CHAPTER I

1. INTRODUCTION

1.1 Poblem Background

Alzheimer's disease is a condition in which nerve cells in the brain die, making it difficult
brain signals transmitted properly. Symptoms of Alzheimer's disease difficult to recognize
early on. A person with Alzheimer's disease have problems with memory, assessment, and
thought, which makes it difficult for people with Alzheimer's disease to work or take part in
everyday life. Death of nerve cells occurs gradually over many years. Medication of
alzheimer usually use rivastigmin. But tablets of rivastigmin can makes user has a digestive
disturb. So, for the solution, rivastigmin is made as transdermal delivery system so that its
side effect can be avoided.

1.2 Problem formulation

1. Definition of alzeimer and rivastigmin
2. Definition of transdermal form
3. Advantages and disadvantages of transdermal form
4. The charasteristic of drug that can be used for transdermal form
5. Transdermal form’s profil
6. The mechanism of transdemal absorption
7. Kind of transdermal form
8. Effort to increase bioavailability of transdermal form
9. relation beween phisiologic factor and pharmaceutic factor of transdermal preparation

2.3 The purpose of the problem

1. Students can learn and understand the definition of alzeimer, rivastigmin and transdermal
preparations
2. Students can be informed about the charasteristic of drug that can be used for transdermal
preparation
3. Studens can learn about a relation beween phisiologic factor and pharmaceutic factor of
transdermal preparation
4. Students can learn about mechanism of transdermal delivery system
5. Students can learn about efforts to increase bioavailability of transdermal preparation

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 CHAPTER II

2. EXPLANATION
2.1 Definition of Alzheimer
Alzheimer's disease is a condition in which nerve cells in the brain die, making it
difficult brain signals transmitted properly. Symptoms of Alzheimer's disease difficult
to recognize early on. A person with Alzheimer's disease have problems with memory,
assessment, and thought, which makes it difficult for people with Alzheimer's disease to
work or take part in everyday life. Death of nerve cells occurs gradually over many
years. Symptoms may not be noticed early on. Often family members of patients aware
of the symptoms when it was too late.

2.2 Definition of rivastigmin

Rivastigmine (sold under the trade name Exelon) is a parasympathomimetic or

cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type
and dementia due to Parkinson's disease. The drug can be administered orally or via a
transdermal patch; the latter form reduces the prevalence of side effects, which typically
include nausea and vomiting. The drug is eliminated through the urine, and appears to
have relatively few drug-drug interactions.
It has been postulated that the strong potency of rivastigmine, provided by its dual
inhibitory mechanism, leads to more nausea and vomiting during the titration phase of
oral rivastigmine treatment. This enforces the importance of taking oral forms of these
drugs as prescribed with food. However, rates of nausea and vomiting are markedly
reduced with the once-daily rivastigmine patch (which can be applied at any time of the
day, with or without food).
In a large clinical trial of the rivastigmine patch in 1,195 patients with
Alzheimer’s disease, the target dose of 9.5 mg/24 hour patch provided similar clinical
effects (e.g. memory and thinking, activities of daily living, concentration) as the highest
doses of rivastigmine capsules, but with three times fewer reports of nausea and
vomiting.

2.3 Transdermal delivery system

1. Definition of transdermal
Transdermal drug delivery through the skin that is a non-invasive to the
systemic circulation. Transdermal administration is one way of drugs with
pharmaceutical dosage forms / drug in the form of creams, gels or patches
(patches) that are used on the skin surface, but able to deliver drugs into the
body through the skin (trans = through; dermal = skin). Generally, the use of
transdermal is on hormone drugs, such as estrogen. The most commonly
encountered may be patches to eliminate cigarette addiction, or eliminates
appetite (functioning as a slimming). Transdermal forms of choice, especially
for drugs which when given orally can give unwanted side effects. Such as the

