1.

0 THE PROBLEM/HYPOTHESIS
1.1 INTRODUCTION
For better therapeutic action and for patient compliance, equilibrium in drug distribution
in blood stream is required. Rate of absorption and rate of elimination is required to
equilibrium of drug in blood but by anyhow it is missing in the conventional type drug
delivery system. Lower equilibrium and many more factors led to the concept of
nonconventional drug delivery system. Nonconventional drug delivery system may be a
sustained release or controlled release drug delivery system (17). Sustained drug
delivery system is the designed to release a drug from dosage form at a predetermined
rate to maintain a constant delivery of the drug with minimum side effects for a specific
period of time. Different type of formulation including liposomes and drug-polymer
conjugates are used to achieve sustained drug delivery.
Controlled drug delivery system is one which delivers drug at a predetermine rate, for
locally or systemically, for a specified period of time or predictable and reproducible
kinetics for predetermine period throughout the course of GIT. From below listed
figures, it is observed that the equilibrium of drug in blood stream in via the rate of
absorption and the rate of metabolism is only in the sustained or controlled drug delivery
system (18).
Chances of toxicity are higher in conventional drug delivery system due to requirement
of larger dose, frequency of administration and lower duration of action. Toxicity related
to the nonconventional drug delivery system is lower compared to conventional drug
delivery system due to efficient utilization of drug, extend or controlled delivery with very
low chances of toxicity, less patient complication, leading to better management of drug
delivery and having good therapy. Main drawback of controlled or sustained release
drug delivery system is the manufacturing or research cost (19). The cost of research is
very high and it is time consuming process to get the available into market compared to
conventional drug delivery system. Compared to conventional drug delivery system, it is
difficult to retrieval of drug in case of toxicity, poisoning and hypersensitivity in controlled
drug delivery system.
1.2 DESCRIPTION AND DETAILS
Transdermal drug delivery system is divided in mainly two part, topical application and
systemic application. Topical drugs delivery system gives effect on the local tissues
after delivered across the skin and systemic drug delivery gives effect after distribution
in the circulatory system. Transdermal therapeutic systems have been designed to
provide controlled continuous delivery of drugs via the skin to the systemic circulation.
There are many advantages in delivery of drug through the skin as a barrier. It will be
likely possible to increase the drug delivery by understanding the mechanisms by which
compounds cross the skin and gives systemic applications.
Stratum corneum of nonviable epidermis is the main barrier during the drug delivery
from transdermal formulation. There are multiple processing steps involve in between
drug first apply on skin to the availability of drug in to systemic circulation. For most of
the molecules stratum corneum is the rate limiting layer for the delivery through skin.
There are essentially three pathways by which drug transfer stratum corneum. The
relative prominence of the shunt or appendage way versus conveyance across the
stratum corneum has been debated by scientists over the years and is further difficult by
the lack of a suitable experimental model to permit separation of the three pathways.
Not any individual pathway is accountable for drug delivery but grouping of these all
three mechanisms is mainly accountable for the drug delivery via skin. In vitro
experimental study tends to include the use of epidermal membranes or hydrated skins
so that opening of the appendages are closed by the enlargement related with the
hydration. Scheuplein and colleagues suggested that a follicular shunt route was
accountable for the pre-steady-state penetration of polar type of molecules and flux of
very large polar molecules or ions that have struggle to diffusing across the intact
stratum corneum (32). However it is generally accepted that as the appendages
comprise a fractional area for permeation of approximately 0.1%, their contribution to
steady state flux of most drugs is negligible. This hypothesis has resulted in the majority
of skin penetration enhancement techniques being focused on increasing transport
across the stratum corneum rather than via the appendages. Exceptions are
iontophoretic drug delivery which uses an electrical charge to drive molecules into the
skin primarily via the shunt ways as they offer less electrical confrontation, and vesicular
delivery.
Considerable research effort has been directed towards gaining a better understanding
of the structure and barrier properties of the stratum corneum. Due to stratum corneum
lipid composition, the lipid phase behavior is changed from that of other biological
artificial membranes like human skin.
The hydrocarbon chains are arranged into regions of crystalline, lamellar liquid crystal
phases and lamellar gel thereby making different domains within the lipid bilayers. The
attendance of intrinsic and extrinsic proteins part of the human skin, such as enzymes
and many more, may also affect at the lamellar structure of the skin layer of stratum
corneum of the skin. Water is a vital constituent of the stratum corneum, which acts as a
plasticizer for the skin to avoid cracking of the skin stratum corneum and is also
participated in the creating of natural moisturizing factor (NMF), which helps to continue
suppleness (33). In order to know how the physicochemical properties of the dispersing
drug and vehicle influence penetration across the stratum corneum of skin and thereby
improve delivery, it is essential to control the principal route of drug permeation within
the stratum corneum.
Conventionally it was thought that hydrophilic molecules diffuse mainly within the
aqueous regions near the outer surface of intracellular keratin threads (intracellular or
transcellular route) whilst lipophilic chemicals diffuse through the lipid layer between the
filaments (intercellular route) (see Fig. 2). However, this is a simplification of the
situation as each route cannot be observed in isolation.
A particle crossing via the transcellular way vital partition into and diffuse through the
keratinocyte, but in order to transfer to the next keratinocyte, the molecule must partition
into and diffuse through the assessed 4-20 lipid lamellae between each of the
keratinocyte of the skin(34).
Figure 14: Graphical demonstration of the stratum corneum and the intercellular
and transcellular routes of permeation

