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ADVANCED DRUG DELIVERY SYSTEMS FOR TAILORED THERAPY TO THE INDIVIDUAL.
INTRODUCTION
A thin line of difference exists between Personalised and precision medicine, yet they are
interlinked to one another. The use of genetic, behavioural and other environmental data of a
particular patient to define patterns of a particular disease is known as precision medicine and the
treatment or medication that is provided tailored to a specific individual based on the data is called
as personalised medicine (Bcbs.com, 2018).
Modern personalised medicine works by taking into account the individual’s genetic makeup and
patient’s disease history. This has bought huge success to personalised medicine in the cancer
treatment. In contrast, traditional personalised medicine uses patient’s family history, lifestyle,
environment, social circumstances etc (Verma, 2012). This essay tries to portray “How triumph of
traditional personalised medicine can be, should be and will be beyond just cancer, with the help of
transdermal patches and medical devices”.
1) INNOVATIVE METHOD FOR SMOKING CESSATION
figure1: (Deaths due to tobacco between years 2005-2030, 2017)
By the end of 2030, roughly about 175 million people (around the world) would have fallen prey to
the hands of tobacco (reference is graph). Cigarette smoking and Nicotine addiction is the root
cause for this statistic. But, with developmental surges in the field of Advanced drug delivery
systems for the human body, that alarming number can certainly go down south. In order to
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accomplish this, Chrono Therapeutics (CT) has innovated a personalised drug delivery product in
order to cease Nicotine addiction.
[Note- Product is in phase 2 clinical trials and holds a pending submission to the FDA and has no
official name yet, therefore referred to as CT product]
People resort to smoking for various different reasons from stress to recreation, which eventually
leads to addiction (Medicine.mc.vanderbilt.edu, 2007) and the current Nicotine Replacement
Therapies (NRT) offer a mere 20% cessation rate per year (Emedicine.medscape.com, 2017).
Nicotine gums and patches have contributed substantially as a source for cessation, but not
entirely, as each individual’s craving pattern, stressors and smoking routines vary. For a particular
medication to function well in one human being and perform unsuccessfully in another is a total
possibility. This CT product is an advanced form of the nicotine patch and unlike the traditional
patch, it provides a tailored therapy to an individual for managing and overcoming their
physiological and psychological cravings.
Craving patterns to smoke vary among individuals, but first thing in the morning and post meal
cravings seem to be common across the globe. 75% of smokers crave for their first smoke inside
30 minutes after waking up (Chrono Therapeutics, 2017). Therefore, this CT product releases
nicotine into the body when the cravings are at its peak and minimises them. Between the peaks,
small doses of nicotine are delivered, thus keeping the withdrawal symptoms at bay without
extending the nicotine dependence (Chrono Therapeutics, 2017).
figure 2: Comparing nicotine deliveries between conventional patch and CT system (Chrono
Therapeutics, 2017)
Smokers are initially treated with doses upto 21mg (varies depending on an individual) for ten
weeks and followed by doses upto 7mg of nicotine, for a couple more weeks. Post this, depending
on the proximity to finish line, the delivery of doses are adjusted accordingly (Chrono Therapeutics,
2017). This way each individual is provided with a tailor made therapy.
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The levels of nicotine delivery, craving patterns, progress charts, and other data are backed up and
tracked on a mobile application via bluetooth pairing with the device. Also, Personalised reminders
are provided to help patients’ path to quit stay right on track. This way quitters can learn and
manage their cravings (Chrono Therapeutics, 2017).
figure 3: Electronic transdermal patch and smartphone with the mobile application (Chrono
Therapeutics, 2017)
Working and Mechanism: Nicotine is released from the device’s cartridge and enters the
bloodstream via the skin. This way the nicotine supply previously supplied from cigarettes
(tobacco) is replaced by the one produced by this device. Unlike the cigarettes, these devices do
not have the harmful carbon monoxide, tar and other chemicals. Rest of the device works like any
other transdermal patch. (Medicine.mc.vanderbilt.edu, 2007)
figure 4: Spot of adhesion (Chrono Therapeutics, 2017)
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figure 5: Parts and methods of usage of electronic patch (Chrono Therapeutics, 2017)
Innovative methods like these are necessary to curb addiction to smoking and nicotine
in a tailored fashion rather than a conventional one-dose-fits-all approach. Smokers have a
30-40% higher risk of diabetes than non-smokers (https://www.cdc.gov/, 2014).
