FORMULATION AND EVALUATION OF FAST DISSOLVING FILMS OF RIZATRIPTAN BENZOATE

ABOUT AUTHORS:
*P. Bhatt, M. Patel
Department of Pharma. Technology,
L.J. Institute of Pharmacy, Ahmedabad, Gujarat, India
bhatt_pari@ymail.com

ABSTRACT:
Rizatriptan benzoateis an anti migraine drug. The therapeutic activity of the drug can most likely be attributed to agonist effects at 5-HT1B/1D receptors. It is well absorbed from the gastrointestinal tract, but its oral bioavailability is low (45%) due to first-pass metabolism which makes it an ideal candidate for rapid release drug delivery system. Hence, an attempt was made to prepare and evaluate fast dissolving oral films containing Rizatriptan benzoate as a model drug by solvent casting method using hydrophilic polymers. Various formulations were developed with varying concentration of polymers like HPMC, PVA, PVP K30, Xanthan gum, Guar gum. Citric acid was used as a saliva stimulating agent and Propylene glycol as a plasticizer. The prepared oral films were evaluated for their physicochemical and mechanical parameters such as Physical appearance, surface pH, thickness uniformity, disintegration time, drug content uniformity, folding endurance, tensile strength, percentage elongation, in-vitro drug release. In-vitro release rate of Rizatriptan benzoate was studied in simulated saliva fluid (pH 6.8). From prepared formulations, the optimized plasticizer and polymer combination was selected and 3² factorial design was applied. On basis of factorial design, RSM and contour plots were applied. From factorial design batches the batch with lower disintegration time and good mechanical properties is optimized. This optimized batch was studied for its stability for 1 month. PG was optimized as plasticizer. It was observed that no single polymer was able to produce the film with desired quality hence polymer combination was used. The polymer combination of HPMC E 15 & PVA was optimized. On applying factorial design to this combination, batch with polymer ratio of 1:7 (HPMC: PVA) was optimized. The formulation was found stable after 1 month.

REFERENCE ID: PHARMATUTOR-ART-2202

INTRODUCTION: ^1-9
Recent developments in the technology have presented viable dosage alternatives from oral route for pediatrics, geriatric, bedridden, nauseous or noncompliant patients, various bioadhesive mucosal dosage forms have been developed, which includes adhesive tablets, gels, ointments, patches and more recently the use of polymeric films for buccal delivery, also known as mouth dissolving films.¹

By definition, a solid dosage form typically size of a postage stamp that dissolves or disintegrates quickly in the oral cavity resulting in solution or suspension without the need of water in a matter of seconds for the rapid release of one or more APIs is known as oral fast dissolving dosage form.^2,3It consists of fast dissolving polymer film embedded with drug, which quickly hydrates and dissolves when placed on the tongue or in the oral cavity (i.e., buccal, palatal, gingival, lingual, or sublingual) to provide rapid local or systemic drug delivery without need of water. The mouth dissolving film is also known as fast dissolving film, quick dissolving film, rapid dissolving film or oral thin film.⁴ In contrast to other existing, rapid dissolving dosage forms, which consist of lyophilized product, the rapid films can be produced with a manufacturing process that is competitive with the manufacturing costs of conventional tablets.⁵

Why Rizatriptan Benzoate In Fast Dissolving Film?
Rizatriptan Benzoate is an anti migraine drug. It is more effective than other triptans as it achieved both Pain relief and Pain Freedom within 2 h after dosing than other oral triptans.⁶
It fits in the parameters for ideal characteristics for drug for FDF

The ideal characteristics for drug for FDFare:²
· The drug to be incorporated should have low dose up to 40mg.

The dose of Rizatriptan Benzoate is 30mg/day.
· The drugs with smaller or moderate molecular weight are preferable.
The molecular weight of Rizatriptan Benzoate is 391.5 gm/mol which is small molecule.
· It should have good stability and solubility in water as well as in saliva.

Rizatriptan Benzoate is freely soluble in water and saliva.
· It should be partially ionized at pH of oral cavity.
· It should have ability to permeate oral mucosal tissue.

