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Formulation and Evaluation of Fast Dissolving Film of Etophylline


Sandip Buddhadev*1 Sheetal Buddhadev2
    1Associate Prof. Govt. Ayurved College, Junagadh
2Assistant Prof. Noble Pharmacy College, Junagadh

ABSTRACT

Recently, fast dissolving films are gaining interest as an alternative of fast dissolving tablets. The films are designed to dissolve upon contact with a wet surface, such as the tongue, within a few seconds, meaning the consumer can take the product without need for additional liquid. This convenience provides both a marketing advantage and increased patient compliance. As the drug is directly absorbed into systemic circulation, degradation in gastrointestinal tract and first pass effect can be avoided. These points make this formulation most popular and acceptable among pediatric and geriatric patients and patients with fear of choking. In order to assist these patients, several fast-dissolving drug delivery system have been The present work aimed at preparing Fast Dissolving Film (FDF) of Etophylline,with the purpose of developing a dosage form for a very quick onset of action, which is beneficial in managing severe conditions of asthma aiding in the enhancement of bioavailability, and is very convenient for administration, without the problem of swallowing and using water.The films of Etophylline were prepared by using polymers such as hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA), as either single polymer or in combination of two, by a solvent casting method. They were evaluated for physical characteristics such as uniformity of weight, thickness, folding endurance, drug content uniformity, surface pH, percentage elongation, and tensile strength, and gave satisfactory results. The formulations were subjected to disintegration, in vitro drug release tests. A marked increase in the dissolution rate was exhibited by fast-dissolving films of Etophylline, containing HPMC as a polymer. Fast dissolving films of Etophylline can be considered suitable for clinical use in the treatment of asthma where a quicker onset of action for a dosage form is desirable along with the convenience of administration.

Key word: HPMC, PVA, FDF

INTRODUCTION

The oral route is one of the most preferred routes of drug administration as it is more convenient, cost effective, and ease of administration lead to high level of patient compliance. The oral route is problematic because of the swallowing difficulty for pediatric and geriatric patients who have fear of choking. Patient convenience and compliance oriented research has resulted in bringing out safer and newer drug delivery systems. Recently, fast dissolving drug delivery systems have started gaining popularity and acceptance as one such example with increased consumer choice, for the reason of rapid disintegration or dissolution, self-administration even without water or chewing. Fast dissolving drug delivery systems were first invented in the late 1970s as to overcome swallowing difficulties associated with tablets and capsules for pediatric and geriatric patients. Buccal drug delivery has lately become an important route of drug administration. 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. The surface of buccal cavity comprises of stratified squamous epithelium which is essentially separated from the underlying tissue of lamina propria and submucosa by an undulating basement membrane [1]. It is interesting to note that the permeability of buccal mucosa is approximately 4-4,000 times greater than that of the skin, but less than that of the intestine [2]. Hence, the buccal delivery serves as an excellent platform for absorption of molecules that have poor dermal penetration [3]. The primary barrier to permeability in otiral mucosa is the result of intercellular material derived from the so-called ‘membrane coating granules’ present at the uppermost 200 μm layer [4]. These dosage forms have a shelf life of 2-3 years, depending on the active pharmaceutical ingredient but are extremely sensitive to environmental moisture [5].

An ideal fast dissolving delivery system should have the following properties: High stability, transportability, ease of handling and administration, no special packaging material or processing requirements, no water necessary for application, and a pleasant taste. Therefore, they are very suitable for pediatric and geriatric patients; bedridden patients; or patients suffering from dysphagia, Parkinson’s disease, mucositis, or vomiting.

This novel drug delivery system can also be beneficial for meeting current needs of the industry. Fast dissolving films (FDF) were initially introduced in the market as breath fresheners and personal care products such as dental care strips and soap strips. However, these dosage forms are introduced in the United States and European pharmaceutical markets for therapeutic benefits. The first of the kind of oral strips (OS) were developed by the major pharmaceutical company Pfizer who named it as Listerine® pocket packs™ and were used for mouth freshening. Chloraseptic® relief strips were the first therapeutic oral thin films (OTF) which contained benzocaine and were used for the treatment of sore throat. Formulation of fast dissolving buccal film involves material such as strip-forming polymers, plasticizers, active pharmaceutical ingredient, sweetening agents, saliva stimulating agent, flavoring agents, coloring agents, stabilizing and thickening agents, permeation enhancers, and superdisintegrants. All the excipients used in the formulation of fast dissolving film should be approved for use in oral pharmaceutical dosage forms as per regulatory perspectives [6,7].