2) TRANSDERMAL METFORMIN- new wave in the field of diabetic treatment
347 million people currently suffer from diabetes and World Health Organisation (WHO) predicts
diabetes to be the 7th leading cause for deaths by 2030 (Wearables and Glucose Monitoring: The
New Frontier in Diabetes Management, 2016). Demand for a novel drug delivery system/
technology is ever increasing and supply of a ground breaking technology is the need of the hour
(R. Nikam et al., 2014). This following innovation aims to exactly do that and potentially eliminate
the use of needles and revolutionise the way millions of diabetics and doctors manage the disease
efficiently. (SBS News, 2016) (Wearables and Glucose Monitoring: The New Frontier in Diabetes
Management, 2016)
2.1 What is the device?
Researchers and Scientists of Institute for Basic Science (IBS) in Seoul, South Korea, have
invented a prototype transdermal patch model, which has the ability to sense a rise in blood
glucose levels (with the help of sweat glucose concentrations) and automatically release the drug
metformin in order to lower those levels. These levels can eventually be tracked and analysed via
a smartphone. A first of its kind (Lee et al., 2016).
2.2 Parts, Working and Science behind the patch
The science behind this innovative patch is quite riveting and complicated. It is essential to break it
down into small parts for a clear comprehension.
Once the stretchable silicone patch is applied onto the skin, temperature rises and eccrine glands
produce sweat. This sweat is instantly monitored by the number of parts and sensors inside the
patch. The micro heaters melts the micro needles (present inside the patch) containing metformin
and this drug is eventually delivered transdermally. A detailed explanation with a figure is as
follows:
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figure 6: A clear alignment of these parts and breakdown of the patch is in the figure below (Lee et
al., 2016)
Sweat Control:
A precise quantity of sweat is absorbed by a fluoropolymer Nafion and carried to device sensors.
Sensors:
The sweat generated is monitored by the humidity sensor and when relative humidity crosses 80%,
other sensors (pH, temperature and glucose) begin their measurements.
The pH sensors (blood acidity levels) measure pH of sweat and temperature sensors measures
the temperature of sweat and glucose sensors corrects the glucose concentration in sweat and all
of this takes place in real time.
Inside the glucose sensors, the glucose oxidase enzyme (present in micro needles) reacts with
sugar (present in sweat) and forms hydrogen peroxide as the product via an electrochemical
reaction. Due to this reaction, current (electricity) from graphene component is extracted. This
produces an electrical signal which is proportional to the amount of glucose present.
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Note: These sensors are electrochemical and are highly sensitive and are mechanically soft in
nature because of Graphene. This Graphene electrode (synthesised by chemical vapour
deposition) has a gold mesh and electrochemical active materials in order to activate reactions
necessary to detect glucose. They are soft, transparent and have high conductivity, hence widely
used in wearable devices. They also hold high sensitivity towards biomarkers.
These sensors are mechanically deformable unlike enzyme based sensors that get affected by
environmental factors (Lee et al., 2016).
2.3 Therapy
The micro needles (1mm tall), that are coated by phase change material (PCM) called tridecanoic
acid and are separated from interstitial fluid in skin, contain metformin. During rise in blood glucose
levels, the micro heaters (gold coated graphene mesh) melts the PCM at a temperature ~41°c.
Due to this, micro needles (made from water soluble PVP) get activated, penetrate the skin and get
dissolved by the biological fluids and eventually drug delivery of metformin takes place. And in
case of hypoglycaemia, strain gauges measures tremors and immediately stops the delivery of
metformin (Lee et al., 2016).
All these components are sealed and incorporated into a thin silicone patch.
