PLENNARY DISCUSSION

“Nicotine Patch and Transdermal Drug Delivery System”

Arranged By :

1. Putri Maharani P. (20190350087)

2. Audri Apriliani (20190350057)

3. Adella Anggita Sari (20190350044)

4. Nuha Haifa Arifin (20190350102)

5. Sonya Puspa W. (20190350030)

6. Afri Elfida H. (20190350005)

7. Wardah Dwi L. (20190350091)

8. Anindya Putri P. S. (20190350049)

9. Haniifah (20190350007)

10. Rifda Hanun Z. (20190350047)

11. Fadhilah Anwar H. (20190350059)

12. Rakhma Fitrianingsih (20190350010)

13. Radhwa Fauztina (20190350050)

PROGRAM STUDI FARMASI

FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN
UNIVERSITAS MUHAMMADIYAH YOGYAKARTA
2020
 PREFACE

Alhamdulillah, praise the presence of Allah SWT who has given His grace and guidance so
that we can complete a paper entitled Nicotine Patch and Transdermal Drug Delivery System.
Prayers and greetings may be devoted to the Prophet and his family.

Thank you to The Lecturers, especially Mrs. Apt. Sabtanti Harimurti, M.Si., Ph.D as
Responsible Person in this 8th block and also have helped us both morally and materially. We also
thank to our compatriots who have supported us so that we can complete this task on time.

We realize that our paper is far from perfect in terms of composition, language and writing.
Therefore, we really expect constructive criticism and suggestions from all readers to be a reference
so that writers can become even better in the future.
Hopefully this paper can add insight to the readers and can be useful for the development and
improvement of science.

Yogyakarta, 9th November 2020

 TABLE of CONTENTS

Table of Contents
PREFACE..................................................................................................................................................
Table of Contents ...................................................................................................................................... i
Chapter I (Introduction) ............................................................................................................................ 1
1.1 Background..................................................................................................................................... 1
1.2 Problem Formulations...................................................................................................................... 2
1.3 Purpose ........................................................................................................................................... 2
Chapter II (Discussion) ............................................................................................................................. 3
2.1 Nicotine Patch ................................................................................................................................. 3
2.1.1 Indications................................................................................................................................ 3
2.1.2 Dosage..................................................................................................................................... 3
2.1.3 How to Use .............................................................................................................................. 3
2.1.4 The Right Place ........................................................................................................................ 4
2.1.5 Drug Interactions ..................................................................................................................... 4
2.1.6 Contraindications ..................................................................................................................... 5
2.1.7 Side Effect ............................................................................................................................... 5
2.1.8 Storage Method ........................................................................................................................ 6
2.1.9 Mechanism ............................................................................................................................... 6
2.1.10 Ways to Stop Smoking ............................................................................................................ 6
2.1.11 NRT (Nicotine Replacement Therapy)...................................................................................... 8
2.1.7 Legal Fatwas .......................................................................................................................... 10
2.2 TDDS (Transdermal Drug Delivery System) ................................................................................... 12
2.2.1 Classification.......................................................................................................................... 12
2.2.2 Components .......................................................................................................................... 12
2.2.3 Factors ................................................................................................................................... 13
2.2.4 Advantages and Disadvantages ................................................................................................ 13
2.2.5 Pathway ................................................................................................................................ 14
2.2.6 Transdermal vs Topical ........................................................................................................... 15
2.2.7 Drug Requirement .................................................................................................................. 16
2.2.8 TDDS’s Requirement ............................................................................................................. 16
2.2.9 Efforts to Increase Bioavailability ........................................................................................... 16
Chapter III (Conclusion) ......................................................................................................................... 18
3.1 Conclusion .................................................................................................................................... 18
3.3 Advice .......................................................................................................................................... 18
REFERENCES....................................................................................................................................... 19

