Orodispersible film drug delivery systems (ODFs) were first developed in the late 1970s as based on the technology of the transdermal patch. An alternative to tablets, capsules and syrups for paediatric and geriatric patients who experienced difficulties in swallowing traditional oral solid dosage forms [1].

ODFs

A solid dosage form that dissolves or disintegrates quickly in the oral cavity, resulting in solution or suspension without need for the administration of water, is known as oral fast dispersing dosage form. These are also called as, orally dissolving films, flash release wafer, wafer, quick dissolving film, soluble or buccal film- preferred by FDA and European medicines agency using oro dispersible films [2].

Significance of ODFs

ODFs have attained remarkable significance in pharmaceutical industry for the reason of possessing unique properties and fast dissolution time ranging from seconds to one minute. ODFs design permits to integrate a variety of drugs for their response effects e.g. antitussive, anti-epileptic, anti-asthmatic, expectorant, etc. High temperature and moisture sensitivity necessitate expensive covering and inability of high dose loading is some disadvantages of ODFs [3,4].

The rationale of the proposed research work, the present investigation was to develop and formulate natural, non-biodegradable, Pullulan based fast dissolving orodispersible films prepared by solvent casting method for indirect absorption of drug via transmucosal lining to the systemic circulation. The present formulation has to improve patient compliance and presents multiple competitive advantages over its marketed oral dosage forms used chemotherapy induced nausea and vomiting patients.

Procurement of Drugs and Chemicals

Granisetron HCl was gift sample obtained from Schon Pharma Laboratories Pvt. Ltd, Indore. Pullulan natural polymer purchased from Tokyo chemical industry Pvt. Ltd. and other analytical grade chemicals and reagents used from the loba chemie laboratories.

Table 1: Composition of Drug Loaded Orodispersible Film

Figure 1: Drug Loaded Film

Experimental Work

Formulation of Orodispersible Film: To optimize the formulation variables, factors selected for studies were concentration of Pullulan and concentration of plasticizer. These variables were taken at different levels. The response or dependent variables studied were wetting time, folding endurance and drug release. All batches were prepared with different concentration of plasticizer and polymer. The composition of drug-loaded films is given in Table 1 (Figure 1).

Calculation of Amount of Drug

Calculation of amount of drug per batch [9].

Dose of drug per film = 2mg

Area of one film = 3.24cm2

Area of Petri dish = 63.585cm2

Drug to be added in one batch = (Dose of drug per film× Area of Petri dish)/Area of one film

= (2×63.585)/3.24

= 39.25mg

Preparation of Drug Loaded Orodispersible Film by Solvent Casting Method

Orodispersible Film was prepared by solvent casting method. Polymeric solution (solution A) was prepared by dissolving desired amount of pullulan in enough quantity of distilled water 70% specific quantity of drug along with polyethylene glycol and other excipients were dissolved in remaining water 30% with continue stirring (solution B). Solution B was slowly added in polymeric solution A with continuous stirring final solution obtained was kept aside for 30mins defoaming. After defoaming, solution was poured in Petri plate and dried at 45ºc in hot air oven for 24h.Film casted in Petri plate was then carefully peeled off and cut into desired shape and size. Different optimized combinations of film containing pullulan with PEG 400 were prepared and evaluated for different evaluation parameters [4].

Evaluation Parameter of Formulation

Physical Appearance: This parameter was simply checked by visual inspection of film and evaluation of surface texture by feel or touch.

Measurement of Film Thickness

Thickness of each film was measured using thickness gauze. Measurement of thickness of each film was done at six different locations (two in middle part and four corners). For each formulation, three randomly selected films were used. Films of size (2× 2 cm2) were cut and all the measurements were done in triplicate. Mean value of film thickness at six different locations was taken as the film thickness [10,11].

Weight Variation

Three films of 2× 2 cm2 size were cut randomly from each film formulation. Film was weighed individually on electronic balance and the mean weight for each batch was calculated.

