1.

AIM AND OBJECTIVE

1.1 AIM OF WORK

Formulation, Development and Evaluation of Gastro retentive Floating Sustain
Release Tablets of Tizanidine Hydrochloride.

1.2 OBJECTIVES OF WORK

The objectives of this study are as follows :
1) To formulate sustained release floating tablets of Tizanidine Hydrochloride
using different polymers by direct compression technique
2) Evaluate the tablets prepared to verify that increase in bioavailability is
achieved.

1.3 NEED OF WORK

The work studies the probability of the dosage form to retain in stomach for an
extended period of time to obtain better bioavailability of drug. FDDS is suitable
for drugs having an absorption window either in the stomach or in upper small
intestine, drugs that are poorly soluble, drugs acting locally in the stomach and for
drugs that are unstable in the intestinal fluid.

Tizanidine is a short-acting drug that has been used for spasticity management.
Tizanidine acts as an agonist at a2-adrenergic receptor sites and probably decreases
the spasticity by increasing presynaptic inhibition of motor neurons. After oral
administration, Tizanidine is absorbed from the upper part of gastrointestinal tract.
Tizanidine being BCS class II drug is having low solubility and high permeability.
It is metabolized by first pass metabolism. Due to above considerations, Tizanidine
HCl has proved to be candidate of choice for preparation of floating tablets. The
absolute bioavailability of Tizanidine HCl is 40% and has a half-life of 2-3 hrs.
Tizanidine HCI tablets are available in market with a dose of 2mg and maximum
of 3 doses are given in 12 hrs. So, a sustain release tablet of Tizanidine would help
to reduce the frequent dosing of the tablets.
Thus, there is a need to study the effect of polymers on the release of Tizanidine
HCl and which give maximum therapeutic effect for prolonged period when taken
orally and to design a formulation of solid oral dosage form of Tizanidine HCl
tablets with good stability of high product quality.
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Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 1

2. PLAN OF WORK

The present research work was planned with the following agendas:

1) Literature survey

2) Procurement of API and excipients

3) Preformulation study:
i.)Thermal characterization of API
ii.)Spectral characterization of API by UV Spectroscopy

4.) Preparation of feasibility trials of floating tablets, evaluation and selection of

optimized batch

5) Formulation of floating tablets using factorial Design for Optimized batch.

6) Evaluation of floating tablets for:

Pre-compression parameters:
i. Bulk Density
ii. Tapped Density
iii. Hausner's Index
iv. Carr's index
v. Angle of repose
Post compression parameters:
i. Thickness
ii. Hardness
iii. Weight variation
iv. Friability
v. Drug Content
vi. Lag time
vii. Swelling study
viii. In vitro dissolution studies
ix. Drug excipient compatibility studies
x. Drug Release Kinetics Study

7) Stability study of the formulation

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Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 2

3. REVIEW OF LITERATURE

1. Shoufeng Li et al., performed a study on HPMC and Carbopol polymer. It was

observed that HPMC and Carbopol interaction had an important impact on the
release and floating properties of the delivery system. The decrease in the drug
release rate was noticed with an upsurge in the viscosity of the polymeric system.
Polymer with higher viscosity (K4M) did not showed much beneficial results than
the polymer with lower viscosity (HPMC K100LV) and thus has improved the
floating behavior of GFDDS. It was observed that the combination of Carbopol
proved to have compromising effect on the release rate of calcium
and floating capacity of GFDDS.

2. Amin et al., (2004) developed a Gastroretentive drug delivery system of

ranitidine hydrochloride which was designed using guar gum, xanthan gum and
HPMC. A gas generating agent sodium bicarbonate was incorporated. The effect of
both citric and stearic acid on floating behaviour and drug release profile was
examined. It was observed that hydrophobic stearic acid reduced the drug
dissolution to greater extend. The results obtained proved that low quantity of citric
acid and a high quantity of stearic acid favors the sustained release of Ranitidine
HCl drug from a Gastroretentive formulation

3. Eikheshen et al.(2004) prepared a sustained release floating system for

verapamil HCl using different polymers, which are HPMC, HPC and ethyl
cellulose. Floating was maintained by adding effervescent mixture of sodium
bicarbonates and citric acid. Results showed that HPMC has floating property

4. Basak SC et al., (2004) formulated a floating matrix using ciprofloxacin as

model drug.The formulation consists of sodium bicarbonate, polymer HPMC, PVP
and lactose. The in-vivo drug release studies showed sustained release of
ciprofloxacin up to 80-89% for 8h