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 effects of oral estrogen caused blood clots, or irritation of the stomach in the
drug-non-steroidal anti-inflammatory drugs and aspirin. Besides the advantages
of transdermal dosage needed is much smaller than the oral dose, because the
drug is expected to go straight to the target, so the toxicity level was lower than
the oral route. For example, in Carbamazepin (anticonvulsants / anticonvulsant,
commonly used for people with epilepsy) transdermal dose of 4 mg capable of
providing the equivalent effect of an oral dose of 1200 mg.
2. Advantages and disadvantages of transdermal preparation
 Advantages of transdermal preparation
Transdermal delivery system has more excellences than the other drug
delivery system. Some advantages of it include:
 It can minimize irregularity of absorption taht can be compared
with the oral route that is influenced by pH, food, speed of
gastric emptying, intestinal transit time, etc.
 The drug can be avoided from first pass efeect metabolism
 It can be protected from degradation by the gastro intestinal tract
 In the event of unwanted side effects (e.g. allergic reactions,
etc.) usage can be easily stopped
 Absorption of drugs is relatively constant and continuous
 Input of drugs into systemic sirculation can be controlled
 Relatively easy to use and can be designed as a freelance
controlled dosage that can be used in a relatively long time (e.g.
in the form of a transdermal patch or some kind of plaster) so
that it can improve patient compliance.
 Disadvantages of transdermal preparation
Besides many of the gains of the transdermal preparations, but these
preparations can not be separated from losses. Some disadvantages of
transdermal preparations include:
 Range limited drug (mainly related to molecular size)
 The dose should be small
 The possibility of skin irritation and sensitivity
 Not all parts of the body can be a place of drug application. For
example soles of the feet, etc.
 Must be aware of pre-systemic metabolism, while the skin also has a
lot of enzymes.

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3. Transdermal preparation’s profil
Transdermal preparations are usually found on the market today is a
transdermal therapeutic system (TTS) is commonly known as plaster. Simply
put, plaster consists of components - the following components (starting from
the outermost layer):

2.3.3.1 Impermeable backing or buffer layer

It usually is made by layers of polyester, ethylene vinyl alcohol (EVA) or
polyurethane coating. This layer is useful to protect the drug from the
water and the like that can ruin the medicine. This layer should be wider
than the layer below to
2.3.3.2 Drug Reservoir or the layer containing the drug (active substance) material
along with amenities such as speed control drug release, etc.
Drug dispersed well in an inert liquid excipient in this layer.
2.3.3.3 Such a layer of adhesive or glue to attach the drug reservoir with an
impermeable backing on the skin.
2.3.3.4 Protective layer that will be discarded when the plaster is used. This layer
is useful for preventing adhesion of an adhesive layer on the packaging
before use.
Sometimes, there are additional layers of the rate-controlling membrane
made of polypropylene and micro porous membrane that serves as a
regulator of the amount and rate of drug release from preparations to the
skin surface.

4. Kind of transdermal preparations

Thereare four main types of transdermal patches:

1. Single-layerDrug-in-Adhesive

In these systems the drug is included directly in the skin-contacting

adhesive. In this type of patch the adhesive layer is responsible for drug
release, and serves to adhere the various layers together, along with the
entire system on the skin. Adhesive layer is surrounded by a temporary
liner and supporters.

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 2. Multi-layer Drug-in-Adhesive

Multi-layer Drug-in-Adhesive is similar to Single-layer Drug-in-

Adhesive in that these drugs are put directly into the adhesive. The
multi-layer system adds another layer of medicine - in the adhesive,
usually separated by a membrane. This patch also has a temporary
layer-liner and permanent support.

3. reservoir

Reservoir transdermal system design includes a liquid compartment

containing a drug solution or suspension of the release liner is separated
by a semi-permeable membrane and adhesive. Component adhesive
products can be as a continuous layer between the membrane and the
release liner or as a concentric configuration around the membrane.

