INTRODUCTION:

Nowdays Sustained drug delivery system becomes more and more popular. The most preferable route of administration for such system is the oral route among the patients because of the self administration and minimal handling problems.

However, this route has certain problems such as unpredictable gastric emptying rate, short gastro intestinal transit time (8-12 h) and existence of an absorption window in the gastric and upper small intestine for several drugs 1,2. Moreover, Sustained delivery also helps to reduce the frequency of drug administration to patients which directly improves patient compliance and health recovery period.

Several approaches are currently used to retain the dosage form in the stomach. These include bioadhesive systems 3, swelling and expanding systems 4, 5, floating systems 6, 7 and other delayed gastric emptying devices 8, 9. The Floating drug delivery system (FDDS) uses the gastro-retentive technique for drugs which are absorbed from the stomach and is poorly absorbed or insoluble in the intestine due to the high pH environment.

Atorvastatin calcium is a HMG-CoA reductase inhibitor used in the treatment of hyperlipidaemia. It has a oral bioavailability of less than 12% because of high first pass metabolism. It is highly soluble in acidic pH and absorbed more in the upper part of the GIT. In order to improve the absorption and its oral bioavailability 10. We have attempted to formulate a floating drug delivery systems using Atorvastatin Ca.

In this present investigation floating drug delivery of atorvastatin Calcium were developed using Hydroxy propyl methyl cellulose (HPMC K₄M) has been reported to enhance the controlled release property. Xanthum gum is used as a release modifying agent 11. Sodium bicarbonate and Citric acid are gas (CO₂) forming agents, (Sodium bicarbonate are alkalizing agents and Citric acid are Buffering agents), Magnesium stearate and Lactose were used as lubricant and diluent respectively

MATERIALS AND METHODS:

Materials:

Atorvastatin Calcium was received as a gift sample from by Emcure Pvt Ltd., Pune. Hydroxy propyl methyl cellulose K₄M (HPMC K₄M), Xanthum gum Sodium bicarbonate, Citric acid, magnesium stearate, Lactose was procured from Research Lab Fine Chem Industries, Mumbai.

Methods:

Preparation of Floating Tablet of Atorvastatin Calcium:

All the ingredients were accurately weighed and pass through sieve No. 60. In order to mix the ingredients thoroughly, Atorvastatin Calcium and HPMC K₄M, Xanthum gum were blended in a mortar for 15 minutes, then Sodium bicarbonate, Citric acid, Lactose, were mixed one by one. After thoroughly mixing these ingredients, finally added magnesium stearate, The powder blend was passed through sieve no.44 and further mixed for additional 2-3 minutes. The tablets were compressed using tablet compression machine. The weight of the tablets were kept constant for all formulation table No.1.

Evaluation of floating tablets of Atorvastatin Calcium:-

Pre-compression parameters :

Bulk density :

Bulk density was determined by pouring the blend into a graduated cylinder. The bulk volume and Mass of the powder was determined. The bulk density was calculated by using below mentioned formula,

Density:

The measuring cylinder containing a known mass of blend was tapped for a fixed time. The minimum volume

occupied in the cylinder and the Mass of the blend was measured. The tapped density was calculated using the following formula,

Carr’s Index :

The simplest way for measurement of free flow of powder is compressibility, a indication of the ease with which a material can be induced to flow is given by carrs’ index which is calculated as follows,

The value below 16% indicates a powder with usually give rise to good flow characteristics, whereas above 23 % indicate poor flowability.

Angle of repose:

Angle of repose was determined using fixed funnel method. The blend was poured through a funnel that can be raised vertically until a maximum cone height (h) was obtained. Radius of the heap (r) was measured and the angle of repose (ө) was calculated using the formula.

θ = tan ^-1(h / r)

Post-compression: parameters:

Weight variation test:

Twenty tablets were selected randomly and average weight was determined. Then individual tablets were weighed and was compared with average weight. The comparison variation within the I.P limits, it passes the weight variation test.

Tablet hardness:

Tablet crushing strength or hardness, the force required to break a tablet in a diametric compression, was measured using Monsanto tablet hardness tester.

Thickness:

The thickness of individual tablets was measured using Sliding caliper scale, which permits accurate measurements and provides information of the variation between tablets.

Table No.1:- Composition of floating tablet of Atorvastatin Ca ( F1 to F9)

Ingredients	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)	F6 (mg)	F7 (mg)	F8 (mg)	F9 (mg)
Atorvastatin ca	20	20	20	20	20	20	20	20	20
HPMC K4M	50	50	50	60	60	60	70	70	70
Xanthan gum	20	30	40	20	30	40	20	30	40
Sodium bicarbonate	20	20	20	20	20	20	20	20	20
Citric acid	30	30	30	30	30	30	30	30	30
Mg stearate	04	04	04	04	04	04	04	04	04
lactose	106	96	86	96	86	76	86	76	66
Total	250	250	250	250	250	250	250	250	250

Tablet strength was tested by using Roche Friabilator. 20 tablets were weighed and placed in the friabilator and operated for 100 revolutions at 25 rpm for 4 min, tablets were taken out and dedusted. The percentage weight loss was calculated by reweighing the tablets. The % friability was then calculated by,

F = {(Wt initial) – (Wt final) / (Wt initial)} x 100

In- Vitro Buoyancy studies:

The in-vitro floating behavior of the tablets was determined by floating lag time. The tablets were placed in 100 ml beaker containing 0.1N HCl having pH 1.2. The floating lag time and total floating time were determined.

