INTRODUCTION:

Sustained release dosage forms are designed to release a drug at a predetermined rate by maintaining a constant drug level for a specific period of time with minimum side effects. The basic rationale of sustained release drug delivery system optimizes the biopharmaceutical, pharmacokinetic and pharmacodynamics properties of a drug in such a way that its utility is maximized, side-effects are reduced and cure of the disease is achieved. Matrix systems are the most popular method among innumerable methods used in the development of sustained release formulations. Hydrophilic polymeric matrix systems are widely used in controlled drug delivery, since they make it easier to achieve a desirable drug release profile, are cost effective and have broad FDA acceptance.^1-4

Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union.

It was designed as a more potent successor to gabapentin. Pregabalin is a (S)-3- amino methyl hexanoic acid, is a structural analogues of γ-amino butyric acid (GABA). They constitute an important group of compounds that are used in the treatment of epilepsy and neuropathic pain. It is a white crystalline solid. It is soluble in water and in both basic and acidic aqueous solutions. The half-life of Pregabalin is also short (5-6.5 hours) which makes it suitable candidate for sustained release formulation. Such a formulation will help to reduce its side effects, decrease dose frequency and improve patient compliance. Keeping these factors in view it was aimed to formulate and evaluate sustained release matrix tablets of Pregabalin to provide a controlled and predictable release of the drug for better management of epilepsy and neuropathic pain^5-7

MATERIALS AND METHODS:

Pregabalin, MCC ( 101 and 102), HPMC K100, Magnesium stearate, and Aerosil (200) were obtained as gift sample from Optimus drugs Pvt. Ltd. Hyderabad, Signet chemical corporation Pvt. Ltd., Mumbai, Diamond corporation, Mumbai, S. Kant healthcare Ltd., Mumbai and Evonic industries, Mumbai, respectively.

Instruments used:

Tablet punching machine: Cadmatch (Accura), Friabilator (Electrolab, Roche type), Hardness tester (Electrilab, Pfizer type), Vernier calliper (Contech, Aerospace), HPLC (Shimadzu, LC 2010 HT), Dissolution Apparatus (Electrolab), FTIR (Shimadzu-IR Affinity-1)

Standard calibration curve of Pregabalin:

100 mg of Pregabalin was dissolved in 100 ml 0.1 N HCl. From this stock solution aliquots of 2, 4, 6, 8, 10 and 12 ml were withdrawn and diluted to 100 ml with 0.1 N HCl. Same solutions were prepared in phosphate buffer pH 6.8 and area was taken by using HPLC, using the same chromatographic conditions used for the dissolution sample analysis. A graph of area versus concentration was plotted.

Procedure for the preparation of matrix tablets:

All ingredients were collected and weighed accurately. Pregabalin and the selected polymers were sifted through sieve no. 60 # and then mixed with remaining excipients. Colloidal silicon dioxide (Aerosil-200) and magnesium stearate were sifted separately, through sieve no. 60 #. Preblending of all ingredients (except lubricant magnesium stearate) was done for 15 minutes. The mixture was again blended for 5-6 minutes then magnesium stearate was added and blended for 5 minutes. Lubricated powder was evaluated for various tests and compressed by rotary machine having circular concave shaped and plain on both sides with pressure of 7-8 tons. Compressed tablets were examined as per official standards and unofficial tests. The composition of different batches of Pregabalin is illustrated in table no.1.

Evaluation of tablet blends:

Bulk density:

Apparent bulk density was determined by pouring a weighed quantity of tablet blends into graduated cylinder and measuring the volume and weight.

Bulk Density =

Tapped bulk density:

It was determined by placing a graduated cylinder, containing a known mass of drug-excipient blend. The cylinder was allowed to fall under its own weight onto a hard surface from the height of 10 cm at 2 second intervals. The tapping was continued until no further change in volume was noted.

Tapped density =

Angle of repose:

The angle of repose of tablet blends was determined by the funnel method. The blends were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

tan θ =

Where ‘h’ and ‘r’ are the height and radius of the powder cone, respectively.

Carr’s index:

Carr’s index shows the compressibility of the blend and it is calculated by the following formula:

CI =

Hausner’s ratio:

A similar index has been defined by Hausner′s^8,9,10

Hausner’s ratio =

Evaluation of Tablets:

Uniformity of weight:

Every individual tablet in a batch should be in uniform weight and weight variation in within permissible limits. The weights were determined to within ±1 mg by using digital balance. Weight control is based on a sample of 20 tablets.

