INTRODUCTION:

Conventional oral dosage forms (tablets or capsules) are pioneer of drug delivery system. These are frequently used because of ease of administration, self-administration, dose accuracy, price effectiveness and patient compliance than other dosage forms.^[1]But these dosage forms suffer from many drawbacks like low bioavailability, delayed onset of action and dysphasia.^[2,3,4] Dysphasia is very common in geriatrics, pediatric patients and patients who are travelling due to which they are unable to continue their drug therapy for a longer time prescribed by the doctor causing ineffective drug therapy.

To overcome it, formulators have developed a modified drug delivery system called as Fast dissolving tablets. According to FDA, the fast dissolving tablets may be defined as solid dosage form when placed on tongue disintegrates within few seconds and disintegration time may be from seconds to about a minute which offers various advantages like administration without water, accurate dosing, improved bioavailability, better taste, good stability, improved safety and efficacy.^[5,6] These are also called as orodispersible tablets, ODT, mouth dissolving tablets, Porous tablets, Fast disintegrating tablets but USP approved all these terms as orodispersible tablets. First FDT came into existence in 1980 and got approval in 1996 from the USFDA for Zydis ODT formulation of Claritin having loratidine drug.^[7,8] The worldwide market for FDT was $1.6 billion in 2006, $6.4 billion in 2009 and $15 billion in 2015.^[9] FDT facilitates quick disintegration due to presence of superdisintegrants which are synthetic as well as natural. But the natural superdisintegrants are gaining more attention as compared to synthetic because they are relatively cheaper, biocompatible, non toxic, less side effects, renewable sources, environmental friendly and better disintegrating property.^[10,11,12]

MATERIALS AND METHODS:

Atorvastatin calcium was obtained from Ranbaxy Labs Ltd., Mumbai, India as a gift sample. Isabgol seeds (Plantago ovata) were purchased from Global herbs, New Delhi, India which was authenticated and preserved in herbal museum of BSA Institute of Pharmacy Faridabad for further reference. Sucralose, Talc and Magnesium stearate were obtained from S.D. Fine-Chem Ltd, Mumbai (India), Sodium starch glycolate and crospovidone from central drug house, New Delhi (India), Aerosil from Yarrow Chem Products, Mumbai (India), Mannitol from Fischer Scientific India Pvt. Ltd., Mumbai (India). All chemicals and reagents used in this work were of analytical grade.

Isolation of mucilage from seeds of isabgol:^[13]

200gm of Isabgol seeds (Plantago ovata) were dipped in distilled water for two days and then boiled the seeds for one hour for complete segregation of mucilage from the seeds. The boiled material was filtered through muslin cloth by squeezing to remove extra material from the mucilage. The filtered mucilage was washed with equal amount of acetone for precipitation. The precipitated mucilage was segregated and kept in hot air oven for drying at a temperature less than 60°c. Dried mucilage was powdered, sieved (≠60mesh), weighed and stored finally in desiccator till use. Dried mucilage was characterized using various evaluation parameters as per literature.

Drug excipient compatibility studies:

The mixtures of drug and excipients were kept in petri-dishes at room temperature for one month and then analyzed using the Fourier transform infra red instrument at ARBRO laboratories, Delhi.

Formulation of fast dissolving tablets:^[14]

Fast dissolving tablets were prepared using the direct compression method. Drug and excipients were passed through ≠20 sieve. The drug and excipients were mixed in poly bag for 10 minutes and compressed the mixture using multi-stationary tablet punching machine. The formulated tablets were packed in amber colored bottle and kept in desiccator for evaluation.

Pre-compression studies of powder blend:^[15]

All formulation batches were studied for pre-compression parameters like bulk density, tapped density, angle of repose, compressibility index and hausner ratio as per methods given in Indian Pharmacopoeia.

Post compression studies:^{[16,17,18,19,20,21,22]}

Thickness and Diameter:

Thickness and diameter of tablets were calculated using the screw gauge for three times and their mean was recorded.

