CHAPTER I

INTRODUCTION

1.1 ISSUE BACKGROUND

Cigarettes and their dangers are one of the health keywords issued by the world
population in both developed and developing countries. The WHO estimates that around
one third of the adult population in the world, or 1.1 billion people, 200 thousand women
are randomized, are smokers. Data shows that around 47% of men and 12% of women
are smokers worldwide. In developing countries, 48% of men and 7% of women are
smokers, while in developed countries 42% of men and 24% of women are smokers.
Every year, tobacco causes 3.5 million deaths, or around 10,000 deaths per day. One
million of these deaths now occur in developing countries. Information dissemination
throughout the world has caused deaths in around 250 children and adolescents, a third
of whom are in developing countries. China, for example, makes predictions that of the
300 million men who now stand 0-29 years, around 200 million will become smokers.
Of the 200 million smokers, around 100 million will end up due to tobacco-related
diseases, and half of these deaths will occur in middle-aged and before 70 years.
Indonesia is ranked fifth in the country with the largest consumption of
cigarettes in the world. In the health kaleidoscope for the 55th anniversary of FK UI,
China consumes 1,643 billion cigarettes per year, the United States 451 billion cigarettes,
Japan 328 billion cigarettes, Russia 258 billion cigarettes, and Indonesia is ranked fifth
with 215 billion cigarettes per year. Cigarette smoke contains thousands of toxic
chemicals and ingredients that can cause cancer (carcinogens). Even dangerous
substances and poisons in cigarettes not only cause health problems to people who smoke,
but also to those around them who do not smoke, most of which are babies, children and
mothers who are forced to become passive smokers because of their father or their
husbands smoke at home. Even though passive smokers have a higher risk of developing
lung cancer and ischemic heart disease. Whereas in fetuses, infants and children have a
greater risk of suffering from low birth weight events, bronchitis and pneumonia, ear
cavity infections and asthma.
Scientific evidence has shown that smoking, the main cause of degenerative
diseases throughout the world which can be prevented. The success of preventing
smoking has a very significant influence on public health. The results showed that the

1
 cessation of smoking habits would result in a significant reduction in the risk of tobacco-
related diseases, so that most of the 10 million deaths could be prevented by intensive
intervention efforts to stop smoking. Smoking habits can cause a person to become
physically dependent on nicotine. For very physical dependence, nicotine patches can be
used as an alternative substitute for the need for dependence on nicotine in a relatively
harmless form to avoid the effects of tobacco smoke such as carbon monoxide, tar, smoke
and other tobacco by-products.

1.2 IDENTIFICATION PROBLEMS

1. What is transdermal preparation?
2. What is Nicotine?
3. What is sustained release preparation?
4. How is penetrate route of transdermal preparation?
5. Type of transdermal preparation?
6. How is drug delivery system of transdermal preparation?
7. What is advantage and disadvantage of transdermal preparation?
8. What is side effect of patch preparation?

1.3 THE AIM OF THE PROBLEMS

1. To know what is trandermal preparation.
2. To know what is Nicotine.
3. To know about sustained release preparation.
4. To know the penetrate route of transdermal preparation.
5. To know types of transdermal preparation.
6. To know the drug delivery system of transdermal preparation.
7. To know the advantage and disadvantage of transdermal preparation.
8. To know the side effect of patch preparation.

1.4 SCENARIO
Mr. BM, 34 years old, consulted to doctor at stop-smoking therapy clinic at Pratama
Firdaus Clinic. The doctor give Mr. BM nicotin patch.

2
 CHAPTER II
DISCUSSION

2.1 Transdermal Preparation

Transdermal patches are patches with adhesives containing medicinal
compounds, which are placed on the skin to release active substances in specific
doses through the skin to the bloodstream. Is a topical drug delivery method in the
form of patches or semisolid which can provide a controlled systemic effect.
Transdermal drug delivery has many advantages compared to conventional drug
delivery methods such as oral administration. Transdermal delivery provides
controlled drug release, avoids hepatic metabolism, avoids the effects of digestion,
relaxes use, and long duration of drug delivery. The mechanism of transdermal drug
delivery is to deliver the drug molecule across the Stratum corneum layer in the skin
by diffusing through the skin's lipid layer
2.2 Nicotine