MATERIALS AND METHODS

Materials

Etophyline was obtained as a gift sample from Chandra labs Hyderabad as a gift sample Polyvinyl alcohol (PVA) and hydroxypropyl methylcellulose (HPMC 15 cps and 50 cps) were procured from CDH Laboratories, New Delhi. All other chemicals used were of analytical grade.

Drug excipient compatibility

Analysis of pure drug, excepient and physical admixtures of the drug with excepients were carried out using DSC. Temperature ranges room temperature to 200oC.

 

Methods

The fast dissolving film of Etophylline were prepared in lab using polymer HPMC and PVA by solvent casting method. The weighed quantities of polymers according to table 1 were kept for swelling overnight in distilled water and dissolved (heated, if necessary). The drug and sucralose were dissolved in distilled water and added to the above mentioned polymer solution along with PEG 400 as a plasticizer, mixed thoroughly to form a homogenous mixture. The volume was made up to 10 ml with distilled water. Entrapped air bubbles were removed by applying vacuum. The solution was casted on pertidish and dried at room temperature for 24 hours. The film was carefully removed from pertidish, checked for any inperfection and cut into required size to deliver the equivalent dose(4*4cm2 per strip).The sample were stored in desiccators at These patches were kept in a desiccator for 2 days for further drying and wrapped in aluminium foil, and packed in self-sealing covers. Fast-dissolving films were prepared with different polymers and ratios by maintaining the concentration of the plasticizer and sweetener. The trials formulation batches are shown in Table No.1

 Table 1: Formulation of Fast Dissolving Film of Etophylline

Formulation

code

Polymer HPMC

(mg)

PVA

(mg)

Drug

(mg)

Sucralose

(mg)

PEG

400                         (ml)

Water

(ml)

F1 HPMC E15 100 0 100 50 1 10
F2 HPMC E15 200 0 100 50 1 10
F3 HPMC E50 100 0 100 50 1 10
F4 HPMC E50 200 0 100 50 1 10
F5 PVA 0 100 100 50 1 10
F6 PVA 0 200 100 50 1 10
F7 HPMC E15+PVA (1:1) 50 50 100 50 1 10
F8 HPMC E15+PVA    (2:1) 100 50 100 50 1 10
F9 HPMC E15+PVA

(1:2)

50 100 100 50 1 10

 Evaluation of fast-dissolving films

 Drug content uniformity

A fast-dissolving film (4×4) was transferred into a graduated flask containing 100 ml of distilled water. The flask was shaken for 4 h in a mechanical shaker. The solution was filtered and after suitable dilutions with distilled water, the absorbance value was measured at 273 nm and the drug content was calculated [21].

Folding endurance

The folding endurance is expressed as the number of folds (number of times the film is folded at the same place) required to break the specimen or to develop visible cracks. This also gives an indication of brittleness of the film. A strip of 4cm × 4cm (16cm2) was subjected to folding endurance by folding the patch at the same place repeatedly several times until a visible crack was observed, and the values were reported [21.]

Surface pH

The film to be tested was placed in a Petri dish and was moistened with 0.5 ml of distilled water and kept for 30 s. The pH was noted after bringing the electrode of the pH meter in contact with the surface of the formulation and allowing equilibration for 1 min. The average of three determinations for each formulation was done [22,23].