4. matrix

Matrix systems have a drug coating of semisolid matrix containing drug

solution or suspension, in direct contact with release liner. Adhesive
layer in this patch surrounds the drug layer partially overlaying it.

5. Characteristic of drug that can be used for transdermal preparations

Not all drugs can be made into transdermal preparations. A characteristics
of drugs that can be made transdermal preparation include:
 Possess a relatively small molecular weight (less than 500 Da). This is
because basically the stratum corneum of the skin is a barrier which is
effective enough to deter foreign molecules into the body. So only very
small molecules that can penetrate it alone.
 It has the middle level of partition coefficient (soluble in both lipid and
water)
 It has a relatively low melting point. This is because to be able to
penetrate into the skin, the drug must be in liquid form
 It has a relatively low effective dose.

6. Mechanism of transdermal absorption

Transdermal absorption preparation process includes the dissolution of
drugs in the base. Then the drug diffuses through the base to the skin surface.
Then the drug experienced two stages transdepidermal and transfolikuler.

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 Transepidermal stage, experienced drug penetration in the stratum corneum
and diffuses across the lipid matrix of stratum corneum protein. At the
transfolikuler stage, drug has penetration in the sebum and diffuses through the
pores of sebaceous lipids. Then, the drug had penetration in the epidermis and
diffuses through the epidermal cell. After that diffusion across the mass fibrous
and toward the dermis. Then diffuses into the capillaries and into the systemic
circulation

7. Effort to increase bioavailability of transdermal preparation

a. Supersaturation of drug
Skin absorption can be enhanced using supersaturated solutions
that have greater thermodynamic activity or chemical potential than the
saturated solutions (Hadgraft, 1999). Supersaturated solutions are
thermodynamically unstable for long-term storage due to drug
crystallization. They have been stabilized by addition of polymers, which
act as anti-nucleants.
b. Eutectic systems
A eutectic mixture is a physical mixture of two components that do
not interact to form a new chemical substance but at certain ratios inhibit
each other’s crystallization, resulting in a substance with a lower melting
point than that of either of the components (Stott et al., 1998). A eutectic
mixture is formed only when the two components are miscible in the
liquid state but remain completely immiscible in the solid state.
c. Ion pair formation
Charged molecules are poorly permeable across the stratum
corneum due to their low lipid partitioning ability. One approach to
enhance transdermal permeation is to add an oppositely charged moiety to
form a lipophilic ion pair that can partition into the stratum corneum lipids
as the charges temporarily neutralize
d. Complexation
Cyclodextrins are cyclic dextrose polymers that are known to
enhance the aqueous solubility and stability of drugs on complex
formation. The ring has a hydrophilic surface with a lipophilic core in
which organic molecules of appropriate size can be held to form
noncovalent inclusion complexes, resulting in increased aqueous solubility
and chemical stability
e. Chemical permeation enhancers
Substances that are known to improve the diffusion of drugs
through stratum corneum and epidermis are called penetration enhancers
(PEs), accelerants, or sorption enhancers (Pfister et al., 1990). Penetration
enhancers are known to improve drug transport across skin by reducing
the resistance of the stratum corneum to drug permeation.

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8. Relation between phisiologic factor and pharmaceutic factor of
transdermal preparation

Physiology factors that influence absorption of transdermal dosage form

- Situation and skin age, influence by :

