to an infusion pump all day, and sometimes all night too. The setting up procedure can be extremely challenging, with the mixing of liquids from ampoules in the correct amounts; remembering to have the pump switched off for part of the procedure; on for another part; and on when left in place. Even when medical staff follow the procedure, it is distressing for the patient.
All invasive procedures, not least injections, can cause inflammation, lumps under the skin that may or may not be diffused by ultrasound or massage, and other complications such as infection. Also, needle-free injections using ultrasound syringes can have dosage problems and cause pain. Implants that deliver drugs can malfunction without it being immediately obvious or they may be rejected by the body. There is, therefore, a requirement for alternative approaches.
Skin patches to deliver drugs and ointments have long been used by physicians and veterinarians. For example, nicotine is delivered to help people stop smoking; oestrogen is delivered by transdermal patch as part of a contraceptive or to counter the symptoms of menopause; and animals are given drugs in skin patches to counter pain. These devices are first generation and are manufactured in large numbers. The patches only work with certain chemicals because the skin is a relatively impermeable barrier; absorption through it is very slow and varies with a variety of factors, such as temperature.
Table I Examples of products incorporating ALZA transdermal technology.
Enter the second generation devices, pioneered by companies such as ALZA (Mountain View, California, USA), Vyteris (Fair Lawn, New Jersey, USA) Empi (St Paul, Minnesota, USA) and Power Paper. These skin patches employ iontophoresis, which is the application of an electric bias to increase penetration. Applying a few volts for a short time can increase penetration by more than 16 times. A tiny electrical current is passed through the skin by electrodes in the patch, typically powered by a small laminar battery in the patch or, for larger quantities, a delivery system to the patch. For example, Power Paper uses its low cost, environmentally safe printed paper battery and printed resistor network.
The cost is low enough for the product to be disposable. This type of patch is usually pre-impregnated, but some versions can be reused as dispensers for ointment. This smart skin patch can even be a product in its own right with no impregnation because its dry activation removes wrinkles for a few hours: an effect greatly valued by some in the trials. This is a new Cinderella story wherein your wrinkles return at midnight! In the single year that the company has been demonstrating its electrical patches, it has signed production licences with five major corporations seeking more efficient delivery mechanisms for such products as antiwrinkle and antiblemish ointments.
Power Paper has not yet applied for US Food and Drug Administration (FDA) approval to deliver drugs with its device, but ALZA and Vyteris have done so for their products in certain applications. Products now incorporating ALZA
transdermal technology include those in Table I. It is suitable for both local and systemic delivery, and is considered particularly beneficial with episodic onset of symptoms, and where precise and rapid delivery is required.
Third generation skin patches are electronic rather than simply electrical devices. There are several reasons for this. For example, it has been found that regularly reversing the bias causes the ointment or drug to penetrate approximately 36 times faster than without iontophoresis; that is, twice as fast as with a simple unswitched electrical bias. Electronics can allow the dose to be adjusted even after loading and during treatment. Also, electronics in the device can permit timed doses and ultimately (with sensors) drug delivery according to monitored need. Thus, human intervention, and therefore, the main cause of errors, can be progressively eliminated.
The Vyteris controlled electrophoretic system is composed of a flexible adhesive pad consisting of two reservoirs that are prefilled respectively with the drug and saline to complete the circuit, and a dose controller. The first Vyteris product is designed to provide rapid, local dermal anaesthesia to minimize pain for medical needlestick procedures such as insertion of IV catheters, hypodermic injections including immunizations, blood draws and dermatological surgery procedures. Lidocaine is used with a small quantity of a vasoconstrictor epinephrine, and 99 doses can be delivered with the small battery. FDA approval was sought for this application in 2002. In 2004, both Vyteris and ALZA received FDA approval for iontophoretic delivery of these drugs.
