“DESIGN, FORMULATION AND EVALUATION OF TRANSDERMAL PATCHES FOR ANTI HYPERTENSIVE DRUG”
A dissertation submitted to Andhra University,
In partial fulfillment for the award of the degree of MASTER OF PHARMACY
In
PHARMACEUTICAL TECHNOLOGY
(2011-2013)
Submitted by
KORUKONDA SRIKANTH KUMAR , B.Pharm(Reg.No: 611289801014)
Under the Joint Guidance of
ACKNOWLEDGEMENTS
Industrial Guide Mr. Santosh Kumar. Tata M.Pharm
Manager Director carpouscles research solutions, Visakhapatnam
Institutional Guide Dr.k.e.v Nagoji M.Pharm PhD.
Principal Sri Venkkateswara college of Pharmacy
SRI VENKATESWARA COLLEGE OF PHARMACY, ETCHERLA
Affiliated to ANDHRA UNIVERSITY VISAKHAPATNAM
I am thankful to Almighty God, whose blessings made it possible to
complete the dissertation work successfully.
I have received great help from many of my teachers and friends in a
number of ways in preparing this dissertation work, I want to thank all of them.
It is my proud privilege to express my heartfelt gratitude to my beloved
institutional guides Dr. K.E.V.NAGOJI M.Pharm., Ph.D, Principal, Sri
Venkateswara College Of Pharmacy, Etcherla for his encouraging words that
enabled me to act with quality and precision. I am highly indebted to him for the
encouragement, patience and help rendered to me at all stages of my work
I take this opportunity to express my greatfulness and gratitude to Ms.
Padmasri , Ms. Lakshmi Deepthi and the entire staff of Sri Venkateswara
College of Pharmacy for their support and encouragement during the course of
my study.
I express my deep sense of gratitude to my industrial guide Mr. Santosh.
Tata Manager and Head and also research guide from, CORPUSCLE
RESEARCH SOLUTIONS, Visakhapatnam
I thank Loving thanks to my dearest friends
swetha ,somesh ,ramareddy ,suresh ,indu ,swamy, padmavathi, chandrashekar,
for their support and encouragement.
I thank specially to Mr. Lokesh, Mr. Lakshmana murthy, Srinivas,
Ramana and all other non-teaching staff for their timely help
Finally, with deep sense of veneration and gratitude, I recall the
affectionate help, endless encouragement and constant support of my parents
shri Satyanarayana and ramadevi .
As a final word, I would like to thank each and every person who have
been a source of support and encouragement and helped me to achieve my goals
and complete my dissertation work successfully
K.SRIKANTH KUMAR
SRI VENKATESWARA COLLEGE OF PHARMACY
NH-5; ETCHERLA, SRIKAKULAM-532410.
(Affiliated to ANDHRA UNIVERSITY), Vishakapatnam
Approved by AICTE & PCI, NEW DELHI.
CERTIFICATEThis is to certify that the project work entitled “ DESIGN,
FORMULATION AND EVALUTION OF TRANSDERMALL
PATCHES FOR ANTI HYPERTENSIVE DRUG ” submitted to Andhra
University,Visakhapatnam for the partial fulfillment of the award of degree of
Master of pharmacy in Pharmaceutical Technology was carried out by
K.Srikanth Kumar (Regd. No.611289801014) in the department of
Pharmaceutics, Sri Venkateswara College of Pharmacy, Etcherla under
my guidance and supervision.
This work is original and has not been submitted in part or full to any other
degree of Andhra University or any other university
Place: Etcherla Dr. K.E.V.NAGOJI, M.PHARM, PhD
Date: Principal
Sri Venkateswara College of Pharmacy
Etcherla.
DECLARATION
I do here by declare that the work presented in this thesis entitled “DESIGN,
FORMULATION AND EVALUTION OF TRANSDERMALL
PATCHES FOR ANTI HYPERTENSIVE DRUG” was out by me at
corpuscle research solutions, Vishakapatnam and in the department of
Pharmaceutics, Sri Venkateswara College of Pharmacy under the supervision
of Sri. Dr. K.E.V.Nagoji, M. PHARM, PhD, Principal of Sri Venkateswara College
of Pharmacy, Etcherla and co-guidance of TATA. SANTOSH, Deputy
manager, Corpuscles Research Solutions, Visakhapatnam.
This work is original & has not been submitted in part or full for the award of
other degree or diploma of any other university.
Place: Etcherla K.Srikanth kumar
Date: Regd. No. 611289801014
LIST OF ABBREVIATIONS
Abs Absorbance
AUC Area under curve
°C Degree Celsius
Cm Centimeter
Cmax Peak plasma concentration
Conc. Concentration
CDR Cumulative Drug Release
CR Controlled release
DMSO Di Methyl sulphoxide
DSC Differential Scanning Calorimetry
e.g., For Example
FTIRFourier transform Infra-red
Spectrophotometer
GIT Gastro intestinal tract
Hrs Hour
HPLC High performance liquid chromatography
ICHInternational Conference on
Harmonization
IP Indian Pharmacopoeia
K-C cell Keshary-Chien diffusion cell
Mg Milligram
min. Minutes
ml Milliliter
Mm Mile meter
NMRNuclear magnetic resonance
spectroscopy
nm Nanometer
PEG-400 Polyethylene glycol
Rpm Revolution per minute
RH Relative humidity
SD Standard deviation
TDDS Transdermal Drug Delivery System
t1/2 Half life
USP United States Pharmacopeia
UV Ultraviolet
Vd Volume distribution
v/v Volume by volume
w/w Weight by weight
g/ml Microgram per milliliter
% Percentage
max Absorption maxima
CONTENTS
CHAPTER
NO.
CHAPTERS PAGE NO.
1. INTRODUCTION 1
2. AIM AND OBJECTIVE 18
3. LITERATURE REVIEW 19
4. DRUG AND EXCIPIENT PROFILE 25
5. METHODOLOGY 32
6. RESULTS & DISCUSSION 42
7. CONCLUSION 81
8. SUMMARY 83
9. BIBLIOGRAPHY 84
LIST OF TABLES
SRN
O
Contents Page
no
1 Ideal properties of drug 3
2 Examples of FDA Approved Transdermal Patches 17
3 Materials Used 32
4 Equipments used 33
5 Spectrophotometric data for construction of standard graph
Labetalol
35
6 Formulation chart of Labetalol transdermal films 38
7 Preformulation studies of Labetalol 42
8 Data of IR spectral peaks of Labetalol and polymers 44
9 Physicochemical parameters of prepared formulation F1-F9 46
10 Comparative data of percentage drug release from the
formulations F1-F9
48
11 Comparison of zero order of in vitro drug release F1-F9 50
12 Comparison of first order of in vitro drug release F1-F9 52
13 Comparison of higuchi model of in vitro drug release F1-F9 54
14 Comparison of Korsmeyer equation of in vitro drug release F1-
F9
56
15 Comparison of orders of in vitro release of Labetalol from the
formulation F1-F9
58
16 Anova for repose surface linear model-Response1 59
17 Estimated regression coefficient-Response1 59
18 Anova for repose surface linear model-Response2 62
19 Estimated regression coefficient-Response2 62
20 Anova for repose surface linear model-Response3 65
21 Estimated regression coefficient-Response3 65
22 Anova for repose surface linear model-Response4 68
23 Estimated regression coefficient-Response4 68
24 Composition of optimized formula- 71
25 Response variable of optimized formula1 71
26 Data of various parameters of model fitting of labetalol of
optimized formulation
71
27 Drug release studies of optimized formula 72
28 Comparison between the Experimental and Predicted value for
the optimized formula
75
29 Physicochemical properties of most satisfactory formulations
F5(after stability)
75
30 In vitro drug diffusion studies of most satisfactory formulations
F5(after stability)
76
LIST OF FIGURES
SRN
OContents
Page
no
1 Cross Section of the Skin 4
2Transepidermal (A) and transappendageal route of transport into
the skin.
8
3 Pentration enhancer activity 11
4 Penetration pathway of drug molecules through the skin 11
5 Types of Transdermal Drug Delivery Systems 16
6 standard graph of Labetalol in phosphate buffer pH7.4 35
7 In-vitro studies by using Franz diffusion cell 40
8 Ex-vivo studies on the rat skin 40
9 FTIR Spectrum of Labetalol 43
10 FTIR Spectrum of physical mixture of drug with Eudragit RSPO 44
11 FTIR Spectrum of physical mixture of drug with Eudragit RLPO 45
12 Drug content of all formulation 47
13 Comparative In-vitro diffusion study of all formulationsF1-F9 49
14 Comparison of zero order of in vitro drug release F1-F9 51
15 Comparison of first order of in vitro drug release F1-F9 53
16 Comparison of higuchi model of in vitro drug release F1-F9 55
17Comparison of Korsmeyer equation of in vitro drug release F1-
F9
57
18Correlation between actual and predicted valu for folding
endurance-Response1
60
19 3D-Graph showing the effect of EUDRAGIT-RSPO,RLPO and 60-61
DMSO ,PEG on folding endurance-Response1
20Correlation between actual and predicted valu for 4th hr drug
release-Response2
63
213D-Graph showing the effect of EUDRAGIT-RSPO,RLPO and
DMSO ,PEG on 4th hr drug release-Response2
63-64
22Correlation between actual and predicted valu for 12th hr drug
release-Response3
66
233D-Graph showing the effect of EUDRAGIT-RSPO,RLPO and
DMSO ,PEG on 12th hr drug release-Response3
66-67
24Correlation between actual and predicted valu for 24thdrug
release-Response4
68
253D-Graph showing the effect of EUDRAGIT-RSPO,RLPO and
DMSO ,PEG on 24th hr drug release-Response4
68-70
26 Zero order kinetics of optimized formula 73
27 First order plot of optimized formula 73
28 Higuhi plot for optimized formula 74
29 Korsmyer-peppas polot for optimized formula 74
30 In vitro drug diffusion studies of most satisfactory formulations
F5(after stability)
77
INTRODUCTION
1. INTRODUCTION
1.1TRANSDERMAL DRUG DELIVERY SYSTEM:
Transdermal drug delivery systems are defined as self-contained discrete dosage
forms which, when applied to the intact skin, deliver the drug(s), through the
skin, at controlled rate to the systemic circulation.1
These techniques are capable of controlling rate of drug delivery, sustaining the
duration of therapeutic activity, and/or targeting the delivery of drug to a tissue.
In responses to these advances, several transdermal drug delivery systems have
recently been developed aiming to achieve the objective of systemic medication
through topical application on the intact skin surface. The principle of
transdermal drug delivery systems is that they could provide sustained drug
delivery over a prolonged period of time. Thus, it is anticipated that transdermal
drug delivery systems can be designed to input drugs at appropriate rates to
maintain suitable plasma-drug levels for therapeutic efficacy, without the periodic
sojourns into plasma concentrations that would accompany toxicity or lack of
efficacy. Ultimately, the success of all transdermal system depends on the ability
of the drug to permeate skin in sufficient quantities to achieve its desired
therapeutic effect.2
1.2 MECHANISM OF DRUG PERMEATION THROUGH THE SKIN:
When drugs are applied on the skin surface, penetration into and through the skin
can occur via various routes.
Drugs penetrate either via the stratum corneum (transepidermal) or via
the appendages (transappendageal) (Figure 3). During penetration through the
stratum corneum, two possible routes can be distinguished.20
i) Penetration alternating through the corneocytes and the lipid lamellae
(transcellular route) and
ii) Penetration along the tortuous pathway along the lipid lamellae (intercellular
route).
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INTRODUCTION
Generally it is accepted that the predominant route of penetration through
the stratum corneum is the intercellular route. This is mainly caused by the
densely cross-linked cornified envelope coating the keratinocytes. However
transcellular transport for small hydrophilic molecules such as water cannot
completely be excluded The appendage route or shunt route includes either the
duct of the eccrine sweat glands or the follicular duct. The content of the eccrine
sweat glands is mainly hydrophilic, while the content of the follicular duct is
lipophilic.
1.3 ADVANTAGES OF TRANSDERMAL DRUG DELIVERY:
1. Prevents the variation in the absorption and metabolism associated with oral drug
administration.
2. Prevents the risk and inconvenience of intravenous therapy.
3. Permits continuous zero-order drug administration and the use of drugs with short
biological half-lives.
4. Increases the bioavailability and efficacy of drugs, since it bypasses hepatic first-
pass elimination.
5. Provide a simple therapeutic regimen, leading to good patient compliance that can
be easily terminated by simple removal of the patch.
6. Transdermal medication delivers a steady infusion of a drug over an extended
period of time. Adverse effects or therapeutic failures frequently associated with
intermittent dosing can also be avoided.
7. Self-medication is possible.
8. Allows continued drug administration permitting the use of a drug with short
biological half-life.1,2,6,7
1.4 DISADVANTAGES:
1. One of the greatest disadvantages of transdermal drug delivery is the possibility
that a local irritation may develop at the site of application.
2. The drug, the adhesive or other excipients in the patch formulation can cause
erythema, itching, and local edema.
3. Another significant disadvantage of transdermal drug delivery is that the skin’s
low permeability which limit the number of drugs that can be delivered in this
manner.
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INTRODUCTION
4. Many drugs especially drugs with hydrophilic structures permeate the skin too
slowly to be of therapeutic benefit.