This sequence of partitioning into and dispersing across multiple hydrophilic and
hydrophobic domains of the skin is uncomplimentary for most drugs. The intercellular
way is now deliberated to be the main pathway for penetration of most drugs across the
stratum corneum.
As a result, the majority of methods to improve the concentration of the penetration of
drugs across the skin are directed towards management of solubility in the lipid domain
or alteration of the ordered structure of this area (35). As an information higher the
solubility of stratum corneum in penetration enhancers, having higher affinity to increase
the penetration of drug from skin and higher the solubility of drug in penetration
enhancer improve the diffusion of the drug from the transdermal formulation.
Figure 15: Diagrammatic representation of the stratum corneum and the
intercellular and transcellular routes of penetration
1/ Shunt route or transferred through ducts: In this pathway drug molecules pass
through the pores of hair follicles and sweat ducts that bypass the barrier of the stratum
corneum. These pores are mai
mainly
nly important for ions and large molecules that struggle
to cross intact stratum corneum. However, below 1.0% of the skin surface area occupy
by these openings onto the skin surface and depend upon the location of the skin. The
contribution of the shut route
te in drug flux is strongly depended on experimental design,
type of the tissue, type of the skin, type of the dosage forms. Onset of action of the
transdermal dosage forms is mainly due to the type of penetration enhancer system and
shut route.

2/ Intracellular route: In this pathway, drug is directly across the stratum corneum and
the molecule crossing the intact stratum corneum faces numerous repeating hurdles.
Hydrophilic keratinocyte provide essential aqueous environment for lipophilic drug.
During transportation,
ransportation, drug partitioning into keratinocytes first and then diffusion through
keratin. After leave the cell drug is partitioning into bilayer lipid layer. In intracellular
pathway, drug pass through the cell of stratum corniem so delivery of drug via this rout
is depend upon thickness of the skin. Due to multiple partitioning and diffusion, these
route is to be avoided but for or highly hydrophilic molecules the transcellular route may
be predominant. Uses of solvent that remove the lipid from stratum corneum inversely
increase the drug delivery for even highly hydrophilic drug.