Weight variation test:

This test is performed to ensure uniform weight of the tablets of a particular batch. Twenty tablets were weighed individually, calculated average weight of the tablet and compared the individual weight to the average weight. The weight variation was calculated using the USP method for it.

Hardness:

It is the force which is required to break a tablet. The resistance of tablet to breakage during handling, storage and transportation depends on hardness of tablet. Hardness of tablet of each formulation was evaluated by Monsanto Hardness tester for three times and mean value was calculated.

Table 1: Formulation of fast dissolving tablets

Ingredients	A1	A2	A3	A4	A0	S1	S2
Atorvastatin calcium (mg)	10	10	10	10	10	10	10
Plantago ovata mucilage (mg)	2%	5%	8%	11%	-	-	-
Sodium starch glycolate (mg)	-	-	-	-	-	5%
Crospovidone (mg)	-	-	-	-	-	-	4%
Magnesium oxide (mg)	16	16	16	16	16	16	16
Sucralose (mg)	6	6	6	6	6	6	6
Aerosil (mg)	5	5	5	5	5	5	5
Talc (mg)	2	2	2	2	2	2	2
Magnesium stearate (mg)	1	1	1	1	1	1	1
Mannitol (mg)	142.5	150.5	146.5	134.5	148.5	148.5	149.5
Orange flavour (mg)	1.5	1.5	1.5	1.5	1.5	1.5	1.5

Friability (%):

Friability may be defined as loss in weight of tablet during transportation. Friability was evaluated using Double drum friabilator. 20 tablets were selected randomly and weighed on digital balance. These tablets were rotated in double drum friabilator at 25rpm for 4 minutes. Then these tablets were removed from friabilator, dusted off and reweighed. % friability was calculated using the formula:

Wetting time:

It is the time required to reach the solvent at the upper surface of the tablet. This test mimics the action of saliva on tablet in human volunteers. A piece of double folded tissue paper was placed in petri dish having 10ml of pH 6.8 simulated salivary fluid and a water soluble dye, Eosin dye. The tablet was positioned on tissue paper and time taken by tablet for complete wetting was recorded in triplicate and mean was calculated.

Water absorption ratio:

A piece of double folded tissue paper was placed in a petri dish having 10ml of water with few drops of Eosin dye. A pre weighed tablet was placed on the surface of tissue paper. The tablet was reweighed after completion of wetting of the tablet. This test was performed in triplicates for each batch and calculated using the formula:

In vitro disintegration time:

Formulated tablet was kept in a beaker having 10ml of 6.8 pH simulated salivary fluid at 37± 0.5°c and the time at which tablet was completely disintegrated was recorded. The test was performed three times for each batch and mean of the results was recorded.

Drug content (%):

Randomly selected ten tablets were weighed and milled in powder form. The powder proportionate to 10mg drug was dissolved in 6.8pH simulated salivary fluid to obtain the solution of 10µg/ml. The absorbance of filtered solution was observed at 247nm using UV Spectrophotometer and drug content was calculated in triplicates.

In-vitro drug release studies^[23,24]:

In-vitro release studies were carried out using IP apparatus type I (Paddle type ) in 900ml 6.8pH simulated salivary fluid as dissolution media at speed of 75rpm and temperature 37±0.5°c. 5ml of the of samples were withdrawn at 0, 2, 4, 6, 8, 10, 15, 20, 25, 30 minutes time interval and replaced with fresh dissolution media at same time. Samples were analysed at 247nm in triplicates using UV spectrophotometer against simulated salivary fluid as blank. The model independent parameters like DE_10min, DE_25min and t_50%, t_90% were calculated.