5. The barrier function of the skin changes from one site to another on the same
person, from person to person and also with age.1,2,6,7
1.5 IDEAL PROPERTIES OF DRUG CANDIDATE FOR
TRANSDERMAL DRUG DELIVERY:
Table1. Ideal properties of the drug
Parameter Properties
Half-life in h 10 or less
Molecular weight <400
Partition coefficientLog P (octanol-water)
between-1.0 and 4
Skin permeability
coefficient>0.5 × 10−3 cm/h
Skin reactionNon irritating and non-
sensitizing
Oral bioavailability Low
Therapeutic index Low
1.6 PHYSIOLOGY AND ANATOMY OF THE SKIN:
1.6.1PHYSIOLOGY OF THE SKIN:
The skin of an average adult body covers a surface area of approximately
2m2 and receives about one-third of the blood circulation through the body. The
permeability barrier in the skin consists of three distinct layers in series.2,3
1) The Stratum corneum (10/μm thick)
2) The Viable epidermis (100/μm thick)
3) The Papillary layer of the dermis (100-200/μm thick)
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INTRODUCTION
This composite structure is pierced at various places by two types of
potential diffusion shunts: hair follicles and sweat glands. These skin appendages
actually occupy only 0.1% of the total human skin surface. This trans-appendage
route of percutaneous absorption, however, provides a very limited contribution
to the overall kinetic profile of transdermal permeation. Therefore, the
transdermal permeation of most neutral molecules at a steady state can, thus be
considered as a process of passive diffusion through the intact stratum corneum in
the inter follicular region.
The skin serves as the port of administration for systemically active drugs, the
drug applied topically is distributed following absorption first into the systemic
circulation and then transported to target tissues. An average adult skin has a
surface area of approximately 2 square meters and receives about one third of the
blood circulating through the body. It is one of the most readily accessible organs
of the human body with a thickness of only a few millimeters (2.97+/-0.28 mm).
Its major roles are to regulate body temperature, protect tissues from infection,
prevent fluid loss, and cushion internal structures. 18,19 The skin is a multilayered
organ composed of many histological layers. It is generally described in terms of
three major tissue layers.2,4
The epidermis – thin protective outer layer.
The dermis – the tough elastic second layer.
The hypodermis – layer of fatty and connective tissue.
1.6.2 ANATOMY OF THE SKIN:
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INTRODUCTION
a. The Epidermis:
The outer (epidermal) layer of the skin is composed of stratified squamus
epithelial cells. The multilayered envelope of the epidermis varies in thickness,
depending on cell size and then number of cells and then number of cell layers,
ranging from about 0.8mm on the palms and the soles down to 0.66mm on the
eyelids. Cells which provide epithelial tissue differ from those of all other organs
provide epithelial tissue differ from those of all other organs in that as they
change in an ordered fashion from metabolically active and dividing cells to
dense, dead, keratinized protein.
b. Stratum germinativum (basal layer):
The basal cells are nucleated, columnar, and about 6 microns wide, with their
long axis at right angles to the dermoepidermal junction; they connect by
cytoplasmic intercellular bridges. Mitosis of the basal cells constantly renews the
epidermis and this proliferation in healthy skin balances the loss of dead horny
cells from the skin surface. The epidermis thus remains constant in thickness.
Below the basal cell layer lies the complex dermoepidermal junction, which
constitutes an anatomic functional unit. The junction serves three functions of
dermal-epidermal adherence, mechanical support for the epidermis, and control
of the passage of cells and some large molecules across the junction.
c. Stratum spinosum (prickle cell layer):
As the cells produced by the basal layer move outward, they alter
morphologically and histochemically. The cells flatten and their nuclei shrink.
These polygonal cells are called as prickle cells because they interconnect by fine
prickles.
d. Stratum granulosum (granular layer):
As the Keratinocytes approach the surface, they manufacture basic staining
particles, the keratohyalin granules. It was suggested that these granules represent
an early form of keratin 3, 4. The term transitional zone is convenient region
between living cells and dead keratin.
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INTRODUCTION
e. Stratum lucidum:
In the palms and the soles an anatomically distinct, poorly staining hyaline zone
forms a thin, translucent layer immediately above layer immediately above the
granular layer. This region is the stratum lucidum.
f. Stratum corneum (horny layer):
The stratum corneum is also normally devoid of nuclei and consist of eosinophilic
layers of keratin. Intraepidermal nerve endings are present in the fromofMerckel
cells which are touch receptors.
g. The Dermis:
The dermis (corium) consists essentially of a matrix of connective tissue woven
from fibrous proteins which embed in an amorphous ground substance on
mucopolysaccharides providing about 20% of the mass. Blood vessels, nerves,
and lymphatics cross this matrix and skin appendages (eccrine sweat glands,
apocrine glands and pilosebaceous units) penetrate it. In man, the dermis divides
into a superficial, thin papillary layer which forms a negative image of the rigid
lower surface of the epidermis, and a thick underlying reticular layer which
merges with the fat-containing subcutaneous tissue.
The dermis needs a rich blood supply which regulates temperature and
pressure, delivers nutrients to the skin and removes waste products, mobilizes
defense forces, and contributes to skin color. The blood supply reaches to within
0.2mm of the skin surface, So that it readily absorbs and systemically dilutes
most chemicals which penetrate past the stratum corneum and the viable
epidermis. The vascular surface available for the viableepidermis. The vascular
surface available for the exchange of materials between local tissues and the
blood is enormous. Of particular relevance to biopharmaceutical studies is the
fact that this generous blood volume usually functions as a “sink” with respect to
the diffusing molecules which reach it during the process of percutaneous
absorption. This sink condition ensures that the penetrant concentration in the
dermis remains near and therefore the concentration gradient across the epidermis
is maximal.
h. The Hypodermis: This is a sheet of fat-containing areolar tissue known as
superficial fascia, attaching the dermis to the underlying structure.
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INTRODUCTION
i. Skin Appendages:
The epidermis and dermis support several appendages: The eccrine,
apocrine and sebaceous glands, the hair follicles and the nails. Of these, hair
follicles and sweat ducts can act as diffusion shunts, i.e. relatively easy pathways
for diffusion through the rate-limiting stratum corneum.
Figure 2.Transepidermal (A) and transappendageal route of transport into the
skin. The transappendageal route (B) includes diffusion via the hair follicle and
the sweat gland.
j. Eccrine Sweat glands: Eccrine sweat glands develop over the skin surface but
not over mucous membranes. The gland density varies greatly with skin site; for
example, the thighs possess about 120 glands per square centimeter and the soles
of the feet have about 620per square centimeter. The composition and the
quantity of the sweat varies greatly with subject, time, environmental conditions,
exertion and skin site.
k. Apocrine Sweat Glands: Apocrine sweat glands are epidermal appendages
which develop throughout the skin of the embryo as part of the pilosebaceous
follicle. Most of the glands subsequently disappear so that the characteristic adult
distribution is in the axilla, the perianal region and the areola of the breasts.
l. Hair follicles: Hair follicles developed over the entire skin surface except the
palms the soles, the red portion of the lips and the parts of the sex organs. The
average fractional surface area of the openings is about 0.1%. Hair contains
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INTRODUCTION
“hard” keratin, which differs from the “soft” keratin of desquamating tissues in its
high sulfur content.
m. Sebaceous Glands: Sebaceous glands are largest and most numerous on the
back. The palms and soles are usually free of them. The flask like sebaceous
glands from ducts which usually open into the neck of the hair follicle. Sebum is
complex mixture of lipids i.e. glycerides, free fatty acids, wax esters, squalene,
cholesterol, esters. Several functions have been attributed to sebum, such as
controlling water loss, and protecting the skin from fungal and bacterial infection.
Figure 3. Penetration pathway of drug molecules through the skin30
1.7 BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY
SYSTEMS:
The components of transdermal devices include:2
a) Polymer matrix or matrices
b) The drug
c) Permeation enhancers
d) Other excipients
a) Polymer matrix:
The Polymer controls the release of the dug from the device. The following
criteria should be satisfied for a polymer to be used in a transdermal system.
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INTRODUCTION
M.Wt, glass transition temperature and chemical functionality of the polymer
should be such that the specific drug diffuses properly and released through it.
The polymer should be stable, non-reactive with the drug, easily manufactured
and fabricated into the desired product and inexpensive.
The polymer and its degradation products must be non-toxic or non-antagonistic
to the host.
The mechanical properties of the polymer should not deteriorate excessively
when large amount of active agent is incorporated into it.
Possible useful polymers for transdermal devices are:
Natural Polymers: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins,
Gums and their derivatives, Natural rubber, starch etc.
Synthetic elastomers:Polybutadiene, Hydrin rubber, Polysiloxane, Silicone
rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadiene rubber, Neoprene
etc.
Synthetic Polymers: Polyvinyl alcohol, Polyvinyl chloride, Polyethylene,
Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone,
Polymethyl methacrylate, Epoxy etc.
b) The Drug:
For successful development of transdermal drug delivery system, the drug should
be chosen with great care.
i. The drug must not induce a cutaneous irritant or allergic response.
ii. Drugs, which degrade in the GI tract or are inactivated by hepatic firstpass effect,
are suitable candidates for transdermal delivery.
iii. Tolerance to the drug must not develop under the near zero-order release profile
of transdermal delivery.
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INTRODUCTION
iv. Drugs, which have to be administered for a long period of time or which cause
adverse effects to non-target tissues can also be formulated for transdermal
delivery.
c) Permeation Enhancers:
These are the compounds, which promote skin permeability by altering the
behaviour of skin as barrier to the flux of a desired penetrant. The flux, J, of
drugs across the skin can be written as21
J=D dc/dx ------- (1)
Where,
D is the diffusion coefficient and is a function of the size, shape and
flexibility of the diffusing molecule as well as the membrane resistance;
C is the concentration of the diffusing species;
x is the spatial coordinate.
Thus enhancement of flux across membranes depends on the considerations of:
Thermodynamics (lattice energies, distribution coefficients)
Molecular size and shape
Reducing the energy required to make a molecular hole in the membrane
Mechanism:
The enhancement in absorption of oil soluble drugs is apparently due to the
partial leaching of the epidermal lipids by the chemical enhancers, resulting in the
improvement of the skin conditions for wetting and for transepidermal and
transfollicular penetration. The miscibility and solution properties of the
enhancers used could be responsible for the enhanced transdermal permeation of
water-soluble drugs.
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INTRODUCTION
Figure 5: Penetration enhancer activity. (a) Action at intercellular lipids. Some
of the ways bywhich penetration enhancers attack and modify the well-organized
intercellular lipid domain of the stratum corneum.
Some of them alter the composition of the cell content while others affect the
cohesiveness between cells and composition of intercellular material or have a
direct effect on cell membrane. The composition of intercellular lipids undergoes
a solid-lipid phase transition at 40oC. It is possible that some penetration
enhancers act to disrupt the structure of intercellular lipids and lower the phase
transition temperature, thereby increasing the permeability of skin to more polar
compounds. To increase the rate of transfer of lipophilic compounds, it is
necessary to modify the partitioning characteristics at the stratum corneum viable
tissue interface. This may be possible by combining a penetration enhancer with a
co-solvent. Some agents can establish a reservoir in stratum corneum, which may
facilitate diffusion of drug, when penetrating the epidermis, may carry drug
through, by acting as a solvent Many of these agents may act by a combination of
various effects on the skin while others may be involved in a direct chemical
insult on the skin, When the specified lipid film, made up of sebaceous secretion,
desquamated cells, sweats and other components, the percutaneous absorption is
enhanced slightly. When lipids are removed from the skin as by means of
prolonged exposure to polar solvents, however, considerably enhanced absorption
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INTRODUCTION
of applied materials. it is quite likely that lipid solvents must damage the lipid
portion of the membrane before much change in passage through the skin can
take place.
Classification of penetration enhancers:
i. Terpenes(essential oils): E.g. Nerodilol, menthol, 1 8 cineol,limonene, carvone
etc.
ii. Pyrrolidones: E.g. N-methyl-2-pyrrolidone(NMP), azone etc.
iii. Fatty acids and esters: E.g. Oleic acid, linoleic acid, lauric acid, capric acid etc.
iv. Sulphoxides and similar compounds: E.g. Dimethyl Sulphoxide(DMSO),
N,Ndimethylformamide.
v. Alcohols, Glycols, and Glycerides: E.g. Ethanol, Propylene glycol, Octyl alcohol.
vi. Micellaneous enhancers: E.g. Phospholipids, Cyclodextrins, Amino acid
derivatives, Enzymes etc.
Desirable characteristics of penetration enhancers:
These are the some of the desirable characteristics of penetration enhancers:
It should be pharmacologically inert within the body, either locally or
systemically.
It should not irritate or induce allergic responses.
The operation of enhancement (both in terms of activity and duration of effect)
should be predictable and reproducible.
The penetration enhancer should work unidirectionally, i.e., should allow
medicaments to enter the body while preventing the release of endogenous
materials.
It should be cosmetically acceptable, being odorless, colorless, and with
appropriate skin feel.
Sulfoxides and other similar compounds:
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INTRODUCTION
Dimethylsulfoxide (DMSO), the archetypal penetration enhancer, is a powerful
aprotic solvent that is colorless, odorless, and hygroscopic; its value as an
enhancer may be predicted from its use chemically as a universal solvent.
Extensive investigations on the accelerant activities of DMSO show it to be
effective in promoting the flux of both lipophilic and hydrophilic permeants, e.g.,
antiviral agents, steroids, and antibiotics. DMSO works rapidly but its effects are
markedly concentration dependent and generally cosolvents containing more than
60% DMSO are needed for acceptable enhancement. The mechanisms of action
of the sulfoxide enhancers are complex. DMSO denatures proteins and on
application to human skin alters the intercellular keratin confirmation, changing it
from an α-helical to a β-sheet. DMSO also interacts with the intercellular lipid
domains of human stratum corneum. Considering its small highly polar nature it
is feasible that DMSO interacts with the head groups of some bilayer lipids to
distort their packing geometry, as well as dissolving in, and extracting, lipids.
