INFLUENCE OF FORMULATION VARIABLES IN

TRANSDERMAL DRUG DELIVERY SYSTEM

CONTAINING TIZANIDINE HYDROCHLORIDE



M. PHIL SYNOPSIS



BY

SAJID ALI CHISHTI
PHARM-D
FACULTY OF PHARMACY


UNDER THE GUI DANCE OF


MR. CH. SHERJEEL ADNAN
Assistant Professor
Faculty of Pharmacy





SESSION 2011-2013


FACULTY OF PHARMACY
THE UNIVERSITY OF LAHORE
1-KM DEFENCE ROAD LAHORE
PAKISTAN
FACULTY OF PHARMACY THE UNIVERSITY OF LAHORE


PROFORMA FOR REGISTRATION OF SUBJECT



TITLE OF THE RESEARCH

INFLUENCE OF FORMULATION VARIABLES IN
TRANSDERMAL DRUG DELIVERY SYSTEM CONTAINING
TIZANIDINE HYDROCHLORIDE


NAME OF THE CANDIDATE

SAJID ALI CHISHTI
Pharm-D
Department Faculty of Pharmacy

Name of the Institution

THE UNIVERSITY OF LAHORE
1-KM DEFENCE ROAD LAHORE


Course of study and subject

MASTER OF PHILOSOPHY
IN PHARMACEUTICS


Date of admission of course


September 2011



Date of submission of synopsis


January 2013


Signature of the candidate







Remarks of the supervisor





NAME AND DESIGNATION OF:

1 Supervisor MR. CH. SHERJEEL ADNAN
Assistant Professor,
Faculty Of Pharmacy,
The University Of Lahore

Signature



2

Co-supervisor

MR.MUHAMMAD FAROOQ
Lecturer,
Faculty Of Pharmacy,
The University Of Lahore



3
Signature

Incharge,
Department of
Pharmaceutics


MR. CH. SHERJEEL ADNAN
Assistant Professor,
Faculty Of Pharmacy,
The University Of Lahore

Signature


5 Head, Faculty Of
Pharmacy
MR. JAVED IQBAL
Head, Faculty of Pharmacy
The University Of Lahore

Signature


6 Dean,
Faculty Of Pharmacy
PROF. DR. BASHIR AHMAD
Dean,
Faculty Of Pharmacy
The University Of Lahore

Signature --------------------------------------------------


7 Remarks ---------------------------------------------------

ANNEXURE-II


TABLE OF CONTENTS


Serial
No.
Contents Page No.
01. Brief review of the intended work

04
1.1 Need for the Study 05
1.2 Literature Review 06
1.3 Justification and possible benefits 09
1.4 Objectives of the Study 09
2.0 Materials and methods

10
2.1 Source of Data 10
2.2 Method of collection of data 11
3.0 References 12










BRIEF REVIEW OF THE INTENDED WORK

1.1 - Need for the Study

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a time-
released dose of medication through the skin for treating systemic illnesses

(Zhao JH. et al.,
2007). The transdermal route of administration is recognized as one of the potential route for
local and systemic delivery of drugs, it also provides a controlled release of medicament into
patients. (Ramesh G. et al., 2007).
Transdermal delivery has many advantages over conventional modes of drug administration.
It avoids hepatic first pass metabolism.
Potentially decreases side effects. (Das MK. et al., 2006).
Additionally, transdermal administration, as compared to other routes, is fairly
noninvasive, patients are quite willing to accept the use of a simple looking patch as it
can be conveniently applied and removed. (Troy DB. et al., 2005).