Percentage Moisture Loss

To determine the integrity and physical stability of the film, percent moisture loss test was done. A film size 2×2 cm2 was cut and weighed. After that the film was placed a desiccator containing fused anhydrous calcium chloride for 3 days. After three days’ film patch was taken out and weighed again. The percentage moisture loss of the film was calculated using the following formula:

Percentage Moisture Loss = (Initial Weight - final weight)/Initial Weight×100

Surface pH

A film (1 × 1 cm2) was swelled in distilled water for 15 min. The film was taken out, drained and the pH of the film was noted using litmus paper

Percent Elongation

When stress is applied the film, sample stretches and is referred to as strain. Strain is basically the deformation of the film divided by the original dimension of the film. Generally, elongation of the film increases as the plasticizer concentration increases. Percentage elongation was calculated by measuring the increase in length of the film after tensile strength measurement by using the following formula. The estimations were carried out in triplicate [2].

% Elongation= (L-L0)/ L0 ×100

where

L: Final length

L0: Initial length

Folding Endurance

Folding endurance value was calculated by folding the film of suitable size at the same place and counting the number of times the film could be folded without breaking.

Determination of Drug Content in Films

To ensure the uniformity of distribution of Granisetron in the film, a content uniformity test was done. Films (1 × 1cm2 equivalents to 2 mg of Granisetron) were cut at three different locations and dissolved in 10 ml of phosphate buffer saline (pH 6.8) by continuous shaking on a water bath at room temperature for 8 h. The solution was filtered through Whatman filter paper and the samples were diluted suitably and analysed using UV spectrophotometer at a λmax 301 nm against a blank (UV‑1800, Double Beam spectrophotometer, SHIMADZU, Japan) [3,4].

In-vitro Permeation Release Studies

Drug permeation studies were carried out using gelatine membrane as a permeation barrier on a standard two chambered Franz diffusion cell to determine the rate and extent of mucosal permeation of Granisetron HCl. The water jacket was maintained at 37±1°C.the receptor compartment was filled with pH 6.8 solutions. The film of size 1×1cm2 was weighed. The film was mounted in donor compartment which was filled 7mL of dissolution medium. The dissolution media was stirred at 50rpm making use of a magnetic bead. Samples were withdrawn at predetermined time interval from the receptor compartment, suitably diluted and analysed by using UV spectrophotometer at a λmax 301 nm against a blank. (UV‑1800, Double Beam spectrophotometer, SHIMADZU, Japan) [6].

In- vitro Dissolution Study

Modified paddle apparatus was used to carry out the drug release studies. The film of size 2 ×2 cm2 was cut and pasted onto the inner side of the dissolution beaker using double sided adhesive tape. Dissolution medium maintained at 37 ±1°C was poured into the beaker and provided with a stirring rate of 50 rpm. During the study, temperature of dissolution medium was maintained at 37 ±1°C. Dissolution apparatus was used to carry out dissolution experiments. The samples were withdrawn at predetermined time intervals and analysed using double beam UV spectrophotometer [7,11].

Differential Scanning Colorimetry (DSC) Analysis

The thermal properties of the pure drug, Pullulan and their mixtures were evaluated using by using differential scanning colorimeter. The analysis was performed with a heating range of 48-50oC and rate of 10oC min-1 in an inert nitrogen atmosphere.

Granisetron HCl (GH) Oro-dispersible films prepared were transparent, colourless, thin and soft, with no spot on the film surface. The prepared orodispersible film was evaluated according to the following parameters: % drug content, thickness, weight variation, surface pH, folding endurance and percentage moisture loss as shown below:

Physical Appearance

Appearance of films was evaluated by visual observation such as transparent and semitransparent natures of film.the result of various evaluation parameters are show in Table 2.

