Suvarna A. Katti. et al. /Asian Journal of Research in Chemistry and Pharmaceutical Sciences. 5(2), 2017, 69-75.

Research Article ISSN: 2349 – 7106

Asian Journal of Research in Chemistry

and
Pharmaceutical Sciences
Journal home page: www.ajrcps.com

FORMULATION AND DEVELOPMENT OF TRANSDERMAL PATCH OF

TIZANIDINE HYDROCHLORIDE
Suvarna A. Katti*1, Sneha B. Suryavanshi2, Ritesh R. Bhirud2
1*
Department of Pharmaceutical Chemistry, MGV’s Pharmacy College, Panchvati, Nashik, Maharashtra, India.
2
Department of Quality Assurance Techniques, MGV’s Pharmacy College, Panchvati, Nashik, Maharashtra,
India.
.
ABSTRACT
Tizanidine Hydrochloride, is an centrally acting myotonolytic skeletal muscle relaxant. It undergoes first pass
metabolism on oral administration resulting in less bioavailability (40%).Present research work was carried out to
formulate and develop transdermal patch of Tizanidine hydrochloride which will overcome the limitation of
bioavailability. In the present study transdermal patches were prepared by solvent-casting method using
hydrophilic polymer HPMC E-5 LV, chitosan, Moringa oleifera gum and Propylene Glycol as plasticizer. The six
formulations were prepared and evaluated. Accelerated stability studies of drug containing films, were performed
according to ICH guidelines. It was found that, Moringa oleifera gum has potential to modify drug release rate
and posses good film former and adhesive property. The transdermal patch has shown promising drug release
within 12 hr (84.36%), good stability and no irritancy.

KEYWORDS
Tizanidine Hydrochloride, Transdermal patch and Moringa oleifera gum.