Ex-Vivo studies^[25,26]:

Ex-vivo studies were carried out using Franz diffusion cell to calculate the drug permeation through the buccal cavity of goat which mimics the in-vivo permeation of drug. Buccal mucosa of goat was obtained from slaughter house. It was washed with distilled water and then in isotonic phosphate buffer solution, 6.8pH for 2 minutes. Epithelium of buccal mucosa was isolated and finally washed with isotonic phosphate buffer solution, 6.8pH. The receiving compartment of cell was filled with 6.8pH simulated salivary fluid and epithelium of buccal mucosa was fixed between the receiving compartment and donor compartment. A speed of 50rpm was maintained using magnetic stirrer to mimic the buccal cavity environment. Then tablet was placed on the epithelium in the donor compartment and one ml of samples were withdrawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 minutes time interval and replaced them with fresh 6.8pH simulated salivary fluid at same time. The samples were analyzed at 247nm using UV spectrophotometer in triplicates against simulated salivary fluid as blank.

Figure 1: Franz diffusion cell

Comparison with marketed formulation:

The best formulation on basis of various parameters was compared with conventional marketed tablet. The comparative study was based on the disintegration time, wetting time, water absorption ratio and in-vitro drug release studies parameters. The DE_10min, DE_25min and t_50%, t_90% were also calculated and compared with formulated tablet.

Stability studies for optimized formulation²⁷:

Stability studies for Optimized formulation A3 were performed using the ICH guideline Q1C at 40±2°c / 75±5% RH for one month in stability chamber. At the end of study, tablets were analyzed for in-vitro drug release studies. Similarity (f2) factor was calculated using the software DD Solver for the tablets after stability studies and before stability studies. If the value of similarity factor (f2) is 50-100, the formulations have no significant difference in dissolution.

RESULT AND DISCUSSION:

Fast dissolving tablets of Atorvastatin calcium were formulated using the mucilage of isabgol seeds (plantago ovata) in concentration of 2-11% along with A0 (without superdisintegrating agent and S1, S2 (with synthetic superdisintegrating agent).

Characterization of isolated mucilage of plantago ovata:

Mucilage of Isabgol (plantago ovata) was isolated and characterized for various parameters given in table. Results of characterization complied with standards revealing that mucilage can be further used for formulation of fast dissolving tablets.

Table 2: Results of evaluation parameters for Plantago ovata mucilage

S.No.	Evaluation parameters	Results
1	% yield	20.2%
2	pH (1% aqueous solution)	6.62±0.09
3	Viscosity (1% aqueous solution)	8.86±0.38
4	% LOD	8.5±0.72
5	% Ash value	2.3±0.32
6	Swelling index	64.89±1.44
7	Melting point	296.6±1.52
8	Particle size	80 - 105µm
9	Bacterial count	20 CFU / gm
10	Fungi count	5CFU / gm

Drug-excipients compatibility studies:

The FT-IR spectrum of test sample showed characteristic peaks at 2970.38 cm^-1 (C-H stretching), 1315.45 cm^-1(C-N stretching), 3363.86cm^-1 (OH group), 3660.89 cm^-1 (N-H stretching), 1157.29cm^-1 (C-F stretching), 810.10cm^-1 and 744.52 cm^-1(C-F stretching) confirming the structure of atorvastatin calcium. The FT-IR spectrum of drug was similar to spectrum of drug with excipients revealing that no molecular interaction was found between drug and excipients.

Figure 2: FT-IR spectra of test sample of pure drug (Atorvastatin Calcium)

Figure 3: FT-IR spectrum of drug with excipients

Pre-compression studies of powder blend:

The powder blend for FDTs was assessed for various pre-compression studies and angle of repose, compressibility index, hausner ratio were 28.20±1.11 to 32.29±2.06, 11.11 to 21.95, 1.12 to 1.25 respectively revealing that powder blend has good flow properties and can be further used for preparation of tablets.