Formula: C10H14N2
Boiling point: 247 ° C
Molar mass: 162.23 g / mol
Density: 1.01 g / cm³
Density: 1.01

Nicotine is a toxic alkaloid which is a tertiary amine compound, of a weak

base with a pH of 8.0. At this pH, 31% of the nicotine is non-ionic and can pass
through the cell membrane. Nicotine is an alkaloid substance that exists naturally
in tobacco plants. Alkaloid substances have been known to have pharmacological
properties, such as the stimulant effect of caffeine which increases blood pressure
and heart rate. Citric acid and malic acid form nicotine citrate and nicotine malate.

 Pharmacokinetics of nicotine
Nicotine absorption through cell membranes is pH dependent. Nicotine
cannot penetrate membranes in an acidic environment because nicotine will be
ionized in that environment. Nicotine can quickly penetrate the membrane at
physiological blood pH because at that pH 31% nicotine is not ionized. Nicotine is

3
 most easily absorbed in the alkaline environment especially through the oral and
nasal mucous membranes because the epithelium of the area is thin and rich in blood
supply. Nicotine is also easily absorbed through the skin. Through these three
absorption pathways, blood nicotine levels will increase significantly because
nicotine does not pass through metabolism in the liver.
Nicotine is distributed quickly and extensively to all body tissues. The nicotine
concentration of arterial and brain blood will increase sharply after exposure,
dropping after 20-30 minutes because nicotine is distributed to other tissues. The
concentration of nicotine in the vein will decrease more slowly. This illustrates the
redistribution of body tissue and the speed of elimination.
Most nicotine is metabolized in the liver and a small part is metabolized in the lungs
and kidneys. The main metabolites are kotinin (70%) and nicotine-N-oxide (4%).
The long half-life of kotinin (16 hours) causes these metabolites to be used as
biochemical markers of nicotine use. A small portion of nicotine is excreted through
urine, which is around 5-10% of total elimination. The half-life of nicotine
elimination is an average of 2 hours.

 Pharmacodynamics of nicotine
Nicotine acts on nicotinic cholinergic receptors in the brain, autonomic ganglia,
adrenal medulla and neuromuscular junction. The nicotinic cholinergic receptor has
two subunits, the α subunit and the β subunit. The response to nicotinic receptor
stimulation involves the sympathetic and parasympathetic nervous system.
The effect of nicotine that can cause addiction is its effect on nicotinic cholinergic
receptors in the brain. The bond between nicotine and its nicotinic receptors in the
ventral tegmental area of the brain causes the release of dopamine in the nucleus,
which will create a pleasure. The emergence of a sense of comfort due to nicotine
in seconds is what causes dependence on cigarettes.

2.3 Sustained Release

Sustained release forms have received much attention in the development of drug
delivery systems because compared to conventional dosage forms, the slow release
form has several advantages. Among other things, slow dosages can reduce side
effects, reduce / reduce the number of uses, reduce drug fluctuations and generally
can increase comfort for patients (Welling, 1997).

4
 Most sustained releases are designed so that the use of a single dose unit presents
the release of a number of drugs immediately after use, appropriately producing the
desired therapeutic effect gradually and continuously releasing a number of other
drugs over an extended period of time usually 8 to 12 hour (Ansel et al., 2005).
According to Rao et al (2001), the main purpose of slow-release preparations is to
maintain therapeutic levels of drugs in the blood or tissue for extended periods. The
advantages of this dosage form produce even blood levels of the drug without the
need to repeat the administration of unit doses.
Drug delivery to the receptor or the place where the drug works is often hampered
by drug side effects or because the drug release is not appropriate for the workplace.
For this reason, the drug is made in the form of a controlled release or the dosage is
controlled. These controlled release preparations regulate the release of drugs in the
body that are intended to increase the effectiveness of the drug at its receptors.
Provision of sustained release or slow dosage preparations is part of a controlled
form of the liver. Slow-release preparations are preparations that cause the drug to
be released into the body for a long time.