3/ Intercellular route: In this rout drug to be transferred via lipid layer in between
keratinocytes. In this case length of this path is higher than the thickness of the skin.
Small molecules and unchanged molecules are to be delivered into systemic circulation
via this pathway. It is complicated to describe delivery mechanisms of this pathway due
to complexity of the stratum corneum.
The skin contains a nonviable layer stratum corneum and viable three layers, the viable
tissue having catechol-o-methyl transferase which is responsible for the metabolism of
the drugs. After leaving the epidermis of the skin, drug molecule enters in papillary layer
micro circulation due to papillary layer contains so many blood capillaries. For
penetration of drug through skin, velocity of the drug molecules and concentration of
drug molecules are most affecting factors (36). Thickness of skin depends upon the part
of the body. Abdominal skin having 10 micron stratum corneum, 100 micrometer
epidermis and 100 micrometer dermis layer.
Outer part of the skin like dermis and epidermis are in hydrophilic in nature and diffusion
from these layers in typically liquid type of diffusion. Stratum corneum is characterized
by semisolid type of diffusion due to semi fibrous structure of that layer. Stratum
corneum having 1000 time higher resistance to diffuse water compared to dermis and
epidermis. Polar molecules and molecules having higher molecular weight have lower
diffusion coefficient that time SC layer become more dominant for permeation process.
In general stratum corneum is most rate limiting layer of the skin. Stratum corneum is
also rate limiting for non-polar molecules (37). As per mathematical model, stratum
corneum has two separate layers of lipid and protein. After application of transdermal
dosage form, drug use for local action and for systemic action.
Figure 16: Distribution of drug for local or system
In general for transdermal drug delivery drug molecule is partitioned and diffused to skin
layer and available in blood to give systemic effect. Below figure describe the sequence
during percutaneous penetration of the drug from skin (38).
Transdermal drug delivery system is really complex formulation compared other
conventional type of drug delivery systems. It’s required the understanding of basic
concept of biopharmaceuticals and pharmacokinetic (39). All type of controlled release
or sustained release drug delivery system is required to deliver the drug in study state
concentration (Css). Css depends upon the amount of drug deliver per time and total
clearance of drug from body. Some of the basic terms like terminal half-life, area under
curve, total clearance and volume of distribution need to understand design and
evaluation of dosage form. Time require to reduce the concentration to half after
equilibrium has been reached is called half-life. Half-life is important parameter for
selection of drug candidate. Total amount of drug deliver from the body and available at
the site of action is called Area under curve. AUC is main parameter to determine
bioavailability of drug. Total amount of drug that is cleared from body or drug pathway is
called total clearance. Apparent volume of distribution is the volume of fluid required to
solubilize the amount of drug which found in blood stream. Apart from the route of
transdermal drug delivery system and physiology of the skin, Mathematical model of the
drug penetration through skin is also most important. To understand the diffusion of
drug from formulation and deliver the drug from skin is understand by the Fick’s low of
diffusion.
Fick first low of diffusion is a fundamental concept of irreversible thermodynamics of
drug flow and it is directly proportional to the suitable potential gradients, at any system
and at any instant at constant temperature.

As per the equation of Fick’s first low, diffusion follow in a opposite way to that of
increase the drug concentrations. In above equation, diffusion coefficient is the D,
concentration is the C and X is the thickness of distance travel from inner to outer layer
of the surface.
Fick second law of diffusion is related to the decrease the concentration of drug at
particular point at particular time to change in rate of concentration gradient. This law is
considered the rate change of drug diffusion rather than change in concentration with
respect to area and time.

Fick’s second low of diffusion is more useful compared to first law on particular point
where design the in-vitro system where try to mimic the in-vivo situation. Most of the in-
vitro model has two compartment model systems.
Two compartments of the model are separate by membrane and cumulative permeation
of drug through membrane depends upon the area, concentration and thickness of the
membrane. But after particular time period, when membrane become saturate then
permeation is related to the concentration gradient only. In-vitro diffusion through skin is
determined by the help of the Franz type diffusion cell. Diffusion is carried out on
vertical or side by side type Franz diffusion cell. Dr. Thomas Franz is the inventor of the
diffusion cell.
FDC has been used diffusion cell with human cadaver skin or artificial membrane to see
the diffusion of dru8g through membrane. Diffusion cell is also use in cosmetic
formulations. According to USFDA Franz diffusion cell is the ideal instrument to find the
diffusion of drug. Diffusion cell has donor and receptor compartment (40). Donor
compartment have our formulation and receptor compartment filled with buffer medium
having skin pH. Below figure is the schematic diagram of vertical and side by side type
of diffusion cell. Diffusion cell have also water jacket to maintain temperature of the
system. The human cadaver skin or artificial membrane is sandwiched between donor
and receptor compartment. Temperature of the system needs to be control and liquid of
donor compartment is in moving condition during performing in-vitro diffusion study
(175).
Figure 17: Franz type diffusion cells
After stratum corneum of the skin and diffusion mechanism of the drug,
physicochemical properties of the drug are given significant impact of drug delivery
through transdermal drug delivery (182). Below listed are some of the physicochemical
properties of the drug with brief discretions.