Further, DMSO dissolved within skin membranes may alter the polarity and
facilitate drug partitioning from a formulation
into this universal solvent within the tissue.
OTHER EXCIPIENTS:
Adhesives:
The fastening of all Transdermal devices to the skin has so far been done by using
a pressure sensitive adhesive. The pressure sensitive adhesive can be positioned
on the face of the device or in the back of the device and extending peripherally.
Both adhesive systems should fulfill the following criteria.
Should not irritate or sensitize the skin or cause an imbalance in the normal skin
flora during its contact time with the skin.
Should adhere to the skin aggressively during the dosing interval without its
position being disturbed by activities such as bathing, exercise etc.
Should be easily removed.
Should not leave an unwashable residue on the skin.
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Should have excellent (intimate) contact with the skin at macroscopic and
microscopic level.
Backing membrane:
Backing membranes are flexible and they provide a good bond to the drug
reservoir, prevent drug from leaving the dosage form through the top, and accept
printing. It is impermeable and protects the product during use on the skin e.g.
metallic plastic laminate, plastic backing with absorbent pad and occlusive base
plate a (aluminum foil), adhesive foam pad (flexible polyurethane) with occlusive
base plate (aluminum foil disc) etc.
1.8 TECHNOLOGIES FOR DEVELOPING TRANSDERMAL DRUG
DELIVERY SYSTEMS:
Several technologies have been successfully developed to provide rate control
over the release and skin permeation of drugs. These technologies can be
classified into four basic approaches.14,17
a) Polymer membrane permeation-controlled TDD Systems
b) Polymer matrix Diffusion-Controlled TDD Systems
c) Drug Reservoir Gradient-Controlled TDD Systems
d) Micro-reservoir Dissolution-Controlled TDD Systems
a) Reservoir System: In this system, the drug reservoir is embedded between an
impervious backing layer and a rate controlling membrane (Fig. 6a) The drug
releases only through the rate-controlling membrane, which can be microporous
or nonporous. In the drug reservoir compartment, the drug can be in the form of a
solution, suspension, or gel or dispersed in a solid polymer matrix. On the outer
surface of the polymeric membrane a thin layer of drug-compatible,
hypoallergenic adhesive polymer can be applied.
Eg.Transderm-Nitro system, Transderm-Scop system, the Catapres TTS system,
the Estraderm system, and the Duragesic system.
Dept of pharmaceutical Technology Page 14
INTRODUCTION
b) Matrix systems: Drug-in-adhesive system: The drug reservoir is formed by
dissolving or dispersing the drug in an adhesive polymer and then spreading the
medicated polymer adhesive by solvent casting or by melting the adhesive (in the
case of hot-melt adhesives) onto an impervious backing layer (Fig. 6b). On top of
the reservoir, layers of unmedicated adhesive polymer are applied.
Eg.Isosorbidedinitrate transdermal therapeutic system (Frandol tape).
c) Matrix-dispersion system: The drug is dispersed homogeneously in a
hydrophilic or lipophilic polymer matrix. This drug containing polymer disk is
then fixed onto an occlusive base plate in a compartment fabricated from a drug-
impermeable backing layer (Fig. 6c). Instead of applying the adhesive on the
face of the drug reservoir, it is spread along the circumference to form a strip of
adhesive rim.
Eg.Nitro-Dur system and the NTS system.
d) Micro-reservoir system: This drug delivery system is a combination of
reservoir and matrix-dispersion systems. The drug reservoir is formed by first
suspending the drug in an aqueous solution of water-soluble polymer and then
dispersing the solution homogeneously in a lipophillic polymer to form thousands
of unleachable, microscopic spheres of drug reservoirs (Fig. 6d).
Eg.Nitrodisc system.
Dept of pharmaceutical Technology Page 15
INTRODUCTION
(a) Reservoir System
(b) Matrix Dispersion System
(c)Peripheral adhesive Design
(d) Microreservoir system
Figure 5. Types of Transdermal Drug Delivery Systems
Dept of pharmaceutical Technology Page 16
INTRODUCTION
Table No. 2: Examples of FDA Approved Transdermal Patches
Product
nameDrug Manufacturer Indication
TransdermSc
op
Scopolamn
eAlza/Norvatis Motion sickness
Transderm
Nitro
Nitroglycei
nAlza/Norvatis Angina pectoris
Vivelle Estradiol
Noven
Pharmaceuticals/No
rvatis
Postmenstrual
syndrome
Catapres-
TTSClonidine
Alza/
BoehingerIngelheimHypertension
Duragesic Fentanyl
Alza/
JanssenPharmaceuti
cl
Moderate/severe
pain
Habitraol Nicotine Novartis Smoking cessation
Androderm TestosteroeTheraTech/
GlaxoSmithKlie
Hypogonadism in
males.
Nuvelle TS
Estrogen/
Progestero
ne
Ethical
Holdings/Schering
Hormone
replacement
Dept of pharmaceutical Technology Page 17
INTRODUCTION
Dept of pharmaceutical Technology Page 18
AIM AND OBJECTIVES
2. AIM
Labetalol is an α and β receptor antagonist. It has a biological
half-life of only 6 to 8 hr and its oral bioavailability is around 25%.
Main reason for selecting the Labetalol is it goes through the
first pass metabolism.To avoid this present work is to formulate a
transdermal film for an anti-hypertensive to improve bioavailability drug
using these polymers like Eudragit-RSPO, RLPO and DMSO
2.1 OBJECTIVE Treatment of chronic diseases like hypertensive disorders by
transdermal route of drug absorption proved and it has several advantages
over other routes. Labetalol is an α and β receptor antagonist. It has a
biological half-life of only 6 to 8hr and its oral bioavailability is around
25%. Therefore, the objective of the present work is to formulate a
transdermal film for an anti-hypertensive drug.
Following are the main objectives of the present study.
1. Optimising and design of matrix type transdermal film of anti-
hypertensive drug by using polymers such as EUDRAGIT RSPO and
RLPO.
2. Studied the effect of polymer concentration on drug release.
3. Preparation of transdermal films of Labetalol by solvent casting method.
4. Characterized the films for various physicochemical parameters and to
investigate In vitro release patterns and In vitro diffusion of the drug.
5. Skin irritation test studies using the rat skin.
6. Short term stability studies on the most satisfactory formulation as per
ICH guidelines.
Dept Of Pharmaceutical Technology Page 18
LITERATURE REVIEW
LITERATURE REVIEW
AgarwalSS et al.,2007,22 Transdermal patch of atenolol and metoprolol
tartrate was prepared by solvent evoparation method by using different
polymers in combination with plasticizer and penetration enhancer. They
used polymers like PVP, CAP, HPMC phthalate and EC, propylene glycol
as plasticizer and 1,8-cineole as penetration enhancer. In-vitro permeation
studies were performed using rat abdominal skin, the results found that at
48h 85% and 44% of atenolol and metoprolol tartrate, respectively.
Anil J et al.,2008,23 Developed transdermal matrix patches of tramadol
hydrochloride using HPMC, ERL-100 and ERS-100 in different ratios
with tri ethyl citrate as plasticizer and di-methyl Sulphoxide as
penetration enhancer. The batch containing ERL-100:HPMC(8:2) showed
79.65% release within 12hrs and batch containing ERS-100:HPMC(2:8)
showed only 58.30% release in 12hrs. This is because that the eudragit
produce crystallization free patch.
Gupta JRD et al.,2009,24 Matrix type of transdermal patches of
glibenclamide were prepared by using HPMC, PVP K-30 and Eudragit
RS-100 as polymers, PEG-400 as plasticizer and Dimethyl Sulphoxide
(DMSO) as penetration enhancer using solvet evaporation technique. On
the basis of in-vitro drug release and skin permeation performance
HPMC:PVP-30K (9:1) is the better than other formulations and it was
selected as the optimized formulation.
Mi-Kyeong kim et al.,2001,25 Reservoir type transdermal delivery system
of testosterone was developed using ethanol/water. Using cosolvent
system as a vehical a new transdermal system for testosterone was
formulated using ethyl vinyl acetate membrane coated with pressure
sensitive adhesive and HPMC as a gelling agent. By conducting the
comparable plasma concentration in-vitro study by comparing with
commercial product
Dept of pharmaceutical Technology Page 19
LITERATURE REVIEW
JamakandiG et al.,2009,26 Designed matrix type transdermal patch of
nicardil using different polymeric grades of HPMC (6cps, 15cps, and
K4M). They used porcine ear skin for exvivo study. Among 6 different
HPMC formulations, transdermal patch with 6cps & 6% w/v DMSO as
parmeation enhancer showed maximum release of the drug.
Prasanna Kumari J et al.,2010,27 Transdermal drug delivery of
metoprolol tartarate were prepared using polymers EC, PVA, eudragit
RL-100, eudragit L-100 and Di-n-butylphthalate as plasticizer. Films were
prepared using solvent casting method. They studied in-vitro diffusion
using rat skin and they conclude the combination of EC, PVA, E L100
and Di-n-butylphthalate can potentially be optimized to develop an
effective transderma drug delivery system for metoprolol tartarate.
Iman IS et al.,2010,28 Prepared transdermal patches of chlorpheniramine
maleate (CPM). They used rabbit ear skin membrane for ex-vitro
diffusion studies and they used polymers like ethyl cellulose, cellulose
acetate, and poly vinyl pyrrolidone with different plasticizers such as
propylene glycol and polyethylene glycol 400. They compare the CPM
transdermal patch with CPM oral tablets and they found the results
showed that CPM transdermal patch has higher bioavailability than oral
tablet of same dose, with lower plasma fluctuation and less administration
frequency.
Samip.S et al.,2010,29 Formulation & evaluation of transdermal patches of
papaverine hydrochloride prepared by the solvent casting method using
EC:PVP, PVA:PVP & ERL-100:ERS-100 using different ratios. The
formulation containing PVA:PVP shows faster release rate (hydrophilic
polymers) compared to ERL-100:ERS-100 (hydrophobic polymers) or
combination of hydrophilic & hydrophobic polymers (EC & PVP).
Sivakumar et al.,2010,30 Designed and evaluated transdermal drug
delivery of ketotifen fumarate with different different ratios of HPMC-E5
(hydrophilic) and EC (hydrophobic) as polymers, 5 % v/w of DMSO as
penetration enhancer, and 10 % v/w of dibutyl phthalate as plasticizer in
Dept of pharmaceutical Technology Page 20
LITERATURE REVIEW
Chloroform and methanol (1:1) as solvent system by solvent evaporation
technique. The diffusion studies shows maximum release is observed with
HPMC-E5 alone.
Ramesh G et al.,2007,31 The matrix type TDDS of NTDP were prepared
by solvent evaporation technique.All formulations carried 6% v/w of
carvone as penetration enhancer and 15% v/w of propylene glycol used as
plasticizer in dichloromethane
&methanol solvent system. The prepared TDDS were evaluated for in vi
tro release,
ex vivo permeation, moisture absorption, and moisture content and mec
hanical properties. The physic chemical interactions between
nitrendipine and polymers were investigated by Fourier Transform
Infrared (FTIR) spectroscopy.
Sadhana PG et al.,2005,32 Metaprolol Tartarate in transdermal drug
delivery system was investigated for controlled release of drug for
extended period of time. Eudragit RL and hydroxy propyl methyl
cellulose were used for fabrication of the formulation. These systems were
characterized for their thickness, tensile strength and drug content. Then it
was evaluated in vitro release kinetics and skin permeation studies and
compared its drug plasma profile with Metaprolol tartarate.
Agrawal SS et al.,1996,33 Rapid permeation of Verapamil hydrochloride
(VHC1) across the skin using finite dose loading was documented.
Transdermal drug delivery systems (TDDS) of VHCI using hydrophilic
polymers like polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP)
and different Concentrations of an enhancer, d-limonene were developed.
In-vitro permeation profiles across the guinea-pig dorsal and human
cadaver skins using a Keshary-Chien diffusion cell are reported. The
permeation rate was enhanced and followed approximately zero order
kinetics.
Manvi FV et al.,2003,34 Formulated transdermal films of ketotifen
fumarate using combination of Eudragit L-100, hydroxypropyl methyl
cellulose and ethyl cellulose HPMC polymeric combinations plasticized
Dept of pharmaceutical Technology Page 21
LITERATURE REVIEW
with polyethylene glycol 400. Effects of permeation enhancers like diethyl
sulphoxide and propylene glycol at different concentrations were studies
on skin permeation kinetics. It was concluded that above polymeric
combinations might be feasible for formulation rate controlled
Transdermal therapeutic system of Ketotifen Fumarate for effective
control and prophylaxis of allergic asthma.
Aqil M et al.,2002,35 The monolithic matrix type transdermal drug
delivery systems of pinacidil monohydrate (PM) were prepared by film
casting technique on mercury substrate and characterised in vitro by drug
release studies using paddle over disc assembly, skin permeation studies
using Keshary Chein diffusion cell on albino rat skin and drug-excipients
interaction analysis. Four formulations were developed which differed in
the ratio of matrix forming polymers, Eudragit RL-100 and PVP K-30, i.e.
8:2, 4:6, 2:8 and 6:4 and were coded as B-1, B-2, B-3 and B-4,
respectively. All the four formulations carried 20% w/w of PM, 5% w/w
of plasticizer, PEG-400 and 5% w/w of DMSO in isopropyl alcohol:
dichloromethane (40:60) solvent system. On the basis of in vitro drug
release and skin permeation performance, formulation B-4 was found to
be better than the other three formulations and it was selected as the
optimized formulation.
