INTRODUCTION:

Fast-dissolving drug delivery is rapidly gaining interest in the pharmaceutical industry. These systems either dissolve or disintegrate generally within a minute, without needing water or chewing. An important benefit is the accurate dosing as compared to liquid dosage forms, mostly used with paediatric patients or in case of dysphasia. Despite of so much of advancements in various delivery system developed for administration of various drugs through different routes such as oral, parenteral, transdermal, nasal, etc., the oral route is considered as the most convenient and the preferred route of administration¹.

It has been well known that after Buccal and sublingual administration drug solutes are rapidly absorbed in to the reticulated vein and are then drained into the systemic circulation ^2,3. The oral fast dissolving dosage forms, also known as fast melt, fast disintegrating dosage forms, are relatively novel dosage technology that involves rapid disintegration or dissolution of the dosage forms, into a solution or suspension in the mouth without need of water^4,5,6,7,8.

Vomiting, also known as emesis, throwing up, among other terms, is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be caused by a wide variety of conditions, it may present as a specific response to ailments like gastritis or poisoning, or as a non-specific sequel of disorders ranging from brain tumours and elevated intracranial pressure to overexposure to ionizing radiation⁹.

Granisetron hydrochloride is chemically endo-1-methyl-N-(9-methyl-9- azabicyclo non-3-yl)-H-indazole-3-carboxamide hydrochloride, a selective 5-HT3 receptor antagonist, which may have beneficial therapeutic effects in the treatment of vomiting and nausea resulting from cancer therapy¹⁰. It has an improved side effect and tolerability profile, a lower risk of drug interactions and a longer duration of action than other 5-HT3 receptor antagonists. It is also an effective and well-tolerated agent in the management of chemotherapy-induced, radiotherapy-induced and post-operative nausea and vomiting in adults and children¹¹. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting centre in the medulla oblongata. Granisetron hydrochloride undergoes extensive hepatic first pass metabolism with a bioavailability of 60%.The terminal elimination half-life is 3 to14 hours after oral administration. Granisetron hydrochloride is about 65% bound to plasma proteins¹².

MATERIALS AND METHODS:

Materials:

Graniserton HCl was generous gift sample from MSN labs, Hyderabad, India. Hydroxy Propyl Methyl Cellulose (HPMC E3, E5 and E15) and flavor were gifted by Aurobindo Pharma, Hyderabad. Maltodextrin, Aspartame, Propylene glycol, Malic acid from SD FINE CHEM LTD, Mumbai. All other chemicals used were of analytical grade.

Methods:

Preparation of Granisetron oral films:

It was aimed to prepare fast dissolving oral films of Granisetron HCl with the dose of 1.12 mg per 4 cm² film. Film forming polymers hypromellose different grades and maltodextrin were weighed accurately, added to a small amount of water in a small beaker, covered with an aluminium foil and soaked for 24 hours to ensure complete hydration. The solution was stirred on a magnetic stirrer at 50 rpm for 2 hours. Then, propylene glycol was added and stirring was continued for 30 minutes at 50rpm. Graniserton, aspartame, malic acid, flavor and color were dissolved in sufficient quantity of water and added to the polymer mixture. This film forming solution was then stirred well to obtain a homogenous solution. Dry and clean petri dish was selected and the solution was poured into it. Drying was carried out at 45°C in a hot air oven for 6 hours. The petri dish was then removed and left aside to cool down to room temperature. The film was then peeled carefully using surgical scalpel by making a small incision in the film on one side of the petri dish. Small films of 4 cm² were cut from one big film and packed primarily in aluminium foil and secondarily in a self- sealing polythene bag to ensure least moisture penetration and the resulting films were evaluated. The composition of Graniserton fast dissolving oral films with different polymers are shown in Table 1, 2 and 3

Table 1: Formulation trails using HPMC E3 and HPMC E5

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
Granisetron HCl (mg)	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92
HPMC E15 (mg)	-	-	-	-	-	-	-	-	-	-
HPMC E3 (mg)	260	230	200	170	140	-	-	-	-	-
HPMC E5(mg)	-	-	-	-	-	260	230	200	170	140
Maltodextrin (mg)	50	50	50	50	50	50	50	50	50	50
PG (mL)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Aspartame (mg)	8	8	8	8	8	8	8	8	8	8
Malic Acid (mg)	2	2	2	2	2	2	2	2	2	2
Pineapple flavor (ml)	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1
Color (ml)	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
Water (ml)	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s