Measurement of Film Thickness

Thickness of the films was found to be between 0.020mm to 0.291mm. A very low standard deviation values indicates that the method used for the formulation of film is reproducible and give film of uniform thickness and hence dosage accuracy in each film can be ensured. The data mention in Table 2.

Table 2: Observation of Various Evaluation Parameters of Granisetron HCl Films

Weight Variation

The films were weighed individually using digital balance and average weight was calculated. As all batches do not have uniform amount of ingredient in it, hence their weight and thickness were varied. Weight uniformity of the films was found to be between 34.1mg-69.1mg. The data mention in Table 2.

Percentage Moisture Loss

The study of percentage moisture loss gives the idea about the stability of the film in different environmental conditions. More the moisture absorption property of the film less stable it will be. However, it was found that the % moisture absorption and percentage moisture loss increased with increase in hydrophilic polymers. Percentage moisture loss was found to be between 1.23 to 3.26. The results are shown in Table No 3.

Table 3: Observation Table for Various Evaluation Parameters

Table 4: Drug Content of Granisetron HCl Film

Figure 2: Graph of in Vitro Drug Release Studies

Figure 3: In Vitro Permeation Profile of Film from Various Formulations

Figure 4: DSC Graph of Granisetron HCl Orodispersible Film

Surface pH

Surface pH of all films was found to be in the range of 6.20 to 6.81. All films were found to be in the range of salivary pH. The results are shown in Table 3.

Percent Elongation (% E)

The Percentage elongation was found to be in the range of 12.5±4% to 33.0±5%. The results are shown in Table 3.

Folding Endurance

Folding endurance measurement gives an indication of fragility of the film. The value depends on hydrophilic polymer as well as plasticizer concentrations used. Folding endurance test result indicated that the film would not rupture and would maintain their integrity.be between 57±6.05 to 105±4.46. The results are shown in Table 3.

Drug Content of Granisetron HCl Film

Prepared Granisetron Hydrochloride films were subjected to uniformity of drug content. The content of preparation 85%-115% and the relative standard deviation is less than or equal to 6.0. Drug content of the films was found to be between 81.8±0.034 to 96.6±0.005%. The results are shown in Table 4.

In vitro Drug Release Stud

Dissolution study indicates the rate and extent of absorption. The in-vitro dissolution of Granisetron hydrochloride films were carried out using 900ml phosphate buffer of pH 6.8 using USP II paddle type apparatus. In-vitro dissolution study for all the batches were performed for 2 minutes. The results are shown in Table 5.

Table 5: In-Vitro Release Studies of Orodispersible Films of Granisetron HCl

Differential Scanning Colorimetry (DSC) Analysis

The thermal properties of the Pullulan based orodispersible film and there were evaluated using differential scanning colorimeter. The analysis was performed with a heating range of 48-50oC and rate of 10oC min-1 in an inert nitrogen atmosphere. This evaluation there was no changes was observed between drug and excipients (Figure 2-4) (Table 6).

Table 6: In Vitro Permeation Release Studies

*values expressed as mean ± S.D. (n = 3)

Orodispersible film of Granisetron HCl Prepared using pullulan as a film forming polymer increase in polymer and plasticizer concentration was found to influence in all the aspects of physiochemical and mechanical properties of the films. These films could be effectively used to provide faster onset of action, increased bioavailability and a prolong drug release for Granisetron HCl. Optimized formulation F4 were found to be stable at accelerated stability.

The formulation F4 is selected for best formulation because its show the 96.8% drug release at time 120sec, folding endurance is 85 times and weight of prepared film is 63.4 mg and thickness 0.283mm of these formulations respectively.

Acknowledgement

We wish to acknowledge to Dr. Dinesh Kumar Mishra (Principal of IIP), Dr. Nadeem Farooqui (HOD Pharmaceutics, IIP) and Mr. Kuldeep Vinchurkar (Co-guide, IIP) for providing platform for conducting the research work and for their support and encouragement.

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