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 CHAPTER I

INTRODUCTION

1.1 Background

At a time when the development of drug delivery systems in the pharmaceutical sector has
developed, one of which is transdermal preparations. Where transdermal preparations are a
form of drug delivery system attached to the skin and provide the expected therapeutic effect
(Barhate et al., 2009). Transdermal preparations can be made in the form of a patch. The patch
preparation consists of various components, namely the liner is part of the patch matrix which
must be removed before use so that the patch can be affixed to the skin. adhesive as an adhesive,
backing layer as a patch layer, matrix as a release control and plasticizer as a viscosity regulator
(Williams, 2004).
Transdermal patches are generally applied to the skin to release the active substance in a
specific dose. However, there are also patch systems applied by the buccal transmucosal route.
The transmucosal patch is a drug delivery system that is placed between the gums and the inner
cheek membrane. The use of drugs through mucous membranes in the mouth, can be divided
into non keratinized areas and keratinized areas, non keratin including under the tongue
(sublingual) and between the cheeks and gums (buccal mucosa). While the keratin area
includes around the gums (gingiva), around the roof of the mouth (palatal mucosa) and near
the lips. The mucous membrane has an area of 100 cm2 and has different characteristics,
including thickness and blood flow depending on the location and activities carried out (Crick,
2005). Drug delivery via the transmucosal route may use mucoadhesive patch preparations.
Mucoadhesive patches have various advantages compared to other conventional dosage forms
such as non-invasive, minimal side effects, able to maintain drug bioavailability, strong
adhesion during use, no need to experience first-pass metabolism, easy to stop drug
administration if an error occurs. administration of drugs so as to prevent toxicity, prevent
damage to drugs that are not resistant to the pH of the digestive tract, and also prevent
gastrointestinal irritation by irritating drugs.
Cigarettes are addictive for anyone who uses them. The cause of the addictive nature of
cigarettes is the presence of nicotine in cigarettes. Nicotine is a tertiary amine consisting of
pyridine and pyrrolidine rings. The most nicotine found in cigarettes is (S) -nichotine which
binds to the cholinergic nicotinic receptors. Another type of nicotine, (R) -nichotine, is found
in small amounts in cigarettes and is metabolized during the pyrolysis process so that this type
of nicotine is a weak agonist for its receptors. When a person inhales a cigarette, nicotine will
be filtered from the cigarette and will be carried into the lungs through the smoke particles that
are inhaled. Furthermore, nicotine will enter rapidly into the blood circulation through the
pulmonary veins, then enter the arterial circulation and move rapidly towards the brain.
Nicotine diffuses directly into the brain and binds to the nicotinic colinergeic receptors which
are ligand-bound ion channels. When nicotine binds to its receptors, sodium and calcium ion
channels open, activating calcium channels and causing calcium influx into cells.

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 Nicotine replacement therapy is a pharmacotherapy that is commonly used to stop smoking.
This therapy has been developed since about 20 years ago. The basic principle of this therapy
is to replace blood nicotine so that it can reduce smoking cessation symptoms such as
depression, irritability, anxiety, headaches, and changes in appetite. This therapy can also
reduce the desire to return to smoking after quitting smoking. The duration of nicotine
replacement therapy ranges from 3 months. This therapy is relatively safer than cigarettes
because it does not contain carcinogenic substances and other harmful chemicals. Nicotine
replacement therapy is available in several forms, namely chewing gum, patches, tablets,
inhalers, and sprays.
Nicotine replacement therapy is relatively safe compared to cigarettes. The nicotine levels
in nicotine replacement therapy are much lower than in cigarettes. Nicotine has a fairly good
effectiveness, namely 1 in 15 people who undergo nicotine replacement therapy successfully
quit smoking completely. With good effectiveness, nicotine replacement therapy does not
cause dependence, this is because the nicotine content is low in the preparation and the nicot ine
is delivered into the body more slowly so the risk of becoming dependent is very small. Long-
term use of nicotine replacement therapy is safer for health than smoking.

1.2 Problem Formulation

1. The meaning of transdermal patch and its delivery system

2. Dosage and how to use the nicotine patch
3. Indications and contraindications for nicotine patch
4. Mechanism of action and side effects of the nicotine patch

1.3 Purpose

1. To know about transdermal patch and its delivery system

2. To know about the dosage and how to use the nicotine patch
3. To know the indications and contraindications of the nicotine patch
4. To find out the mechanism of action and side effects of the nicotine patch

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 CHAPTER 2

DISCUSSION

Scenario :

Mr. BM, 34 years old, consulted to the clinic doctor for Stop Smoking Therapy at the
Firdaus Clinic. The doctor gave Mr. BM a nicotine patch.

Unfamiliar Terms :

Nicotine Patch is a Square plaster that provides a stable and controlled dose of nicotine
throughout the day and also claimed as Therapeutic methods that deliver nicotine through the
skin as an effort to control smoking attempts.

2.1 Nicotine Patch

2.1.1 Indications of Nicotine Patch

Nicotine patches are used for smoking cessation. Nicotine is released from the patches
and absorbed through the skin. Released nicotine binds to nicotine receptors in the body,
reducing nicotine craving and withdrawal symptoms associated with smoking cessation. The
FDA approved the grit nicotine patch in November 1991.

Nicotine patch also helps quit smoking, helps nicotine dependence therapy or used to
treat nicotine withdrawal and it is used to curb the craving to smoke.

2.1.2 Dosage of Nicotine Patch

If the smoker smokes at least 10 cigarettes or more per day, the dose that can be given
is 21 mg / day or 15 mg / 16 hours. Nicotine in patch form is used for long-term therapy and
is effective for reducing cravings but not preventing or reducing acute cravings for smoking.
On another source said that nicotine patch comes in 3 doses. If you smoke 11 or more cigarettes
a day start with the 21 mg patch (step 1). If you smoke 10 or less cigarettes a day start with the
14 mg patch (step 2).

If you miss a dose you can use a missed dose as soon as you think about it then if it is
close to the time for your next dose, skip the missed dose and go back to your normal time.
Please keep a note, don’t use 2 doses at the same time or extra doses.
2.1.3 How to use Nicotine Patch

• Put patch on clean, dry, healthy skin on the chest, back, belly, or upper arm. Move
the site with each new patch.

• Put patch on a site without hair.