- Skin is a effective diffusion barrier and there is effectivity will be decrease
if happen a change and damage on horn layer cell
- Exim
- Burned down
- Injured
- Fungus
- Diffusion also dependent in subject age, childern skin more than
permeability equivalent adult people skin texture.
- Blood circulation, influence by :
- discharge in skin area will be change speed of molecul penetration
- many more blood circulation, speed of molecul penetration will be more
the best.
- Place basting
 The amount that is absorbed to a similar molecule will be different
and depends on the anatomical structure of the basting.
 The thickness of the horny layer (stratum corneum) are different in
every part of the body, between 9 μm for up to 600 μm scrotum
skin to leather palms and soles of the feet.
- Humidity and Temperature
 Humidity 5-15% of normal stratum corneum
 Can be upgraded to 50% dg topically interchangeable carrier
material clog: vaseline, oil or an impermeable bandage.
 Stratum corneum moisture has the same affinity to Non soluble
substance in water or in other lipid structures → cell histology by
the horn and the threads of keratin that can expand in water and
lipids in the media that permeated the surrounding amorphous
 In vivo, skin temperature measured at the normal state, is relatively
fixed and has no effect on the absorption event.
- Drugs factor
 Drug concentration → Generally, the amount of drug that is
percutaneously absorbed per unit surface area per unit time will
increase, if the drug concentration increased.
 Drug release profile of the carrier → depends on the affinity of the
drug on the carrier, solubility of drug in the carrier, and the pH of
the carrier.

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  Partition coefficient of drug prices depending on their solubility in
water and oil price → This determines the transfer rate through the
absorption → partition coefficient can be changed by modifying the
chemical groups in the structure of the drug and carrier variations.
 PH conditions will affect the degree of dissociation and solubility
of drugs that are lipophilic.
 Carriers that can increase skin moisture will encourage the
percutaneous absorption of drugs.
 Drug contact time with the skin.
 The surface area where the drug is applied.

9. Design of patch preparation

There are two dominant design in the manufacture of the patch system.
They are membranecontrolled system and matrix systems.
1. Membrane controlled system
This system generally consists of three main components of a
reservoir, a rate controlling membrane and adhesive layer attached to
the skin. Drug in the reservoir area should be able to diffuse through
the membrane. The active ingredient in the reservoir can be dispersed
in the form of suspense, liquid, or gel (Florence and Attwood, 1988)
2. Matrix system
In this system, disperse the drug in the reservoir was replaced by
adhesive. Drugs and additional ingredients, such as polymers,
enhancer, formulated into a single into the adhesive solution which
was then the solvent was evaporated to make matrix film.
Furthermore, the matrix and the adhesive film is attached to a backing
film. The main components of the system matrix that is adhesive and
backing material. Advantages of the system matrix is a preparation
patch will form a thin and elegant, making it convenient to use as well
as the manufacturing process is easy, fast and cheap (Venkrataman et
al, 2000)
Schematic design system patches

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 CHAPTER III
3. CLOSING

3.1 Conclusions
Alzheimer's disease is a condition in which nerve cells in the brain die,
making it difficult brain signals transmitted properly. Symptoms of Alzheimer's
disease difficult to recognize early on. A person with Alzheimer's disease have
problems with memory, assessment, and thought, which makes it difficult for
people with Alzheimer's disease to work or take part in everyday life. Death of
nerve cells occurs gradually over many years. Medication of alzheimer usually
use rivastigmin. But tablets of rivastigmin can makes user has a digestive disturb.
So, for the solution, rivastigmin is made as transdermal delivery system so that its
side effect can be avoided. Transdermal drug delivery through the skin that is a
non-invasive to the systemic circulation.

3.2 Suggestion

So we put this paper, of course, many shortcomings both in terms of

content or delivery. Therefore, we expect criticism and suggestions for the
perfection of our papers. Hopefully this paper is useful for the reader.

3.3 Closing

For finishing this paper, we thanks to Faculty of Medicine, Department of

Pharmacy. Our, lecturer, and all of friends in tutorial 2 who have active for
drafting this paper.

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 REFERENCES

 http://abidinblog.blogspot.com/2010/01/gejala-penderita-penyakit-alzheimer.html

 http://coretanfifi.wordpress.com/2010/12/06/sediaan-transdermal/

 http://en.wikipedia.org/wiki/Rivastigmine#Side_effects

 Kulkarni, V., 2010, Hand Book of Non Invasive Drug Delivery System, United States of
America

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