Table 2: Formulation trails using HPMC E15 and HPMC E3+E5

Ingredients	F11	F12	F13	F14	F15	F16	F17	F18	F19	F20
Granisetron HCl (mg)	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92
HPMC E15 (mg)	260	230	200	170	140	-	-	-	-	-
HPMC E3 (mg)	-	-	-	-	-	260	230	200	170	140
HPMC E5 (mg)	-	-	-	-	-	50	50	50	50	50
Maltodextrin (mg)	50	50	50	50	50	50	50	50	50	50
PG (mL)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Aspartame (mg)	8	8	8	8	8	8	8	8	8	8
Malic Acid (mg)	2	2	2	2	2	2	2	2	2	2
Pineapple flavor (ml)	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1
Color (ml)	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
Water (ml)	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s

Table 3: Formulation trails using HPMC E3+E15 and E5+E15

Ingredients	F21	F22	F23	F24	F25	F26	F27	F28	F29	F30
Granisetron HCl (mg)	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92	17.92
HPMC E15 (mg)	260	230	200	170	140	50	50	50	50	50
HPMC E3 (mg)	50	50	50	50	50	-	-	-	-	-
HPMC E5 (mg)	-	-	-	-	-	260	230	200	170	140
Maltodextrin (mg)	50	50	50	50	50	50	50	50	50	50
PG( mL)	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Aspartame (mg)	8	8	8	8	8	8	8	8	8	8
Malic Acid (mg)	2	2	2	2	2	2	2	2	2	2
Pineapple flavor (ml)	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1	0.1
Color (ml)	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
Water (ml)	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s

Evaluation of Graniserton Fast Dissolving Oral Films:

Physical characterization of FDOFs:

Physical characterization of FDOFs can be carried out by visual inspection for characteristics such as color, brittleness, peeling ability, tack property and film forming capacity.

The prepared films were subjected for in vitro evaluation tests like Surface pH, Thickness, Dimensions of the film, Folding Endurance, % Drug content, Percent elongation, Tensile strength, moisture content, In vitro Disintegration time, In vitro dissolution studies and in vivo studies in healthy human volunteers.

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 30s. 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 reported¹³.

Thickness and Dimensions of the film:

The film thickness was measured using Digital Vernier caliper (Mitutoyo.) at six different places and the average value was calculated¹⁴. Dimension of the film is 4 cm² (2 × 2 cm2).

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 4 cm²was subjected to folding endurance by folding the film at the same place repeatedly several times until a visible crack was observed, and the values were reported¹⁵.

% Drug content:

Three films (4 cm² of each) were transferred in to separate graduated flasks containing 100 ml of phosphate buffer pH 6.8 and continuously stirred for 2 hrs. The solutions were filtered, suitably diluted and analysed at 301 nm and the drug content was calculated¹⁶.

Percent Elongation:

This mechanical property was evaluated using the Instron universal testing instrument (Model F. 4026, Instron Ltd., Japan) with a 5-kg load cell. The percentage increase in the length of a film (L₂), when it is pulled under standard conditions of stress just before the point of break is known as percent elongation. The initial length of a film is L₁, the increase in length is (L₂-L₁). It is measured in terms of percentage. Percent elongation and tensile strength was carried only for optimized formulations¹⁷.

(L₂-L₁)

Percent elongation =------------------------------------X 100

L₁X Cross sectional area

Tensile strength:

Tensile strength is the maximum stress applied to a point at which the strip specimen breaks. Film strip of dimension 5 × 2 cm ² and free from air bubbles or physical imperfections was held between two clamps positioned at 3 cm apart. A cardboard was attached on the surface of the clamp via a double-sided tape to prevent the film from being cut by the grooves of the clamp. During measurement, the strips were pulled at the bottom clamp by adding weights in pan till the film breaks. The force was measured when the films broke. It is calculated by the applied load at rupture divided by the cross‐sectional area of the strip as given in the equation below¹⁸

load at failure

Tensile strength = -----------------------------------------

strip thickness x strip width

Moisture Content:

The patches were weighed and kept in a desiccator containing calcium chloride at 40^oC for 24 hr. The final weight was noted when there was no further change in the weight of patch. The percentage of moisture content was calculated as a difference between initial and final weight with respect to initial weight¹⁹.

In- vitro disintegration studies:

Disintegration test was performed to ensure the disintegration of the film in phosphate buffer pH 6.8. 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 phosphate buffer pH 6.8 and the apparatus was operated until the film disintegrated²⁰.