INTRODUCTON
Author for Correspondence: Today about two third of drugs (available in
market) are taken orally, but these are not as
effective as required1. Conventional oral dosage
Suvarna A. Katti,
forms are required to be administered in multiple
Department of Pharmaceutical Chemistry, doses at a specific time interval in aspecific amount
for an effective therapy. Administration of the drugs
MGV’s Pharmacy College,
in multiple dosage has several drawbacks such as
Panchvati, Nashik, Maharashtra, India. inconvenient administration, chances of overdose if
administered prior to time interval, lack of patient
compliance, skip of dose by the patient, fluctuation
Email: [email protected] of drug plasma level, first pass metabolism, to avoid
such complications transdermal drug delivery
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 Suvarna A. Katti. et al. /Asian Journal of Research in Chemistry and Pharmaceutical Sciences. 5(2), 2017, 69-75.
systems are designed2. Transdermal therapeutic HydoxyPropyl Methyl Cellulose and Chitosan were
systems are self-contained, discrete dosage forms purchased from local market.
which, when applied to the intact skin deliver the Moringa oleifera gum
drug, through the skin at a controlled rate to the Collection and authentification
systemic circulation9. Thus, it is anticipated that The Moringa oleifera tree was identified. The tree
transdermal drug delivery system deliver drug at trunk was incised working from the base up towards
appropriate rates to maintain suitable plasma drug the branches. The incisions were 10-15 mm long
levels for therapeutic efficacy by using skin as the and 4-5 mm deep. The gum then started seeping out
port of entry of drug. from the incisions and coagulated in 10-20 days.
Tizanidine Hydrochloride, is an centrally acting The gum was collected after drying and
myotonolytic skeletal muscle relaxant. It undergoes authenticated by Ayurved Seva Sangh’s Ayurved
first pass metabolism on oral administration Mahavidyalaya, Ganeshwadi, Panchvati, Nashik
resulting in less bioavailability (40%) hence there is Isolation and purification of gum
need to develop formulation to overcome limitation The dried gum was ground, and passed through
of bioavailability. Thus the main objective of the sieve no 80 and (10 g) was stirred in distilled water
present study was to formulate and develop (250 ml) for 6- 8 hr at room temperature. The
transdermal patch of tizanidine hydrochloride. supernatant was obtained by centrifugation. The
Anatomy of skin3-7 washing of residue was done with water and the
Human skin comprises of three distinct but washings were added to separate supernatant. The
mutually dependent tissues, the stratified, vascular, procedure was repeated four more times. Finally the
cellular epidermis, underlying dermis of connective supernatant was made up to 500 ml and treated with
tissues and Hypodermis. twice the volume of acetone by continuous stirring.
Principles of transdermal permeation7 The precipitated material was washed with distilled
The various steps involved in transport of drug from water and dried at 50-60°C under vacuum.
patch into systemic circulation are as follows: Evaluation of Moringa oleifera gum
• Diffusion of drug from drug reservoir to the The gum was evaluated for loss on drying, pH
rate controlling membrane. determination, test for Tannin, test for Starch, test
• Diffusion of drug from rate limiting for Sucrose and fructose, Swelling power test as per
membrane to stratum corneum. official procedure in IP12.
• Sorption by stratum corneum and Compatibility Studies
penetration through viable epidermis. A compatibility study for Tizanidine Hydrochloride
• Uptake of drug by capillary network in the was carried out with potential formulation
dermal papillary layer. excipients i.e.Chitosan, Moringa oleifera gum, PG
Transdermal patches8,9 and HPMC. These samples were mixed together as
A transdermal patch is also known as skin patch per formula, stored for 30 days at elevated
which is used to deliver the specific amount of dose temperature and humidity conditions of 40 ± 2 0C /
through skin and it directly goes into the blood 75 ± 5 % RH. After30days IR spectra of these
stream. stored samples was obtained.DSC was performed to
check if any large shift of exothermic peak of drug
MATERIAL AND METHODS in mixture. Mettler DSC 820 (SHIMADZU60).The
Material assay of drug was performed using U.V.
Tizanidine Hydrochloride was gifted by Blue cross, Spectrophotometer.
Nashik. Moringa oleifera gum was naturally Formulation of Transdermal patch of Tizanidine
collected from stem of plant of Moringa oleifera. Hydrochloride
The composition of Tizanidine Hydrochloride
transdermal patches is given in Table No.1
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Preparation of transdermal patches 7.4. The medium was stirred, filtered and analyzed
Solvent casting technique for drug content at 318nm by
The transdermal patches prepared by solvent casting UVspectrophotometeter.
technique are of matrix diffusion controlled In-vitro drug release studies
systems. Preparation of rat Abdominal Skin
Procedure for patches containing Chitosan and The male rats were sacrificed by excess Diethyl
HPMC ether inhalation and hair on the abdominal skin was
For (F1 to F3): The polymer was weighed and removed with a razor. The shaved skin was excised
stirrerd in distilled water for 2 hrs. Then Propylene from the animal and kept in the beaker containing
glycol was added to the polymeric solution, mixed distilled water covered with Aluminum foil.
thoroughly by means of Magnetic stirrer. Tizanidine In-vitro Drug Release
Hydrochloride 6mg was added prior dissolving in The fabricated film was placed on the rat skin and
sufficient of water then the resulting solution was attached to the diffusion cell such that the cell’s
poured in to petri plate. This petri plate were kept drug releasing surface was towards the receptor
into hot air oven for 12hrs at 45° C, the patches compartment which was filled with phosphate