Changshun Ren et al.,2009,36 Develop and evaluated novel drug in
adhesive transdermal system for indapamide. The in-vivo study was
conducted by comparing the pka parameters like Tmax, Cmax, Mean
residual time, AUC (0-t) and T1/2 with oral administration of indapamide.
Kulkarni RV et al.,2002,37 Monolithic matrix type transdermal drug
delivery systems of atomoxetine hydrochloride (A-HCl) were prepared
by the film casting on a mercury substrate and characterized by
physicochemical characteristics like thickness, weight variation, drug
content, flatness, folding endurance and in vitro drug release studies, ex-
vivo skin permeation studies.
Amit Misra et al.,1996,38 Which is the method of choice in the adhesive
tape industry.Three series of formulation of adhesive dispersion variety
Dept of pharmaceutical Technology Page 22
LITERATURE REVIEW
were prepared and coated on to fabric.Uniformity of the thickness, weight
and content was estimated with in batches and between the batches.
Jain S et al.,2007,39 Matrix type transdermal drug delivery system of
haloperidol lactate was prepared using different ratios of ethyl cellulose:
polyvinyl pyrrolidone by solvent-evaporation technique. Physicochemical
parameters were characterized, and dissolution studies of the formulated
films were performed. In vitro permeation studies were done using
modified Franz diffusion cell through human cadaver skin utilizing 20%
PEG 400 in normal saline. Higuchi and Peppas models were used for
optimizing the formulation.
Wahid A et al.,2008,40 Ethosomal formulations were prepared using
lamivudine as model drug and characterized in vitro, ex vivo and in vivo.
Transmission electron microscopy, scanning electron microscopy, and
fluorescence microscopy were employed to determine the effect of
ethosome on ultra structure of skin. The optimized ethosomal formulation
showed 25 times higher transdermal flux (68.4 ± 3.5 μg/cm2/h) across the
rat skin as compared with that of lamivudine solution (2.8 ± 0.2
μg/cm2/h). The results of the characterization studies indicate that lipid
perturbation along with elasticity of ethosomes vesicles seems to be the
main contributor for improved skin permeation.
Nirvaseth et al.,2011,41 Designed and formulated transdermal drug
delivery of eugenol using HPMC, PVC, EC and glycerol is plasticizer.
Then it was evaluated in vitro release kinetics, drug release, skin
permeation studies.
Kelvin et al.,2009,42 Transdermal films of Diclofenac Sodium were
formulated by using natural polymer gelatin and plasticizer glycerin in
different proportion. The placebo and medicated films were evaluated for
physical and mechanical properties and also medicated films were
evaluated for area variation, drug content and percent cumulative drug
release. Optimized gelatin to glycerin ratio containing transdermal films
shown effective physical and mechanical property along with in vitro drug
release profile. The release rate was found to follow first order rate and
Dept of pharmaceutical Technology Page 23
LITERATURE REVIEW
Higuchi model. Primary irritation study shows that the transdermal films
are non-irritant.
Manvi FV et al.,2003,43 Monolithic matrix transdermal system containing
tramadol HCl were prepared using various ratios of polymer blends of
HPMC and Eudragit S100 with triethyl citrate as a plasticizers. The
concentration of HPMC and Eudragit S100 were used as independent
variables, while drug was selected as dependent variables. In Vitro
diffusion studies were performed using cellulose acetate membrane (pore
size 0.45) in Franz diffusion cell. The concentration of diffused drug was
measured using UV-visible spectrophotometer at 272 nm. The
experimental result shows that the transdermal drug delivery system
containing Eudragit in higher proportion gives sustained release of drug.
Sanap GS et al.,2008,44 Formulated transdermal films of ketotifen
fumarate using combination of Eudragit L-100, hydroxypropyl methyl
cellulose and ethyl cellulose HPMC polymeric combinations plasticized
with polyethylene glycol 400. Effects of permeation enhancers like diethyl
sulphoxide and propylene glycol at different concentrations were studies
on skin permeation kinetics. It was concluded that above polymeric
combinations might be feasible for formulation rate controlled
Transdermal therapeutic system of Ketotifen Fumarate for effective
control and prophylaxis of allergic asthma.
Agrawal SS et al.,2008,45 Transdermal drug delivery systems of
indapamide have been formulated by using solvent casting method.
Monolithic systems were prepared by using hydroxy propyl methyl
cellulose (HPMC) and ethyl cellulose (EC) polymers by incorporating
glycerine and dibutyl phthalate as plasticizers, respectively. A total of
eight monolithic systems were prepared by using a drug polymer ratio of
1:4 and incorporated different vegetable oils as permeation enhancers in
different concentrations. The in vitro release studies revealed that the
release was sustained up to 24 h and it follows zero-order kinetics. All the
films were found to be stable at 37°C and 45°C with respect to their
physical parameters and drug content.
Dept of pharmaceutical Technology Page 24
DRUG & EXCIPIENT PROFILE
DRUG PROFILE
LABETALOL 9
Synonyms : Labetalol Hcl, labetalol hydrochloride,
labetalolum Labrocol, trandate, presdate
Chemical Structure :
IUPAC name : (RS)-2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-
phenyl
propyl) amino] ethyl}benzamide
Chemical Formula : C19H24N2O3
Molecular weight : 328.406
Melting point (°C) : 1880C
Category : anti-hypertensive
Description : white powder.
Solubility : Freely soluble in Water & methanol, very slightly
soluble in Acetone
Storage : Store in tightly closed container
Pharmacokinetic and metabolism
Bioavailability (%) : 25%
Bound in plasma (%) :50%
Half life : 6-8hours
Vd (L/kg) :3-16L/kg
Cmax (ng/ml) : 300 mg/ml
Tmax(hrs) : 1.2
Log P : 3.09
Dept of pharmaceutical Technology Page 25
DRUG & EXCIPIENT PROFILE
Mechanism of action: Labetalol combines both selective, competitive,
alpha-1-adrenergic blocking and nonselective, competitive, beta-
adrenergic blocking activity in a single substance. In man, the ratios of
alpha- to beta- blockade have been estimated to be approximately 1:3 and
1:7 following oral and intravenous (IV) administration, respectively. The
principal physiologic action of labetalol is to competitively block
adrenergic stimulation of β-receptors within the myocardium (β1-
receptors) and within bronchial and vascular smooth muscle (β2-
receptors), and α1-receptors within vascular smooth muscle. This causes a
decrease in systemic arterial blood pressure and systemic vascular
resistance without a substantial reduction in resting heart rate, cardiac
output, or stroke volume, apparently because of its combined α- and β-
adrenergic blocking activity.
Pharmacokinetics: Labetalol is well absorbed from gastrointestinal tract
but it subjected to extensive first pass metabolism in liver; the absolute
bioavailability is about 25%. Peak plasma concentration occurs in 2 hrs
after drug administration. Volume of distribution of approximately 3-16
L/Kg& only50% bound to plasma proteins. It is extensively metabolized
in liver, the metabolites excreted mainly in urine. The elimination half-life
is about 5.5 h.
Metabolism: The metabolism of labetalol is mainly through conjugation
to glucuronide metabolites. These metabolites are present in plasma and
are excreted in the urine and, via the bile, into the feces. Approximately
55% to 60% of a dose appears in the urine as conjugates or unchanged
labetalol HCl within the first 24 hours of dosing.
Elimination: Total body Cl is 430 to 610 mL/min. Creatinine Cl is 5
mL/min.
Dept of pharmaceutical Technology Page 26
DRUG & EXCIPIENT PROFILE
DRUGINTERACTIONS
TOLAZAMIDE The beta-blocker, labetalol, may decrease symptoms of
Hyperglycemia.
TOBUTAMIDE The beta-blocker, Labetalol, may decrease symptoms of
Hyperglycemia
SALBUTAMOL Antagonism.
Food Interactions: Always take at the same time with respect to meals,
avoid alcohol, take with food.
Contraindications: obstructive air way disease, overt cardiac failure,
cardiogenic shock, severe bradycardia
Storage: Protect from moisture and sun light, stored below 400c.
Dose: 50, 100, 200 and 300.
EXCIPIENTS PROFILE
A. Review of polymers:
1. EUDRAGIT RLPO10
Nonproprietary name : Ammonio Methacrylate Copolymer(BP),
Methacrylic Acid Copolymer(USP-NF),
.
Synonym : Eastacryl; Eudragit,
Kollicoat MAE,
polyacrylatis Dispersio 30 per centum;
polymeric methacrylates.
Dept of pharmaceutical Technology Page 27
DRUG & EXCIPIENT PROFILE
Structural formula:
Where R1=H,CH3 ;R2=CH3,C2H5; R3=CH3
Chemical Name: Poly(ethyl acrylate, methyl methacrylate,
Trimethylammonioethyl methacrylate chloride) 1 : 2 :0.2.
Functional category: Coating agent, film-former, rate-controlling
polymer for sustained release, tablet binder, tablet diluent.
Molecular Weight : 32,000 g/mol
Description: Eudragit RLPO in form of white powder with a faint amine-
like odour
Density : 0.816-0.836 g/cm3
Solubility: Soluble in acetone, alcohols, dichloromethane and ethyl
acetate.Insoluble in water and petroleum ether
Stability and storage conditions:Eudragit RLPO powder is a stable at
temperature less than 30ºC. above this temperature powders tend to form
clumps. Eudragit RLPO powder should be stored in a well-closed
container, in a cool & dry place.
Applications:
Eudragit RLPO used to form water-insoluble film coats for sustained
release products.
Polymethcrylates are primarily used as oral capsule and tablet
formulations as film-forming agents.
Polymethacrylates are also used as binder in both aqueous & organic wet
granulation process.
Larger quantities (5-20%) of dry polymer are used to control the release of
an active substance from a tablet matrix.
Dept of pharmaceutical Technology Page 28
DRUG & EXCIPIENT PROFILE
2. EUDRAGIT RSPO11
Synonyms : Eudragit, poly methacrylates.
Structure:
R1 = H, CH3, R2 = CH3, C2H5, R3 = CH3
Molecular formula : (C5H8O2)n
Chemical name : Poly (ethyl acrylate, methyl methacrylate,
Trimethylammonio ethyl methacrylate chloride)
Fuctional category : 1. Film forming agent
2. In the preparation of sustained release dosag forms.
Molecular weight : 32,000 g/mol
Grades : Eudragit RSPO, Eudragit RS 12.5, E RS 100, EudragitRS 30D
Description : EUDRAGIT® RS PO is a copolymer of ethyl acrylate,
methyl methacrylate and a low content of methacrylic acid ester with
quaternary ammonium groups.The ammonium groups are present as salts
and make the polymers permeable. It is a solid substance in the form of
white powder with a faint amine – like odour.
Density : 0.816 to 0.836 G/cm3
Solubility: Soluble in methanol, ethanol, and isopropyl alcohol as well
as in acetone, ethyl acetate and ethylene chloride to give clear to
cloudysolutions.
Dept of pharmaceutical Technology Page 29
DRUG & EXCIPIENT PROFILE
Storage: Protect from warm temperature and moisture. Dry powders are
stable for atleast 3 years in tightly closed container at less than 30°C.
Safety : A daily intake of 2 mg/kg body weight of Eudragit may be
regarded as essentially safe in humans. It generally regarded as nontoxic
and nonirritant materials.
Incompatibilities: Incompatibilities occur with certain polymethacrylate
dispersion depending upon the ionic and physical properties of the
polymer & Solvent
Application : It is used to form water-insoluble films. Primarily used in
capsule and tablet formulations and transdermal delivery. It is also used as
binders in both aq. and organic wet granulation. Larger quantities (5-20%)
of dry polymer are used to control the release of active substance from a
tablet matrix. Solid polymers may be used in direct compression process
in quantities of 10-50%
B. Review of plasticizers:
POLY ETHYLENE GLYCOL-40010
Synonym : Carbowax,PEG,polyoxyethylene glycol.
Structural Formula:
Chemical Name: α-Hydro-ω-hydroxypoly (oxy-1,2-ethanediyl)
Molecular Formula: C16H22O4
Molecular Weight: 380-420
Category : Plasticizer, solvent, ointment base.
Description : It is a clear, colourless or slightly yellow-coloured,
viscous liquid.
Dept of pharmaceutical Technology Page 30
DRUG & EXCIPIENT PROFILE
Density : 1.120 g/cm3
Boiling Point : 330oC
Refractive Index : 1.465
Solubility : soluble in water, acetone, alcohols, benzene, glycerine
and insoluble in mineral oils.
Storage : It should be stored in a tightly-closed container.
C. Review of permeation enhancers
DIMETHYL SULFOXIDE10
It increases in drug penetration have been reported with dimethyl
sulfoxide concentrations as low as 15%, but significant increases in
permeability generally require concentrations higher than 60–
80%.Dimethyl sulfoxide is now incorporated into a number of regulated
products for healthcare and drug delivery applications,including
stabilizing product formulations, sustained-release applications,and for the
delivery of medical polymers.
Structural formula :
Chemical name : Sulfinylbismethane
Molecular formula : C2H6OS
Molecular weight : 78.13g/mol
Category : It is used as a penetration agent, solvent.
Description : It is colorless, viscous fluid.
Boiling point : 1890C
Dept of pharmaceutical Technology Page 31
DRUG & EXCIPIENT PROFILE
Solubility : It is miscible with water, alcohol, and ether.
Storage : It should be stored in air tight, light resistant container.
Dept of pharmaceutical Technology Page 32
METHODOLOGY
4. MATERIALS AND EQUIPMENTS
Table No. 3: Materials Used:
Materials Source
LABETALOL
Yarochem pvt ltd,
MUMBAI.
EUDRAGIT RSPO Evonik Degussa (P)
Ltd.
EUDRAGIT RLPO Evonik Degussa (P)
Ltd.