5. Ozdermis et al., (2004) prepared floating dosage to enhance the bioavailability

of furosemide. The solubility was increased by forming inclusion complex with
betadex (betacyclodextrin). Dissolution, swelling and other various parameters was
studied.AUC values of floating dosage forms were about 1.8 times greater than
those of the conventional tablet

6. Talukder et al., (2006) developed a floating multi particular system with

potential for intra-gastric sustained drug delivery. Cross-linked beads were
[Date]

prepared by methoxylated pectin and sodium alginate. Model drugs for

encapsulation used were Riboflavin, tetracycline and methotrexate. It appeared that
Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 3
the nature of crosslinking, drug solubility and production approach were important
and provide the opportunity and potential for development of a gastro retentive
drug delivery system.

7. Narendra et al., (2006) developed an optimized gastric floating dosage form

containing metoprolol tartrate as model drug. The results proved that total content
of polymer to drug ratio and ratio of polymer to polymer significantly affect the
floating time and drug release property of formulated bilayer tablets.

8. Ganesan V et al., (2008) formulated and evaluated matrix tablets of Ambroxol

HCl using guar gum and concluded that slow, controlled and complete release of
Ambroxol over a period of 12h was obtained from matrix tablets containing 30 %
w/w of low-viscosity, 25% w/w medium viscosity or 20 % w/w high viscosity guar
gum respectively.

9. Antesh K Jha et al., (2009) concluded that the hydrophilic matrix of HPMC
alone cannot control the Metoprolol Succinate release efficiently for 16 hours.
Also, it was observed that the matrix tablets prepared with HPMC and a
granulating agent of a hydrophobic polymer serve to be a better system for once
daily sustained release of a highly water-soluble drugs like Metoprolol Succinate.

10. R Enayatifard et al., (2009) proved that by using HPMC and Ethyl Cellulose
as polymers the release profile of diltiazem HCl from their matrices can be slowed
down. Incorporation of Ethyl Cellulose in HPMC matrix tablets was found to have
a control drug release.

11. VD Havaldar et al., (2009) formulated and evaluated floating tablets of

Atenolol with use of polymers like different grades of HPMC and natural polymer
Xanthum gum. The objective was to improve bioavailability and to compare and
study the swelling indices of the polymers used. All the formulations retarded the
release of drug for eight hours by exhibiting the better matrix integrity. The
swelling studies were compared, and it was proved that the formulations
comprising of xanthan gum has higher swelling indices than HMPC K100M and
HPMC K4M concluded that formulations with higher swelling indices retarded the
release of drugs more than those with lower swelling indices
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Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 4

12. Bomma et al., (2009) prepared floating matrix tablets of norfloxacin by using
wet granulation technique which were developed to prolong gastric residence time
resulting to an increase in bioavailability of drug using polymers such as HPMC
K4M, HPMC K10OM and Xanthan gum. The tablets which exhibited prolonged
drug release profile and controlled release while floating in dissolution medium
proved to be the best drug release mechanism.

13. Ravi Kumar et al., (2009) developed floating matrix tablets of Aceclofenac to
prolong gastric residence time and to increase bioavailability. Rapid
gastrointestinal transit above the absorption window may result in incomplete drug
release from the delivery system which leads to reduced efficacy of the
administered dose. Floating matrix tablets comprising of 100 mg
aceclofenac were formulated using different bees wax mixtures. The tablets were
formulated by melt granulation technique by using polymers such as acetyl
alcohol, ethyl cellulose, hydroxypropyl methylcellulose (HPMC K15M), bee’s wax
and glycerin monostearate alone or in combination and other excipients. Sodium
bicarbonate was used as a gas-generating agent

14. Mukhopadhyay et al., (2001) formulated floating-bioadhesive tablets of

Ciprofloxacin HCI which is mainly absorbed in the proximal areas of the
gastrointestinal tract thus the purpose of the study was that the formulation should
remain in absorption area for extended period of time and also reduce the dosing
frequency by enhancing the bioavailability. These tablets were formulated by
direct compression method by using polymer like hydroxy propyl methyl cellulose
(HPMC), sodium carboxy methyl cellulose (SCMC), Carbopol in different ratios.
Citric acid and sodium bicarbonate were used in 1:1 ratio for preparing the
effervescent base. It was noticed that tablet with 10% effervescent base showed
lesser control in drug release in comparison to that of 5%