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 • Wash your hands after use.

• Each patch can stay on for 16 to 24 hours. If you crave cigarettes when you wake
up, wear the patch for 24 hours.

• Do not leave on the skin for more than 24 hours.

• Do not put on more than 1 patch at a time.

• Do not use patches that are cut or do not look right.

2.1.4 The Right Place of Nicotine Patch

For nicotine patch use, smokers are instructed to place a new patch on a relatively
hairless location, typically between the neck and waist at the start of each day. It is
recommended to rotate the site of application to reduce local skin irritation. Smokers who
experience sleep disturbances are recommended to remove the 24-h patch before bedtime or
use the 16-h patch, which is designed for use while the smoker is awake. Nicotine patches,
however, do not alleviate craving episodes for smoking (Herman & Sofuoglu, 2013).

Nicotine patches are applied to the skin and deliver nicotine through the skin at a
relatively steady rate. The main advantage of nicotine patches over acute NRT formulations is
that compliance is simple; the patient simply places the patch on the body in the morning, rather
than actively using a product throughout the day. Moving the site of patch application daily as
instructed can reduce the incidence of skin reactions to the patch (Wadgave & Nagesh, 2016).

2.1.5 Drug Interactions of Nicotine Patch

Some products that may interact with this drug include: medications for high blood
pressure (including beta blockers such as labetalol, prazosin), bronchodilators/decongestants
(e.g., isoproterenol, phenylephrine). Stopping smoking can change the way the liver removes

4
certain drugs from the body (including acetaminophen, caffeine, insulin, oxazepam,
pentazocine, propoxyphene, propranolol, theophylline, tricyclic antidepressants such as
amitriptyline/imipramine, "water pills"/diuretics such as furosemide).

2.1.6 Contraindications of Nicotine Patch

Absolute contraindications of Nicotine patch is included: severe eczema or serious skin

conditions, allergy to nicotine patch, pregnancy, breastfeeding, heart attack in the past 2
months, ongoing angina, peptic ulcer disease, arrhythmia, or uncontrolled blood pressure.
Potential contraindications included stroke in the past 6 months, insulin therapy, and a current
diagnosis of liver, kidney or heart disease. Participants reporting an absolute contraindication
were ineligible for the drug and were offered the option of bupropion. Research staff faxed a
list of any potential contraindications to the primary care physician who either approved or
disapproved the drug for the participant (Cupertino, et al., 2008).

2.1.7 Nicotine Patch Side Effects

Nausea, dizziness, headache, influenza-like symptoms, palpitations, dyspepsia,

insomnia, vivid dreams, myalgia. Other reported side effects include: chest pain, changes in
blood pressure, anxiety, irritability, somnolence, impaired concentration, dysmenorrhea; with
patches: skin reactions. (discontinue if heavy effect).

Even though it may be rare, some people may have very bad and sometimes deadly side
effects when taking a drug. Tell your doctor or get medical help right away if you have any of
the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling
skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing,
swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue,
or throat.

• Signs of high blood pressure like very bad headache or dizziness, passing out, or
change in eyesight.

• Mood changes.

• Feeling confused.

• Chest pain or pressure, a fast heartbeat, or an abnormal heartbeat.

• A burning, numbness, or tingling feeling that is not normal.

• Dizziness.

• Upset stomach or throwing up.

• Diarrhea.

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 • Drooling.

• Shakiness.

• Feeling tired or weak.

• Cold sweats.

• Blurred eyesight.

• Change in hearing.

2.1.8 Storage Methods for Nicotine Patches

This drug is best stored at room temperature, away from direct light and damp places.
Don't keep it in the bathroom. Don't freeze it. Other brands of this drug may have different
storage rules. Observe the storage instructions on the product package or ask your pharmacist.
Keep all medicines away from children and pets.

Do not flush medicines down the toilet or down the drain unless instructed to do so.
Discard this product when it has expired or when it is no longer needed. Consult your
pharmacist or local waste disposal company about how to safely dispose of your product. After
you take off a skin patch, be sure to fold the sticky sides of the patch to each other. Throw away
used patches where children and pets cannot get to them.

2.1.9 Nicotine Patch Mechanism of Action

Works systematically → sticks to or is absorbed by the skin → diffusion of release of

active substances → binds to lipids in the stratum cornium → diffusion of the epidermis →
enters the body → is transmitted → spread through the systemic (blood).

Nicotine patch provides low levels of nicotine by reducing the physical symptoms of addiction

2.1.10 Ways to quit smoking other than the use of nicotine patches

a. Strong determination

The first thing to do to quit smoking is a strong determination to quit. Everything comes
from oneself. If in the middle of the process of quitting starts to slack off, immediately rethink
the reasons and original determination to quit. Self-motivation is key.

b. Keep yourself busy

1. Make a list of reasons to quit smoking. To build motivation and enthusiasm

to quit smoking, there are many benefits that can be taken from quitting smoking, such
as:

• The body is healthier overall. Blood pressure will be more stable, the risk of heart
attack, stroke and cancer will be reduced.

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• No more bad breath.