1.3 HISTORY
Happiest situation for any of the nation depend upon the social health and wealth of the
society. The pharmacist’s roll is a crucial towards the healthcare management in the
society of any nation through his research and development. Pharmaceutical research
include all type of the knowledge like technology required to manufacture, simple as
well as complicated remedies for patients and doctors of the country. The cost in term of
time and money required to develop new molecular entity needs to be considering as a
research focus for any of the pharmaceutical company (1). In last 50 years of
development of our entire world, excellent steps have been made in pharmaceutical
research and development to get desired drug delivery and target the drug delivery on
effected area of the body with as low as possible side effects or adverse effects. Lots of
invention and research has been made in pharmaceutical fields. It is a very well
demanding field for research and development.
Safe and effective drug molecules development and delivery of that particular molecule
on target area and delivering up to desired time and amount been is the major effort
involving area in pharmaceutical research. Discovering and testing of new molecules
have become very massive due to all type of testing is related to the safety and efficacy
on human and it’s involve the large amount of budget of the investors. There are lots of
types of approach to make different type of drug delivery system (2). Now day
pharmaceutical firms try to make a single product that gives a solution of all type of
health related problem. In last decade of pharmaceutical development, there were lots
of development had been made related to the delivery of drug for sustain time period.
Most of drug delivery is related to the oral drug delivery, but now days oral drug delivery
or other routine drug delivery become conventional type of drug delivery and we need to
increase our way of thinking to deliver the drug in more economic, efficacious and
elegant manner.
Many of the pharmaceutical firms now start to investing there resource in drug delivery
that gives patient benefits throughout dose regime. They all are involving in the
development of controlled or sustained type of drug delivery systems. Development of
drug delivery system in controlled drug delivery from conventional can significant
improve the patient compliance in term of safety, efficacy. In controlled drug delivery
system can control the delivery of drug from dosage form to specific site of body for
predetermine time period (3). Control delivery of drug in body can prevent the many
type of problem related to the conventional type of dosage form. Most of firm are
involved in development of platform type technologies to deliver the drug on
predetermine rate and on predetermine target. Based on this type of discovery, they try
to improve the patient life and also increase their profit by increase the market
requirement of the product. Due to lots of invention in controlled delivery of drug and
polymer and different type materials that are responsible for controlled delivery, field of
excipients are most attracting field of invention.
In chronic type of disease like cancer, Alzheimer, Blood pressure, cardiac related
problem, blindness etc., needs to take a treatment for longer period of time. Many types
of medicine need to take at single times to cure the problem. It is required to develop
the newer formulation or medicine for cardiovascular disease, cancer, bronchial
asthma, AIDS, hepatitis, coronary heart diseases etc. from natural and easily available
sources.
Apart from other type of chronic disease, cardiovascular problem is most dreadful
disease. Day by day our food habits becoming worst and worst and due to high
cholesterol level in food, lack of exercise, lots of junk food and hectic working style, our
body become more prominent toward problem related to the heart. Ischemic heart
diseases and coronary heart problem are the most reason for death among the other
diseases.
Heart diseases are responsible for the approximately 30% death in USA and as per the
WHO report out of total death 30% death is due to the cardiovascular disease. Every
year millions of patients suffer myocardial infraction. Similarly in India every year lots of
patients suffer by heart related problems. In India 30% to 40% of deaths are due to
inflammatory heart disease (4). Due to continuous acceptance of junk food and hectic
life style, our community comes in the whirl wind of heart disease. Heart related
problems are not only responsible for death but also responsible for economic loss of
the nation. Development in drug related to the cardiac problem is not only increase the
profit of the pharma company but also improve the quality of the life. Every year 20%
increase in the development of cardiac drug.
As far as world is concern, WHO release guide and practical tool to prevent and control
the chronic disease in the name of “Stop the global epidemic of chronic problem in
human body”. The guide presents a simple seven stage for active support, counting
identifying target viewers, developing key messages and selecting implementation
strategies. In that guideline they cover the following facts,
1. In 1999 78% of cardiac death in low and middle income courtiers
2. As per assessment 20 million people will be die due to cardiac problem
3. In 2010 cardiac problem is the leading reason for death in developing countries
4. In 1999, Cardiac problem is the third reason for death
5. Most of the cardiac problems are controllable
6. No any boundaries for cardiac problem like socio commercial, topographical or
femininity
As per WHO, US $558 billion estimated economic is loosed due to cardiac problem.
Many of the drugs used for cardiac problem is having good pharmacokinetic and
biopharmaceutical profile like Nifedipin, diltiazem, verapamil, atenolol. That drugs
having good absorption, good bioavailability, less hepatic metabolism.
In spite of advancement in drug delivery system, the transdermal drug delivery system
having the preferred choice for administration of drug because of ease to application
and cost of therapy with high level of patient compliance. Delivery of the drug from skin
by patch system are the novel type of pharmaceutical system having tendency to deliver
the drug for extended period of time with constant and effective drug level (5).
Transdermal drug delivery system had the experimentation period in the year of 1970.
Transdermal drug delivery (TDS) is not deliver only simple base drug like scopolamine,
nicotine, clonidine but complicated molecules like nitroglycerin, insulin, acyclovir etc.
could be delivered by TDS route.
Fabrication techniques and type of pressure sensitive adhesives is also developed.
Other than pressure sensitive adhesives, penetration enhancement techniques,
microneedles, iontoporesis, sonophoresis, microelectronics, liposomes etc. are different
type of method to increase the penetration of drug through skin to deliver drug to meet
required delivery of drug for specific period of time. Over last 15 years more than 10000
transdermal related documents are issued in world wide.
Below are listed some of the marketed available transdermal drug delivery systems.