2.4 Penetrate Route of Transdermal Preparation

At present, transdermal drug delivery is the most promising method of using drugs
to increase the amount of drug sent to the systemic circulation through the skin.
Transdermal drug delivery through the skin into the systemic circulation provides
convenient services and offers many benefits, such as first-rate metabolic removal,
increase efficiency and maintain therapeutic plasma drug stability, reducing the
frequency of drug use, reduce side effects and improve patient adherence (Jadhav
and Sreenivas, 2012). Parameter ideal drug selected as a transdermal preparation
which has a molecular weight <500 Daltons, pH 5-9, melting point <200 0 C,
solubility in water> 1 mg / mL and lipophilicity 10 <Ko / w <1000
Candidates for drugs suitable for transdermal drug release, namely: reactions not to
irritate the skin, low therapeutic index, lower oral bioavailability of the drug, half-
life of 10 hours or less medication, lower dosage of the drug . Examples of
transdermal drug formulations such as gels, creams, ointments, fillings and so on.
Transdermal gels are more popular because of their ease of use and better absorption
(Saroha, et al., 2013). Transdermal drug delivery is a way of controlled drug release
and sustained through the skin into the systemic channels. Topical application of

5
the drug to the skin epidermis or dermis tissue to achieve a therapeutic effect locally
where the fraction of the drug will be delivered into the blood circulation channel.
On the skin stratum corneum is the primary barrier to drug penetration. A correct
understanding of the structure and function of the skin and how to change it will
facilitate the development of transdermal drug delivery

A. Skin
The skin is a very wide organ of up to 15% of total weight (Richardson and
Certed, 2003). The skin is a perfect body armor for external influences, both
physical and chemical. Although the skin is relatively impermeable to chemical
compounds, but in certain circumstances the skin can be penetrated by drugs
or hazardous substances that can cause therapeutic effects or toxic effects. In
the study of systemic effects, active substances must enter the bloodstream
which are then brought to the tissue sometimes located far from the user and at
certain concentrations can cause pharmacological effects (Aiache, et al., 1993).

The skin has the main function as a protective layer of various external disorders
and stimuli. This protection function occurs through a number of biological
mechanisms, such as the formation of a continuous horn layer (keratinasi and
release of dead cells), respiration and regulation of body temperature,
production of sebum and sweat, and the formation of skin cells melanin to
protect the skin from ultraviolet light, as touch and taste, and defense against
stress and infection from the outside (Tranggono and Latifah, 2007).
Microscopic skin is divided into two main layers of the epidermis and dermis.
Structure shell can be seen in Figure 2.1.

6
 Figure 2.1 Structure of the skin (Ramteke, et al., 2012)

1.1 Epidermis
The thickness of the epidermis is 0.1-1 mm. Keratinocytes are the main
component (> 90%) and are responsible for barrier functions. Other cells found in
the epidermis are melanocytes and Langerhans cells (Ramteke, et al.,2012).
Epidermal keratinocytes have the main cell type which is the result of cell
division in the most epidermis in the basal layer (basal layer), which grows steadily
towards the surface of the skin. Keratinocytes undergoes "terminal differentiation"
to form the surface layer cells (stratum corneum). During differentiation, keratin
filing in coresing aggregation in which this process is called keratinization, and
filament bundles to form complex intracellular tissue in matrix proteins originating
from the granular layer (glanular layer). The coated epidermis of a squamous
epithelium seen in Figure 2.2

Figure 2.2 Epidermis (Graham, et al., 2005)

 Stratum corneum

Are keratin cells flattened, without cell nuclei and cytoplasm. The adjacent cells
overlap each other and together with intercellular fat forms a very effective defense.

7
 Stratum corneum thickness varies in the palms and soles of the feet (Graham, et al.,
2005). The stratum corneum consists of flat cells, dead, has no nucleus, does not
undergo a metabolic process, is colorless and contains little water (Tranggono and
Latifah, 2007). The outermost layer of skin that acts as a physical barrier for
substances in contact with the skin. The stratum corneum is composed of ten to
twenty layers of cells found throughout the body. Each cell is shaped flat, having a
length of about 34-44 μm, 25-36 μm wide, and 0.15 to 0.2 μm thick with a surface
area of 750-1200 μm2in which the one with the other collected to form an
arrangement that resembles a brick (Pathan and Setty, 2009).