In vitro dissolution studies:

The phosphate buffer pH 6.8 was taken as the dissolution medium to determine the drug release. The dissolution profile of quick release films of Graniserton was carried out in USP basket type apparatus containing 300 ml of the phosphate buffer pH 6.8. The film was placed in the basket, maintained at 37 ± 0.5°C and the agitation speed was 50 rpm. Aliquots (5 ml) of the dissolution medium were withdrawn at 1, 3, 5, 7, 9, and 10 minutes time intervals and the same amount was replaced with the fresh medium. Samples were analyzed spectrophotometrically at 301 nm and the cumulative percentage of drug release was calculated²¹.

Drug Excipient Compatibility Studies:

The drug excipient compatibility studies were carried out by Fourier Transmission Infrared Spectroscopy (FTIR) method and Scanning electron microscopy²².

Fourier Transform Infrared Spectroscopy (FTIR):

FTIR spectra for pure drug, physical mixture and optimized formulations were recorded using a Fourier transform Infrared spectrophotometer. The analysis was carried out in Shimadzu-IR Affinity 1 Spectrophotometer. The IR spectrum of the samples was prepared using KBr (spectroscopic grade) disks by means of hydraulic pellet press at pressure of seven to ten tons.

SEM studies:

The surface characteristics of film were determined by scanning electron microscopy (SEM) (HITACHI, S-3700N). Photographs were taken and recorded at suitable magnification.

Stability studies:

The stability study of the optimized fast-dissolving films was carried out under different conditions according to ICH guidelines. The film was packed in the aluminium foil and stored in a stability chamber for stability studies. Accelerated Stability studies were carried out at 40 ⁰C / 75 % RH for the best formulations for 6 months. The patches were characterized for the drug content and other parameters during the stability study period.

Evaluation of Optimized Film in Human Volunteers:

The Optimized film were evaluated in healthy human volunteers with their consent (n =8; 8males) for mouth feel, bitter taste masking, and in vivo disintegration time in oral cavity. The protocol for the human studies was approved by the Ethical Committee with approval no: IHEC/VGOPC/066/2016. Each volunteer was randomly given Optimized film (single blind design) with a potable water rinse at start. The volunteers were asked to place the film on the tongue. Volunteers were not restricted later with respect to tongue movement^23,24.

RESULTS AND DISCUSSION:

Preparation of Graniserton oral films:

It was aimed to prepare fast dissolving oral films of Graniserton with the dose of 1.12mg per 4 cm² film. Total 30 formulations were prepared using three different polymers, HPMC E3, HPMC E5 and HPMC E15 and the resulting films were shown in Figure 1.

Figure 1: Granisetron Hydrochloride films

Physical Characterization of films:

Physical characterization of FDOFs was carried out by visual inspection and the following results were observed.

The films were evenly colored and no migration of color was observed. All formulations were found to be excellent in film forming property, non-tacky, thin, flexible and easy to peel.

Evaluation of fast dissolving oral films of Granisetron:

Surface pH:

Surface pH of all mouth dissolving films prepared by using different polymers was found to be in the range of 6.50±0.1 to 6.92±0.1 pH (Table 5), which was 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

Thickness and Dimension of the film:

Thickness of all mouth dissolving films was measured with Digital Vernier caliper (Mitutoyo). All the mouth dissolving formulations of different polymers are show thickness value in the range of 0.217±0.05 to 0.269±0.16 mm (Table 5). The optimized film has thickness of 0.244±0.04mm. A result of thickness measurement showed that as the concentration of polymer increases, thickness of mouth dissolving film also increases.

Folding endurance:

Folding endurance gives an indication of brittleness of the film. It was shown that as the concentration of polymer and plasticizer increases, folding Endurance of mouth dissolving film increases. The folding endurance value of the prepared films ranged from 91±1to110±2 (Table 5). The optimized film (F14) has folding endurance value of 106±3, which was desirable.

%Drug content:

Drug content in the films was evaluated and the values were found to be between 92.56±0.05 to 99.86±0.54 % (Table 5) for three different cuts from each film. No significant difference in the drug content among the films indicated good content uniformity.

In vitro disintegration studies:

The disintegrating time of all the formulations was ranges from 9±0.28 to 19±0.46 sec. The disintegration time of optimized formulation (F14) was found to be 9±0.28 sec, which was very less and desirable for quick onset of action (Table 5).