Table 3: List of the marketed available transdermal drug delivery systems

Molecule Innovator/ Excipients used in transdermal formulation

Generics
Clonidine Catapres Mineral Oil, Colloidal Silicondioxide,
TTS polyisobutylene
Estradiol Climara Acrylate adhesive, fatty acid ester
Estradiol Vivelle-Dot Acrylic adhesive, silicone adhesive, oleyl alcohol
NF, povidone, USP and dipropylene glycol
 Estraderm Drug reservoir of estradiol USP and alcohol USP,
Gelled with hydroxypropyl cellulose NF an
adhesive formulation of light mineral oil NF and
polyisobutylene
Alora Sorbitan monooleate dissolved in an Acrylic
adhesive matrix
Lidocaine Lidoderm Dihydroxyaluminum aminoacetate, Disodium
edetate, Gelatin, Glycerin, Polyvinyl alcohol,
Propylene glycol, Propylparaben, Kaolin,
Methylparaben, Polyacrylic acid, Tartaric acid,
Urea Sodium carboxymethylcellulose, Sodium
polyacrylate, D-sorbitol.
Nitroglycerin Nitro-dur, Gelva 3011, Gelva 2397, Aerotax, Sod.
Polyacrylate,
Formaldehyde
Methylpheni Daytrana acrylic adhesive, a silicone adhesive, and
date methylphenidate
Nicotine Habitrol acrylate adhesive, aluminized polyester, cellulose
paper, methacrylic acid copolymer
Nicotine Nicoderm Ethylene vinyl acetate-copolymer, polyisobutylene
and high density polyethylene between clear
polyester backings 2.ethylene vinyl acetate-
copolymer, polyisobutylene and high density
polyethylene between pigmented and clear
polyester backings
Diclofenac Flector 1,3-butylene glycol, dihydroxyaluminum
Epolamine aminoacetate, disodium edetate, D-sorbitol,
fragrance (Dalin PH), gelatin, kaolin,
methylparaben, polysorbate 80, povidone,
propylene glycol, propylparaben, sodium
carboxymethylcellulose, sodium polyacrylate,
 tartaric acid, titanium dioxide, and purified water