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Fast dissolving films offer fast, accurate dosing in a safe, efficacious format that is convenient and portable, without the need for water or measuring devices.⁷ Dissolution within oral cavity also permits intra-oral absorption, thus bypassing first pass effects.⁸

Migraine is a chronic neurological disorder characterized by recurrent moderate to severe headaches often in association with a number of autonomic nervous system symptoms. Approximately 15% of the population is affected by migraines at some point in life. Typically the headache affects one half of the head, is pulsating in nature, and lasting from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light, sound, or smell. The pain is generally made worse by physical activity. Up to one-third of people with migraine headaches perceive an aura: a transient visual, sensory, language, or motor disturbance which signals that the headache will soon occur. Symptoms can be visual, sensory or motor in nature and many people experience more than one.⁹

Symptoms may include a wide variety of phenomena, including altered mood, irritability, depression or euphoria, fatigue, craving for certain food, stiff muscles (especially in the neck), constipation or diarrhea, and sensitivity to smells or noise. The pain is frequently accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to smells, fatigue and irritability. In a basilar migraine, a migraine with neurological symptoms related to the brain stem or with neurological symptoms on both sides of the body, common effects include a sense of the world spinning, light-headedness, and confusion. Nausea occurs in almost 90% of people, and vomiting occurs in about one-third. Symptoms may include blurred vision, nasal stuffiness, diarrhea, frequent urination, pallor, or sweating. Swelling or tenderness of the scalp may occur as can neck stiffness. Often a feeling of pins-and-needles begins on one side in the hand and arm and spreads to the nose-mouth area on the same side. Numbness usually occurs after the tingling has passed with a loss of position sense.⁹

For this a dosage form which has Fast disintegration, Rapid release, faster absorption, quick on set of action is needed which is fulfilled by FDFs.

Hence formulation of fast dissolving films of rizatriptan benzoate is done.

MATERIALS AND METHODS:
Rizatriptan benzoatewas obtained as a gift sample form SMS Pharmaceuticals lmt, Hyderabad. HPMC E-15 were procured from Colorcorn Pvt Lmt, India, PVP K 30, PVA(cold soluble), Guar Gum and Xanthan Gum were procured from ACS Chemicals and all other ingredients were obtained from Astron Chemicals. All ingredients were of analytical reagent grade.

EXPERIMENTAL WORK:
Solvent Casting Technique: ^{10, 11}
In this method, the water and the drug along with other excipients is dissolved in suitable solvent. Then both solutions are mixed and stirred and finally casted into the Petri plate and dried.

Fig I: Solvent Casting Method

Evaluation of the mouth dissolving film: ^12-24
Mouth dissolving film should be stiff, flat and should not curl on the edges. The mouth dissolving film strip must be robust enough to be removed from the unit-dose packaging and to be handled by the consumer without breaking. The film must also dissolve readily in order to deliver the active agent rapidly when placed in the oral cavity. Mechanical property of mouth dissolving film plays an important role in deciding all these things. Therefore, the mechanical property of mouth dissolving film is as important as its solubility rate. So the prepared mouth dissolving films were evaluated for the following parameters:

1. Film Separability:
The ease of film separation from the mould (separability) and disintegration time were considered for the selection of best film from various batches prepared (preliminary batches) as well as for the selection of the polymer for further studies.

Table I: Criteria for film separability:

Term	Code
Poor	-
Moderate	+
Good	++

2. Disintegration time: ^12,13,14,15
The film was kept in petri-dish filled with simulated saliva fluid pH 6.8 and time at which it starts to break or disintegrate is recorded as disintegration time.

3. Measurements of Mechanical Properties:
The mechanical properties of the film gives idea about to what extent the film can withstand the force or stress during processing, packaging, transport and handling. The measurement of mechanical properties gives an indication of the strength and elasticity of the film, reflected by the parameters, tensile strength, elastic modulus and elongation at break.