 Stratum granulosum
Is the layer that is above the stratum spinosum composed of flat cells and contains
many dark particles called granules keratohialin (Graham, et al., 2005). Granular
layer composed of keratinocytes cells polygonal shaped, coarse grained, nucleated
shrink (Tranggono and Latifah, 2007).
stratum spinosum
Layers like spikes of spiny cells with Langerhans cells scattered between them.
These cells are immunological defenses against external antigens (Graham, et al.,
2005). The stratum spinosum layer has cube-shaped cells and similar spines. The
core of this large layer, oval and each cell contains small filaments consisting of
protein fibers (Tranggono and Latifah, 2007).

 Stratum basale
Consists of columnar cells attached to the basal membrane. Between basale there
are melanocyte cells that play a role in melanin production (Graham, et al., 2005).

1.2 Dermis
The dermis is the skin layer of up to 90% of the skin, consisting of connective tissue
that supports the epidermis (Ramteke, et al., 2012). The dermis is a layer located
below the epidermis and is the largest part of the skin. The main image of the dermis
form of woven fibers binds to one another, most of which are collagen fibers but
partly in the form of elastin fibers. The dermis consists of fibroblasts, mast cells and
macrophages. Fidroblasts forming a matrix of connective tissue in the dermis that
is usually adjacent to collagen and elastin fibers. Mast cells contain significant

8
granules including mediators such as histamine, prostaglandins, leukotrienes and
eucinophil factors and neutrophil chemotaxis. Macrophages are phagocytic cells
originating from the bone marrow. The dermis also contains blood vessels,
lymphatics, nerves and sensory receptors. Under the dermis there is a subcutaneous
fat layer that separates the skin from the muscles below it (Graham, et al., 2005).
The dermis is the thickest layer or connective tissue containing blood, clear banana,
sweat glands and skin nerves (Bavaskar, et al. , 2015) . The main role is as nutrition
of the dermis enabler into the epidermis and fibrous support tissue with an average
thickness of 3-5 mm, (Aiache, et al., 1993).

 Drug penetration through the skin

Drugs can penetrate intact skin after topical application through the walls of hair
follicles, sweat glands or oil glands or between corneal cells. The drugs used by the
actual ingredients easily get into damaged or cracked skin, but the penetration of
percutaneous absorption is not correct. If the skin is intact, the main way to
penetrate the drug is generally through the epidermal layer, rather than through hair
follicles or sweat glands (Ansel, 2008). Topical preparations are used to obtain local
effects in the application site by penetrating the drug into the skin layer or mucous
membrane. The main advantage of the topical delivery system is to avoid the first
pass effect, avoid the risk of inconvenience of intravenous therapy, changes in pH
and time of gastric emptying. In all the diversity of semi-solid formulations to
dominate topical delivery system preparation (Sharma, et al., 2012).
To reduce stratum corneum resistance and variability of biological penetration
enhancers (promoters to accelerate absorption) are included in skin preparation
(Jadhav and Sreenivas, 2012 ).
There are two main pathways that penetrate the drug to penetrate the stratum
corneum, namely: the transepidermal line and the pore pathway.

9
Figure 2.3 Pathway of drug penetration through the stratum corneum (Trommer and
NEUBERT, 2006)

Transepidermal hiking is divided into transselular pathways and intercellular

pathways. On the transcellular pathway, the drug passes through the skin to directly
penetrate the stratum corneum lipid and dead cytoplasmic keratinocytes. This
pathway is the shortest path, but the drug experiences significant resistance because
it must penetrate the lipophilic and hydrophilic structures. The more common
pathway for drugs to penetrate through the skin is the intercellular pathway. In this
pathway, the drug penetrates the space between the corneocytes (Trommer and
NEUBERT, 2006).
The pathway through the pores can be divided into the transfollular and
transglandular pathways. The glands and hair follicles only occupy about 0.1% of
the total area of the human body, so contributing to the penetration of these services
is considered small. However, the transfollicular pathway can be an important
pathway for the penetration of topically administered drugs. This is because the hair
follicles provide an efficient reservoir for substances that penetrate the skin. On the
transfollicular line, substances can only penetrate open hair follicles. To open closed
hair follicles do light massage (Lademann, et al., 2004).
Diffusion through the membrane
Diffusion is the process when a drug crosses the membrane so that the
molecule decreases the concentration gradient. Penetration occurs because of
differences in concentration without the need for energy, thus achieving equilibrium
in both membranes. Most active substances are alkaline or organic acids, then the
molecules are partially dissolved in an ionized form and some in the non-ionized

10
 form. Only a small portion of the active substance is not ionized and soluble fat can
be through the membrane by passive diffusion (Aiache, et al., 1993).