Table 4: Evaluation parameters of Graniserton HCl mouth dissolving films

Formulation code	Thickness (mm)	Disintegration time (sec)	Drug Content (%)	Moisture content (%)	Folding Endurance (count)	Surface pH
F1	0.256±0.02	17±0.42	97.28±0.02	4.99±0.42	98± 1	6.50±0.1
F2	0.244±0.06	18±0.23	96.46±0.45	4.50±0.22	99±2	6.53±0.2
F3	0.235±0.01	14±0.19	97.21±0.61	4.68±0.16	95±2	6.52±0.1
F4	0.225±0.08	16±0.85	97.56±0.46	4.22±0.23	97±2	6.51±0.2
F5	0.217±0.05	15±0.36	96.28±0.25	4.90±0.31	96±3	6.59±0.5
F6	0.256±0.04	19±0.46	96.89±0.13	4.82±0.35	91±1	6.62±0.4
F7	0.245±0.07	16±0.35	92.56±0.05	4.80±0.22	92±2	6.60±0.1
F8	0.227±0.03	13±0.68	95.19±0.48	4.51±0.30	94±2	6.72±0.1
F9	0.225±0.05	15±0.76	96.19±0.12	4.01±0.35	95±3	6.75±0.2
F10	0.218±0.08	18±0.46	97.38±0.08	4.21±0.65	98±1	6.79±0.1
F11	0.254±0.08	16±0.62	96.5±0.04	4.41±0.30	105±4	6.81±0.1
F12	0.235±0.04	14±0.35	95.86±0.51	4.82±0.30	105±1	6.85±0.2
F13	0.225±0.08	15±0.54	96.22±0.18	4.09±0.28	105±2	6.78±0.1
F14	0.224±0.04	9±0.28	99.52±0.85	4.10±0.34	106±3	6.92±0.1
F15	0.218±0.07	10±0.74	97.89±0.05	4.50±0.51	102±1	6.87±0.1
F16	0.268±0.02	18±0.24	96.59±0.25	4.93±0.47	105±2	6.87±0.1
F17	0.256±0.07	16±0.52	95.58±0.28	4.29±0.38	105±2	6.81±0.2
F18	0.245±0.04	15±0.18	96.46±0.36	4.99±0.62	104±2	6.82±0.2
F19	0.235±0.05	16±0.19	95.56±0.38	4.19±0.18	104±3	6.67±0.3
F20	0.223±0.06	15±0.42	96.86±0.68	4.85±0.33	103±1	6.62±0.2
F21	0.266±0.05	18±0.35	97.98±0.25	4.12±0.20	110±1	6.63±0.3
F22	0.254±0.02	16±0.34	97.86±0.86	4.64±0.26	108±2	6.81±0.2
F23	0.249±0.19	16±0.56	95.51±0.36	4.48±0.26	107±1	6.51±0.2
F24	0.237±0.19	14±0.46	96.86±0.54	4.01±0.25	107±3	6.71±0.1
F25	0.227±0.09	15±0.33	97.93±0.38	4.20±0.12	105±2	6.73±0.2
F26	0.269±0.16	18±0.36	96.26±0.03	4.41±0.20	110±1	6.74±0.1
F27	0.258±0.18	18±0.14	95.35±0.32	4.34±0.31	110±2	6.76±0.2
F28	0.249±0.15	16±0.45	96.86±0.67	4.09±0.18	108±1	6.76±0.3
F29	0.248±0.13	15±0.38	95.56±0.59	4.23±0.37	106±1	6.77±0.1
F30	0.234±0.06	15±0.32	96.84±0.18	4.01±0.25	105±1	6.79±0.2

*Values are expressed in mean± SD (n=3)