PEG-400 Karnataka fine chem.
DMSOYarochem pvt ltd,
MUMBAI.
Dept of pharmaceutical Technology Page 32
METHODOLOGY
Table No. 4: Equipments used:
Equipments Model/ Company
UV-Visible
Spectrophotometer
Shimadzu UV-VIS
Spectrophotometer.
UV – 1700, Japan.
Electronic Analytical
balanceShimadzu AUX-224
FTIRPerkin Elmer Spectrum
Gx
Melting point apparatus
DBK programmable Melting Point apparatus
pH meter 7007EUTECH Instruments,
pH tutor.
Humidity chamber Thermo lab.
Hot air ovenServe well instruments
Pvt LTD.
Franz diffusion cell Scientific works.
Screw gauge Bioaids Instruments.
Dept of pharmaceutical Technology Page 33
METHODOLOGY
METHODOLOGY
Methods:
Analytical methods:
a) Determination of λmax:
100 mg of Labetalol was dissolved in 100ml 0.2Hydrochloric acid;
suitable dilutions were made and finally scanned for maximum
absorbance using U.V spectrophotometer (double beam) in the U.V.
rangefrom 200 to 400 nm. Averages of triplicate readings were taken.
b) Estimation of Labetalol:
In present study, the spectrophotometric method was adopted for the
estimation of Labetalol using double beam U.V. spectrophotometer.
c) Preparation of pH 7.4 phosphate buffer: Fifty ml of 0.2M potassium
dihydrogen phosphate was taken in 200 ml volumetric flask, to which
39.1 ml of 0.2 M sodium hydroxide solution was added and the volume
was made up to the mark with distilled water.
d) Preparation of Standard Stock Solution:
100 mg Labetalol drug was accurately weighed and transferred to 100 ml
of volumetric flask and the volume was made with 0.2 hydrochloric acid
to get stock solution of concentration 1000 µg/ml. 1 ml of this solution
was diluted to 100 ml which gives a stock solution of 10µg/ml. From the
resulting 10 µg/ml solution 10, 15, 20, 25, 30 ml diluted to 10ml, the
resulting solution gives the concentration 10-30 µg/ml. The absorbance of
the resulting solution was measured spectrophotometrically at 240 nm.
Dept of pharmaceutical Technology Page 34
METHODOLOGY
Table.No.5. Spectrophotometric data for construction of standard
graph Labetalol
Concentration(µg/
ml) Absorbance
0 0
10 0.080±0.07
15 0.126±0.13
20 0.168±0.17
25 0.219±0.19
30 0.261±0.25
*n=3
Fig. No.6. standard graph of Labetalol HCL in 0.2M
Hydrochloric acid
5 10 15 20 25 30 350
0.05
0.1
0.15
0.2
0.25
0.3
f(x) = 0.00893999999999999 x − 0.0093999999999998R² = 0.999684798270893
Chart Title
Series2Linear (Series2)
Axis Title
Axis
Title
Dept of pharmaceutical Technology Page 35
METHODOLOGY
Preformulation studies of the selected drug:
a) Solubility determination: The solubility of the selected drug was
determined in distilled water andphosphate buffer of pH 7.4 using
standard method.
Procedure
Excess amount of the selected drug was taken and dissolved in a
measuredamount of above solvents separately in a glass beaker to get a
saturated solution. Thesolution was shaken intermittently to assist the
attainment of equilibrium with theundissolved drug particles. Then
measured quantity of the filtered drug solution waswithdrawn after 24hrs
and successively diluted with respective solvents and theconcentration
was measured Spectrophotometrically. Averages of triplicate readings
weretaken.
b) Melting point determination: Melting point of the drug was
determined by taking a small amount of the drug inacapillary tube closed
at one end and was placed in Thiel’s melting point apparatus andthe
temperature at which the drug melts was noted. Averages of triplicate
readings were taken.
c) Partition coefficient:
A drug solution of 1mg/ml was prepared in n-octanol. 25ml of this
solution wastaken in a separating funnel and shaken with an equal volume
of phosphate buffer of pH7.4 (aqueous phase) for 10 minutes and allowed
to stand for two hrs. Then aqueous phase50 and organic phase were
collected separately and centrifuged at 2000 rpm. Both the phases were
analyzed for the drug concentration using U.V. spectrophotometer.
Partitioncoefficient was calculated by taking the ratio of the drug
concentration in n-octanol to drug concentration in aqueous phase.
Triplicate readings were taken.
Dept of pharmaceutical Technology Page 36
METHODOLOGY
d) Permeability coefficient: The permeability coefficient of drug was
calculated by “Potts and Guy equation”,
Log Kp = -2.7 + 0.71 x log Ko/w – 0.0061 x Molecular weight
. Where,
Log Kp = Permeability coefficient
Ko/w = Partition coefficient
e) Infrared (IR) absorption spectroscopy:
To investigate any possible interaction between the drug and the utilized
polymers ( EudragitRLPO, RSPO), IR spectrum of pure drug (Labetalol)
and its physical mixture was carried by using FTIR the range selected was
from 400cm-1 to4000 cm-1
Preparation of transdermal films:
The matrix-type transdermal films containing Labetalol were
prepared by solvent casting method. Eudragit RSPO and RLPO were used
as polymers in the preparation of transdermal films. PEG-400 was used as
a plasticizer, DMSO was used as a penetration enhancer and aluminum
foil was used as backing membrane.24,26,39
Weighed required quantity of polymers and dissolved in 4 ml of solvent
mixture consisting of 1:1 ratio of Dichloromethane and Ethanol. The
polymeric solutions were kept a side for swelling. Then required quantity
of plasticizer and drug solution are added and vertexed for 10 minutes.
Further, it is set-a side for some time to exclude any entrapped air and is
then poured on to the mercury surface in a petriplate and this was kept a
side for solvent evaporation. The rate of solvent evaporation was
controlled by inverting a glass funnel over the petriplate. After overnight,
the dried films were cut into a 2 cm2 piece and stored in desiccators until
further use.
Dept of pharmaceutical Technology Page 37
METHODOLOGY
Table No. 6: Formulation chart of Labetalol transdermal films
Formulatio
n Code
Amoun
t of
Drug
(mg)
% of Eudrag
it RSPO(mg)
% of Eudra
git RSPO
(mg)
PEG-
400(m
)
DMSO(l)
Amount
of
Solvent
(ml)
F1 168.8 160 120 0.75 1 4
F2 168.8 200 120 1 0.75 4
F3 168.8 160 160 1 0.5 4
F4 168.8 200 160 0.5 1 4
F5 168.8 200 200 0.75 0.5 4
F6 168.8 120 120 0.5 0.5 4
F7 168.8 120 160 0.75 0.75 4
F8 168.8 160 200 0.5 0.75 4
F9 168.8 120 200 1 1 4
Evaluation:
The prepared transdermal patches were evaluated for the following;
1. Physical appearance
2. Weight variation
3. Film Thickness
4. Folding endurance
5. Drug content uniformity
6. Percentage of moisture content
7. Percentage of moisture uptake
Dept of pharmaceutical Technology Page 38
METHODOLOGY
8. In vitro drug diffusion studies
9. In vivo study includes:
a. Skin irritation test
10. Stability studies at different temperature (37˚C and 45˚C)
1. Physical appearance:
All the transdermal patches were visually inspected for color, clarity,
flexibilityand smoothness.
2. Weight Variation:
Weight variation was studied by individually weighing 3 randomly
selected films. Such determination was performed for each formulation.37,
38
3. Film Thickness:
The thickness of films was measured at three different places using a
Screw gauge and mean values were calculated.37, 38
4. Folding Endurance:
Folding endurance was determined by repeatedly folding the film at the
same place until it broke. The number of times the film could be folded at
the same place without breaking was the folding endurance value.37
5. Determination of Drug Content in the Film:
The uniformity of drug distribution was evaluated by determining drug
content of the film by a spectrophotometric method. A known weight of
film was dissolved and diluted subsequently with ethyl alcohol and the
concentration of Labetalol was spectrophotometrically measured at 302
nm against the blank ethyl alcohol solution containing the same amount of
polymer and plasticizer without drug.37
6. Percentage of Moisture Content:
The films were weighed individually and kept in desiccator
containing activated silica at room temperature for 24 h. Individual films
were weighed repeatedly until they showed a constant weight. The
Dept of pharmaceutical Technology Page 39
METHODOLOGY
percentage of moisture content was calculated as the difference between
initial and final weight with respect to final weight.31
% Moisture content = Initial weight – Final weight X 100
Final weight
7. Percentage of Moisture Uptake:
A weighed film kept in a desiccator at room temperature for 24 h was
taken out and exposed to 84% relative humidity (a saturated solution of
aluminum chloride) in a desiccator until a constant weight for the film was
obtained. The percentage of moisture uptake was calculated as the
difference between final and initial weight with respect to initial weight.31
% moisture uptake = Final weight – Initial weight X 100
Initial weight
8. In Vitro Drug Diffusion Studies:
In vitro diffusion studies were performed by using a Franz diffusion cell
with a receptor compartment capacity of 140 ml. The dialysis membrane
was mounted between the donor and receptor compartment of the
diffusion cell. The film was placed on cellulose acetate membrane and
covered with aluminum foil. The receptor compartment of the diffusion
cell was filled with phosphate buffer pH 7.4. The whole assembly was
fixed on a hot plate magnetic stirrer, and solution in the receptor
compartment was constantly and continuously stirred using magnetic
beads and the temperature was mentioned at 37 ± 0.5°C. The samples
were withdrawn at different time intervals and analyzed for drug content
spectrophotometrically. The receptor phase was replenished with an equal
volume of phosphate buffer at each sample withdrawal. 25, 30, 31
Dept of pharmaceutical Technology Page 40
METHODOLOGY
Fig.No.7: Invitro studies by using Franz diffusion cell
9. In-vivo studies:
a. skin irritation test: A primary skin irritation test was performed
since skin is vital organ through which drug is transported. Test was
carried out on healthy rabbits weighing 1.3 to 1.5 k.g. Drug free polymeric
film of diameter 4.1 cm were used as control. The dorsal surface of rabbit
was cleared well and the skin was cleared with rectified spirit. The
patches were applied to the shaved skin of rabbits and secured using
adhesive tape USP. On one side the back control patche (with out
drug,group1) and other side an experimental patch( group II) were
secured. A 0.8%v/v aqeous solution of formaldehyde was applied as a
standard irritant(group III) and its effect was compared with test.The
animal were observed for any size of erythema or odema for a period of 7
days.
10. Stability Studies:
The purpose of stability testing is to provide evidence on how the quality
of a drug substance or drug product varies with time under the influence
of a variety of environmental factors such as temperature, humidity and
light and to establish a re-test period for the drug substance or a shelf life
for the drug product and recommended storage conditions. To assess the
drug and formulation stability, stability studies were done according to
ICH guidelines Q1C.
Stability studies were carried out on the films of most satisfactory as per
ICH Guidelines Q1C. The most satisfactory formulation stored in sealed
Dept of pharmaceutical Technology Page 41
METHODOLOGY
in aluminum foil. These were stored at room temperature for 2 months.
Films were evaluated for In vitro drug release, In vivo diffusion study and
various physical characteristics.52
Dept of pharmaceutical Technology Page 42
RESULTS AND DISCUSSION
5. RESULTS
Table No. 7: Preformulation studies of Labetalol
s.no Drug
name
Melting
point(0C)
Solubility
(mg/ml)
Partitioncoefficient (P) Log P
Water Buffer
pH 7.4
Amount in
aqueous
phase
(mg/ml)
Amount in
octonolol
(mg/ml)
1 Labetalol 201.5 0.588 0.125 61.42 39.88 3.09
Dept of pharmaceutical Technology Page 42
RESULTS AND DISCUSSION
Labetalol pure
Fig.No.8: FTIR Spectrum of Labetalol
Dept of pharmaceutical Technology Page 43
RESULTS AND DISCUSSION
RSPO+drug
Fig.No.9: FTIR Spectrum of physical mixture of drug with Eudragit-RSPO
Dept of pharmaceutical Technology Page 44
RESULTS AND DISCUSSION
RLPO+drug
Fig.No.10: FTIR Spectrum of physical mixture of drug with Eudragit-RLPO
Dept of pharmaceutical Technology Page 45
RESULTS AND DISCUSSION
Table No. 9: Physicochemical parameters of prepared formulations F1-F9
Formulation
code
Weight
variation
(mg)
Film
thickness
(mm)
Folding
endurance
% Conten
t
uniformity
% Moisture
content
% Moisture
uptake
F1 267±0.0430.27 ±
0.01103± 0.9 95.6± 2.5 2.13 ± 1.42 1.21 ± 1.58
F2308±
0.026
0.21 ± 0.0
3116 ± 2.1 96.5± 7.6 1.98 ± 2.42 1.59 ± 1.01
F3301±
0.068
0.24 ± 0.0
6107 ± 10 97.6± 2.9 1.99 ± 0.53 1.67 ± 0.44
F4 344±0.0050.21 ± 0.0
1114± 4 95.7± 5.6 1.84 ± 0.31 1.25 ± 2.07
F5 384 ±0.010.29 ± 0.0
4123 ± 2 97.0± 0.9 1.15 ± 1.25 3.66 ± 0.96
F6232±
0.047
0.20 ± 0.0
497 ± 7 99.1 ± 6.8 1.67± 0.37 1.65 ± 1.29
F7 273±0.015 0.17 ± 0.0 114 ± 1.5 96.8± 4.6 1.59 ±1.27 1.25 ± 2.42
Dept of pharmaceutical Technology Page 46
RESULTS AND DISCUSSION
1
F8 340±0.0300.21 ± 0.0
1108 ± 3 98.3± 5.8 1.54± 0.61 1.34 ± 0.91
F9 312±0.020.23 ± 0.0
2105 ± 1.6 97.5± 6.5 1.64± 0.24
1.94 ±
0.71
n=3
Fig .No.11: Drug content
f1 f2 f3 f4 f5 f6 f7 f8 f993
94
95
96
97
98
99
100
Series1
IN VTRO DIFFUSION STUDY:
Dept of pharmaceutical Technology Page 47
RESULTS AND DISCUSSION
In vitro diffusion studies of Labetalol transdermal films were carried
out by using dialysis membrane and diffusion cell in PBS pH 7.4
solution. The release data were given in the Tables 9 to 17 respectively for
formulation F1 to F9.