Figure 2.4 Multilayer skin shows permeation of transdermal drugs for systemic
release (Jadhav and Sreenivas, 2012).
When this drug is used topically, the drug will experience passive diffusion to
the surface of the skin tissue then. Mass transfer passes through the stratum corneum to
the epidermal layer to the next and then to the dermis to the blood circulation.

2.5 Type of Transdermal Preparation

Transdermal Patch Type
1. A single layer of drug in the adhesive

The Single layer drug in adhesive system is characterized by the inclusion of the drug
directly within the skin contacting adhesive. In this transdermal system design, the
adhesive not only serves to affix the system to the skin, but also serves as the
formulation foundation, containing the drug and all the excipients under a single
backing film.
2. Multi layer drug in adhesive

The Multi layer drug in adhesive is similar to the single layer drug in adhesive in that
the drug is incorporated directly into the adhesive. However, the multi layer
encompasses either the addition of a membrane between two distince drug in adhesive
layers orthe addition of multiple drug in adhesive layers under a single backing film.

11
 3. Matrixa system
The matrix system design is characterized by the inclusion of a semi solid matrix
containing drug solution or suspension which is in direct contact with the release liner.
The component responsible for skin adhesion is incorporated in an overlay and forms a
concentric configuration around the semisolid matrix.

4. Reservoir system

The reservoir transdermal system design is characterized by the inclusion of a liquid

compartment containing the drug solution or suspention separated from the release liner
by a semi permeable membrane and adhesive. The adhesive component of the product
responsible for skin adhesion can either be incorporeted as a continuous layer between
the menbrane and the release liner or in a concentric configuration around the
membrane.

2.6 Drug Delivery System of Transdermal Preparation

 Transdermal Delivery Active
A. Iontophoresis
Iontophoresis is the method where the movements of ions across a membrane
enhanced using an externally applied potential difference. When the membrane
under consideration is skin, the method is called transdermal iontophoresis. The
principle barrier to the transport of the molecules into an across the skin is stratum
corneum (SC), this is the uppermost layer of the epidermis with a thickness of
between 10-100 μm. The SC consists of several layers of corneocytes (a nucleate
keratin filled cells) inlaid in a lipid matrix, a continuous medium through the SC,
arranged mainly in bilayers2,3. The intercellular lipids consist of approximately
equal quantities of ceramides, cholesterols and free fatty acids4.
Percutaneous absorption may take place simultaneously by any combination
of the three main pathways4–7that include; the intercellular (paracellular) pathway
between the conneocytes along the lamellar lipids, the intracellular (transcellular)
pathway through the cells or the appendageal (shunt) pathway via hair follicles,
sweat ducts and secretary glands.