• The skin becomes brighter and cleaner.

• Teeth no longer turn yellow.

• The people around you avoid the harmful effects of smoking.

2. Manage stress. Stress can be one reason someone chooses to smoke. After
smoking, a person feels calmer. Try several ways to relieve stress, such as listening to
music, massage, yoga, or doing a hobby. In addition, at the beginning of the trial period
to quit, as much as possible avoid situations that could be stressful.

3. Stay away from triggers. As much as possible avoid factors and habits that
can make you smoke again. For example, hanging out with fellow smokers, drinking
coffee, and consuming liquor. If you are used to smoking after eating, try to find other
ways to replace it. For example, eating gum or brushing your teeth.

4. Cleaning the house. Clean the house from the smell of cigarettes and
anything that can trigger your habit of smoking in large quantities. You can wash
clothes, sheets, carpets, or curtains that smell like cigarettes. Also use air freshener to
help get rid of the smell of cigarette smoke.

5. Exercise routine. Exercise can help reduce and divert from nicotine cravings
or cravings. Once you want to smoke, wear sports shoes and start doing sports activities,
such as running or just walking, even swimming. Joining a fitness class with healthy
people can also help.

6. Eat healthy foods. On average, people who have a smoking habit feel no
appetite because of the nicotine effects of cigarettes which interfere with the sense of
taste. When quitting smoking, eating a healthy diet can be a step to meet essential
nutrients for the body. Not only that, healthy food can remind you to have a healthy
lifestyle.

7. Hypnosis. Hypnosis itself is a method performed by influencing a person's

subconscious by special practitioners. Later, it will be like being in a very relaxed
situation and open to accepting any suggestions. Hypnosis practitioners will help
strengthen the will to quit smoking and give bad suggestions about smoking.

8. Behavioral therapy. How to quit smoking through behavioral therapy is a

form of counseling that helps to focus on smoking cessation strategies. This therapy is
done by talking to the counselor in psychotherapy sessions, but it can also be done in
group sessions. To maximize success, this therapy can be combined with nicotine
replacement therapy and / or drugs. Behavioral therapy can be used not only as a way
to quit smoking, but also to help with mental health and behavioral problems such as
stress or depression.

9. Nicotine-Replacement Therapy (NRT). Nicotine is a substance in

cigarettes that makes a person feel addicted. Nicotine replacement therapy can help
reduce nicotine addiction for heavy smokers. Research in the Cochrane Database

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 System states that this method can stop smoking cessation by 50-70%. However,
nicotine replacement therapy is a way to quit smoking that must be done under a
doctor's supervision. The doctor will adjust the nicotine dose that will be given to
prevent adverse effects on your body. This nicotine replacement therapy consists of
several types, namely:

• Patch, Nicotine patches are a type of bandage that is applied to certain areas of the
skin. This patch helps provide nicotine which will be absorbed directly by the skin.
• Nicotine lozenges or candy, the effects of nicotine in the form of lozenges or candy
are usually more pronounced. You are not advised to eat and drink for
approximately 15 minutes before consuming this candy. Food and drink are
believed to affect nicotine absorption.
• Inhalers and nasal sprays, Nasal inhalers and sprays are among the most effective
methods of therapy. However, because the effects tend to be rapid, the risk of
addiction is quite high. Both inhalers and nasal sprays require a doctor's
prescription.

10. Don't forget to ask for support from people around you. Tell your
relatives and close circle of friends that you are in the process of quitting smoking. The
support of others can play a role in helping to quit smoking. They will remind and help
keep the situation more conducive so that goals are more easily achieved.

11. Keep trying. As stated above, how to stop smoking must be done gradually.
Therefore, failure is a natural thing to happen. Failure does not mean you will not
succeed in escaping cigarettes. Many people have finally succeeded in quitting smoking
after trying several ways and over and over.

2.1.11 Nicotine Replacement Therapy (NRT)

Nicotine Replacement Therapy (NRT) is a therapy that aims to replace most of the
nicotine from cigarettes to reduce smoking motivation and nicotine withdrawal symptoms,
thereby facilitating the transition from smoking to quitting completely. The three main
mechanisms of action of NRT are to reduce nicotine withdrawal symptoms, reduce the
nicotine-strengthening effect and provide the effects previously obtained from smoking. Use
of Nicotine Replacement Therapy (NRT) is effective, well tolerated and has mild side effects.
Nicotine Replacement Therapy (NRT) has several dosage forms, including transdermal
nicotine, gum, lozenges, sublingual tablets, inhalers and nasal sprays.
• Transdermal Nicotine
Transdermal nicotine is a multilayer unit that can deliver nicotine after
application to the skin. It is estimated that 68% of the nicotine released by the
transdermal system will enter the circulation. Transdermal nicotine is available in
various strengths, depending on the length of use and strength of the dose. Based on
the length of time of use, it can be divided into two, namely preparations used for 16
hours and 24 hours. The dosage used for 16 hours consists of several dosages, namely
5 mg, 10 mg and 15 mg. Meanwhile, the dosage used for 24 hours consists of 3
dosages, namely 7 mg, 14 mg and 21 mg. The component that limits its absorption is