Table No.10:Comparative data of percentage drug release from the formulations F1 to F9
Dept of pharmaceutical Technology Page 48
RESULTS AND DISCUSSION
Fig. No. 12: Comparative In-vitro diffusion study of formulation F1-F5
Dept of pharmaceutical Technology Page 49
Time(hr) f1 f2 f3 f4 f5 f6 f7 f8 f9
0 0 0 0 0 0 0 0 0 0
1 4.193 6.896 3.261 6.057 2.236 3.261 3.448 8.014 9.132
2 8.137 8.995 8.689 8.616 5.420 5.428 5.70910.21
410.03
6
311.92
2 9.71110.98
810.82
1 7.043 6.771 6.58812.71
013.36
9
416.38
713.97
3 12.9312.94
7 9.143 8.683 9.15118.29
818.30
9
518.18
018.17
218.23
917.69
811.81
713.96
313.96
820.75
721.88
6
623.06
121.18
922.74
820.24
612.92
617.78
917.60
828.07
828.00
4
727.60
225.15
828.31
225.79
218.42
118.47
318.57
033.30
734.07
1
828.91
328.12
931.12
028.86
220.69
322.51
622.24
137.82
739.34
2
933.77
430.93
437.20
832.88
322.70
225.65
525.28
541.25
944.79
2
1037.17
737.11
343.15
136.65
326.68
027.79
127.88
447.78
946.82
3
1141.72
038.86
147.27
239.88
830.59
332.27
032.08
454.73
655.34
7
1245.54
945.74
554.68
146.96
635.83
750.01
250.75
763.31
563.55
7
2485.65
489.85
992.14
887.17
580.25
690.05
993.04
695.62
297.26
4
RESULTS AND DISCUSSION
0 5 10 15 20 25 300
102030405060708090
100
f1f2f3f4f5
Time(hr)
%DR
Fig. No. 13: Comparative In-vitro diffusion study of formulation F6-
F9
0 5 10 15 20 25 300
20
40
60
80
100
120
f6F7F8F9
time
%cd
r
Kinetics of drug release:
Table No. 11: comparison of zero order of in vitro drug release F1-F9
Dept of pharmaceutical Technology Page 50
RESULTS AND DISCUSSION
Time(hr) f1 f2 f3 f4 f5 f6 f7 f8 f9
1 4.193 6.896 3.261 6.057 2.236 3.261 3.448 8.014 9.132
2 8.137 8.995 8.689 8.616 5.420 5.428 5.709 10.214 10.036
3 11.922 9.711 10.988 10.821 7.043 6.771 6.588 12.710 13.369
4 16.387 13.973 12.93 12.947 9.143 8.683 9.151 18.298 18.309
5 18.180 18.172 18.239 17.698 11.817 13.963 13.968 20.757 21.886
6 23.061 21.189 22.748 20.246 12.926 17.789 17.608 28.078 28.004
7 27.602 25.158 28.312 25.792 18.421 18.473 18.570 33.307 34.071
8 28.913 28.129 31.120 28.862 20.693 22.516 22.241 37.827 39.342
9 33.774 30.934 37.208 32.883 22.702 25.655 25.285 41.259 44.792
10 37.177 37.113 43.151 36.653 26.680 27.791 27.884 47.789 46.823
11 41.720 38.861 47.272 39.888 30.593 32.270 32.084 54.736 55.347
12 45.549 45.745 54.681 46.966 35.837 50.012 50.75763.315
4 63.557
24 85.654 89.859 92.148 87.175 80.256 90.059 93.04695.622
7 97.264
Fig. No. 14:comparison of zero order of in vitro drug release F1-F5
Dept of pharmaceutical Technology Page 51
RESULTS AND DISCUSSION
0 5 10 15 20 25 300
102030405060708090
100
zero order
f1f2f3f4f5
Time(hr)
%cd
r
Fig. No. 15:comparison of zero order of in vitro drug release F5-F8
0 5 10 15 20 25 300
20
40
60
80
100
120
zero order
f6F7F8F9
time
%cd
r
Dept of pharmaceutical Technology Page 52
RESULTS AND DISCUSSION
Table No. 12: comparison of Firstorder of in vitro drug release F1-F9
Time(hr)
F1 F2 F4 F5 F6 F7 F8 F9
1 1.973 1.961 1.965 1.984 1.979 1.979 1.952 1.948
2 1.955 1.952 1.953 1.969 1.969 1.968 1.943 1.944
3 1.937 1.947 1.943 1.962 1.962 1.963 1.929 1.927
4 1.914 1.927 1.931 1.952 1.954 1.952 1.903 1.903
5 1.904 1.904 1.909 1.939 1.928 1.928 1.888 1.883
6 1.878 1.890 1.893 1.934 1.909 1.909 1.847 1.847
7 1.851 1.866 1.864 1.906 1.905 1.905 1.812 1.810
8 1.845 1.851 1.846 1.894 1.883 1.886 1.783 1.773
9 1.817 1.833 1.821 1.885 1.866 1.869 1.761 1.736
10 1.794 1.795 1.796 1.861 1.855 1.855 1.716 1.719
11 1.762 1.783 1.775 1.837 1.825 1.830 1.645 1.646
12 1.735 1.734 1.724 1.805 1.698 1.692 1.564 1.570
24 1.159 1.010 1.108 1.295 0.997 0.838 0.661 0.438s
Dept of pharmaceutical Technology Page 53
RESULTS AND DISCUSSION
Fig. No.16: comparison of Firstorder of in vitro drug release F1-F5
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
f(x) = − 0.0284763996138422 x + 2.08718366466246R² = 0.899227687008401f(x) = − 0.0359784016400436 x + 2.09259985579111R² = 0.918201860280524f(x) = − 0.0455148375726418 x + 2.13227571410842R² = 0.923194672530634f(x) = − 0.0394038289873515 x + 2.11367182659306R² = 0.889587596879513f(x) = − 0.0338353537414168 x + 2.07551385450958R² = 0.932230901925438
first order
f1Linear (f1)f2Linear (f2)f3Linear (f3)f4Linear (f4)f5Linear (f5)
Time(hr)
log
of re
mai
ng
Fig. No.17: comparison of First order of in vitro drug release F6-F9
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
f(x) = − 0.0631581470083122 x + 2.19934090029599R² = 0.894076399748058f(x) = − 0.0548347662809895 x + 2.15415480789699R² = 0.920493332602919f(x) = − 0.0468098498122515 x + 2.18114829898843R² = 0.847497953032005f(x) = − 0.0407736577911099 x + 2.14563658482255R² = 0.871741137972752
first order
f6Linear (f6)f7Linear (f7)f8Linear (f8)f9Linear (f9)
time
log
of re
mai
ng
Dept of pharmaceutical Technology Page 54
RESULTS AND DISCUSSION
Table No. 13: comparison of Higuchi model of in vitro drug release F1-F9
SQRT of time F1 F2 F3 F4 F5 F6 F7 F8 F9
1 4.193 6.896 3.261 6.057 2.236 3.261 3.448 8.014 9.132
1.414 8.137 8.995 8.689 8.616 5.420 5.428 5.709 10.214 10.036
1.732 11.922 9.711 10.988 10.821 7.043 6.771 6.588 12.710 13.369
2 16.387 13.973 12.93 12.947 9.143 8.683 9.151 18.298 18.309
2.236 18.180 18.172 18.239 17.698 11.817 13.963 13.968 20.757 21.886
2.449 23.061 21.189 22.748 20.246 12.926 17.789 17.608 28.078 28.004
2.645 27.602 25.158 28.312 25.792 18.421 18.473 18.570 33.307 34.071
2.828 28.913 28.129 31.120 28.862 20.693 22.516 22.241 37.827 39.342
3 33.774 30.934 37.208 32.883 22.702 25.655 25.285 41.259 44.792
3.162 37.177 37.113 43.151 36.653 26.680 27.791 27.884 47.789 46.823
3.316 41.720 38.861 47.272 39.888 30.593 32.270 32.084 54.736 55.347
3.464 45.549 45.745 54.681 46.966 35.837 50.012 50.757 63.315 63.557
4.898 85.654 89.859 92.148 87.175 80.256 90.059 93.046 95.622 97.264
Dept of pharmaceutical Technology Page 55
RESULTS AND DISCUSSION
Fig.No.18: comparison of Higuchi model of in vitro drug release F1-F5
0 10 20 30 40 50 60 70 80 900
102030405060708090
100
f(x) = 0.808724887695931 xR² = 0.97716337881528f(x) = 0.808724887695931 xR² = 0.97716337881528
f(x) = 0.993140593634322 xR² = 0.997801297834615
f(x) = 1.09332492112834 xR² = 0.996066053899067f(x) = 0.998222357713358 xR² = 0.996226955402873
higuchif1f2Linear (f2)f3Linear (f3)f4Linear (f4)f5Linear (f5)Linear (f5)
SQRT(Time)
%CD
R
Fig. No. 19: comparison of Higuchi model of in vitro drug release F6-F9
0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.50
20
40
60
80
100
120
f(x) = 15.3391360181027 xR² = 0.943831257999233f(x) = 15.0549920246767 xR² = 0.941333868313028f(x) = 11.0759719347602 xR² = 0.82341535362968f(x) = 10.918805333017 xR² = 0.832629225750772
HIGUCHI
f6Linear (f6)f7Linear (f7)f8Linear (f8)f9Linear (f9)
SQRT
%CD
R
Dept of pharmaceutical Technology Page 56
RESULTS AND DISCUSSION
Table No. 14: comparison of Korsmeyers-peppasequation of in vitro drug release F1-F9
Log T f1 f2 f3 f4 f5 f6 f7 f8 f9
0 0.769 0.924 0.708 0.882 0.546 0.671 0.669 1.019 1.048
0.301 0.991 1.016 1.027 1.007 0.828 0.836 0.843 1.085 1.079
0.477 1.128 1.052 1.101 1.087 0.915 0.915 0.903 1.174 1.187
0.602 1.253 1.189 1.161 1.161 1.011 0.999 1.013 1.297 1.301
0.698 1.293 1.294 1.297 1.275 1.116 1.181 1.178 1.355 1.373
0.778 1.388 1.347 1.385 1.335 1.148 1.275 1.273 1.470 1.471
0.845 1.461 1.423 1.469 1.428 1.289 1.290 1.290 1.545 1.548
0.903 1.476 1.462 1.504 1.473 1.334 1.370 1.363 1.593 1.608
0.954 1.536 1.502 1.582 1.527 1.366 1.423 1.414 1.625 1.657
1 1.576 1.574 1.642 1.573 1.435 1.453 1.452 1.680 1.677
1.041 1.624 1.594 1.678 1.605 1.494 1.520 1.509 1.746 1.745
1.079 1.658 1.660 1.735 1.672 1.558 1.699 1.705 1.801 1.798
1.380 1.932 1.953 1.964 1.940 1.904 1.954 1.968 1.979 1.987
Dept of pharmaceutical Technology Page 57
RESULTS AND DISCUSSION
Fig. No. 20: comparison of Korsmeyers-peppasequation of in vitro drug release F1-F5
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60
0.5
1
1.5
2
2.5
f(x) = 0.963951071972092 x + 0.48086707039718R² = 0.979570710331028f(x) = 0.800910507725789 x + 0.762657279164125R² = 0.964759319647131f(x) = 0.930909370689302 x + 0.684021383514926R² = 0.986865488590058f(x) = 0.777195841176939 x + 0.782968970547218R² = 0.95124255895885f(x) = 0.843350654046961 x + 0.738834617172486R² = 0.996312327445671
peppasf1Linear (f1)f2Linear (f2)f3Linear (f3)f4Linear (f4)f5Linear (f5)
Log T
log
of cd
r
Fig. No. 21: comparison of Korsmeyers-peppasequation of in vitro drug release F6-F9
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60
0.5
1
1.5
2
2.5
f(x) = 0.772333661668658 x + 0.901261654264482R² = 0.951921659685113f(x) = 0.781662934323325 x + 0.885531212475262R² = 0.956518551842836f(x) = 0.964868740645544 x + 0.529226846095218R² = 0.951326310281287f(x) = 0.962043277889753 x + 0.531734506961068R² = 0.953896166084995
peppas
f6Linear (f6)F7Linear (F7)F8Linear (F8)F9Linear (F9)
log t
log
of cd
r
Dept of pharmaceutical Technology Page 58
RESULTS AND DISCUSSION
Table No. 15:Comparison of orders of in vitro release of Labetalol from the formulation F1 to F9.