In-vitro Drug Release Study:

The release rate of floating tablets was determined using USP Type II Apparatus. The dissolution test was performed using 900 ml of 0.1N HCl, at 37 ± 0.5˚C at 50 rpm for 24 h. A 5 ml sample was withdrawn from the dissolution apparatus at specified time points andthe samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45 μm membrane filter and diluted[9]. Absorbance of these solutions were measured at 245 nm using UV Visible Spectrophotometer. Percentage cumulative drug release of optimized batches is shown in Fig.no 1.

RESULT AND DISCUSSION:

Precompression Parameters:

Determination of Bulk Desnsity, Tapped density:-

Results are shown in table no. 2

Table No:-2 Precompression Parameters of formulation F1 to F9

Formulation	Angle of repose (⁰)	Bulk density (gm/cc)	Tapped density (gm/cc)	Carr’s index (%)
F1	32.12	0.825	1.005	17.91
F2	32.32	0.844	0.976	13.52
F3	33.48	0.856	0.998	14.22
F4	34.36	0.886	0.989	10.41
F5	34.38	0.815	0.969	15.89
F6	33.78	0.824	0.976	15.57
F7	34.46	0.796	0.948	16.03
F8	28.03	0.792	0.983	19.43
F9	33.98	0.786	0.946	16.91

Carr’s index:

It found in between 10.41% to 19.43% which indicates thatpowder blends have the required flow property for compression. Results are shown in table no. 2

Angle of Repose:

It found in between 28.03% to 34.46%. Results are shown in table no. 2

Post-compression: parameters:

Shape of the Tablet:

^M^{icroscopic examinations of tablets from F1-F9 were} found to be circular shape with no cracks.

Weight variation:

The percentage weight variations for all formulations were tabulated in table no.3. All the formulated (F1 to F9) tablets passed weight variation test as the % weight variation was within the pharmacopoeial limits of ± 7.5% of the weight. The weights of all the tablets were found to be uniform with low standard deviation values.

Hardness Test:

The measured hardness of tablets of each batch ranged between 5.1±0.1 to 5.5±0.4 Kg/cm². This ensure good handling characteristics of all batches. The result is shown in the table no. 3

Friability Test:

The value of friability test were tabulated in table no. 3. The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable.

Drug Content Uniformity:

The percentage of drug content for (F1 to F9) was found to be in between 95.06 to 99.04 of Atorvastatin Calcium, it complies with official specifications. The results are shown in table no. 3.

Table No.3 : Post-compression parameters of Formulations (F1-F9)

Parameters	Weight variation	Hardness (Kg/Cm²)	Thickness (mm)	Friability (%)	Drug content (%)
F1	248±5%	5.3	4.1	0.82	95.06
F2	252±5%	5.4	4.2	0.89	98.09
F3	266±5%	5.2	4.1	0.72	97.92
F4	260±5%	5.3	4.2	0.76	98.32
F5	251±5%	5.1	4.3	0.85	97.62
F6	262±5%	5.5	4.4	0.96	96.23
F7	253±5%	5.4	4.6	0.92	96.04
F8	255±5%	5.1	4.1	0.86	99.04
F9	252±5%	5.2	4.8	0.76	98.03

In-Vitro Buoyancy study:

Tablet of each formulation F1-F9, On immersion in 0.1 ^{N HCL (PH 1.2) Buffer at 37o C,
the tablets floated, and} remained buoyant without disintegration. Table No. 4 shows the results of Buoyancy study.

Table No. 4 : In Vitro Buoyancy study of formulations (F1-F9)

Batch No.	Total lag time(sec)	Total floating time(hrs.)
F1	129	12
F2	124	11
F3	118	12
F4	133	11
F5	127	12
F6	113	11.4
F7	122	12
F8	119	>14
F9	111	12

^{Swelling study:}

Swelling study was performed on all the batches (F1 to F9) for 6 hrs. The result of swelling index are shown in^{Table No.5.}

In vitro drug release studies:

The Result of In- vitro drug release studies are shown in table no.6

Table No.5: Swelling index of Floating Tablets of different Batches (F1 to F9)

TIME (Hrs.)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
1	12.30	9.36	11.63	9.83	10.84	11.93	13.14	14.83	11.90
2	18.29	11.33	14.9	18.62	18.87	16.43	24.42	26.39	28.09
3	23.63	26.89	28.98	24.36	23.30	25.44	30.33	38.63	35.82
4	28.36	34.35	32.68	36.60	30.66	34.88	35.85	42.22	42.63
5	34.84	38.64	40.62	41.30	37.23	41.22	45.87	52.30	48.00
6	43.12	46.82	44.92	48.96	46.92	53.32	52.88	58.32	52.36

Table no. 6: In vitro Drug release studies of Batches (F1 to F9)