8
the state of the skin in which it is used transdermal. Transdermal nicotine can be used
on all clean, dry, hairless skin. The elimination half-life is quite long, which is about
3-6 hours.
• Nicotine Chewing Gum
Nicotine gum contains nicotine that is bound to a resin complex. Nicotine gum
is available in two doses, 2 mg and 4 mg. For people who smoke more than 20
cigarettes per day can use a 4 mg dosage and for people who smoke less than 20
cigarettes per day can use a 2 mg dosage. Users of this preparation were instructed to
use gum every 1-2 hours for the first 6 weeks, then reduce it every 2-4 hours for 3
weeks, and every 4-8 hours for 3 weeks.
• Nicotine Suction Tablets
Nicotine lozenges are available in 1 mg, 2 mg and 4 mg formulations. For
smokers who smoke more than 20 cigarettes a day can use a dosage of 4 mg and for
those who smoke less than 20 cigarettes per day can use a dosage of 2 mg. The first
time you smoke in the morning is a strong index for determining nicotine dependence
and is a method that can be used to measure the nicotine requirement of each smoker.
Smokers who start smoking within 30 minutes are advised to use 4 mg preparations
and for smokers who start smoking in more than 30 minutes it is recommended to use
2 mg preparations. Lozenges can be used every 1-2 hours. The lozenges of nicotine are
absorbed slowly (within 30 minutes) through the buccal mucosa. This preparation must
not be chewed. The amount of nicotine absorbed from lozenges is greater than chewing
gum.
• Nicotine Sublingual Tablets
One sublingual nicotine tablet has a strength of 2 mg. The way to use this
preparation is to place it under the tongue and let it dissolve. The rate of nicotine
absorption is increased at alkaline oral pH compared to acidic pH. Smokers who use
less than 20 cigarettes a day can use 1 sublingual tablet every hour and smokers who
use 20 or more cigarettes a day can use 2 sublingual tablets per hour. Use in one day
should not be from 40 tablets. This dose can be used for up to 12 weeks. After 12
weeks, the dose should be tapered off.
• Nicotine Inhaler
Nicotine inhalers consist of a mouthpiece and a plastic cartridge filled with
nicotine. When the inhaler is sprayed, nicotine will pass through the mouthpiece into
the mouth. Each cartridge inhaler contains 10 mg of nicotine. Of these 10 mg, 4 mg
will enter the mouth and 2 mg will be absorbed. The nicotine that is sprayed does not
enter the bronchi or lungs, but is deposited and absorbed by mouth. Most of the nicotine
will enter the oral cavity (36%), esophagus and stomach (36%), and a small portion
(4%) reaches the lungs. The best effect is obtained when used for 20 minutes. The use
of this preparation is recommended for 3 months, after which the dose can be gradually
tapered over 6-12 weeks.
• Nicotine Nasal Spray
Nicotine nasal sprays are designed to deliver nicotine doses to smokers faster
than other Nicotine Replacement Therapy (NRT), therefore nicotine nasal sprays can

9
 be used to satisfy sudden smoking cravings. This preparation will deliver the nicotine
directly to the nasal membrane and then it will be absorbed into the blood vessels. The
nasal spray device is a multidose bottle with a pump that will dispense 0.5 mg of
nicotine per spray. One dose means two sprays (releases 1 mg of nicotine). Patients
can start with 1 or 2 doses per hour and can be increased to a maximum of 40 doses
per day.

2.1.12 Legal Fatwas of Smoking

One of the smoking laws is regulated in the Fatwa of the Tarjih and Tajdid Council,
Muhammadiyah Central Leadership No. 6 / SM / MTT / III / 2010 concerning Smoking Law.
This was written in Yogyakarta on March 8, 2010 M. The contents of the fatwa are as follows:
FATWA REGARDING SMOKING LAW
First: Amar Fatwa
1. It is obligatory to strive for the maintenance and improvement of the highest public
health status and to create a conducive environment for the realization of a healthy
living condition which is the right of everyone and is part of the objectives of sharia
(maqasid asy-syari'ah);
2. Smoking is haram because:
i) smoking is included in the category of doing khaba'is which is prohibited in Q. 7:
157,
ii) the act of smoking contains the element of dropping oneself into destruction and is
even an act of suicide slowly so that therefore it is against the prohibitions of the
Koran in Q.2: 195 and 4: 29,
iii) the act of smoking harms oneself and others who are exposed to cigarette smoke
because smoking is an addictive and dangerous substance as agreed by medical
experts and academics and therefore smoking is against the sharia principles in the
Prophet's hadith that there is no harm to oneself and endanger others,
iv) Cigarettes are recognized as addictive substances and contain harmful toxic
elements, although not immediately, but for some time, therefore smoking is
categorized as doing something which is debilitating so that it contradicts the
hadith of the Prophet which prohibits every intoxicating and debilitating case.
v) Because smoking is clearly harmful to the health of smokers and people around
who are exposed to cigarette smoke, spending money on cigarettes means doing
redundant acts (wasteful) which is prohibited in Q. 17: 26-27,

