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.

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
E
is the Young's modulus (modulus of elasticity)
F
is the force exerted on an object under tension;
A0
is the original cross-sectional area through which the force is applied;
ΔL
is the amount by which the length of the object changes;
L0
is the original length of the object

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