Tizanidine, an imidazoline derivative, is
2 -
adrenergic agonist and centrally acting myotonolytic
skeletal muscle relaxant with a structure unrelated to other muscle relaxants. It was approved as
an antispastic drug by the United States Food and Drug Administration in 1996. It reduces
spasticity by increasing presynaptic inhibition of motor neurons and also reduces increased
muscle tone associated with spasticity in patients with multiple sclerosis or spinal cord injury.
(Mahadik KR. et al., 2003). The oral bioavailability of Tizanidine hydrochloride is only about
1030% due to extensive pre-systemic metabolism, with CYP1A2 being crucial to its
metabolism and also has low therapeutic drug concentration. (JT. Backman et al.,2006). The
transdermal route maintains the plasma drug level for a longer period of time. The tizanidine
solubility studies and apparent partition coefficient shows the suitable drug for transdermal
delivery. The physicochemical and pharmacokinetic parameters of tizanidine suggest that it is an
ideal drug candidate for transdermal drug delivery. (Mutalik S. et al., 2009).
The aim of present study is to formulate and evaluate Tizanidine hydrochloride transdermal
patches.


Other pharmacokinetic and physicochemical aspects regarding Tizanidine are as follows:
Available routes . Oral, Intranasal, Injection
Protein binding ..... 30%
Metabolism ... CYP1A2
Half Life (t
1/2
) ... 2-2.5 hours
IUPAC Name 5-chloro-N-(4,5-dihydro-1H-imidazol-
2yl)benzo[1,2,5]thiadiazol-4-amine
Chemical Formula C
9
H
8
Cl N
5
S
Molecular Mass 253.712 g/mol
Oral bioavailability .. 1030%
Partition coefficient 2.72
Volume of distribution . 2.4kg/L
Peak Plasma Concentration (t
max
) .1.5 hours
Pka..8.2
(Gururaj S. Kulkarni et al., 2012).