10
 vi) Smoking is against the elements of the objectives of sharia (maqasid asy-syari'ah),
namely (1) protection of religion (hifz ad-din), (2) protection of body / soul (hifz
an-nafs), (3) protection of reason ( hifz al-'aql), (4) family protection (hifz an-nasl),
and (5) property protection (hifz al-mal).
3. Those who have not or do not smoke are obliged to refrain from trying to smoke
themselves and their families in accordance with Q. 66: 6 which states, "O believers,
save yourself and your family from hellfire."
4. Those who have already become smokers are obliged to make efforts and try according
to their ability to quit smoking by remembering Q. 29: 69, "And those who are sincere
in Our path, We will truly show them Our way. , and verily Allah is truly with those
who do good, "and Q. 2: 286," Allah will not burden someone unless according to his
ability; he will get the result of what he has earned and bear the consequences of what
he did; " and for that health centers within Muhammadiyah should make eff orts to
provide facilities to provide therapy to help people who are trying to quit smoking.
5. This fatwa is applied keeping in mind the principles of at-tadrij (gradually), at-taisir
(convenience), and 'adam al-haraj (not to complicate things).
6. With the issuance of this fatwa, the fatwas on smoking which had previously been
issued by the Tarjih Council and the Muhammadiyah Central Leadership Tajdid were
declared invalid.
Second: Tausiah
1. It is recommended to the Muhammadiyah Organization to actively participate in
tobacco control efforts as part of the maintenance and improvement of optimal public
health status and within the framework of amar makruf nahi munkar.
2. All Muhammadiyah Organization board functionaries at all levels should be role
models in the effort to create a society free from the dangers of smoking.
3. The government is expected to ratify the Framework Convention on Tobacco Control
(FCTC) in order to strengthen the foundation for tobacco control efforts in the context
of optimal public health development, and adopt consistent policies in tobacco control
efforts by increasing tobacco excise to the highest limit permitted by law. -law, and
prohibit cigarette advertising that can stimulate the young generation of young people
to try smoking, as well as assist and facilitate diversification and business transfer
efforts and crops for tobacco farmers.

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2.2 Transdermal Drug Delivery System

2.2.1 Classification of Transdermal Patches

1. Reservoir System (Membrane), In terms of understanding topic

preparations are preparations that are used on the skin in order to produce a local
effect. Examples: lotio, ointments and creams. Meanwhile, transdermal preparations
are preparations that allow the drug to enter into the skin and have a systemic effect,
namely by sticking it through the skin, so these preparations are said to be different
even though the effect and location of administration are the same, i.e. they are both
given to the skin and have a local or systemic effect, however these preparations
differs because transdermal preparations are more affixed preparations such as
patches while topical preparations are more towards topical or semi-solid
preparations, such as lotio, ointments.

2. Matrix system, The matrix system in the transdermal patch consists of 2

main components, namely the backing layer and the matrix. In this system, the drugs
in excipients such as polymers, plasticizers, permeation enhancers and adhesives are
formulated together, which are then allowed to dry to form a matrix. Next, the matrix
is attached to the backing layer. The advantage of the matrix system is that it will
form a thin patch so it is comfortable to use 3. Drug In Adhesive System In this
system the adhesive layer contains medicinal components. In this type of adhesive
layer not only serves to stick the various layers together during the process of the
system in the skin, but is also responsible for the release of the drug. The adhesive
layer is between the temporary liner and the backing layer.

2.2.2 Components of Transdermal Patch:

• Backing layer, part of the patch so that no other parts are lost, to protect it from the
outside environment.

• Drug Reservoir: Contains active drug ingredients

• Drug Release Membrane: controls drug release

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• Adhesive: wet skin when applied

• Liner: is a part of patch which must be removed before applying

2.2.3 Factors that Affect Transdermal Preparations

1. Stratum Corneum

The main dye of the drug is to earn into the skin. So it is needed modification
for the drug to make more penetration into the skin, usually added enhancer.

2. Target of drug action

There are studies that state the absorption of drugs from the skin depends on
their properties and characteristics, which vary in different regions. For example, some
areas of the skin are more permeable, for example the genitalia, specifically the
scrotum, armpits, face, scalp, etc.

3. Skin Conditions

Various skin disease conditions such as psoriasis (skin thickening, dryness, and
scaling) also result in changes in the lipid / protein composition of the stratum corneum.
Thus, application of a transdermal design is recommended for normal skin.

4. Age

Aging results in enormous variations in the vital functions of the skin; such as
normal water loss from intact skin, degeneration, etc. With increasing age, that is, in
older subjects, the skin texture changed and was sensitive to peeling.

2.2.4 Advantages and Disadvantages of Transdermal Patch

Advantages:

1. Avoiding the gastrointestinal environment where medicine can be degraded

(Singh et al., 2012),

2. Avoiding first pass effect where a molecule of active medicine can be

converted into inactive molecules or ones that have side effects (singh et al., 2012),

3. Easy to use and non-invasive or inoffensive to the skin and leave no

impression.