15. Zafar Iqbal et al., (2010) formulated and evaluated matrix tablets of
Diclofenac Sodium using PVP K90 and natural polymers. The work determined
that PVP K90 and gum is used in 1:3 ratio sustained the release of the drug for
about 12 hours, The addition of the buffers increases the initial release of the
[Date]

diclofenac from the dosage form however, drug release was sustained for about 10

Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 5

hours. The combination of PVP K90 and natural gum also sustained the
release of the diclofenac sodium for about 12 h however, the best similarity and
differential factors were obtained with the combination of PVP K90 and gum
tragacanth

16. Madhusudan pogula et al., (2010) concluded that the use of microcrystalline
cellulose one can achieves the tablets with good hardness and also concluded that
HPMC K 100 shows better drug control compared to HPMC K4

17. Prajapati B. G. et al., (2010) prepared once daily sustained release matrix
tablets of Losartan Potassium and concluded that HPMC alone could not control
the Losartan Potassium release effectively for 24 hrs. It was evident from the
results that a matrix tablet prepared with hydrophilic polymer and hydrophobic
polymer proved to be a good sustained release system of a highly water-soluble
drug like Losartan Potassium

18. Marina Oland et al., (2010) prepared mucoadhesive films of Losartan

Potassium for buccal delivery using HPMC and retardant polymers Ethyl cellulose
or Eudragit RS 100 and concluded that it was possible to formulate mucoadhesive
films of Losartan Potassium with the intention of obtaining better therapeutic
efficiency by monitoring drug release which increased the bioavailability by
decreasing dosing and fewer side effects thus improving patient compliance. The
use of retardant polymers succeeded in delaying drug release, however, higher
percentage of these tend to decrease the mucoadhesive properties.

19. Jaimini Man ish et al., (2011) Formulated and evaluated floating effervescent
matrix tablets of Losartan potassium by using two different grades of methocel
K100 and K15 by effervescent technique. The effect of two diverse grades of
methocel and citric acid on floating property and drug release profile were
examined. A mixture of citric acid and sodium bicarbonate has shown to attain
optimum in-vitro buoyancy. It was noticed that tablet was doating for 8-10 hrs.
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Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 6

20. Naveen M et al, (2011) Formulated and evaluated floating tablets of Losartan
potassium by direct compression method using sodium bicarbonate as the
effervescent base. HPMC K4M, HPMCK15M, HPMC K100M, were used as
polymers to prepare the floating tablets and to study the drug release for 12hr in
stomach. It was noticed that the stability of the dosage form rises with increase in
concentration of the swelling agent

21. A. Suman et al., (2011) Formulated and evaluated Losartan potassium floating
tablets by using HPMC K100M, HPMC K15M, HPMC K4M, by effervescent
technique. A gas-generating agent sodium bicarbonate was incorporated. The
formulated floating tablets were evaluated, and it was observed that the tablets
swelled axially and radially during in vitro buoyancy studies

22. Lingaraj S. Danki et al., (2011) Developed and evaluated gastro retentive
drug delivery system of Losartan Potassium. Formulations were prepared using
wet granulation method, employing polymers like HPMCK4M, HPMC K15M,
Carbopol 934P and sodium alginate. Gas generating agents like citric acid and
sodium bicarbonate were used. Tablets were evaluated for various properties which
includes in vitro drug release, polymer interaction studies and short-term stability
studies. Drug release analysis was also performed on the basis of Higuchi-
Korsmeyer model. This concluded that diffusion is the primary mechanism that
has controlled the release of drug.

23. Parikh Bhavik Anjankumar et al., (2011) Formulation and Evaluation of

Floating Tablet of Atenolol by direct compression technique: Functionality of
Natural and Synthetic Polymer. The tablets were evaluated for both pre-
compression and post-compression parameters. A comparison was done between
the drug release patterns of natural and synthetic polymers. Per the data, it was
noticed that the natural polymer showed better sustained release pattern than
Formulation, Development and Evaluation of Gastro retentive Floating SR Tablets
of Tizanidine HCI
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Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 7

24. R. Vijaya Muthumanikandar et al., (2011) Developed and evaluated Bucco
adhesive tablets of Losartan Potassium and concluded that Hardness of the Bio
adhesive tablets varied with various type and ratio of the Bio adhesive polymers.
The variation in the tablet's hardness showed no effect on the release of the drug
from the hydrophilic matrices.