Table 6: Cumulative Percent Drug Release for HPMC E3, HPMC E5 of F1-F10

Time (min)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	Marketed product
0	0	0	0	0	0	0	0	0	0	0	0
1	26.61±1.12	29.81±1.21	53.51±2.95	48.21±2.69	32.70±1.49	39.21±1.48	35.34±2.87	42.37±2.97	49.49±4.97	63.87±3.67	20.81±0.51
3	37.45±2.21	56.97±3.21	71.92±3.44	65.14±3.34	45.11±2.11	40.74±2.78	43.87±3.19	62.59±3.64	52.44±2.22	76.15±4.28	35.51±1.21
5	48.74±2.87	79.47±4.11	82.53±4.43	73.87±3.66	55.49±3.47	62.84±3.57	63.33±3.14	78.47±4.36	68.59±3.49	88.85±4.49	48.0.5±1.09
7	57.74±3.14	94.13±5.01	91.31±5.01	85.33±4.94	61.97±3.21	71.89±3.19	75.39±4.97	84.42±4.45	74.24±4.22	92.11±5.87	61.01±0.52
9	64.33±4.38	98.28±5.41	95.21±4.01	97.31±5.15	82.41±4.78	82.89±4.11	81.94±4.67	97.17±5.12	87.15±4.55	95.89±6.01	70.8±1.41
10	84.57±5.19	----	----	----	96.53±5.78	92.31±5.19	96.79±5.39	----	94.25±5.33	---	78.5±2.22

(Values are expressed in mean± SD (n=3))

Table 7: Cumulative Percent Drug Release for HPMC E15 and HPMC E3+E5 of F11-F20

Time (min)	F11	F12	F13	F14	F15	F16	F17	F18	F19	F20
0	0	0	0	0	0	0	0	0	0	0
1	31.45±1.21	47.71±2.13	38.44±1.66	65.51±3.18	32.17±1.87	45.71±3.47	40.14±2.99	42.31±2.44	45.32±1.77	31.24±1.26
3	47.16±2.13	55.42±3.21	51.44±2.75	90.77±4.69	68.49±2.96	61.48±4.91	56.48±3.51	58.88±3.97	64.43±2.97	52.66±2.27
5	59.46±2.55	67.63±3.52	67.17±3.49	96.59±5.22	79.37±3.97	76.97±5.22	67.29±3.67	69.76±3.52	85.71±3.57	65.44±3.90
7	69.57±3.11	78.96±4.14	81.29±4.94	99.69±6.27	85.67±4.19	86.27±4.22	75.14±4.42	74.94±4.97	94.52±4.95	79.22±3.16
9	85.66±4.14	80.16±4.78	95.95±5.71		96.77±5.17	95.25±5.42	81.22±4.97	83.22±4.24	98.95±5.44	85.8.1±4.21
10	96.47±5.12	95.61±5.24					97.24±5.22	97.37±5.67		96.52±5.47

Values are expressed in mean± SD (n=3)

Table 8: Cumulative Percent Drug Release for HPMC E3+E15 and HPMC E5+E15 of F21 – F30

Time (min)	F21	F22	F23	F24	F25	F26	F27	F28	F29	F30
0		0	0	0	0	0	0	0	0	0
1	37.31±1.19	35.54±1.19	36.71±1.55	39.54±1.19	36.54±1.57	30.31±1.49	49.15±2.46	35.28±1.14	39.57±1.56	31.17±1.47
3	58.53±2.45	55.56±2.88	49.86±2.40	47.57±2.87	49.57±2.97	40.55±2.14	55.84±3.42	49.76±2.66	50.49±2.96	42.19±1.24
5	69.75±3.49	65.39±3.52	58.55±3.76	59.29±3.99	65.59±3.55	53.94±3.96	68.44±3.49	57.58±3.94	61.55±3.52	54.36±2.65
7	79.47±3.51	73.52±3.43	78.51±3.93	75.15±3.26	81.37±4.44	69.39±3.85	79.27±4.44	68.42±3.55	74.26±3.66	69.22±3.66
9	89.69±4.12	75.54±4.90	96.79±4.18	89.24±4.49	95.95±5.73	79.67±4.63	88.66±4.49	83.16±4.97	81.21±4.22	88.79±4.24
10	96.44±4.79	91.72±5.15		96.12±5.63		93.45±5.46	96.14±5.51	95.39±5.12	93.54±5.07	96.36±5.14

Values are expressed in mean± SD (n=3)

Figure 2: Cumulative % drug release for different film formulations of F1-F10

Figure 3: Cumulative % drug release for different film formulations of F11- F20

Figure 4: Cumulative % drug release for different film formulations of F21 –F30

The optimized formulation of Granisetron HCl mouth dissolving film (F14) was best explained by first order, as the plots showed the highest linearity (r2 = 0.992), followed by Korsmeyer Peppas (r2=0.975), Higuchi (r2 = 0.951) and then zero order (r2 = 0.833). The corresponding plot for the Korsmeyer-Peppas equation of the optimized formulation F14 indicated good linearity. The release exponent ‘n’ was found to be for F14 is 0.448, which appears to indicate Fickian diffusion and may indicate that the drug release was controlled by first order release.