4. Distribution of drugs can be halted any time after the removal of patches from
the skin surface.

5. Increased obedience because it provides comfort so it can increase

biocapability, the best route for pediatric patients

13
 6. Routes are best for unusual patients who take medications and puke when
taking them

7. Overdose is less likely because of a controlled release of drugs

Disadvantages:

1. In some patients it may cause dermatitis, redness or itching on contact at the

application site, especially sensitive skin.

2. Not all drugs can be made transdermal dosage forms

3. Not all parts of the body can be used as a place for drug application, such as
on the soles of the feet. Putting the patch on the sole of the foot comes off easily as the
skin is thick and wrinkles easily

2.2.5 Pathway of Transdermal Drug

The transdermal drug route is defined as the movement of a substance (eg drugs) across
the stratum corneum (outermost layer of skin) into the systemic circulation (blood). In other
words, it delivers the active compound through the skin directly to where it is desired to achieve
more effective results.

Percutaneous absorption involves passive diffusion of the substances through the skin
A molecule may use two diffusional routes to penetrate normal intact skin, the appendageal
route and the epidermal route.

There are critically three ways in which a drug molecule can cross the intact stratum
corneum: via skin appendages (shunt routes); through the intercellular lipid domains; or by a
transcellular route (Figure 3). Appendageal route (shunt route) and Epidermal (Transcellular,
Paracellular)

14
 Appendageal route: Appendageal route comprises transport via sweat glands and hair
follicles with their associated sebaceous glands. These routes circumvent penetration through
the stratum corneum and are therefore known as “shunt” routes. This route is considered to be
of minor importance because of its relatively small area, approximately 0.1 % of the total skin
area.

Epidermal route:

1) Transcellular: Pathway means transport of molecules across epithelial cellular

membrane. These include passive transport of small molecules, active transport of ionic and
polar compounds and endocytosis and transcytosis of macromolecules.

2) Paracellular: Paracellular pathway means transport of molecules around or between

the cells. Tight junctions or similar situations exist between the cells. The principal pathway
taken by a permeant is decided mainly by the partition

2.2.6 Transdermal vs Topical

Generally, the terms topical and transdermal are used synonymously, but there are
major differences between them. Topical drug distribution is the term used for application of
the dosage form to controlled areas of the skin to obtain a localized effect. It is usually
applied to the therapeutic management of dermatological disorders such as eczema or
psoriasis where treatment is not intended for systemic distribution. Drugs that are usually
given topically are corticosteroids, antifungals, antivirals, antibiotics, antiseptics, local
anesthetics. Conventional topical dosage forms are solutions, emulsions, powders, creams,
pastes, gels, ointments, and lotions. Cosmetic topical preparations→ as a protective,
emollient and cleaning agent.

Transdermal drug administration involves diffusion of the drug through the skin into a
systemic or circulating layer of blood to induce a therapeutic effect. The best examples are the
transdermal patches of clonidine and nitroglycerin used for the treatment of hypertension and
angina respectively.

15
 2.2.7 The Drug Requirements Can be Formed into a Patch Preparation

a. A drug having a molecular weight <500 Da (very small) which can penetrate the stratum corneum
b. Has a moderate partition coefficient that is soluble in both lipids and water
c. Has a low melting point, less than 200 C
d. Has a relatively small water content
e. The surface of the patch must be flat and not wrinkle during storage
f. Medicinal and additives must be evenly distributed
g. Capable of releasing sufficient amount of active ingredients
h. Able to penetrate into the skin according to treatment goals

2.2.8 The Requirements for a Transdermal Drug Delivery System

a. The system can deliver drugs at a controlled drug rate, from the moment it attaches to the patient's
skin until absorption occurs in the systemic circulation.
b. The system must provide the proper physicochemical characteristics in order to release medicinal
substances into the stratum corneum
c. The system can occlude the skin to ensure a direct current of the drug flux rate
d. The transdermal system has a more beneficial therapeutic effect than other dosage forms and drug
delivery systems
e. The adhesives, carriers, and active ingredients in the transdermal system should not irritate the
patient's skin
f. The transdermal system is an occlusion system and does not allow the development of skin
bacteria.
2.2.9 Efforts to Increase Bioavailability Through The Preparation of Patches in The
Blood

Chemical penetration enhancer on penetration of transdermal preparations which can

reduce the skin barrier and are known as accelerators or which can increase the flux of the drug.
Several types of chemical penetration are used in transdermal medicine: Water, Water is the
best penetration enhancer reported. Hydrated skin better absorbs drug molecules due to the
increased flux needed for penetration. Its mechanism of action is to disrupt the structure of the
lipid bilayer in the lower layer of the stratum corneum (SC) and thereby increase the drug
diffusion coefficient, extract lipids from SC, change the properties of SC solvents and
consequently modify the drug partition coefficient, acting on intracellular keratin. Water will
open a rigid protein structure and cause an increase in the diffusion coefficient through
corneocytes (Chauhan, 2017).