12
 Ions prefer the routes of the least electrical resistance; in the SC this is believed
to be via the pores. Some investigations indicate that these pores are sweat glands8,9,
others that transport occurs through both hair follicle and sweat glands10–12.
The physicochemical properties of the molecules have an effect on the
contribution of the follicular and non follicular routes of penetration. Hydrophilic
molecules tend to localize in the hair follicles, whereas lipophilic molecules are
mostly distributed in the lipid intercellular regions of the SC and the lipid
membranes of the epidermal keratinocytes13. Since passive transdermal permeation
of the majority of the drugs needs enhancement to achieve clinically relevant
plasma concentrations, both chemical and physical enhancement methods have
been developed. Iontophoresis is one of the physical methods.
In iontophoresis, cationic or neutral therapeutic agents are placed under an
anode or anionic therapeutic agents under a cathode. When a low voltage and low
current density is applied, according to simple electrorepulsion, ions are repelled
into and through the skin. Cationic drugs are driven into and through the skin by the
anode (active electrode), which also extracts anion from the tissue underneath the
skin into the anode. At the cathode (return electrode) anionic buffer ions are driven
into the skin and cations from the tissues are extracted into the cathode. (fig. 1) It is
also possible to include an additional charged drug in the return electrode to be
delivered simultaneously or to use a mixture of drugs in the active electrode to
enhance the desired effect or to increase skin permeation, depending on which
drugs/molecules are used14–16.
B. Electroporation
The stratum corneum (SC) is a primary rate limiting barrier to permeation of
drug molecules through the skin. Small molecular weight lipophilic drugs that are
effective at low doses can be effectively delivered by passive transdermal delivery.
The SC does not permit passage of polar/hydrophilic and macromolecules. Passive
and physical penetration enhancements strategies are used to overcome this barrier
property of the SC. Passive penetration enhancement techniques include use of
supersaturated solutions and penetration enhancers. In general, the drug delivery
potential of chemical modalities is limited. Therefore, physical permeation
enhancement techniques gained a lot of focus in the recent past. Physical
penetration enhancement techniques include iontophoresis, electroporation and
sonophoresis. Electroporation utilizes high voltage pulses that are applied for a very
short time to permeabilize the skin to facilitate transport of macromolecules and
hydrophilic compounds. Several drugs have been administered via this system
successfully. This review presents an overview of in-vitro and in-vivo studies
demonstrating therapeutic benefits offered by electroporation assisted permeation.
Factors affecting electroporation, synergism between electroporation and other
penetration enhancing strategies are also discussed.
C. Micro-needle
The success of transdermal drug delivery has been severely limited by the
inability of most drugs to enter the skin at therapeutically useful rates. Recently, the
use of micron-scale needles in increasing skin permeability has been proposed and
shown to dramatically increase transdermal delivery, especially for
macromolecules. Using the tools of the microelectronics industry, microneedles

13
 have been fabricated with a range of sizes, shapes and materials. Most drug delivery
studies have emphasized solid microneedles, which have been shown to increase
skin permeability to a broad range of molecules and nanoparticles in vitro. In vivo
studies have demonstrated delivery of oligonucleotides, reduction of blood glucose
level by insulin, and induction of immune responses from protein and DNA
vaccines. For these studies, needle arrays have been used to pierce holes into skin
to increase transport by diffusion or iontophoresis or as drug carriers that release
drug into the skin from a microneedle surface coating. Hollow microneedles have
also been developed and shown to microinject insulin to diabetic rats. To address
practical applications of microneedles, the ratio of microneedle fracture force to
skin insertion force (i.e. margin of safety) was found to be optimal for needles with
small tip radius and large wall thickness. Microneedles inserted into the skin of
human subjects were reported as painless. Together, these results suggest that
microneedles represent a promising technology to deliver therapeutic compounds
into the skin for a range of possible applications.
D. Vesicle
Transdermal administration of drugs is generally limited by the barrier function
of the skin. Vesicular systems are one of the most controversial methods for
transdermal delivery of active substances. The interest in designing transdermal
delivery systems was relaunched after the discovery of elastic vesicles like
transferosomes, ethosomes, cubosomes, phytosomes, etc. This paper presents the
composition, mechanisms of penetration, manufacturing and characterization
methods of transferosomes as transdermal delivery systems of active substances.
For a drug to be absorbed and distributed into organs and tissues and eliminated
from the body, it must pass through one or more biological membranes/barriers at
various locations. Such a movement of drug across the membrane is called as drug
transport. For the drugs to be delivered to the body, they should cross the
membranous barrier. The concept of these delivery systems was designed in an
attempt to concentrate the drug in the tissues of interest, while reducing the amount
of drug in the remaining tissues. Hence, surrounding tissues are not affected by the
drug. In addition, loss of drug does not happen due to localization of drug, leading
to get maximum efficacy of the medication. Therefore, the phospholipid based
carrier systems are of considerable interest in this era.
E. Chemical Enchancher
Chemical penetration enhancers (CPEs) are present in a large number of
transdermal, dermatological, and cosmetic products to aid dermal absorption of
curatives and aesthetics. This wide spectrum of use is based on only a handful of
molecules, the majority of which belong to three to four typical chemical
functionalities, sporadically introduced as CPEs in the last 50 years. Using >100
CPEs representing several chemical functionalities, we report on the fundamental
mechanisms that determine the barrier disruption potential of CPEs and skin safety
in their presence. Fourier transform infrared spectroscopy studies revealed that
regardless of their chemical make-up, CPEs perturb the skin barrier via extraction
or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand,
correlated with the denaturation of stratum corneum proteins, making it feasible to
use protein conformation changes to map CPE safety in vitro. Most interestingly,