KINETIC VALUES OBTAINED FROM THE FORMULATION F1-F9:Formulation Zero – order First – order Higuchi Peppas
R2 K R2 K R2 R2 N
F1 0.996 3.680 0.932 0.075 0.928 0.996 0.84
F2 0.994 3.68 0.889 0.089 0.989 0.951 0.77
F3 0.986 4.024 0.923 0.103 0.988 0.986 0.93
F4 0.995 3.659 0.918 0.082 0.993 0.964 0.80
F5 0.965 2.99 0.899 0.064 0.948 0.979 0.96
F6 0.947 3.409 0.871 0.092 0.629 0.953 0.96
F7 0.939 3.471 0.847 0.105 0.616 0.951 0.96
F8 0.959 4.448 0.920 0.124 0.800 0.956 0.78
F9 0.959 4.526 0.894 0.145 0.811 0.951 0.77
HALF – LIFE VALUES OBTAINED FOR THE FORMULATIONS F1 TO F9
Formulation Zero – order First – order
K t1/2 (hrs.) K t1/2 (hrs.)
F1 3.680 22.9 0.075 9.24F2 3.68 22.9 0.089 7.786F3 4.024 20.9 0.103 6.72F4 3.659 23.06 0.082 8.45F5 2.99 28.22 0.064 10.82F6 3.409 24.75 0.092 7.53F7 3.471 24.31 0.105 6.6F8 4.448 18.9 0.124 5.58F9 4.526 18.6 0.145 4.7
Response 1: Folding endurance
Dept of pharmaceutical Technology Page 59
RESULTS AND DISCUSSION
Table No. 16: ANOVA for Response Surface linear Model :
source
Sum of
squraes Df
Mean
squares F VALUE
P-Value
Prob>F
Model 495.333 6 82.555 6.816 0.133
A-RSPO 321.555 2 160.777 13.275 0.070
B-RLPO 69.555 2 34.777 2.871 0.258
C-DMSO 104.222 2 52.111 4.302 0.188
Residual 24.222 2 12.111 - -
Cor Total 519.555 8 - - -
Table No.17: Estimated Regression Coefficients:
Factor Coefficient estimate Standard DF
A-1 -3.888 1
A-2 -4.555 1
B-1 -3.888 1
B-2 2.444 1
C-1 -4.222 1
C-2 4.111 1
Final Equation in Terms of Coded Factors: Coded factor for folding
endurance=109.22-3.88*A[1]-4.55*A[2]-3.88*B[1]-2.44*B[2]- 4.22*C[1]+4.11C[3]
Fig. No.22. Correlation between actual and predicted values for Folding
endurance (R1)
Dept of pharmaceutical Technology Page 60
RESULTS AND DISCUSSION
Design-Expert® Softwarefolding endurance
Color points by value offolding endurance:
123
97
Actual
Pre
dic
ted
Predicted vs. Actual
95.00
100.00
105.00
110.00
115.00
120.00
125.00
95.00 100.00 105.00 110.00 115.00 120.00 125.00
Fig. No.23. 3-D graph showing effect of Eudragit-RSPO,RLPO and
DMSO and Poly Ethylene Glycol Folding endurance (R1)
Design-Expert® SoftwareFactor Coding: Actualfolding endurance
Design points below predicted value
X1 = A: RSPOX2 = B: RLPO
Actual FactorsC: DMSO = 0.5D: PEG-400 = 0.5
120
160
200
120
160
200
80
90
100
110
120
fo
ldin
g e
nd
ura
nc
e
A: RSPO B: RLPO
Dept of pharmaceutical Technology Page 61
RESULTS AND DISCUSSION
Design-Expert® SoftwareFactor Coding: Actualfolding endurance
Design points below predicted value
X1 = C: DMSOX2 = D: PEG-400
Actual FactorsA: RSPO = 120B: RLPO = 120
0.5
0.75
1
0.5
0.75
1
80
90
100
110
120
fo
ldin
g e
nd
ura
nc
e
C: DMSO D: PEG-400
Design-Expert® SoftwareFactor Coding: Actualfolding endurance
Design points below predicted value
X1 = B: RLPOX2 = C: DMSO
Actual FactorsA: RSPO = 120D: PEG-400 = 0.5
0.5
0.75
1
120
160
200
80
90
100
110
120
fo
ldin
g e
nd
ura
nc
e
B: RLPO C: DMSO
Dept of pharmaceutical Technology Page 62
RESULTS AND DISCUSSION
Response 2: Drug Release at 4th hr.
Table No. 18:ANOVA for Response Surface Linear Model:
Source
Sum of
squares Df
Mean
square F-value
P-value
Prob>F
Model 51.074 6 8.512 0.234 0.9294
A-RSPO 30.288 2 15.144 0.417 0.7054
B-RLPO 11.527 2 5.763 0.158 0.8629
C-DMSO 9.258 2 4.629 0.1276 0.8868
Residual 72.529 2 36.264 - -
Cor Total 123.603 8 - - -
Table No. 19: Estimated Regression Coefficients:
FACTOR COEFFICIENT
ESTIMATE
STANDARD DF
A[1] -1.204 1
A[2] 2.592 1
B[1] -0.354 1
B[2] 1.528 1
C[1] -0.041 1
C[2] 1.262 1
Final Equation in Terms of Coded Factors:coded factor for 4th hr release=14.77-
1.204*A[1]+2.59*A[2]-0.35*B[1]+1.52*B[2]-0.04*C[1]+1.26*C[2]
Dept of pharmaceutical Technology Page 63
RESULTS AND DISCUSSION
Fig. No.24. Correlation between actual and predicted values for Drug
Release at 4thhr (R2)
Design-Expert® Softwaredrug release 4th hr
Color points by value ofdrug release 4th hr:
20.01
9.9
Actual
Pre
dic
ted
Predicted vs. Actual
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00
Fig. No.25. 3-D graph showing effect of Eudragit-RSPO,RLPO and
DMSO, Poly Ethylene Glycol Drug Release at 4thhr (R2)
Design-Expert® SoftwareFactor Coding: Actualdrug release 4th hr
Design points below predicted value
X1 = A: RSPOX2 = B: RLPO
Actual FactorsC: DMSO = 0.5D: PEG-400 = 0.5
120
160
200
120
160
200
-10
0
10
20
30
40
d
rug
re
lea
se
4th
hr
A: RSPO B: RLPO
Dept of pharmaceutical Technology Page 64
RESULTS AND DISCUSSION
Design-Expert® SoftwareFactor Coding: Actualdrug release 4th hr
Design points below predicted value
X1 = B: RLPOX2 = C: DMSO
Actual FactorsA: RSPO = 120D: PEG-400 = 0.5
0.5
0.75
1
120
160
200
-10
0
10
20
30
40
d
rug
re
lea
se
4th
hr
B: RLPO C: DMSO
Design-Expert® SoftwareFactor Coding: Actualdrug release 4th hr
Design points below predicted value
X1 = C: DMSOX2 = D: PEG-400
Actual FactorsA: RSPO = 120B: RLPO = 120
0.5
0.75
1
0.5
0.75
1
-10
0
10
20
30
40
d
rug
re
lea
se
4th
hr
C: DMSO D: PEG-400
Dept of pharmaceutical Technology Page 65
RESULTS AND DISCUSSION
Response 3: Drug Release at 12th hr.
Table No. 20: ANOVA for Response Surface Linear Model:
Table No. 21: Estimated Regression Coefficients:
Final Equation in Terms of Coded Factors: coded factor for12th hr
release=50.51+3.75*A[1]+3.855*A[2]-3.41*B[1]+3.88*B[2]+2.92*C[1]-
2.64*C[2]
Dept of pharmaceutical Technology Page 66
SourceSum of squares Df
Mean square F- value
p-valueProb>F
Model 388.486 6 64.747 0.679 0.698A-RSPO 260.695 2 130.347 1.367 0.422B-RLPO 80.962 2 40.481 0.424 0.701C-DMSO 46.828 2 23.414 0.245 0.802Residual 190.602 2 95.301 - -Cor Total 579.088 8 - - -
FACTOR COEFFICIENT
ESTIMATE
STANDARD DF
A[1] 3.755 1
A[2] 3.855 1
B[1] -3.411 1
B[2] 3.888 1
C[1] 2.922 1
C[2] -2.644 1
RESULTS AND DISCUSSION
Fig. No.26. Correlation between actual and predicted values for Drug
Release at 12th hr (R3)
Design-Expert® Softwaredrug release 12th hr
Color points by value ofdrug release 12th hr:
63.3
36.1
Actual
Pre
dic
ted
Predicted vs. Actual
35.00
40.00
45.00
50.00
55.00
60.00
65.00
35.00 40.00 45.00 50.00 55.00 60.00 65.00
Fig. No.27. 3-D graph showing effect of Eudragit-RSPO,RLPO and
DMSO, Poly Ethylene Glycol Drug Release at 12thhr (R3)
Design-Expert® SoftwareFactor Coding: Actualdrug release 12th hr
Design points below predicted value
X1 = A: RSPOX2 = B: RLPO
Actual FactorsC: DMSO = 0.5D: PEG-400 = 0.5
120
160
200
120
160
200
0
20
40
60
80
100
d
rug
re
lea
se
12
th h
r
A: RSPO B: RLPO
Dept of pharmaceutical Technology Page 67
RESULTS AND DISCUSSION
Design-Expert® SoftwareFactor Coding: Actualdrug release 12th hr
Design points below predicted value
X1 = B: RLPOX2 = C: DMSO
Actual FactorsA: RSPO = 120D: PEG-400 = 0.5
0.5
0.75
1
120
160
200
0
20
40
60
80
100
d
rug
re
lea
se
12
th h
r
B: RLPO C: DMSO
Design-Expert® SoftwareFactor Coding: Actualdrug release 12th hr
Design points below predicted value
X1 = C: DMSOX2 = D: PEG-400
Actual FactorsA: RSPO = 120B: RLPO = 120
0.5
0.75
1
0.5
0.75
1
0
20
40
60
80
100
d
rug
re
lea
se
12
th h
r
C: DMSO D: PEG-400
Dept of pharmaceutical Technology Page 68
RESULTS AND DISCUSSION
Response 4: Drug Release at 24th hr.
Table No. 22:ANOVA for Response Surface Linear Model:
Source
Sum of
squares Df
Mean
square F value
p-value
prog>f
Model 143.763 6 23.960 0.630 0.720
A-RSPO 95.095 2 47.547 1.250 0.444
B-RLPO 21.691 2 10.845 0.285 0.778
C-DMSO 26.976 2 13.488 0.354 0.738
Residual 76.035 2 38.017 - -
Cor Total 219.799 8 - - -
Table No. 23: Estimated Regression Coefficients:
FACTORS COEFFICIENT
ESTIMATE
STANDARD DF
A[1] 3.413 1
A[2] 0.96 1
B[1] -1.62 1
B[2] 2.093 1
C[1] 0.813 1
C[2] -2.406 1
Final Equation in Terms of Coded Factors:Coded factor for drug
release=90.04+3.14*A[1]+0.96*A[2]-1.62B[1]+2.093*B[2]+0.813*C[1]-
2.40*C[2]S
Dept of pharmaceutical Technology Page 69
RESULTS AND DISCUSSION
Fig. No.28. Correlation between actual and predicted values for Drug
Release at 24th hr (R4)
Design-Expert® Softwaredrug release 24th hr
Color points by value ofdrug release 24th hr:
97.2
80.2
Actual
Pre
dic
ted
Predicted vs. Actual
80.00
85.00
90.00
95.00
100.00
80.00 85.00 90.00 95.00 100.00
Fig. No.29.3-D graph showing effect of Eudragit-RSPO, RLPO and
DMSO Poly Ethylene Glycol Drug Release at 24thhr (R4)
Design-Expert® SoftwareFactor Coding: Actualdrug release 24th hr
Design points below predicted value
X1 = A: RSPOX2 = B: RLPO
Actual FactorsC: DMSO = 0.5D: PEG-400 = 0.5
120
160
200
120
160
200
60
70
80
90
100
110
d
rug
re
lea
se
24
th h
r
A: RSPO B: RLPO
Dept of pharmaceutical Technology Page 70
RESULTS AND DISCUSSION
Design-Expert® SoftwareFactor Coding: Actualdrug release 24th hr
Design points below predicted value
X1 = B: RLPOX2 = C: DMSO
Actual FactorsA: RSPO = 120D: PEG-400 = 0.5
0.5
0.75
1
120
160
200
60
70
80
90
100
110
120
d
rug
re
lea
se
24
th h
r
B: RLPO C: DMSO
Design-Expert® SoftwareFactor Coding: Actualdrug release 24th hr
Design points below predicted value
X1 = C: DMSOX2 = D: PEG-400
Actual FactorsA: RSPO = 120B: RLPO = 120
0.5
0.75
1
0.5
0.75
1
60
70
80
90
100
110
120
d
rug
re
lea
se
24
th h
r
C: DMSO D: PEG-400
Dept of pharmaceutical Technology Page 71
RESULTS AND DISCUSSION
5.5. Optimized formula:
Table No. 24: Composition of the optimized formula:
Ingredients R
labetalol 0.168
Eudragit-RSPO 0.160
Eudragit-RLPO 0.160
DMSO 1
PEG-400 0.5
All the quantities expressed are in gm but DMSO and PEG in ml
Table No. 25: Response variables of optimized formula:
Formulation Code Folding endurance
Optimized Formula 107 ± 10
Table No. 26: Data of various parameters of model fitting for
Labetalol for optimized formulation:
Zero order First order Higuchi Korsmeyer-
Peppas
0.986 0.923 0.957 0.986
Dept of pharmaceutical Technology Page 72
RESULTS AND DISCUSSION
Table No. 27:Drug release studies of optimized formula(F3):
Time (hrs) % CDR
0 0
1 3.261
2 8.689
3 10.988
4 12.34
5 18.239
6 22.748
7 28.312
8 31.120
9 37.208
10 43.151
11 47.272
12 54.370
24 93.231
Dept of pharmaceutical Technology Page 73
RESULTS AND DISCUSSION
Fig. No.30.Zero order kinetics of optimized formula:
0 5 10 15 20 25 300
102030405060708090
100f(x) = 4.02040819920243 x + 0.0516716773322372R² = 0.985981890305445
zero order
zero orderLinear (zero order)
Time(hr)
%cd
r
Fig. No.31.First order kinetics of optimized formula:
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
f(x) = − 0.0455148375699973 x + 2.13227571405835R² = 0.92319467284128
first order
first orderLinear (first order)
Time
log
of re
mai
ng
Dept of pharmaceutical Technology Page 74
RESULTS AND DISCUSSION
Fig. No 32.Higuchi plot for optimized formula:
0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.50
102030405060708090
100
f(x) = 23.3025938182498 x − 29.614094964659R² = 0.957166993904025
Higuchi
HiguchiLinear (Higuchi)
SQRT(Time)
%cd
r
Fig. No.33.Korsmeyer-Peppas plot for optimized formula
Table No. 28.Comparison between the experimental (E) and predicted (P) values
for the optimal formulation
Optimize
d formula
Drug release
at 4thhr (%)
Drug release
at 12thhr
Drug release
at 24thhr
Folding
endurance
Dept of pharmaceutical Technology Page 75
RESULTS AND DISCUSSION
(%) (%)
Pred. 17.674 57.977 94.686 107.22
Exp. 15.314 54.681 92.331 107.122
8)
Stability study:
STABILITY STUDY OF MOST OPTIMIZED FORMULATION
Table No. 29. Physicochemical properties of most satisfactory formulations
(After stability)
Dept of pharmaceutical Technology Page 76
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60
0.5
1
1.5
2
2.5
f(x) = 0.930909370661006 x + 0.684021383517411R² = 0.986865488576466
peppas
peppasLinear (peppas)
LOG T
log
cdr
Formulation code F3
Time (Days) 30 60
Folding
endurance*
A 111.66 ±7.6 112 ± 11.01
% Content
uniformity*
A 96.04 ± 0.15 94.19 ± 2.92
% Moisture
content*
A 1.99 ± 0.53 1.42 ± 0.91
% Moisture
uptake*
A 1.67 ± 0.47 1.47± 0.42
RESULTS AND DISCUSSION
Where A: 40°C±2°C/75%±5% RH.*n = 2
Table No. 28:In vitro drug diffusion studies of most satisfactory
formulations
(After stability)
W he
re A:
40°C±2°C/75%±5% RH.