a. Cyclodextrins, These compounds can form inclusion complexes with lipophilic

drugs by increasing their solubility, especially in aqueous solutions. However,
cyclodextrins alone are less effective as a penetration enhancer than combined
with fatty acids and propylene glycol (Amrit, et al., 2016).
b. Essential oils, terpenes or terpenoids, Many terpenes are used as medicines as
well as flavoring and fragrances. Less strong hydrocarbon terpenes, alcohols and
ketones containing moderate terpenes, whereas oxides and terpenoids showed the
largest increase. Smaller tarps are more active than bigger ones. Non-polar agents
(limonene) are active for lipophilic drugs and polar (methanol) for hydrophilic

16
 drugs. Modifying the solvent properties of the stratum corneum can increase drug
partition. Changing the thermodynamic activity of terpenes can also change the
diffusivity of the drug through the membrane. Terpenes (1,3,3- Trimethyl-2-
oxabicyclo [2.2.2.] - octane) are found in essential oils and compounds that
consist only of carbon, hydrogen and oxygen atoms, but do not have aromatic
rings. The essential oil of eucalyptus, chenopodium, has been found to be an
effective chemical penetration enhancer for 5-flouorouracil and can penetrate into
human skin invivo. Many terpenes absorb well into human skin and large amounts
of terpenes have been found in the epidermis after application with a matrix type
patch. Terpenes can also modify drug diffusivity through membranes (Ahmed, et
al., 2015; Aqil, et al., 2007).
c. Derivate of Fatty Acids and Ester, Most of the fatty acids and their esters have
been used as penetration enhancers for chemical penetration. In general,
unsaturated fatty acids are more effective at increasing percutaneous drug
absorption than saturated fatty acids. It was reported that there was a 6.5-to 17.5-
fold increase in the permeability of flurbiprofen through the skin of mice by
unsaturated fatty acids, while there was no significant increase with saturated fatty acids
(Dinda et al., 2006).
d. Urea, Urea can increase transdermal permeation by increasing the hydration of the
stratum corneum and by the formation of hydrophilic diffusion channels within the
barrier. The cyclic urea permeation enhancer is biodegradable and a toxic molecule
consisting of a polar parent part and a long chain alkyl ester group. As a result, the
increased mechanism is due to hydrophilic activity and disrupts lipid s (Singh, et al.,
2007).
e. Surfactans, Surfactants are added to a variety of therapeutic, cosmetic and
agrochemical preparations. Typically, surfactants are added to formulations to
stabilize emulsions and suspensions or to dissolve lipophilic active ingredients,
thereby potentially dissolving lipids in the stratum corneum. Usually consisting of
lipophilic alkyl or aryl fatty chains, with a hydrophilic head group, the surfactants
are often described in terms of the hydrophilic portion properties. Anionic
surfactants include sodium lauryl sulfate (SLS), cationic surfactants including
acetyltylrimethyl ammonium bromide, nonoxinol surfactants are nonionic
surfactants and zwitterionic surfactants including dodecil betaine. Anionic and
cationic surfactants have the potential to damage human skin. SLS can cause strong
irritation and Pharmacical Supplement Volume 15 Number 3 32 increases
transepidermal water loss in human volunteers in vivo and both anionic and cationic
surfactants can cause inflammation of the stratum corneum and interact with
intracellular keratin. Nonionic surfactants cause much less damage to the stratum
corneum, but are less than optimal as a chemical penetration enhancer (Touitou, et
al., 2007). The effect of adding surfactants on low cutaneous penetration. To
facilitate the release of substances through the membrane or intercellular space,
micelles must be formed so that they are more lipophilic and easy to penetrate the
skin membrane. This transition depends on the surfactant concentration. Sorpotdar
and Zatz observed uptake of two nonionic surfactants, polysorbate 20 and 60. An

17
 increase in lidocaine flow was observed for both surfactants in the presence of
propylene glycol. The effect of increasing polysorbate varies based on the
concentration of propylene glycol showing synergism between cosolvents and
polysorbate (Amrit, et al., 2016). Cyclodextrins. These compounds can form
inclusion complexes with lipophilic drugs by increasing their solubility, especially
in aqueous solutions. However, cyclodextrins alone are less effective as a
penetration enhancer than combined with fatty acids and propylene glycol (Amrit,
et al., 2016)

CHAPTER III

CONCLUSION & ADVICE

2.2 Conclusion

Transdermal drug delivery system is a system that facilitates drugs or active substances
into the systemic circulation through the skin with therapeutic doses and provides a systemic
effect. There are several factors that influence transdermal drug delivery, including
physiological factors and formulation factors. A method that can be used to facilitate
transdermal drug delivery is to add a penetration enhancer. There are several ways to improve
transdermal delivery described, namely by using ultrasonic, namely sonophoresis, while
using electric currents, namely iontophoresis and electroporesis. Transdermal drug has two
general pathways such as trancellular and paracellular

2.3 Advice

The author expects readers to better understand the transdermal drug delivery system, its
advantages and disadvantages, how to overcome its shortcomings, and know how to increase
drug penetration through the skin.

18
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