Buprenorphie Butrans Oleyl Oleate, Levulinic acid, PVP-K90, Acrylic

Polymer (Crosslink)

Scopolamine TRANSDER Reservoir of scopolamine, light mineral oil, and

M polyisobutylene and adhesive formulation of
SCOP mineral oil, polyisobutylene, and scopolamine
Rotigotine Neupro Silicone polymer 4301,4201, Na-Metabisulphite,
Ascorbyl palmitate, α-tocopherol, PVP
Norelgestromi Ortho-Evra Lauryl Lactate, Crospovidone, Indopol H-1900,
ne & Ethinyl Polyisobutylene polymer
Estradiol
Rivastigmine Exelon Acrylic copolymer, Poly(butylmethacrylate,
methylmethacrylate), silicone adhesive, silicone
oil, and vitamin E
Fentanyl Durogesic Polyacrylate adhesive
D-trans

Table 4: Innovator information with brand name and manufacture

Drug Indications Brand Name Manufacturer

Nicotine Pharmacological NicotinellR Novartis

smoking cessation

Fentanyl Pain relief patch MatrifenR Nycomed

Norelgostromin/ Postmenstrual Ortho EvraTM ORTHO-McNEIL

Ethinyl Estradiol syndrome
Diclofenac Anti-Inflammatory NuPatch 100 Zydus Cadila
diethylamine

Rigotine early-stage idiopathic NeuproR UCB and Schwarz

Parkinson’s disease Pharma

Estradiol Postmenstrual Alora TheraTech/Proctol

syndrome and Gamble

Nicotine Smoking cessation NicodermR Alza/GlaxoSmith

Kline

Estradiol Postmenstrual Estraderm Alza/Norvatis

syndrome

Estradiol Postmenstrual Climara 3M pharmaceuticals

syndrome /Berlex Labs

Testosterone Hypogonadism in Androderm TheraTech/Glaxo

males SmithKline

Nitroglycerin Angina pectoris Nitrodisc Roberts

Pharmaceuticals

Scopolamine Motion sickness Transderm- ScopR Alza/Norvatis

Estrogen/Proge Hormone Nuvelle TS Ethical

sterone replacement therapy Holdings/Schering

Nitroglycerin Angina pectoris Deponit Schwarz-Pharma

Nitroglycerin Angina pectoris Nitro-dur Key Pharmaceuticals

Clonidine Hypertension Catapres TTSR Alza/Boehinger

Ingelheim
Estradiol Postmenstrual FemPatch Parke-Davis
syndrome

Nitroglycerin Angina pectoris Minitran 3M Pharmaceuticals

Estradiol Postmenstrual Climaderm Ethical Holdings
syndrome /Wyeth-Ayerest

Fentanyl Moderate/severe DuragesicR Alza/Janssen

pain Pharmaceutical

Estradiol Postmenstrual Estraderm Alza/Norvatis

syndrome

Estrogen Postmenstrual Fematrix Ethical Holdings

syndrome /Solvay Healthcare

Nitroglycerin Angina pectoris Transderm- NitroR Alza/Norvatis

Testosterone Hypogonadism in Testoderm TTSR Alza

males

oxybutynin Overactive bladder OxytrolR Watson Pharma

Nicotine Smoking cessation Prostep Elan Corp./Lederle

Labs

Pharmaceutical industry of the transdermal drug delivery system is growing, worldwide.