2.4 Discussion
Daily life and technology go hand in hand (HuffPost UK, 2017), so taking advantage of all the latest
available resources and combining them wisely can only better the current management of this
deadly disease. A continuous glucose monitor (CGM) available in the market, for example
Freestyle Libre (FSL) by Abbott, can be used to attain the blood glucose readings. FSL has a
sensor that is attached to the arm and monitors the glucose levels. Tapping a scanner on the
sensor, live results are displayed and these can be accessed via a mobile application similar to the
metformin smart patch. Both the datas (patch and CGM) can be accessed by the doctor over a
basic smartphone and accordingly provide precise tailor made therapy or treatment to the patient.
This personalised approach towards an epidemic disease can avoid the 65,000 injections and
80,000 times of blood measuring over a lifetime (HuffPost UK, 2017).
Realistically, it could take upto a decade for this to get approved and finally commercialised
(Diabetes Self-Management, 2016), during which limitations like long term reliability, stability issues
and the incapability to sense very low levels of glucose etc can be overcome (Graphene patches
over diabetes treatment, 2016). As this approach of treatment not only increases compliance, it
also reduces costs, empowers diabetics to become actively involved with their doctors and vice
versa (Diabetes Self-Management, 2016).
3) UNPARALLELD. But, Controversial treatment for psychotic disorders
“An electronic sensor into the human gut”. Sounds dangerous and unattainable. Abilify MyCite
(Otsuka Pharmaceutical Co., Ltd.) has successfully bought Digital drug delivery system to the
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world. This advanced drug delivery system has taken personalised medicine to the next level from
an innovation standpoint.
3.1 Atypical tablet
Abilify MyCite is an atypical method of treatment intended for use in psychiatric diseases and
disorders. The drug-device combination consists of an Aripiprazole tablet and an Ingestable Event
Marker (IEM) sensor incorporated into it. Along with this, a wearable patch, is to be worn on to the
area near the abdomen. A mobile application and web-based dash board facilities are provided and
requires to be downloaded on the individual’s smartphone (Fda.gov, 2017).
The tablet is composed of cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium
stearate, and microcrystalline cellulose, Colorants include ferric oxide (yellow or red) and FD&C
Blue No. 2 Aluminum Lake (Accessdata.fda.gov, 2017). The IEM is composed of copper,
magnesium and silicon. All of these are considered to be safe ingredients in foods (Belluck, 2017).
figure 7: IEM sensor incorporated into the Aripiprazole tablet
3.2 Mechanism
This tablet like any normal tablet is ingested by an individual orally. The IEM sensor in the tablet
comes in contact with stomach fluids (which acts as a power source) and gets activated. This
activation allows communication with the externally worn patch, which detects and records date,
time on tablet intake, physiological data like activity level etc. It takes roughly about thirty minutes
to two hours to detect a tablet intake.
The data collected in the patch is communicated to and received by the smartphone application via
bluetooth, which can eventually be tracked by the individual, doctor and caregivers with consent.
The additional web-based dashboards provides access to ingestion patterns and an overall clarity
of the status of the tablet, patient’s well being to the physicians (Abilifymycite.com, 2017).
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The involvement of IEM sensor, patch, mobile application etc indicates treatment being
personalised and tailored to an individual in every sense. It provides an opportunity to passively
extract digital data which can be crucial in bettering health industry (Susan Scutti, 2017).
The mechanism of action of this Aripiprazole is like any other conventional one. Efficacy of the API
can be arbitrated through the amalgamation of agonist D2 action and 5-HT 1A receptors and 5-HT
2A antagonist action. The tablet is absorbed well and reaches a peak plasma concentration within
3-5 hours and has an oral bioavailability of 87% (Accessdata.fda.gov, 2017).
figure 8: The ins and outs of ingestible sensor tablet
3.3 Working
There is a lot happening in this system of treatment and has one too many elements to it. It is
essential to break it down into small bits and look at what goes where.
The API Aripiprazole is formulated into a tablet and the IEM sensor is compressed into it. According
to Otsuka, the sensor is as small as a size of a sand grain. This combination of drug+sensor pill
goes right into the patient’s gut.
With regard to the wearable patch, patient must clean the area (left side of the abdomen and just
under the rib cage). The patch can remain in that place for upto 7 days, post that it should be
replaced. The working of the patch is like any other transdermal patch (Pharmacytimes.com,
2017).