There is considerable scope for administration of Lidocaine in this way. In the US, there are more than 300 million needlestick procedures every year, of which 33 million are paediatric and 80 million are immunizations, according to Bruskin Research. Vyteris is to prioritize migraine and Parkinson's disease treatments as its next applications of iontophoresis. It reports that 23 million people in the US suffer severe migraine attacks and 1.5 million have Parkinson's disease. Currently, triptan compounds are taken orally for migraines and their action is unsatisfactorily slow with a possibility that there may be no protection against follow on attacks. The electronic control of these patches can ensure a strong first dose followed by a more modest follow on dose.
The potential benefit of the dopamine and dopamine agonist orally administered treatments of Parkinson's disease is the reduction of patients experiencing nausea (50%) and those hallucinating (33%). There may be some hope of replacing the needlestick administration of the dopamine agonist apomorphine as well. This cannot be administered orally because it breaks down, yet it is the most efficient dopamine agonist currently known. Vyteris has also started clinical tests on the daily administration of parathyroid hormone to patients with osteoporosis and pulses of gonadotropin-releasing hormone every 90 min to women preparing for in vitro fertilization.
Microprojection arrays. ALZA has also had success with human growth hormone and vaccines. With some regimes, lower doses are effective compared with injection by syringe. In these cases, ALZA's
. Here, a disposable, thin titanium screen has precision microprojections that, when applied to the skin, create superficial pathways through the skin's dead barrier allowing transport of macromolecules. It can be used as a passive skin patch or an electroactive one employing iontophoresis and is particularly appropriate for synthetic drugs, proteins and vaccines. The applicator is reusable. Further generations of skin patch could even involve arrays of needles to auto-inject timed doses of the more intractable drugs. Something of this nature may be necessary to assist the iontophoretic delivery of large molecules such as apomorphine.
However, before we have such speculative developments, it is appropriate to consider the closed loop system to replace timers. By this I mean the use of electronics in the patch to sense patient parameters and respond appropriately. The drug is administered according to need rather than the time of day. Diagnostic information linked to a unique identity number could even be radioed back to professional staff for review in critical cases. Disposable patches that do not deliver drugs, but simply radio back and/or record essential parameters against a unique electronic identity number will be another possibility.
With closed loop control it is not necessarily ideal to have the sensors at the same sites as the drug administration. Two or more smart patches signalling to each other may be more efficient. In late 2003, researchers at the University of Bremen (Germany) came up with an elegant solution to this. They told the World Congress on Medical Physics and Biomedical Engineering held in Sydney (Australia) that they have designed sensors that can share data by sending electrical signals through the body. Applications can include measuring pulse or blood chemistry.
This research was initially funded by EADS Astrium, the European space company. It hopes to use the technique to monitor astronauts' vital signs. The researchers believe there will also be applications in monitoring soldiers and firefighters.
For all electronic skin patches, there is a need to reduce the cost if they are to be disposable and used in large volumes rather than in niche applications. The cheapest silicon chips have stuck at a price of 5-10 cents for more than 20 years and, with the cost of a fabrication facility for silicon chips growing exponentially beyond today's $3 billion dollars, it is not safe to assume that silicon chips will become much cheaper in the quantities required for patches. There are famines in the supply of silicon chips every 4 years or so and, at these times, the producers ration the simpler, low profit items first. Another problem with silicon chips is that other circuit components, such as batteries, lights and electronic chimes, cannot usually be made in the same process, so the reliability, cost and size problems of separately connected devices must be suffered.
However, help may be at hand with the new thin film transistor circuits, particularly the cheaper types. They consist of printed polymer circuits without the poisons used in the manufacture of silicon chips and are expected to be on the market by 2005. Electronically, they are crude devices that do not work at high frequencies, but they will be perfectly adequate for a host of disposable applications in medicine including most smart skin patches. More information regarding this and related technology can be found at the Smart Labels 2004 conference and exhibition, 12-13 October, Nice (France), and Printed Electronics (New Orleans, Louisiana, USA), 7-8 December.