Thickness and Diameter:

The thicknesses and diameter of the tablets were determined using a Vernier caliper, 10 tablets from each batch were used and average values were calculated.

Hardness and friability:

For each formulation, the hardness and friability were determined using the Pfizer hardness tester and Electro lab friabilator test apparatus, respectively.^8-12

Table 1: Materials used for the blend preparation

Sr. No.	Name of Material	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)	F6 (mg)	F7 (mg)	F8 (mg)
1	Pregabalin	150	150	150	150	150	150	150	150
2	MCC 101	110	-	100	90	-	85	-	90
3	MCC 102	-	110	-	-	100	-	45	-
4	HPMC K100	27	26.5	36	44	35	40.5	90	40
5	PVPK30	10	10	10	12	11	20	10	15
6	Aerosil (200)	0.5	1.0	1.5	1.5	1.5	2.0	2.5	2.5
7	Magnesium stearate	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
8	Wt. of Tab.	300	300	300	300	300	300	300	300

In vitro drug release studies:

Dissolution parameters:

Apparatus Basket apparatus (USP Apparatus I)

Dissolution media For first 2 hours hydrochloric acid pH 1.2 (900 ml)

For 2 to 12 hours Phosphate buffer pH 6.8 (900 ml)

Speed 50 rpm

Time 0 to 12^thhour

Temperature 37°C ± 0.5°C

Sampling 5 ml at the interval of 0, 1, 2, 4 and 8 hour

Chromatographic conditions:

Mobile phase Buffer solution of pH 7.5: Acetonitrile (95:5)

Detector Spectrophotometer set at 205 nm

Column BDS hypersil C18 250 mm X 4.6 mm, 5µm

Column Temp. 40°C

Flow rate 1.5 ml/min

Injection volume 50 µl^13-15

Assay of Pregabalin SR tablets:

Standard solution:

160.0 mg of Pregabalin standard drug was dissolved in water and diluted the solution to 100 ml with the same solvent. Further 10 ml of the solution was diluted to 100 ml with the same solvent.

Sample solution:

10 tablets were crushed and powder containing 16 mg of Pregabalin was weighed, dissolved in water and diluted upto 100 ml with the same solvent.

Both solutions were analyzed on HPLC by using the same Chromatographic condition as that of dissolution study^13-15

RESULTS:

The powder blend was evaluated for various tests like bulk density, tapped density, angle of repose, Carr′s index, Hausner′s ratio and the results are mentioned in Table no.2

Table 2: Physical parameters of powder blend

Sr. No.	Parameter	F1	F2	F3	F4	F5	F6	F7	F8
1	Bulk density (gm/ml)	0.33 ±0.0058	0.34 ±0.0057	0.36 ±0.0057	0.35 ±0.0058	0.36 ±0.0058	0.37 ±0.0058	0.37 ±0.0055	0.38 ±0.0058
2	Tapped density (gm/ml)	0.42 ±0.0057	0.41 ±0.0056	0.42 ±0.0058	0.41 ±0.0058	0.42 ±0.0057	0.43 ±0.0058	0.42 ±0.0056	0.43 ±0.0057
3	Angle of repose	32°23´ ±1.25	29°17´ ±1.27	28°33´ ±1.29	28°16´ ±1.25	26°26´ ±1.26	26°39´ ±1.27	26˚23′ ±1.25	26˚15′ ±1.28
4	Carr′s index (%)	21.42 ±0.2517	17.03 ±0.2526	14.28 ±0.2620	14.63 ±0.2357	14.28 ±0.2358	13.95 ±0.2366	11.90 ±0.2365	11.63 ±0.2353
5	Hausner′s ratio	1.27 ±0.0202	1.21 ±0.0207	1.17 ±0.0214	1.17 ±0.0212	1.17 ±0.0223	1.16 ±0.0215	1.14 ±0.0213	1.13 ±0.0216