The application is downloaded on patient and their associates’s smartphones which provides
reminders, tracking as to wether or not the patient has consumed the medicine, tracking moods etc
(Accessdata.fda.gov, 2017) (Belluck, 2017).
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3.4 Why this tablet?
Why this product over conventional product?
It is used in/as (adults only) :
1. treatment of Schizophrenia
2. treatment of Bipolar 1 disorder
3. Acute manic and mixed episodes as mono-therapy
4. Adjunct to lithium or valproate
5. Adjunctive treatment for major depressive disorder (Fda.gov, 2017).
The other benefits of this system is it allows the physician to closely monitor the patient’s progress
or regress via the application and dashboard, this way the doctor can makes changes accordingly
and provide the best tailor made therapy to a particular individual based on their needs,
characteristics and preferences, and personalised medicine is all about that. However, it has its
own limitations.
“There’s an irony in it (digital pill) being given to people with mental disorder that can include
delusions. It’s like biomedical Big Brother” -Dr Jeffrey Lieberman, chairman of psychiatry at
Columbia University (Belluck, 2017), echoed to the Times’ articles as to how apart from the usual
nausea, dizziness, insomnia, constipation, akathisia side effects (Accessdata.fda.gov, 2017), there
are other broader concerns apropos to this and has had a few eyebrows raising (Mole, 2017).
“The digital pill has the potential to improve medical health, BUT, if used improperly, it could foster
more mistrust instead of trust”-Ameet Sarpatwari, instructor in medicine at Harvard Medical School
(Belluck, 2017). Similarly, other experts from the industry were certainly perplexed that the
treatment for schizophrenia was chosen for the first ever digital pill, because this disorder causes
hallucination, thinking disorder, delusions like hearing voices and that someone is reading their
mind or spying (Mole, 2017). This can surely cause issues like anxiety and high levels of paranoia
about the doctor and the doctor’s intentions (Mole, 2017).
These are a few potential downsides which can surely be tackled in course of time and expertise.
3.5 Current status
The initial rollout of these digital pills into the market is set to be in 2018 (Susan Scutti, 2017) and
in doses of 2, 5, 10, 15, 20, and 30mg (Accessdata.fda.gov, 2017).
The current status is the approval from FDA (13th November 2017) (Drugs.com, 2017). This
approval opens the door for tablets beyond mental disorders to be digitalised (Ong, 2017).
The safety of this product has been established (with regard to psychiatric disorders mentioned
above) via clinical trials for aripiprazole (Accessdata.fda.gov, 2017).
However, the FDA emphasised on the fact that there is no substantial affirmation this digital
product improves patient’s compliance and adherence, which remain an area of concern (Susan
Scutti, 2017) (Mole, 2017).
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Up until now, most therapies for mental diseases lacked a systemic approach to impartially track
patients progress and the mere fact as to wether or not the patient has taken their meidcation
(Fda.gov, 2017). Therefore, with this personalised approach of drug delivery and tracking, by
simply tracing patient’s pill ingestion, experts estimate to save upto $100 billion a year without the
need to spend on additional treatment and hospitalisation (Belluck, 2017).
Discussion
Every year, 20% of the total USA’s population suffer from mental illness and 40% of them resort to
tobacco (nicotine) usage (Anon, 2009). Now, the necessity to treat nicotine addiction becomes
essential. It is important to attain 100% cure from a particular disease or disorder, if not one
disease will lead to another and this is inevitable.
Only 30-70% of the patients respond positively to traditional method of treatment. Therefore, by
resorting to personalised mode of treatment, this figure can hopefully be bettered and the scenario
of one disease leading to another disease/disorder/addiction can be prevented.
CONCLUSION
Innovative methods and distinctive devices like these where pharmaceutical sciences meet
engineering certainly seems intriguing and effective. “Future of personalised medicine lies in
wearables. Critical to this is integrating data into healthcare without the help of technology” -
Edward Abrahams, President of personalised medicine coalition (AJMC, 2017). The real challenge
now lies in the ability to transform these prototype models into a reality.
The above three examples of advanced drug delivery systems for tailored therapy in individuals,
are just a few of the many innovative medical devices. With the help of these, many chronic
diseases and disorders can be treated and cured on personalised level for better patient
compliance and success rate.
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