 

Elongation and tensile strength

This mechanical property was evaluated using the Instron universal testing instrument with a 5 kg load cell. Film strips in a special dimension and free from air bubbles or physical imperfections were held between two clamps positioned at a distance of 3 cm. During measurement, the strips were pulled by the top clamps at a rate of 100 mm/min; the force and elongation were measured when the film broke. Results from film samples, which broke at and not between the clamps, were not included in the calculations. Measurements were run in triplicate for each film. Two mechanical properties, namely, tensile strength and percentage elongation were computed for the evaluation of the film. Tensile strength is the maximum stress applied to a point at which the film specimen breaks and can be computed from the applied load at rupture. Disintegration test was performed to ensure the disintegration of the film in water. One film from each formulation was introduced into one tube of disintegration apparatus IP. A disc was added into the tube. The assembly was suspended in a beaker containing simulated saliva and the apparatus was operated until the film disintegrated [24].

 

In vitro dissolution studies

The simulated salivary fluid was taken as the dissolution medium to determine the drug release. The dissolution profile of quick release films of Etophyline 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 (5 ml) of the dissolution medium were withdrawn at 15, 30, 45, 60, 75, 90, 105 and 120 s time intervals and the same amount was replaced with the fresh medium. Samples were assayed spectrophotometerically at 273 nm. Three trials were carried out for all the samples and the average value was taken. The percentage of the drug dissolved at various time intervals was calculated and plotted against time [25].

Stability studies

The stability study of the formulated fast-dissolving films was carried out under different environmental conditions. The film was packed in the aluminum foil and stored in a stability chamber for stability studies at 2-8°C (45% RH), 25-30°C (60% RH), and 45-50°C (75% RH) for a period of 45 days. The patches were characterized for the drug content and other parameters during the stability study period [26].

 RESULTS AND DISCUSSION

Calibration Curve for Etophylline

 Figure 1:  in 6.8 PH saliva solution at 273 nm in U.V.Drug excipient compatibility studies

The DSC thermo grams of the pure drug and drug: HPMC E15: PVA mixture was shown in Figure1 sharp peak at 131.97°C and good compatibility with polymers. These study concluded that no excipient incompatibility.

Fast-dissolving films of Etophyline were prepared by the solvent casting method on pertidish using HPMC 15 cps, HPMC 50 cps, and PVA as polymers. Polylethylene glycol was used as a plasticizer and Sucralose as a sweetener. Distilled water was used as a solvent for HPMC and PVA. The effect of the concentration ratio of polymers and nature of polymers was studied by preparing various formulations of Fast dissolving films. In all these formulations, a constant amount of drug (100 mg) was maintained. The casting solution (10 ml) was poured into petridish having area 64cm, so that each square centimeter contains approximately 25mg of the drug. Polymers were used in different concentrations and the concentration of other ingredients such as plasticizer and sweetener were kept constant. Fast-dissolving films of Etophyline were evaluated for various parameters. In the present study, nine formulations were prepared by varying the polymer concentration, and by using different polymers.

Effect of the polymer concentration

Different formulations (F1, F2, F3, F4, F5, F6, F7, F8, and F9) were prepared using HPMC 15 cps, HPMC 50 cps, PVA, and a combination of HPMC 15 cps and PVA in different concentrations. Table 2 show the effect of polymers/concentration on the physicochemical properties.

Drug content of the fast-dissolving films

The physical appearance of the films was evaluated. All the films prepared with different polymer concentrations were found to be flexible, smooth, transparent, non-sticky, and homogeneous. The thickness of the films in each set was measured. The marginal difference in the thickness was observed among each group indicated that more the amount of polymer, higher the thickness values. All the films, except F1 showed good folding endurance (>210), indicated that the films have good flexibility. The effect of concentration of polymers was observed on the percentage elongation and tensile strength (1.2-1.7 kg/mm). It was found that as the concentration of PVA increased, the percentage elongation and tensile strength also increased. HPMC films showed a better tensile strength due to the hydrophobic nature of the polymers. No significant difference in the drug content among the films (approximately 100%), indicated good content uniformity. When placed over the tongue, the film dissolved instantly. Dissolution was also found to be improved due to salivary stimulation in the presence of the sweetener (sucralose).

It was observed that there was no significant difference in the thickness among the films, which indicated that the films were uniform, and the surface pH was found to be in the range of 6.6-7.2, which is close to the neutral pH, which indicated that films may have less potential to irritate the sublingual mucosa, and hence, more acceptable by the patients.