Post-compression studies:

The formulated FDTs were assessed for various post-compression parameters revealing that formulation A3 having Isabgol (plantago ovata) mucilage in 8% concentration is comparable with other formulations of mucilage as well as formulation of synthetic superdisintegrant which indicate that mucilage in 8% concentration has desirable characteristic for a good fast dissolving tablet. The tablet of A3 formulation has hardness, % friability, thickness, diameter, wetting time, disintegration time, water absorption ratio, drug content in range of 3.05kg/cm², 0.53%, 3.37±0.42mm, 7.89±0.76mm, 26±0.5sec, 18±1sec, 68.43±0.06%, 98.76±1.56% respectively better than other formulations. The main parameters for assessing the FDTs are disintegration time, wetting time, water absorption ratio which are 18±1sec, 26±0.5sec, 68.43±0.06% respectively for A3, higher among all formulations revealing that mucilage in concentration of 8% has better super disintegrating property. The results of post-compression studies indicate that on increasing the concentration of mucilage of Isabgol from 2 to 8% the super disintegrating property also increased but beyond that concentration the super disintegrating property decreased because mucilage behaves like a gelling agent beyond that concentration. A3 formulation (8% mucilage) has better results as compared to S1 and S2 (Synthetic super disintegrating agents) revealing that mucilage of Isabgol seeds could be a better super disintegrating agent than synthetic super disintegrating agents.

Table 4: Post compression studies of various formulations using natural Disintegrants (A1 to A4), without disintegrant (A0) and Synthetic Disintegrants ( S1to S2)

Formulations (code)	A1	A2	A3	A4	A0	S1	S2
Diameter (mm)	8.05 ±0.04	8.21 ± 0.32	7.89 ± 0.76	8.04 ± 0.23	8.13 ± 0.23	8.02 ± 0.12	8.03 ± 042
Thickness (mm)	3.56 ± 0.23	3.48 ± 0.31	3.37 ± 0.42	3.64 ± 0.13	3.43 ±0.67	3.56 ± 0.76	3.62 ± 0.13
Weight variation	Pass	Pass	Pass	Pass	Pass	Pass	Pass
Hardness (kg/cm²)	3.75±0.25	3.46±0.25	3.05±0.16	5.12±0.32	4.58±0.32	3.11±0.14	3.12±0.23
Friability (%)	0.32	0.46	0.53	0.15	0.22	0.43	0.44
Wetting time (sec)	53±1	46±0.5	26±0.5	192±1.73	186±0.5	31±2.6	32±0.5
Water absorption ratio (%)	54.23±0.12	57.56±0.19	68.43±0.06	41.21±0.12	41.71±0.03	63.32±0.29	62.64±1.12
D.T. (sec)	41±1.5	32±1.5	18±1	181±2.51	167±1	26±2.5	27±2
Drug content (%)	94.12 ±1.12	95.62 ±1.04	98.76 ±1.56	93.76±2.12	94.53±1.92	96.43±1.05	96.95±0.76

In-vitro drug dissolution studies:

The formulation A3 (with 8% mucilage) has better drug release profile as compared to other formulations. The formulation A3 released 88.07±1.5% drug in 10 minutes which was higher among all formulations. As concentration of mucilage increased, the drug release profile was also increase up to 8% due to decreasing disintegration time of tablet but after this, drug release profile decreased which might be due to high disintegration time of tablet beyond that concentration. Formulations S1 and S2 having synthetic superdisintegrating agents also have good drug release profile but slightly lesser than A3 having 8% mucilage revealing that mucilage of isabgol seeds could be a better choice as a super disintegrating agent. The model independent parameters T_25%, T_80% and %DE_10min, %DE_20min were calculated for all formulations using the software DD solver revealing that A3 has T_25%and T_80%,%DE_10min and %DE_20minof 0.87min and 9.28min, 56.39% and 74.05% respectively which were best among all formulations revealing that A3 is the best among all formulations and comparable with S1 and S2 formulations having synthetic super disintegrating agent.