25. Mohd Azharuddin et al., (2011) Formulated and evaluated controlled release
matrix tablets of antihypertensive drug Losartan Potassium using natural and
synthetic hydrophilic polymers and concluded that the polymer concentration plays
a major role in drug release. The polymer concentration was increased, and the
drug release was extended in a controlled manner

26. Raju G et al., (2012) formulated and evaluated extended release tablets of
Venlafaxine HCI better drug release control over an extended period time and also
concluded that higher viscosity grades of polymer concentrations will retard the
drug release effectively.

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Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 8

4. Drug Profile of Tizanidine Hydrochloride USP:

Brand name: Zanaflex

Chemical Structure:

Chemical Name: 5-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl) -2, 1, 3-

benzothiadiazol-4-amine hydrochloride

Description: Tizanidine HCl is white to slightly yellow, crystalline powder. It is

fast-acting drug
used for the muscle spasm management, that result from the effects of stroke,
multiple sclerosis an
acquired brain injury, or a spinal cord injury

Categories: Muscle Relaxant, Adrenergic Agonist, Anti-convulsant, Analgesic

Molecular Weight: 290.172 g/mol

Molecular Formula: CoH9ClNsS

Melting Point: 278° C

Solubility: It is slightly soluble in water and in common organic solvents, such as

Acetonitrile and
Methyl Ethyl Ketone.
[Date]

Absorption Maxima: 228nm and 319nm

Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 9

Half Life: 2-3 hrs.

pКа: 7.47

Dose: 2-4 mg in daily divided doses

Therapeutic uses: Management of spasticity associated with cerebral or spinal

injury, alone or in
conjunction with other standard therapies.

Indications: Tizanidine is indicated for the relief of muscle spasticity, in order to

perform normally
the daily activities. Since, Tizanidine has short duration of action, it is
recommended to reserve
tizanidine use for interval of time when there is a specific need for relief.

Pharmacodynamics: Tizanidine is a rapidly acting drug indicated for the relief of

muscle spasticity which is needed while performing particular activities. It acts as
an agonist at alpha-2 adrenergic receptor and give relief from the symptoms of
muscle spasticity, allowing the continuation of normal daily activities. When tested
in animal models, Tizanidine HCI has not been shown to exert direct effects on the
neuromuscular junction or skeletal muscle fibers and has shown no important
effect on monosynaptic spinal reflexes (comprising of the communication between
1 motor neuron and sensory neuron). The frequency of muscle spasm is proven to
be decreased by tizanidine.

Mechanism of Action: Tizanidine decreases the spasm by triggering presynaptic

inhibition of
motor neurons through agonist actions at Alpha-2 adrenergic receptor sites. This
drug is centrally
acting and leads to a reduction in the release of amino acids like glutamate and
aspartate that cause neuronal firing and results in muscle spasm. These reduction in
neurotransmitter release leads to presynaptic inhibition of motor neurons.
Tizanidine also binds to alpha-1 receptors with weaker affinity and shows a
temporary effect on the cardiovascular system

Pharmacokinetics
Absorption: This drug significantly undergoes first-pass metabolism. After oral
[Date]

administration
Tizanidine is absorbed in upper part of GIT. The absolute oral bioavailability of
Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 10
tizanidine is about 40%. It was observed that food increase the absorption of
Tizanidine HCl. Also, it is proved that the amount absorbed from the capsule is
about 80% of the amount absorbed from the tablet. Thus, in order to increase the
absorption, it is recommended to take Tizanidine HCl with food specifically in
tablet form

Volume of distribution: This drug has been widely distributed throughout the
body. The average
volume of distribution in steady state is 2.4 L/kg. It is observed that approximately
30% of the drug bound to plasma proteins

Metabolism: About 95% of the ingested dose of tizanidine is metabolized. The

main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2
Tizanidine 5-chloro-4-(guanidino)-2, 1, 3-benzothiadiazole Tizanidine 5-chloro-4-
(2- imidazolin-4-on-2-ylamino)-2, 1, 3-benzothiazdiazole.

Elimination: This drug is mainly eliminated by the kidney. Tizanidine clearance is

found to be decreased by more than 50% in elderly patients with renal
insufficiency (creatinine clearance<25ml/min) compared to healthy elderly
subjects.

[Date]

Formulation, Development and Evaluation of Gastroretentive Floating SR Tablets of Tizanidine HCL 11