Dept of pharmaceutical Technology Page 77
Formulation codeF3
30Days 60 Days
A A
% C
umul
ativ
e dr
ug d
iffus
ion
± SD
1 5.111 3.261
2 10.643 8.689
3 12.634 10.988
4 14.489 12.34
5 19.516 18.237
6 24.285 22.748
7 29.458 28.312
8 31.968 31.120
9 38.196 37.208
10 43.922 43.151
11 47.699 47.272
12 54.681 54.370
24 92.176 92.176
RESULTS AND DISCUSSION
0 5 10 15 20 25 300
102030405060708090
100
30days60days
time
%cd
r
Fig.No.34: %cumulative drug permeation Vs time profile of most satisfactoryFormulationF3(After stability)
6. DISCUSSION:
The pure drug Labetalol which was obtained as a gift sample from
Yarochem pvt(ltd), Mumbai, was used in the present investigation. In the
first phase of ourstudy the drug was subjected to various Preformulation
parameters namely solubility, melting point, partition coefficient (aqueous
& octonolol), permeability coefficient. The results are shown in table 7.
The solubility of drug in water and buffer of pH 7.4, melting point,
partitioncoefficient and permeability coefficients were found to be 0.588
mg/ml, 0.125 mg/ml, 201.50C, 61.42 mg/ml, 39.88 mg/ml and
3.09respectively. The λmax of the selected drug found to be 232 nm and it
wasused throughout the study for the estimation of drug in the
formulations.
The peaks observed in the Table No.8 can be considered as
characteristic peaks of Labetalol. These peaks were not affected and
prominently observed in IR spectra of Labetalol along with polymers as
Dept of pharmaceutical Technology Page 78
RESULTS AND DISCUSSION
shown in Figures 8 to 10. This indicates there is no interaction between
Labetalol and polymers.
Transdermal patches of Labetalol were prepared successfully
by solvent casting method using different polymers ( Eudragit
RSPO,RLPO) in different combinations and proportions. PEG used as a
plasticizer, DMSO used as permeation enhancer.
Physicochemical properties
The films prepared by general procedure were evaluated for the following
properties:
Weight Variation Test:
The results of weight variation test for various transdermal films are
shown in Table No. 9.weight variation of the developed formulation F1 to
F9 varied from 0.232 to 0.340 mg. Results of weight variation test
indicated uniformity in weight of patches, as evidenced by SD values.
Thickness Variation Test:
Thickness of the developed formulations F1 to F9 varied from 0.21 to
0.29 mm andwas found to be uniform. The thickness increased with
increase in RLPOandRSPO concentration. The SD values were less than
11 for all formulations, an indication of more uniform patches (Table No.
9).
Folding endurance:
Folding Endurance of the developed formulations F1 to F9 varied from 95
to 123. Folding Endurance of the film increases with increase in the
Eudragit proportion.
Dept of pharmaceutical Technology Page 79
RESULTS AND DISCUSSION
Drug content uniformity:
Good uniformity in drug content was observed in all transdermal
patches as evidenced by Table No.9. The drug content is ranged from 94.6
to 99.03%. From the results obtained (i.e., lowest SD values), it was clear
that there was proper distribution of Labetalolin the film formulations.
Hence it was concluded that drug was uniformly distributed in all the
formulations.
Moisture content test:
Moisture contentof the developed formulations F1 to F9 varied
from 2.13to 1.15%. The formulations F1 which is having high moisture
absorption was found to be 2.13%. The formulations F5 which is having
less moisture absorption was found to be 1.15%.Theresultsrevealed
thatthemoisturecontentwasfoundto increasewithincreasing concentration
o f lipophilic polymer(RLPO,RSPO).The moisture content of the prepared
formulations was low, which could help the formulations remain stable
and reduce brittleness during long term storage.
Moisture uptake test:
Moisture uptakeof the developed formulations F1 to F9varied from
3.36 to 1.25%. The formulations F5 which is having high moisture
content was found to be 3.36%. The formulations F7 which is having less
moisture absorption was found to be 1.25%.so that based on results
increasing the lipophillic polymer concentration(RSPO) moisture uptake
was increases.The moisture uptake of the formulations was also low,
Dept of pharmaceutical Technology Page 80
RESULTS AND DISCUSSION
which could protect the formulations from microbial contamination and
reduce bulkiness.
In-vitro Drug Release Studies from Transdermal Patches:
Fig.No.12, 13.Show the release profile of Labetalol from the transdermal
patches. Formulation F8 and F9 exhibits greatest(95%,97%) percentage
of drug release values (Table no.10),when increasing the concentration
of the RSPO releasing property of following formulation are
decreases(F5, and F1,F4).In these present observed that depending on
the concentration RLPO the releasing of the drug is substantially
increased. And based on the kinetics(zero order, first order, higuchi and
Peppas).Higuchi most appropriate model to describe the kinetics from all
patches. The ‘n’ value(0.77,< n> 0.96) it indicates that amount of released
drug was by non-fickian diffusion
Skin irritation test: A primary skin irritation test of patch formulation 3
on rabbit was studied. No signs of erythema, oedema or ulceration were
observed on the skin of albino rabbits after 7 days.
Stability Study:
Stability studies were carried out on most satisfactory formulation
as per ICH Guidelines Q1C. The most satisfactory formulation was sealed
in aluminum foil and stored in stability chamber. These were stored at
room temperature for 2 months, after 2 months drug content of most
satisfactory formulation was determined by method discussed previously
in entrapment efficiency section. Tables 29 showed that there were no
Dept of pharmaceutical Technology Page 81
RESULTS AND DISCUSSION
significant changes found in physicochemical parameters and in vitro
diffusion of the most satisfactory formulations (F3) after stability study.
Dept of pharmaceutical Technology Page 82
CONCLUSION
7. CONCLUSION:
The present investigation is concern with the development of the
transdermal films and to increase the bioavailability of the drug and its
half life.
The following conclusions were drawn from results obtained;
1) A suitable method of analysis of Labetalol by UV Spectroscopy was
developed. Labetalol showed maximum absorption at wave length 232nm
in 0.2hcl. The value of regression coefficient of standard curve was found
to be 0.997 which showed linear relationship between concentration and
absorbance. Preformulation studies for drug-polymer compatibility by
FTIR gave confirmation about their purity and showed no interaction
between the drug and selected polymers.
2) Various formulations were developed by using release rate controlling
polymers like Eudragit-RSPO RLPO in combination by solvent casting
method to these formulation following evaluation are conducted required
physicochemical properties such as drug content uniformity,folding
endurance, weight uniformity,thickness uniformity, moisture content
&moisture uptake .
3) From the results of the drug content determination, it shows that drug was
proper distribution of drug in films and deviations are within the
level.Optimized Formulation F3(Eudragit RSPO-0.120 RLPO-0.160) was
found to be best among all batches of its consistent release rate for 24 hrs
and the extent of drug release 94.20%.
4) Graphical treatment of F5 according to Higuchi’s equation has shown the
drug release was diffusion mediated.Primary skin irritation studies
revealed that the formulation F3 has shown no erythema and edema.
5) Stability study of the formulations showed no significant changes in the
drug content as well as physical characteristics of the film.
Dept of pharmaceutical Technology Page 81
CONCLUSION
It is concluded from the present studies that the transdermal patches of
Labetalol are capable of exhibiting controlled release with thestability and
the formulation F3 EudragitRSPO,RLPO (1:9%) has fulfilled the
objectives of the present study like reduction in the frequency of
administration, improved patient compliance.
Studies have shown promising results, and there is a scope for
furtherpharmacodynamic and pharmacokinetic evaluation. There is a need
to conduct toxicity studies using various experimental animals and
evaluate the safety and efficacy of selected formulations.
Dept of pharmaceutical Technology Page 82
SUMMARY
8. SUMMARY
Preformulation studies : A Preformulation study for the estimation
of labetalol was developed and drug-polymer compatibility studies were
carried out. Method was developed for estimation of drugs and
calibration curves in simulated 0.2m hydrochloric acid were obtained for
labetalol(range 10-30μg/ml). FT-IR study was carried out to rule out any
possible interactions between the drug and the polymers, thus confirming
the compatibility between the selected range of drug and the polymers. As
next step, various formulations were developed for the selected drug.
Transdermal films of Labetalol HCL:
The half-life of labetalol HCL is 6 to 8 h. Transdermal films of
labetalol were developed by Eudragit RSPO&RLPO and using solvent
casting method. In present study, PEG-400 was used as plasticizer and
DMSO was used as permeation enhancers in different proportions.
Uniformity in drug content among the batches was observed with all
formulations and ranged from 96.5 to 99.2%. Folding endurance of the
films ranged from 95 ± 2.1 to 123.3 ± 3, which was satisfactory. The
thickness and weight variation of the films ranged from 0.21 ± 0.01 to
0.29±0.01mm and232 ± 0.047 to 340 ±0.30 mg respectively. Percentage
moisture content of the developed formulations F1 to F9was varied from
2.13± 0.31 to 1.15± 2.42%. Moisture uptakeof the developed formulations
F1 to F9was varied from 1.21± 1.58 to 3.36± 0.96%.In vitro diffusion
studieswere conducted using modified Franz diffusion cell with dialysis
membrane as a permeation barrier. The amount of drug permeated at the
end of 24h was found to be higher from formulations F7 to F9 compared
to formulations F1 to F4 which could be due to the presence of RLPO at
higher concentrations. Formulations F5 showed slow release due to
presence of RSPO. Optmized F3was the most satisfactory formulations as
it closely met to expected data and continuously permeated drug for 24 h
that can maintain desired therapeutic concentration in
plasma.Optimized F3 were subjected to short term stability studies which
showed slight change in physicochemical parameters and drug diffusion
profiles.
Dept of pharmaceutical Technology Page 83
BIBLIOGRAPHY
9. BIBLIOGRAPHY
1. Jain NK. Controlled and novel drug delivery. 1st ed. New Delhi: CBS
publishes; 1997;100-29.
2. Chein YW. Novel drug delivery systems, revised and expanded. 1st ed.
Marcel Dekker Inc. New York; 2005;335-44.
3. Rang HP, Dale MM, Ritter JM, Mone RK. Pharmacology. 5th ed.
2005;515-24.
4. Sathoskar RS, Bhandarkar SD, Nirmala NR. Pharmacology and Pharmco
therapeutics. 21st ed. 2009;199-203.
5. Tripathi KD. Essential of medical pharmacology 5th ed. 2003;399-402.
6. Donald L. Handbook of pharmaceutical controlled release
technology. Marcel Dekker Inc. New York; 2008: 445-52.
7. Chopda G. Transdermal drug delivery system a review. (Cited 8/10/10). A
vailable at URL: http://www.pharmainfo.net/reviews/transdermal-drug-
delivery-systems-review.
8. Richard H Guy, Jonathan Hadgraft. Selection of drug candidate for
transdermal drug delivery. Vol 35. New York: Marcel Dekkar Inc; 1995.
9.Labetalol drug profile (cited 8/10/12). Available at URL: www.drugbank.co
m.
10. Raymond C. Rowe, Paul J. Sheskey and Paul J. Weller. Handbook of
Pharmaceutical excipients, 6th ed. 326-29,225-27,446-48.
11. Raymond C. Rowe, Paul J. Sheskey and Paul J. Weller. Handbook of
Pharmaceutical excipients, 4th ed. 297-300.
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