were removed and stored in desiccator for further buffer solution of pH 7.4 at 37±100C. The aliquots
use. (5ml) were withdrawn at predetermined time
Procedure for patches containing Moringa intervals and replaced with same volume of
oleifera gum and HPMC phosphate buffer of pH 7.4. The samples were
For (F4 to F6): The drug reservoir was prepared by analyzed for drug content using
dissolving Moringa oleifera gum and HPMC in UVspectrophotometer at 318 nm.
distilled water. Propylene glycol and Tizanidine Kinetics of drug release
Hydrochloride6mg dissolved in sufficient amount The cumulative release data were fitted to models
of water was added under slow stirring. It was representing zero order (Q v/s t), first order [Log
poured in petri plate. Which was kept in hot air (Q0-Q) v/s t], Higuchi’s square root of time (Q v/s
oven for1 hrs at 45°c, and then the patches were t1/2) and KorsemeyerPeppas double log plot (log Q
removed and stored in desiccator. v/s log t) respectively, where Q is the cumulative
Physicochemical evaluation of transdermal percentage of drug released at time t and (Q0-Q) is
patches11 the cumulative percentage of drug remaining after
The transdermal patches were evaluated for. time t.
Uniformity of weight Skin irritation study
Three different patches from individual batch were The skin irritation study was conducted with prior
weighed average weight was calculated. permission of Institutional Animal Ethical
Thickness of the patch committee (IPEC) under the purview of Committee
It was measured by usingvernier caliper at different for the Purpose of Control and Supervision of
points and average value was calculated. Experimental Animals (CPCSEA), on male Wistar
Percentage Moisture loss rats. The dorsal side of rat was applied with hair
It was calculated for three different patches from remover cream, under anesthesia, 24 hr. before the
individual batches by keeping them in desiccators beginning of experiment. The animals were divided
containing calcium chloride at 37°c for 24 hrs. into 4 groups. Each group was consisting of 5 rat:
Folding Endurance Group I served as control, Group II was applied 0.5
This was determined by repeatedly folding one film ml of a 0.8% V/V aqueous formalin solution
at the same place till it broke. topically as a standard irritant. Group III was
Drug content determination applied with diclofenac transdermal patch as
It was determined by cutting patch of size 1cm2 standard, Group IV was treated with medicated
diameter and dissolving it in Phosphate buffer of pH Patch. The application site was examined for edema
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and erythema after 24 and 72 hr, and graded (0-4) Thickness
according to visual scoring scale always by the The average thickness of all the films is given in
same investigator, the final score represents the Table No.3 the average thickness of all the
average of 24 and 72 hr. reading. The erythema transdermal patch ranged from 0.99± 0.0212 to
scale was: 0- none, 1- slight, 2- well define, 3- 2.36± 0.04716 mm.
moderate, 4- scare formation. Edema scale was: 0- % Moisture loss
none, 1- slight, 2- well define, 3-moderate, 4-severe. The value of % moisture loss was found to be
Stability study for F4 between0.99-2.36 for all formulations.
Stability studies of formulation F4 was done as per Drug content uniformity
ICH guidelines. In which the formulation was Tizanidine HCl has shown maximum absorbance at
stored at 450c and 75%RH for 90daysand evaluated 319nm in phosphate buffer pH7.4 hence percentage
for physical changes, hardness, friability, drug drug content was determined by UV
content and percentage drug release. spectrophotometer in phosphate buffer.
Folding endurance
RESULTS AND DISCUSSION The number of folding required to break or crack a
Evaluation of isolated and purified Moringa film was taken as the folding endurance. The
oleifera gum folding endurance was found to be increased with
The evaluation of Moringa oleifera gum was an increasing concentration of chitosan and
carried out, the evaluation test results are shown in Moringa oleifera gum.
Table No.2. Ex Vivo Drug Release Studies
Drug-Polymers Interaction Studies Ex Vivo skin permeation study shows a drug release
Infrared Spectroscopy profiles are shown in Figure No.1 and Figure No.2.
Drug-excipients interaction study showed no And drug release was successfully observed for all
interaction between Tizanidine Hydrochloride and patches. The drug release profile shown in Table
selected polymers as there was no significant shift No.4
of peaks in IR spectrum. Kinetics of Drug Release
Differential Scanning Calorimetry The kinetic Drug release study was performed for
DSC analysis was performed by taking 2 to 5 mg all batches of transdermal patches. From this, drug
sample. Results have shown that the sharp release profile of optimised batch F4 is given
exothermisc peak was observed of the drug below. The release data of formulation F4 was fitted
individually at 2820C, corresponding to its melting into release rate equations such as zero-order, first
point (2820C -2900C).Thus the Tizanidine order, Higuchi’s square root time dependent
Hydrochloride was found to be compatible with the diffusion and Korsmeyer-peppasexponential
selected excipients. equation. It was found it follows Zero-order with
Evaluation of transdermal patches diffusion controlled mechanism. By fitting in the
Physical appearance Korsemeyer–Peppas equation the release kinetics
All patches from F1-F6 were found to be smooth in follows Fickian and non-fickian kinetics. As the
nature and had good appearance. range of ‘n’valueforKorsemeyer- Peppa’s equation
Weight Uniformity is 0.726.
The average weight and thickness of all the films is h. Accelerated Stability Studies
given in Table No.3.Weight variation values (mg) In the results of stability studies performed on batch
of different Tizanidine Hydrochloride films were F4, after the 90 days, it was found that there was no
found to be in the range of 625± 0.0247 to 734± change in appearance of the films and negligible
0.0433 mg. change in thickness.