1.2 Literature Review
Praveen M. and Someswara Rao B. et al., (2011) formulated transdermal drug delivery
systems of Tizanidine hydrochloride using solvent casting method. Matrix diffusion controlled
systems were prepared by using HPMC and EC polymers by incorporating glycerol and oleic
acid as plasticizer and permeation enhancer respectively. The drug and polymer compatibility
was studied by using infrared spectroscopy shows absence of incompatibility. The in-vitro drug
release studies were performed on rat skin using a franz diffusion cell. Also skin irritation test
was performed on Albino rabbits.
S.K. Senthilkumar et al., (2012) developed a matrix-type transdermal therapeutic system
containing Ramipril with different ratios of hydroxypropyl methyl cellulose E5 and ethyl
cellulose. All formulations carried dimethyl sulphoxide as penetration enhancer for Ramipril and
di butyl phthalate as plasticizer in acetone as solvent system.
V.N.L. Sirisha et al., (2012) developed a matrix-type transdermal patch containing Propranolol
hydrochloride with different ratios of Eudragit polymeric systems by the solvent evaporation
technique, using di-butyl phthalate as plasticizer. The physicochemical compatibility of the drug
and the polymers studied by infrared spectroscopy suggested absence of any incompatibility.
Jaydatt K. Jadhav et al., (2011) developed a matrix-type transdermal patch containing
Indomethacin with different ratios of hydroxypropryl methylcellulose E5 and ethyl cellulose
polymeric combinations by the solvent evaporation technique. All formulations carried dimethyl
sulfoxide as penetration enhancer and dibutyl phthalate as plasticizer in chloroform and methanol
as solvent system. The prepared transdermal patches were evaluated for in vitro release.
S. Jayaprakash et al., (2010) prepared Celecoxib transdermal patches by using different
polymers such as hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), Polyvinyl
pyrolidone (PVP).The in-vitro release of the drug from the formulations were studied using
commercial semi permeable membrane. The prepared formulation were subjected to various
physicochemical evaluation test, in-vitro dissolution studies, kinetics studies shows diffusion
might be one of the prominent mechanism influencing the drug release.
P. Vuppala et al., (2009) developed a matrix-type transdermal patch containing Buspirone
hydrochloride with polymer hydroxypropyl methyl cellulose E 15 and propylene glycol as a
plasticizer by solvent evaporation technique. Six formulations composed of Eudragit RL 100 and
hydroxypropyl methyl cellulose E 15 were then prepared.
Sadashivaiah R. et al., (2008) studied the design and invitro evaluation of haloperidol lactate
transdermal patches containing ethyl cellulose-povidone as film polymers. Various
physiochemical parameters such as solubility studies, partition coefficient, flux, enhancement
ratio and dissolution studies of the formulated films were performed. The prepared films were
subjected to Scanning Electron Microscopy (SEM), and Fourier Transform Infrared spectroscopy
(FT-IR) spectra analysis. The results indicate that the formulation was found to be best for
sustained release once a day formulation.
Chandrashekar NS. et al., (2008) described physiochemical and pharmacokinetic parameters in
drug selection and loading for transdermal drug delivery, the ideal properties for selection of a
drug candidate for transdermal drug delivery, the factors to be considered for transdermal dose
calculation.
Ekapol Limpongsa et al., (2008) developed a transdermal drug delivery system for Dilitiazem
using varying issue of hydroxypropyl cellulose and ethyl cellulose and influence of enhancers
including isopropyl myristate, isopropyl palmitate, N-methyl-2-pyrrolidone, oleic acid,
polyethylene glycol 400, propylene glycol, and Tween80 on permeation was evaluated.
Yuveraj ST. et al., (2007) developed and evaluated transdermal patches of carvedilol, in this
study transdermal patches of carvedilol were formulated using the hydrophilic polymer matrix of
hydroxy propyl methyl cellulose (HPMC) in order to achieve controlled release of the drug, the
prepared patches were characterized for physiochemical properties, invitro permeation profile
across excised hairless guinea pig skin and skin irritation studies in albino rabbits.
Shakeel F. et al., (2007) prepared nanoemulsions as vehicle for transdermal delivery of
aceclofenac. The study investigated the potential of nanoemulsion formulation for transdermal
delivery of aceclofenac and the prepared nanoemulsion were subjected to different
thermodynamic stability studies like droplet size, refractive index and viscosity. The invitro skin
permeation profile of this formulation was compared with conventional dosage form, the results
suggested that nanoemulsions are potential vehicles for improved transdermal delivery of
aceclofenac.
Yu Liu et al., (2007) developed a matrix-type transdermal patch containing Diclofenac
diethanolamine using Eudragit E100 and polyvinylpyrrolidone as the adhesive polymer by the
solvent evaporation technique. The effects of different pressure-sensitive adhesive and various
permeation enhancers (Tween-80, propylene glycol, Azone, N-methyl-2-pyrrolidone, menthol)
on the vitro percutaneous absorption of Diclofenac across rat skin were evaluated using a 2-
chamber diffusion cell system.
Bagyalakshmi J. et al., (2006) evaluated pharmacodynamics of ampicillin sodium transdermal
patches in an invitro infection model. This study was to examine the activity of ampicillin
sodium transdermal patches using different kinds of polymers such as sodium alginate, cellulose
acetate phthalate, HPMC, chitosan and carboxy methyl cellulose studied through colony-forming
units (CFU). It was found that against Escherichia coli the drug releasing capacity of HPMC was
the best polymer followed by carboxy methyl cellulose, chitosan, cellulose acetate phthalate and
sodium alginate.
Shaila L. et al., (2006) investigated design and evaluation of matrix type and membrane
controlled transdermal delivery systems of nicotine, suitable for use in smoking cessation, in-
vitro release studies of transdermal patches.
Derle DV. et al., (2006) developed microemulsion as a vehicle for transdermal permeation of
nimesulide. Topical microemulsions of Nimesulide, a poorly water soluble nonsteroidal anti-
inflammatory drug using olive oil as oil phase and tween 80 as surfactant. Various
concentrations of surfactant, co-surfactants were used in constructing a pseudoternary phase
diagram. Invitro permeation study of the gel was carried out through excised hairless rat skin and
compared with a marketed preparation.
Sanap GS. et al., (2008) described the preparation of transdermal monolithic systems of
Indapamine by solvent casting method and the use of vegetable oil as permeation enhancer. In
this transdermal monolithic systems of Indapamine were prepared by using HPMC and ethyl
cellulose polymers. The in-vitro studies shows that HPMC containing films have better release
than that of ethyl cellulose containing films without any permeation enhancer.
Bhakshi A. et al., (2008) developed a novel metered dose transdermal spray formulation for
oxybutynin. In this oxybutynin release from a series of ethanol/acetone/methylal based
formulaton was assessed to various physicochemical parameters studies, diffusion studies, and
skin irritation studies. It suggests that oxybutynin was the best metered dose transdermal spray
formulation.