14
 the understanding of underlying molecular forces responsible for CPE safety and
potency reveals inherent constraints that limit CPE performance. Reengineering this
knowledge back into molecular structure, we designed >300 potential CPEs. These
molecules were screened in silico and subsequently tested in vitro for molecular
delivery. These molecules significantly broaden the repertoire of CPEs that can aid
the design of optimized transdermal, dermatological, and cosmetic formulations in
the future.
 Transdermal Delivery Pasif
The skin has evolved as a formidable barrier against invasion by
external microorganisms and against the prevention of water loss.
Notwithstanding this, transdermal drug delivery systems have been designed
with the aim of providing continuous controlled delivery of drugs via this
barrier to the systemic circulation. There are numerous systems now available
that effectively deliver drugs across the skin. These include reservoir devices,
matrix diffusion-controlled devices, multiple polymer devices, and multilayer
matrix systems. This review article focuses on the design characteristics and
composition of the main categories of passive transdermal delivery device
available.
Mechanisms controlling release of the active drug from these systems as
well as patch size and irritation problems will be considered. Recent
developments in the field are highlighted including advances in patch design as
well as the increasing number of drug molecules now amenable to delivery via
this route. From the early complex patch designs, devices have now evolved
towards simpler, matrix formulations. One of the newer technologies to emerge
is the delivery-optimized thermodynamic (DOT) patch system, which allows
greater drug loading to be achieved in a much smaller patch size. With the DOT
technology, drug is loaded in an acrylic-based adhesive. The drug/acrylic blend
is dispersed through silicone adhesive, creating a semi-solid suspension. This
overcomes the problem with conventional drug-in-adhesive matrix patches, in
which a large drug load in the adhesive reservoir can compromise the adhesive
properties or necessitate a large patch size.
Transdermal drug delivery remains an attractive and evolving field
offering many benefits over alternative routes of drug delivery. Future
developments in the field should address problems relating to irritancy and
sensitization, which currently exclude a number of therapeutic entities from
delivery via this route. It is likely that further innovations in matrix composition
and formulation will further expand the number of candidate drugs available for
transdermal delivery.

2.7 Advantage and Disadvantage of Transdermal Preparation

- The advantages of a transdermal drug delivery system :
1. Avoid the first cross metabolism of drugs.
2. Reducing the occurrence of fluctuations in drug levels in the plasma, thereby
reducing the side effects that may occur.
3. Useful for drugs with a short half-life and a small therapeutic index.

15
 4. Prevent damage to drugs that are not resistant to the digestive tract pH and also
prevent irritation of the gastrointestinal tract by irritating drugs.
5. It is easy to stop giving the drug if there is an error in the administration of the
drug so that it can prevent the occurrence of toxicity.
6. Reducing the frequency of drug dosing so that it can improve patient compliance.
- The disadvantages of a transdermal drug delivery system :
1. The therapeutic effect arises more slowly than oral administration.
2. Not suitable for drugs that irritate the skin.
3. Only drugs with certain criteria (which can penetrate the skin) so that not all drugs
are suitable for transdermal administration.
4. Requires a special formulation design so that the drug can be effective if given
transdermally.

2.8 Side Effects of Patch Preparation

Side effects that can arise are relatively mild, so these preparations can be well
tolerated. Side effects that often arise are irritation in the skin where transdermal
nicotine is attached. The risk of skin irritation can be reduced by changing the
attachment every day. Sleep disorders sometimes occur in the use of transdermal
nicotine for 24 hours (including at night when sleeping).

16
 CHAPTER III
CLOSING
3.1 Conclusion
1. Nicotine replacement therapy (NRT) has proven to be an effective method for
smoking cessation therapy. Various NRT products that circulate officially in the
world market have their advantages and side effects which are more or less equal.