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 Suvarna A. Katti. et al. /Asian Journal of Research in Chemistry and Pharmaceutical Sciences. 5(2), 2017, 69-75.
i.Skin irritation study
Skin irritation test was performed on Wistar Rats
for F4 formulation and there were no signs of
redness or erythma observed for 72hrs after
application of patch10.

Table No.1: Composition of Tizanidine Hydrochloride transdermal patches

S.No Ingredients Formulation code
1 F1 F2 F3 F4 F5 F6
2 Tizanidine HCl(mg) 6 6 6 6 6 6
3 HPMC(mg) 200 200 200 200 200 200
4 Chitosan(mg) 30 75 120 - - -
5 Moringa oleifera gum - - - 30 75 120
6 Propylene Glycol(ml) 0.5 0.5 0.5 0.5 0.5 0.5
7 Distilled water(ml) 10 10 10 10 10 10
8 Acetic acid(ml) q.s q.s q.s - - -
Table No.2: Evaluation of isolated and purified Moringa oleifera gum
S.No TEST OBSERVATION
1 pH 4.7(Acidic)
2 LOD 47.5%
3 Test for Tannin Absent
4 Test for Starch Absent
5 Test for Sucrose and Fructose Absent
6 Swelling power 30.28 ml
Table No.3: Physicochemical evaluation parameters of Tizanidine Hydrochloride transdermal patch
Weight Drug content
Thicknessb Folding
FC Uniformity % moisture loss uniformityb
(mm) enduranceb
(mg) (mg)
F1 633± 0.1071 0.260± 0.01 2.36± 0.04716 105.8 ± 7.07 152 ± 2
F2 634± 0.0240 0.271± 0.00854 1.466± 0.0387 109.5 ± 6.30 158 ± 1.595
F3 625± 0.0247 0.279± 0.0524 1.116± 0.1587 102.59 ± 8.70 165.3 ± 2.38
F4 664±0.00552 0.0733± 0.00067 2.25± 0.02 105.82 ± 4.85 208 ± 1.581
F5 697±0.01977 0.0783± 0.00735 1.286± 0.0360 110.33 ± 10.41 210.6 ± 2.310
F6 734± 0.0433 0.0887±0.00961 0.99± 0.0212 105.30 ± 8.847 217 ± 3.08
Table No.4: drug release profile of F1- F6 for Ex Vivo skin permeation study
S.No. Timein hrs F1 (%) F2 (%) F3 (%) F4 (%) F5 (%) F6 (%)
1 2 17.63886 16.75943 15.37746 21.78474 18.26702 16.88506
2 4 28.51238 26.01543 22.32496 38.70435 27.33457 25.9055
3 6 40.59512 36.2922 32.53891 48.98112 43.15489 33.52827
4 8 50.76196 48.73613 45.72094 57.34199 55.41038 41.60647
5 10 65.04328 56.46884 55.46377 70.74387 68.60811 61.3057
6 12 83.98872 74.34639 70.98572 84.36562 77.59715 76.41934

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 Suvarna A. Katti. et al. /Asian Journal of Research in Chemistry and Pharmaceutical Sciences. 5(2), 2017, 69-75.
Table No.5: Kinetic parameters of Tizanidine Hcl transdermal patch
Zero order First order Higuchi Korsmeyer-Peppas
FC
r2 r2 r2 r2 N
F1 0.987 0.977 0.987 0.987 0.85107887
F2 0.988 0.975 0.988 0.985 0.816341
F3 0.988 0.987 0.988 0.974 0.860057
F4 0.991 0.934 0.991 0.993 0.72679585
F5 0.994 0.955 0.994 0.988 0.840374
F6 0.963 0.990 0.963 0.956 0.820347

Figure No.1: Comparative Ex Vivo skin permeation study of F1 – F3 transdermal patches of Tizanidine
Hydrochloride

Figure No.2: Comparative Ex Vivo skin permeation study of F4 – F6 transdermal patches of Tizanidine
Hydrochloride
CONCLUSION study has shown drug release 84.36% within 12 hr,
The six formulations transdermal patches were It has shown no irritancy in skin irritation studies.
prepared by solvent-casting method and evaluated There was no significant change in the physical
for physical parameters along with Ex vivoskin parameters when stored at temperature and
permeation studies and skin irritation studies. It was humidity conditions of 40 ± 2ºC / 75 ± 5% RH in
found that, folding endurance was increased with an stability studies carried out as per ICH guidelines.
increase in chitosan and Moringa oleifera gum Thus, Moringa oleifera gum has potential to modify
concentration. Optimized batch F4 showed good drug release rate and posses good film former and
folding endurance i.e. 208. Ex Vivo skin permeation adhesive property.
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ACKNOWLEDGEMENT 8. Sidharth M Patil, Muddasar G Bagawan. A
Authors are thankful to the Principal, M.G.V’s Review: Transdermal Drug Delivery System
Pharmacy College Panchavati, Nashik, and the – Basic Understanding for Development,
Management, for providing the necessary facilities International Journal of Institutional
to carry out this research work. Pharmacy and Life Sciences, 3(6), 2013,
2249-6807.
CONFLICT OF INTEREST 9. Gazzi S, Chegonda K K, Chandrashekhara R
We declare that we have no conflict of interest. G, Kumar B V and Prabhakar R Veerareddy.
Formulation and Evaluation of Bioadhesive
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Please cite this article in press as: Suvarna A. Katti et al. Formulation and development of transdermal patch of
Tizanidine hydrochloride, Asian Journal of Research in Chemistry and Pharmaceutical Sciences, 5(2), 2017, 69-75.

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