Drug excipient interactions studies by FTIR spectroscopy:

Interpretation of FTIR data:

The FTIR Spectra of pure Granisetron Hydrochloride (Figure 5) displayed band at 3320 cm^-1 due to C-H stretch, at 1653 cm^-1 due to C=O stretching, at 1590 due to hetero cyclic C=C stretching. The spectra also showed bands at 1253 due to C-N stretching at 1612 due to N-H stretching. The FTIR spectrum of film containing Granisetron Hydrochloride (Figure 6) such as bands at 3322 cm^-1 due to C-H stretch, at 1650 cm^-1 due to C=O stretching at 1580 due to hetero cyclic C=C stretching , at 1250 due to C-N stretching , at 1620 due to N-H stretching. Thus, the presence of characteristic absorption bands of Granisetron Hydrochloride and the film containing Granisetron Hydrochloride suggest that there is no interaction takes place between the drug and excipients used in the formulation.

Figure 5: FTIR Spectroscopy of GranisetronHydrochloride Pure Drug

Figure 6: FTIR Spectroscopy of Granisetron Hydrochloride optimized mouth dissolving film (F14)

Scanning electron microscopy:

SEM of Granisetron mouth dissolving film shows the rough and uneven surface with circular pits with the absence of particles suggesting the presence of the drug in dissolved state in the polymer HPMC. They further ensure the loss of crystallinity when formulated as a film comprising amorphous HPMC (Figure 7).

Figure 7: Scanning electron micrograph of Granisetron optimized mouth dissolving films

Stability Studies for optimized formulation

Optimized formulation was selected for stability studies on the basis of high cumulative % drug release. Disintegrating time, drug content and In vitro drug release studies were performed for 6 months according to ICH guidelines. From these results it was concluded that, optimized formulation F14 is stable and retained their original properties with minor differences which depicted in the table 9.

Table 9: Physicochemical characteristics of optimized formulation stored at 40 ±2ºC /75 ±5%RH

Retest Time for Optimized formulation	Disintegrating Time (sec)	Drug Content	In vitro drug release profile (%)
0 days	09	99.52	99.69
90 days	11	97.54	97.12
180 days	12	96.04	96.12

In Vivo Disintegration time, mouths feel effect and taste evaluation of optimized formulation (F14):

The films of formula F14 was evaluated in eight male healthy human volunteers with their consent for mouth feel, bitter taste masking, and in- vivo dissolution time in oral cavity. Each volunteer was randomly given optimized film (F14) formulation (single blind design) with a potable water rinse at start. The volunteers were asked to place the film on the tongue. Volunteers were not restricted later with respect to tongue movement. Optimized ODF formulation F14 was placed on the tongue until complete disintegration. The In vivo disintegration for Optimized formulation was found to be 10 seconds (Table 10 and Figure 8). All the volunteers preferred the flavoured films (F14) to the unflavoured film and reported that the films were fast dissolving. All the eight volunteers had expressed mouth feel effect as very good for optimized F14 formulation. This indicates that the incorporation of flavour considerably improved the acceptability of the films. Taste was evaluated and assigned according to bitterness sensation scale, i.e. 0= Unacceptable, 1= Acceptable, 2= moderately acceptable 3= highly acceptable.

SUMMARY AND CONCLUSION:

Based on the encouraging results, the mouth dissolving films of Granisetron HCl can be considered suitable for clinical use in the treatment of chemotherapy induced nausea and vomiting, where a quicker onset of action for a dosage form is desirable along with the convenience of administration. The method of preparation was found to be simple and requires minimum excipients, thus making the product cost-effective. A further in vitro-in vivo study proved that the mouth dissolving films of Granisetron HCl produced a faster onset of action as compared to the conventional tablets.

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Received on 26.08.2017 Modified on 06.09.2017

Research J. Pharm. and Tech. 2018; 11(1): 236-244.

DOI: 10.5958/0974-360X.2018.00044.6

Volunteers	Taste Evaluation Bitterness sensation	Mouth feel effect	*In vivo* Disintegration Time( seconds) Mean ± SD (n=3)
1	3	Very Good	9±0.1
2	3	Very Good	10±0.2
3	3	Very Good	9±0.2
4	3	Very Good	9±0.3
5	3	Very Good	10±0.2
6	3	Very Good	9±0.3
7	3	Very Good	9±0.2
8	3	Very Good	10±0.2