2. Transdermal patches are patches with adhesives containing medicinal compounds.

Transdermal patches are placed on the skin to release active substances in specific
doses through the skin to the bloodstream.

3. Nicotine patch is one of the transdermal patches. Nicotine patches cannot be

removed. Installed all day as a substitute for cigarettes (16-24 hours).

4. There are 3 nicotine patch dosage preparations based on the amount of nicotine
absorbed in 24 hours, which is 21 mg / day, 14 mg / day and 7 mg / day.

5. The biopharmaceutical mechanism of nicotine patches is as follows: carrier

substances from nicotine patch will liberate and partition to the stratum corneum, then
release nicotine and diffuse into variable epidermis. In the epidermal variable a
dissolution process occurs and diffuses again nicotine into the dermis so that it
absorbs and enters the blood circulation to produce an effect. After absorbing nicotine
contained in the blood circulation, it immediately experiences excretion.

6. Differences from conventional and transdermal drug delivery systems are transdermal
drugs, after being absorbed by drugs in the blood circulation they are immediately
eliminated. While the drug in topical administration, drugs that are on the target tissue
will be distributed and then enter the bloodstream after it has just been eliminated.

3.2 Suggestion
Be aware of pre-systemic metabolism considering that the skin also has metabolizing
enzymes.

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3.3 REFERENCES

Jadhav, K.J., dan Sreenivas S.A. (2012). Riview On Chemical Permeation Enhancer
Used Transdermal Drug Delivery System. International Journal Of Science Innovations And
Discoveries. (6): 204-217.
Saroha, K., Sarabjeet, S., Ajay, A., dan Sanju, N. (2013). Transdermal Gel-An
Alternative Vehicle For Drug Delivery. International Journal Of Pharmaceutical, Chemical
And Biological Sciennce, 3(3): 495-503.
Richardson, M., dan Certed, BO. (2003). Understanding The Structure And Function
of The Skin. www.Nursingtimes.net. 99(31).
Aiache, J.M., Devissaguet, J., dan Guyot, A.M. (1993). Farmasetika Biofarmasi .
Penerjemah: Widji Soerartri. Dr.Surabaya: Airlangga University Press. Halaman 34-35.
Ramteke, K.H., Dhole S.N., and Patil S.V. (2012). Transdermal Drug Delivery
System A Review. Journal of Advanced Scientific Research. 3(1): 22-35.
Graham, R., Brown., dan Burn, T. (2005). Lecture Notes Dermatologi. Edisi
Kedelapan. Jakarta: Penerbit Erlangga. Halaman 2,3,7,8.
Tranggono, R.I., dan Latifah, F. (2007). Buku Pegangan Ilmu Pengetahuan Kosmetik.
Jakarta: PT. Gramedia Pustaka Utama. Halaman 12
Pathan dan Setty. (2009). Chemical Penetration Enhancer For Transdermal Drug
Delivery Systems. Topical Journal of Pharmaceutical Research. 8(2): 173-179.
Bavaskar, K., Jain, M., Patil, M., dan Kalamkar, R. (2015). The Impact Of
Penetration Enhancers On Transdermal Drug Delivery System: Physical and Chemical
Approach. International Journal Of Pharma Research And Review. ISSN 2278-6074.
Ansel, H.C. (2008). Pengantar Bentuk Sediaan Farmasi. Edisi Keempat. Jakarta:
Penerbit Universitas Indonesia. Halaman 496.
Sharma, G,N., Sanadya, J., Kaushik, A., dan Dwivedhi, A. (2012). Penetration
Enhancement of Medicinal Agent. International Research Journal of Pharmacy. 3(5): 82-85.
Trommer, H., dan Neubert, R.H.H. (2006). Overcoming The Stratum Corneum: The
Modulation of Skin Penetration. Skin Pharmacology and Physiology. (19): 106-121.
Lademann, J., Otberg, N., Richter, H., Jacobi, U.,Schaefer, H., Blume, P.U., dan
Sterry, W. (2004). Folicular Penetration: An Important Pathway for Topically Applied
Substances. Hautarzt. (54): 321-323.
www.kalbemed.com/Portals/6/09_189Nicotine%20Replacement%20Therapy.pdf
eprints.ums.ac.id/14813/2/03_BAB_I.pdf
http://slutions.3m.com

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