Table II: Mechanical Properties of Film: ¹⁶

Type of polymer	Tensile Strength	Elastic Modulus	Elongation at break
Soft and Weak	Low	Low	Low
Hard and Brittle	Moderate	High	Low
Soft and Tough	Moderate	Low	High
Hard and Tough	High	High	High

A suitable film should have a relatively moderate tensile strength, high % elongation at break but a low elastic modulus. Mechanical properties of film were evaluated using Tensilometer, Ponco Machine Tools. Film strip with dimension 2x2 cm² and free from air bubbles or physical imperfections was held between two clamps positioned at certain distance. The force (gm) was applied by pulling one clamp. The values of mechanical properties were recorded when the film broke. Measurements were run in triplicate for each film. Three mechanical properties namely tensile strength, % elongation and elastic modulus of films were evaluated.

· Tensile strength: ^12,17
It is measured by Tensilometer. Tensile strength is the maximum stress applied to a point at which the strip specimen breaks. It is calculated by the applied load at rupture divided by the cross-sectional area of the strip.
T.S= load applied (gm)/ Cross-sectional area of film (cm²)

· % Elongation: ^12,17
When stress is applied, a strip sample stretches and this is referred to as strain. Strain is basically the deformation of strip divided by original dimension of the sample. Generally elongation of strip increases as the plasticizer content increases.
It is calculated as =Increase in length /Original length * 100

· Young’s Modulus:¹⁸
Young's modulus, E, can be calculated by dividing the tensile stress by the extensional strain in the elastic (initial, linear) portion of the stress–strain curve:

Where
Eis the Young's modulus (modulus of elasticity)
Fis the force exerted on an object under tension;
A₀is the original cross-sectional area through which the force is applied;
ΔLis the amount by which the length of the object changes;
L₀is the original length of the object

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4. Folding endurance: ^12,17
Folding endurance was determined by repeatedly folding the film at the same place till it break. The numbers of times the film can be folded at the same place without breaking give the value of folding endurance.

5. Thickness of film:¹²
The thickness of each sample was measured using a micrometer at five locations (center and four corners), and the mean thickness calculated.

6. Drug content uniformity: ^19,20,21
The film unit (n=3) of the dimensions 2 cm× 2 cm was placed in 100 ml of simulated saliva fluid pH 6.8.After complete solubilization, the solution was diluted appropriately, filtered and analyzed at 220nm using UV-Visible Spectrophotometer (Shimadzu 1800). The average of three films was taken as the content of drug in one film unit.

7. In vitro dissolution studies:²²
The simulated salivary fluid was taken as the dissolution medium to determine the drug release. The dissolution profile was carried out in a beaker containing 30 ml of the simulated salivary fluid (pH 6.8) as a dissolution medium, maintained at 37 ± 0.5°C. The medium was stirred at 100 rpm. Aliquots of the dissolution medium were withdrawn at determined time interval and the same amount was replaced with the fresh medium. Samples were assayed spectrophotometerically. The percentage of the drug dissolved at various time intervals was calculated and plotted against time.

8. Evaluation of Taste Masking: ^{23, 24}
In the present work, the taste acceptability was measured by a taste panel. Each formulation was given to a taste panel expert and was held in the mouth for 10-15 seconds, then spat out and the bitterness level was recorded. Volunteers were asked to gargle with distilled water between the film sample administrations. The scale mentioned in Table C was used further in the study for the taste evaluation of the film formulation.

Table III: Bitter Index Level

Numerical value	Scale
4	Strong bitter
3	Moderate to strong
2	Slight to moderate
1	Slightly bitter
0	Tasteless or taste masked

Calculation of dose of Rizatriptan Benzoate:
Oral dose of Rizatriptan is 5mg.
269.40mg Rizatriptan= 391.46mg of Rizatriptan benzoate

So,
5mg Rizatriptan= 5 x 391.46/269.40
= 7.265mg of Rizatriptan benzoate.

Each film should contain 7.265mg of Rizatriptan benzoate.