Representing more than 12% of the worldwide drug delivery trade, this market was
valued at $21.5 billion in year of 2010 and is expected to touch $31.5 billion by 2015.
The yearly U.S. transdermal system market was projected at more than $3 billion in
2010, with leading contraceptive, hormone replacement, and pain release produces
accounting for more than half of total sales. Drug delivery, biotechnology and
pharmaceutical companies continue to evaluate new applications for transdermal drug
delivery including treatments for osteoporosis, migraine restless leg syndrome, stroke
and HIV (6). The future development of successful transdermal drug delivery systems in
a widening array of therapeutic areas will play an important role in improving patients’
quality of life by providing alternatives to conventional oral and injectable drugs.
Beyond the branded products industry, the generic product industry is rapidly expanding
the market with bioequivalent transdermal drug delivery systems. The sanction process
for transdermal drug delivery generic products has been simplified by the FDA with
commendations outlining the essential trainings for indicating not only bioequivalence
(systemic delivery), but also not inferior for irritation, adhesion, and sensitization to the
reference product. The FDA has also freshly issued a guidance connected to drug
residual content for transdermal drug delivery systems.
Developing new transdermal systems presents challenges in identifying the best body
site for submission, creating bioavailability, monitoring ability, defining the suitable
duration or time of application, and quantifying residual drug after application. Irritation,
adhesion and sensitization must also be measured. A well designed and united
development plan is needed to achieve rapid approval of the transdermal formulations.
Transdermal drug delivery gives a solution to bioavailability. Also economically
transdermal market is growing at the rate of 15 % per year; offers a good economic gain
along with some distinct advantages over other conventional type of controlled release
drug delivery system.

1.4 CRITICALITY
Most of the drugs need to be admin two to three times in a day due to short biological
half-life. Some of the drugs are susceptible to hepatic metabolism need to be
administered in a higher dose to get the requirement of steady state plasma
concentration for therapeutic effect. Some of the drugs react with food and decrease the
absorption of that drug (7). Due to interaction with food, doctor prescribes the some of
the drug in empty stomach. Drug molecules are converted in degradation product due to
oxidation and hydrolysis in stomach and degrade product is not absorb in stomach,
some of the drugs are specially prescribe through other drug delivery systems.
Apart from the greatest advantages of transdermal delivery system, only limited
numbers of drugs are suitable to administration by this type of drug administration. It
has been challenging to deliver the hydrophilic drugs through transdermal route. There
has been lots of method available in market to improve the penetration of the drug.
Fundamental problem of the transdermal drug delivery system is to deliver the drug
from skin. Some of the other problem after developing of transdermal is also possible.
The aim of the present investigation is to develop semi solid suspension type of
transdermal drug delivery system to get the desired drug delivery from minimum patch
size (8). Captopril is used as a model drug (126). There are numerous patents and
research papers available in adhesive or polymer based drug delivery system as
vehicles for controlled release delivery. The use of pressure sensitive adhesive to
control the delivery of a variety of drugs from polymer devise has become very
significant in the development of controlled release dosage form.
In the early of 2005, the FDA publicized document having investigational report of death
and other side effect due to overdose of fentanyl transdermal drug delivery. Initial stage
of duragesic patch after approval, patch is available in the form of reservoir type system
but lots of problem and marketed complain afterward Duragesic patch converted into
matrix type of transdermal system. Not only innovator formulation has issue but other
generic formulation faced the issues related to the overdose of fentanyl. Many of the
marketed batches were withdraw from market due to delivery issues. In the year of
2007, Noven Pharmaceuticals, withdraw several lots of Daytrana ADHD patch due to
patch separating from release liner during storage. In Europe, Rotigotine transdermal
system was withdraw due decease the efficacy of the transdermal system NEUPRO®.
During storage Rotigotine drug is converted into other polymorphic form of Rotigotine
(9). So after lots of investigation, UCB pharmaceutical completely replace the existing
formulation with new formulation having stable form of the Rotigotine. In new
formulation of Rotigotine in USA they change the crystal form of the Rotigotine, after
facing the problem in stability they used the stable form of the Rotigotine.