Figure 2: DSC thermo grams of a) Etophyline pure drug, b) Etophyline pure drug and HPMC E15+PVA (1:1)

Table 2: Evaluation Parameter for Fast Dissolving Film of Etophylline

No Test F1 F2 F3 F4

 

F5 F6

 

F7 F8 F9
1 Weight variation (mg) 20.75±0.20 21.20±0.85 21.50±0.58 21.70±0.50 20.25±0.75 20.50±0.50 21.45±0.50 21.9±0.55 21.9±0.35
2 Folding endurance 185 215 230 240 210 220 227 232 222
3 Thickness

(mm)

0.040±

0.010

0.043±

0.015

0.044±

0.018

0.047±

0.008

0.040±

0.007

0.042±

0.025

0.044±0.010 0.043±0.020 0.042±0.015
3 Surface pH

 

6.65±0.48 6.78±0.54 6.90±0.56 6.78±0.52 6.70±0.50 6.75±0.52 6.68±0.48 7.20±0.50 6.60±0.52
4 Elongation and tensile strength 1.2± 7.5 1.35±5.0 1.5±4.5 1.6±4.0 1.55±3.75 1.6±2.5 1.7±3.5 1.6±2.6 1.4±4.5
5 Disintegration time (sec) 24.2 ± 1.12 38.5± 0.63 26.6±1.25 39.8± 2.5 25± 7.5 35±7.5 20.7±6.8 24.9±7.5 34.4 ± 8.2
6 Drug content (%) 97.9±1.1 98.9± 2.2

 

98.7±1.4

 

99.2±2.1

 

98.5±1.3

 

99.4±2.1

 

99.8±1.4

 

97.6±1.6 98.6±.6

 

In vitro drug release study

From the in vitro drug release, it was observed that in formulations containing a single polymer, the drug release was found to be faster from films containing PVA as a polymer, and among the HPMC films, lower viscosity resulted in a faster release of drug. The release of the drug from HPMC 50 cps, was found to be slower compared to all other films containing a single polymer (F1-F6). Among the combination of polymers (F7, F8, and F9) it was found that the presence of PVA increased the drug release from films compared to films containing only HPMC 50 cps (F3 and F4). Further, as the concentration of the polymer increased, the drug release was found to be decreased due to the increase in the time required for wetting and dissolving the drug molecules present in the polymer matrices. The drug release was found to be in the following order: F5 > F1 > F3 > F6 > F2 > F4. For the group of formulations containing a combination of polymers, the drug release was found to be in the following order: F7 > F8 > F9 (Figure 2). Among the nine formulations (F1, F2, F3, F4, F5, F6, F7, F8, and F9) prepared, formulations F7, F5, and F1 were found to be the best formulations in terms of drug release.

 Figure 3: In vitro release profile of formulations

Stability studies

The DSC of the optimized formulation after subjecting to accelerated for 45 days at 2-8°C (45% RH), 25 -30°C (60% RH), and 45-50°C (75% RH) has been constructed and compared with that of the DSC thermograms. The characteristic peak of the Etophyline was well retained in optimized formulation without any significant change after being subjected to the accelerated stress conditions for 45 days.

The films were observed for physical change, drug content, and % drug release. Fast-dissolving films of Etophyline were found to be physically and chemically stable as they showed no significant change in terms of physical characteristics and drug content at a lower temperature and room temperature. However, when stored at 45-50°C for 45 days, films became brittle.

Figure 4: DSC thermo grams of a) Etophyline pure drug, b) Etophyline pure drug and HPMC E15+PVA (1:1) after stability period

 CONCLUSIONS

Based on the encouraging results, the fast-dissolving films of Etophyline can be considered suitable for clinical use in the treatment of asthma where a quicker onset of action for a dosage form is desirable along with the convenience of administration. The films prepared by HPMC E15 and PVA had shown good mechanical strength, drug release, disintegration time and stability. Etophyline administered in the form of fast dissolving films will be potential novel drug dosage form for pediatric, geriatric and also for general population by providing faster release and better patient compliance.

 Acknowledgement

Authors are highly thankful to Department of Pharmacy, Noble group of Institution to provide necessary facilities during research work.

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