Table 3: Physical parameters of prepared tablets

Sr. No.	Parameter	F1	F2	F3	F4	F5	F6	F7	F8
1	Average Wt. (mg)	307.5 ±2.5623	308.6 ±2.8732	309.7 ±2.5535	311.2 ±2.5721	306.2 ±2.7620	305.1 ±2.7865	306.2 ±2.4222	307.8 ±2.3221
2	Thickness (mm)	4.42 ±0.0342	4.45 ±0.0363	4.49 ±0.0358	4.47 ±0.0386	4.48 ±0.0359	4.46 ±0.0365	4.48 ±0.0346	4.47 ±0.0359
3	Diameter (mm)	9.48 ±0.2232	9.51 ±0.2321	9.55 ±0.2234	9.54 ±0.2245	9.59 ±0.2231	9.57 ±0.2365	9.58 ±0.2220	9.59 ±0.2226
4	Hardness (Kg-cm²)	7.2 ±0.5033	7.8 ±0.5039	6.4 ±0.5041	7.6 ±0.5039	8.0 ±0.5035	8.2 ±0.5037	8.0 ±0.5023	8.2 ±0.5036
5	Friability (%)	0.56 ±0.1686	0.49 ±0.1615	0.68 ±0.1647	0.52 ±0.1751	0.24 ±0.1643	0.22 ±0.1662	0.23 ±0.1656	0.21 ±0.1645

Table 4: Cumulative % drug release of formulation F1 to F8

Time in hours		Cumulative percentage drug release (%)
Time in hours		F1	F2	F3	F4	F5	F6	F7	F8
In 1.2 N Hydrochloric acid	0	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
	1	20.23	24.45	25.36	25.44	19.74	23.65	19.78	22.58
	2	42.35	46.56	48.52	40.61	38.91	48.76	39.88	45.67
In phosphate buffer pH 6.8	4	74.56	73.26	74.82	58.45	56.95	76.56	58.34	79.64
	8	80.05	83.78	87.32	94.34	79.94	89.26	88.32	90.45
	12	-	-	-	-	93.03	-	95.80	-

Figure 1: In-vitro cumulative drug release profile of batch F1 to F8

DISCUSSION:

Evaluation of blend:

The blends of different formulations were evaluated for angle of repose, bulk density, tapped density, Carr´s index and Hausner´s ratio. The results of these parameters are satisfactory and are mentioned in table 2.

Evaluation of tablets:

The tablets were evaluated for the following parameters and the results are mentioned in table 3.

Uniformity of weight:

The weight of tablets of eight batches was found to be 300 mg and it complies with the USP limits.

Thickness:

The thickness of tablets of eight batches was found in the range of 4.42 to 4.49 mm. The thickness of the tablets of all the batches ensured uniformity.

Diameter:

The diameter of tablets of eight batches was found in the range of 9.48 to 9.59 mm. The diameter of the tablets of all the batches ensured uniformity.

Hardness:

The hardness of tablets of eight batches was found in the range of 6.4 to 8.2 mm. The result indicated that the tablet have the sufficient mechanical stability.

Friability:

The % friability for various batches was found in the range of 0.21 to 0.68. The result indicates percentage loss is not more than 1%.

In vitro dissolution study:

The in vitro dissolution study was carried out for 12 hours using basket method and 1.2 N HCl for first two hours and phosphate buffer (pH 6.8) for further 2 to 12 hours as dissolution media. Dissolution results of all the batches are mentioned in table 4. Formulation F1, F2, F3, F4, F6 and F8 failed to give sustained release for 12 hours and formulation F5 and F7 shows 93.03 % and 95.80 % of drug release at the end of 12 hours. It was observed that on increasing the proportion of HPMC K-100 and MCC 102 the drug release from matrix gets retarded which may be due to slow hydration of matrix and its property to form a thick gel layer, which may be responsible for retardation of the drug release from the tablet. It is expected that the developed formulation should have 100% drug release profile for 12 hrs. Formulations F1, F2, F3, F4, F6 and F8 failed to meet the required theoretical drug release profile. Formulation F5 and F7 complied the required theoretical drug release profile and exhibited the sustained action. Formulation F7 exhibited 95.80 % drug release at the end of 12 hours; therefore it was considered the best formulation among all the eight formulations of this series (figure-1).