Time (Hrs.)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
1	9.25±0.9	11.02±0.2	8.25±0.1	9.56±0.2	10.25±0.3	13.25±0.6	8.96±0.9	11.26±0.3	10.25±0.7
2	22.36±0.2	19.25±0.3	22.26±0.2	21.56±1.2	23.45±0.2	21.89±0.2	22.89±0.5	23.56±0.5	21.48±1.4
3	26.58±0.3	30.50±1.1	25.15±0.3	28.56±1.5	30.56±0.9	31.56±0.6	26.45±0.9	28.56±0.6	25.15±1.5
6	52.87±0.1	50.26±0.2	44.15±0.6	45.12±0.2	50.26±0.5	51.03±0.9	49.45±1.2	50.51±0.7	49.12±0.5
9	78.75±1.1	75.15±0.8	68.65±0.9	65.14±0.9	68.17±0.3	72.89±0.5	68.96±0.1	70.25±0.6	67.85±0.9
12	96.25±0.8	92.15±0.2	84.23±0.8	86.87±1.1	87.96±0.2	92.25±0.7	86.25±0.6	90.24±0.9	87.25±0.6
13		96.15±0.3	89.15±1.1	92.45±0.2	94.25±0.6	98.64±0.4	92.25±0.2	94.88±0.6	92.54±0.5
14			96.85±0.6	97.15±0.3	98.54±0.5		96.25±0.7	99.07±0.2	96.26±0.6

Fig No. 1 :- In-vitro dissolution of atorvastatin calcium floating tablets of different batches (F1 to F9)

CONCLUSION:

The present study was carried out to develop the floating drug delivery system using HPMC K₄M and Xanthum gum as carriers. The result of experimental studies of Atorvastatin Calcium floating Tablets proved that the powder blends showed good flow properties, tablet evaluation test are within the acceptable limits, The new oral controlled release system shows good in vitro buoyancy in an acidic medium. Presence of effervescent agent (Sodium bicarbonate) in the tablets is necessary for in vitro buoyancy. In this research work the use of combination of HPMC K₄M and Xanthum gum result in the formation of good matrix forming floating Tablet. From above study the F8 formulation was optimized because of their drug release in 14 hrs was 99% , floating lag time also good as compared the other formulations. we concluded that floating type gastro retentive drug delivery system holds a lot of potential for drug having stability problem in alkaline PH or which mainly absorb in acidic PH. And resulted into the improved bioavailability and ensured therapy with many existing drugs.

ACKNOWLEDGMENT:

The authors are thankful to Emcure Pvt Ltd., Pune for providing gift sample of Atorvastatin calcium. ^{The authors are grateful to}JSPM’S Jayawantrao Sawant College of Pharmacy and Research, Pune, Maharashtra, for providing necessary facilities to conduct the experimental studies.

REFERENCES:

1. Agyilirah GA, Green M, Ducret R. Evaluation of the gastric retention properties of cross linked polymer coated tablet versus those of a non-disintegrating tablets. Int J Pharm. 1991; 75: 241-247.

2. Hoffman AF, Pressman JH, Code CF, Witzterm KF. Controlled entry of orally-administered drugs; physiological considerations. Drug DevInd Pharm. 1983; 9: 1077.

3. Santus G, Lazzarini G, Bottoni G. An in vitro- in vivo investigation of oral bioadhesive controlled release Furosemide formulations. Eur J Pharm Biopharm.1997; 44:39-52.

4. Deshpande AA, Rhodes CT, Shah NH, Malick AW. Controlled release drug delivery system for prolonged gastric residence; an overview. Drug DevInd Pharm. 1996; 22: 531-539.

5. Deshpande AA, Shah NH, Rhodes CT, Malick W. Development of a novel controlled release system for gastric retention. Pharm. Res. 1997; 14: 815-819.

6. Menon A, Ritshel WA, Sakr A. Development and evaluation of monolithic floating dosage form for Furosemide. J Pharm Sci.1994; 83: 239-245.

7. Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating dosage forms: an in vivo study demonstrating prolonged gastric retention. J Control Release. 1998; 55: 3-12.

8. Singh B, Kim K, Floating drug delivery system: an approach to oral controlled drug delivery via gastic retention. J Control Release. 2000; 63: 235-259.

9. Chawla G, Bansal A. A means to address regional variability in intestinal drug absorption. Pharm Tech. 2003; 27: 50-68.

10. Ozaki K, Kubo T, Imaki R, Shinagawa H, Fukaya H, Ohtaki K, Ozaki S, Izumi T, Aizawa Y (August 2006). "The anti-atherosclerotic effects of lipid lowering with atorvastatin in patients with hypercholesterolemia". 13 (4): 216–9.

11. Sweta Arora, Javed Ali, Alka Ahuja, Roop K Khar, Sanjula Baboota, Floating drug delivery system: A review. AAPS Pharm Sci Tech. 2005; 6 (3): E 372-E 390.

Received on 02.09.2015 Modified on 17.09.2015

Res. J. Pharm. Dosage Form. and Tech. 7(4): Oct.-Dec., 2015; Page 256-260

DOI: 10.5958/0975-4377.2015.00036.1