Figure 4: In-vitro drug release profile of FDT formulations

Table 5: Model independent parameters

Formulations	T_25%(min)	T_80% (min)	%DE_10min	%DE_20min
A1	2.12	17.79	39.83	56.12
A2	1.45	14.84	46.12	62.04
A3	0.87	9.28	56.39	74.05
A4	7.78	63.09	17.42	27.63
A0	6.85	64.34	19.13	29.39
S1	1.09	13.05	44.76	63.76
S2	1.80	13.37	45.03	63.38

Ex-vivo studies:

Formulation A3 (with 8% mucilage) showed higher and A4 (11% mucilage) showed least drug permeation through buccal mucosa revealing that lower the disintegration time, higher would be drug permeation through buccal mucosa. On basis of this study, A3 formulation was selected best formulation which released 11.23% drug in one minute through buccal mucosa which was also comparable with S1 and S2 having super disintegrating agents. Ex-vivo studies revealed that there might be increase in bioavailability of drug because some amount of drug reaches directly to the systemic circulation through the oral mucosa and rest of the amount absorbed from whole of the gastrointestinal tract. Drug permeation through buccal mucosa also might be responsible for quicker onset of action.

Figure 5: Drug permeation through buccal mucosa for FDT formulations

Comparison with marketed conventional tablet:

The best formulation A3 was compared with marketed conventional tablet on the basis of in-vitro drug release profile and ex-vivo drug release profile through buccal mucosa revealing that fast dissolving tablets having mucilage of plantago ovata in 8% concentration were successfully formulated. Comparison of drug release through buccal mucosa for A3 (best formulation) with marketed formulation showed that drug permeation through buccal mucosa for A3(19.11%) was more than marketed formulation (3.94%) in five minutes which was due to higher disintegration time of the marketed formulation than A3. Best formulation A3 could have better absorption and quick onset of action and hence improved efficacy showed by the drug release through buccal mucosa. Hence it was proved that fast dissolving tablets of Atorvastatin calcium were formulated successfully which could be a promising formulation in future for the treatment in lowering of lipid profile of body with superior release rate kinetics with increased efficacy.

Figure 6: Comparison of dissolution data of best formulation (A3) with marketed formulation

Figure 7: Comparison of ex vivo results of A3 with marketed formulation

Stability studies for optimized formulation:

Best formulation A3 was analyzed for stability studies on basis of drug release profile. Similarity factor was found as 71.08 revealing that best formulation A3 was stable after accelerated conditions of temperature and humidity.

Figure 9: Dissolution profile of A3 before and after stability studies

CONCLUSION:

On the basis of above study, it was concluded that fast dissolving tablets of Atorvastatin calcium were formulated successfully using the mucilage (8% w/w) of plantago ovata showed maximum super disintegrating property which was superior in comparison with synthetic super disintegrants as discussed in result and discussion . The drug release through ex vivo studies ( buccal mucosa) correlated with the in-vitro drug release data shows IVIVC( In vitro in vivo coreleation). The optimized formulation A3 was found to have drug permeation through buccal mucosa (19.11%) higher than other formulations.

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Received on 02.07.2018 Modified on 30.07.2018

Research J. Pharm. and Tech 2018; 11(11): 5001-5007.

DOI: 10.5958/0974-360X.2018.00912.5

Formulations (code)	Bulk density (g/cc) ± S.D.	Tapped density (g/cc) ±S.D.	Carr’s index (%) ±S.D.	Hausner’s ratio ±S.D.	Angle of repose (°) ±S.D.
A1	0.28±0.005	0.34±0.01	17.64	1.21	29.23±0.87
A2	0.34±0.005	0.42±0.01	19.04	1.23	28.20±1.11
A3	0.33±0.005	0.41±0.01	19.51	1.24	30.38±1.29
A4	0.31±0.001	0.39±0.01	20.51	1.25	31.1±1.40
A0	0.30±0.032	0.37±0.02	11.11	1.23	29.43±1.32
S1	0.28±0.005	0.33±0.01	15.15	1.17	30.04±1.39
S2	0.26±0.03	0.31±0.05	16.12	1.19	28.45±1.21