Area of each film= 2*2= 4cm²
Area of petridish= πr²
Where, r= radius of petridish =4.45cm
According to this, Area of petridish= 62.17cm²

For a film, 4cm² contains 7.265mg Rizatriptan benzoate.

So, in a petridish of 62.17cm² contains,
= 62.17*7.265/4
= 112.91mg Rizatriptan benzoate.
≈113 mg Rizatriptan benzoate was taken

Formulations for Optimization of Plasticizer (PEG 400, PG, DBP, Glycerin):

Table IV: Batches for Plasticizer (PEG 400, PG, DBP, Glycerin) optimization

INGREDIENTS (mg)	P1	P2	P3	P4
HPMC E15	200	200	200	200
Polyvinyl pyrrolidone K30 (PVP K30)	100	100	100	100
Polyethylene Glycol 400 (PEG 400)	116	-	-	-
Propylene Glycol (PG)	-	116
Di-butyl phthalate (DBP)	-	-	116	-
Glycerin	-	-	-	116
Mannitol	36	36	36	36
Citric acid	36	36	36	36
Tween 80	q.s	q.s	q.s	q.s
Water	q.s	q.s	q.s	q.s

Evaluation Parameter For P1 To P4 Batches:

Table V: Evaluation Parameter For P1 To P4 Batches

EVALUATION PARAMETER	P1	P2	P3	P4
1.Appearance	Poor	Good	Poor	Passable
2.Mechanical Properties:
Folding endurance	40	200	150	150
Tensile strength(gm)	2	16.66	2.5	13.63
% Elongation	4.5	11.36	4.5	6.81
Tear resistance(gm/cm²)	50	410	60	300
3. Thickness(mm)	0.13	0.12	0.1	0.11
4. Surface pH	7	7	7	7
5. Disintegration time (sec)	40	15	20	30

Discussion:
P1 batch contains PEG 400 as plasticizer. Films thus prepared were found to be sticky. They werenot transparent but hazy. Tensile strength and folding endurance were less.

P2 batch contains PG as plasticizer. Films with good folding endurance and desired plasticity were obtained. They were transparent.

P3 batch contains DBP as plasticizer. Plasticity was found to be good but on addition of DBP to polymer solution, the solution became hazy and films produced were not transparent.

P4 batch contains glycerin as plasticizer. Films were found to be hard.

According to this, Batch P2 produced the films of desired quality hence PG is optimized as plasticizer.

Formulations for Optimization of Polymer (HPMC E 15, PVP K30, PVA, Guar Gum, Xanthan Gum):

Table VI: Batches for Polymer (HPMC E 15, PVP K30, PVA, Guar Gum, Xanthan Gum) optimization

INGREDIENTS (mg)	P5	P6	P7	P8	P9
API (Rizatriptan benzoate)	112	112	112	112	112
HPMC E15	300	-	-	-	-
Polyvinyl pyrrolidone K30	-	300	-	-	-
Poly vinyl alcohol	-	-	300	-	-
Guar Gum	-	-	-	50	-
Xanthan Gum	-	-	-	-	50
Propylene Glycol	116	116	116	116	116
Mannitol	36	36	36	36	36
Citric acid	36	36	36	36	36
Tween 80	q.s	q.s	q.s	q.s	q.s
Water	q.s	q.s	q.s	q.s	q.s

Evaluation Parameter For P5 To P9 Batches:

Table VII: Evaluation Parameter for P5 to P9 Batches

EVALUATION PARAMETER	P5	P6	P7	P8	P9
1.Appearance	Good	Sticky	Good	Sticky	Sticky
2.Mechanical Properties:
Folding endurance	300	-	300	250	250
Tensile strength(gm)	25.22	-	30	2	0.09
% Elongation	13.63	-	18.18	2.27	4.54
Tear resistance(gm/cm²)	400	-	610	40	30
3. Thickness(mm)	.09	-	0.1	0.1	0.11
4. Surface pH	7	-	7	7	7
5. Assay(%)	85.32	-	78.43	71.69	69.78
6. Disintegration time (sec)	5	-	25	30	45