Table 1: Abbreviations used in manuscript and their meaning

Sr. no.	Abbreviations	Abbreviations used for
1.	N	Normal
2.	HPLC	High performance liquid chromatography
3.	FDA	Food and drug administration
4.	Pvt.	Private
5.	Ltd.	Limited
6.	FTIR	Fourier transform infrared spetrophotometer
7.	Mg	Milligram
8.	Ml	Mililitre
9.	Cm	Centimeter
10.	USP	United state pharmacopoeia
11.	Rpm	Rotation per minute
12.	ºC	Degree centigrade
13.	Nm	Nanometer
14.	BDS	Base deactivated silica
15.	µm	Micrometer
16.	µl	Microlitres
17.	Gm	Gram
18.	Kg	Kilogram
19.	Mm	Millimeter

The abbreviations used in the manuscript and their meaning are mentioned in table 5.

REFERENCES:

1) Paul B., Gupta P.K., Ara H.D., John E.H. Remington the science and practice of pharmacy. 21^st edition. New York: Wolter kluwer, Lippincott wiliams and Wilkins; 2006. 939-962.

2) Edith M. Encyclopedia of controlled drug delivery. 1^st edition. New York: A Wiley Interscience publication; 2009. 381-385.

3) Lachman L, Herbert A.L., Joseph L.K. The Theory and Practice of Industrial Pharmacy. 3rd edition. Bombay: Varghese Publishing House; 1986. 430-455.

4) Joseph R.R., Vincent H.L.L. Controlled drug delivery fundamentals and applications. 2^nd edition revised and expanded. New York: Marcel Dekker Inc; 1987. 3-56.

5) Gilbert S.B., Christopher T.R. Modern Pharmaceutics. 3^rd edition revised and expanded. New York: Marcel Dekker Inc; 1995. 575-608.

6) Dalim Kumar Baidya, Anil Agarwal, Puneet Khanna, Mahesh Kumar Arora. Pregabalin in acute and chronic pain. Journal of Anaesthesiology Clinical Pharmacology 27(3); 2011, 307-14.

7) L. Arnold, L. Pauer, E. Whalen, J. Barrett, T. Leon. Pain changes in pregabalin-treated fibromyalgia patients associate with anxiety and depression changes. The Journal of Pain 9(4); 2008, 48.

8) Pawar S. D, Pawar R. G., Gadhave M.V., Jadhav S.L., Gaikwad D.D. Formulation and Evaluation of Pregabalin Sustained Release Matrix Tablets. International Journal of Pharmaceutical Research and Technology. 4(02); 2012, 153-159.

9) S.H. Lakade, M.R. Bhalekar. Formulation and Evaluation of Sustained Release Matrix Tablet of Anti-Anginal Drug, Influence of Combination of Hydrophobic and Hydrophlic Matrix Former. Research Journal of Pharmaceutical Technology. 1(4); 2008, 410-413

10) Dinanath Gaikwad, Jadhav R.T., Amol Limkar, Sangeeta S., Kisan Bobe, Manoj Patil. Formulation and Evaluation of Sustained Release Tablet of Aceclofenac by Film Coating. International Journal of Research in Pharmaceutical and Biomedical Sciences 2(1), 2011, 310-318.

11) Sourabh Jain, S.K. Yadav, U.K. Patil, Preparation and evaluation of Sustained release matrix tablet of Furosemide using Natural polymers. Research Journal of Pharmaceutical Technology. 1(4); 2008, 374-376.

12) Durgacharan A. Bhagwat, Pravin S. Kawtikar and Dinesh M. Sakarkar, Sustained release matrices of Verapamil HCl Using Glyceryl Monostreate and Stearic acid. Research Journal of Pharmaceutical Technology. 1(4); 2008, 405-409.

13) Indian Pharmacopoeia 2010, Volume-III, 6^th edition, 1960-1962.

14) Rajinder Singh Gujral, SK Manirul Haque and Sanjeev Kumar, A novel method for the determination of pregabalin in bulk pharmaceutical formulations and human urine samples. African Journal of Pharmacy and Pharmacology 3(6); 2009, 327-334.

15) Prashant Pingale, Tamnay Singasane. Development and validation of HPLC method for the determination of pregabalin in bulk and in pharmaceutical formulations. Research Journal of Pharmacy and Technology 5(6); 2012, 829-833.

Received on 06.08.2013 Modified on 12.09.2013

Research J. Pharm. and Tech. 6(11): November 2013; Page 1190-1194