1.3 Justification and possible benefits:
1.3.1. Topical patches are a painless, noninvasive way to deliver substances directly into
the body.
1.3.2. Topical patches have a controlled, steady delivery of medication over long periods
of time.
1.3.3. Topical patches have fewer side effects than oral medications or supplements.
1.3.4. Topical patches are easier to use and remember. Improved patient compliance.
1.3.5. Topical patches over an alternative to people who cannot, or prefer not to take
medications or supplements orally.
1.3.6. Topical patches are cost-effective.
1.3.7. Reduction in gastrointestinal side effects.
(Dipen Patel et al., 2012; Debjit Bhowmik et al.; 2010; Eseldin Keleb et al., 2010)

1.4 - Objectives of the Study
1.4.1. To formulate and evaluate Tizanidine hydrochloride transdermal patches using
different polymers.
1.4.2. To evaluate the patch for organoleptic properties.
1.4.3. To evaluate the moisture content of the patch.
1.4.4. To evaluate the In vitro permeation studies.
1.4.5. To evaluate skin irritation tests on animal models.
1.4.6. To demonstrate the stability (temperature) of the patch.
1.4.7. To reduce the dosing frequency and provide sustained availability of the drug.
2. MATERIALS AND METHODS
Materials:
Drug : Tizanidine hydrochloride
Polymers : High permeable and low permeable grades of Eudragit, Ethyl Cellulose,
Poly Vinyl Pyrollidine, Propylene glycol, different grades of PEG, Natural
and synthetic penetration enhancers, etc.
Diffusion cell : Franz diffusion cell / Modified Franz diffusion cell.
Reagents : The reagents, solvents and other excipients of analytical grade.

Methods:
Solvent casting technique / standard procedure to be followed.

2.1 - Source of Data
Review of Literature from
Journals such as,
European Journal of Pharmaceutical Sciences
International Journal of Pharmaceuticals
International journal of current pharmaceutical research
The Journal of Pharmaceutics & Drug Delivery Research (JPDDR)
International Journal of Research in Pharmaceutical Sciences
International Journal of Pharmaceutical Sciences and Research (IJPSR)
Journal of Pharmaceutical technology and drug research
International journal of pharmaceutical research and allied sciences (IJPRAS)
Journal of Pharmaceutical and Biomedical Analysis
Journal of Nano pharmaceutics and Drug Delivery
Journal of Pharmaceutical Sciences and Research (JPSR)
Indian Journal of Pharmaceutical Sciences
World Wide Web
Library: Faculty of pharmacy; The university of Lahore
E-library: Faculty of pharmacy; The university of Lahore



2.2 - Method of collection of data
2.2.1. Development of transdermal drug delivery system
2.2.2. Studies such as:
Solubility
Partition coefficient
2.2.3. Characterization study such as
Uniformity of weight
Tensile strength
Folding endurance
Percentage moisture absorption
Percentage moisture loss
Water vapor transmission rate
Drug content
In-vitro diffusion study
Skin irritation test on Rabbits
Stability study
2.3 - Does the study require any investigations or interventions to be conducted on patients or
other humans or animals? If so, please describe briefly.

YES- Skin irritation test of prepared transdermal patches will be carried out on
rabbits.




REFERENCES

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