INTRODUCTION:

This is novel type of dosage form for oral administration in which one layer contains extended release metoprolol succinate and another layer contains immediate releasing drug amlodipine besilate. Therapy with metoprolol alone and the combination of metoprolol and amlodipine was well tolerated in patients with mild to severe heart failure, as evidenced by a lack of adverse effects on heamodynamic improvement with long-term treatment.

Amlodipine besilate is an oral long-acting dihydropyridine calcium channel blocker. It is indicated for the treatment of hypertension, chronic stable angina, vasospastic angina (Prinzmetal’s variant angina) and angiographically documented coronary artery disease. Metoprolol is a beta1-selective (cardio selective) adrenoreceptor-blocking agent. It is indicated in for the treatment of hypertension, angina pectoris, heart failure and also for symptomatic heart failure of ischemic, hypertensive, or cardiomyopathic origin.

The present work aims to develop a stable and optimized bilayer dosage form containing one immediate release drug amlodipine besilate and another extended release drug metoprolol succinate as extended release dosage form.

MATERIAL AND METHOD -

Experimental Details :-

Table No. 1 Brief summary of Formulation of Metoprolol succinate

Formulation Ingredients	1	2	3	4	5	6	7	8
Metoprolol succinate	47.5	47.5	47.5	47.5	47.5	47.5	47.5	47.5
MCC	35	20	47	43	37	33	27	22
HPMC	70	65	50	50	55	55	60	60
Carbomer	--	25	18	22	18	22	18	22
Povidone	25	25	30	30	30	30	30	30
Isopropyl alcohol	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.
HPMC	65	60	50	50	55	55	60	60
Magnesium stearate	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5

Table No. 2 Brief summary of Formulation of Amlodipine Besilate

Formulation Ingredients	1	2	7	8
Amlodipine Besilate	6.95	6.95	6.95	6.95
Microcrystalline cellulose	41.8	37	37	37
Anhydrous Calcium Hydrogen Phosphate	41	41	41	41
Croscarmellose Sodium	3.0	3.0	3.0	3.0
Lake of sunset yellow	0.5	0.5	0.5	0.5
Purified water	q.s.	q.s.	q.s.	q.s.
Starch paste	4.0	4.0	4.0	4.0
Sodium Starch Glycollate	--	6.0	6.0	6.0
Colloidal silicon dioxide	1.5	1.5	1.5	1.5
Magnesium stearate	1.0	1.0	1.0	1.0
Lake of sunset yellow	0.25	0.25	0.25	0.25

METHOD :-

Metoprolol part:

Ø Metoprolol, microcrystallinecellulose, hydroxy propyl methyl Cellulose and carbomer-71G were sifted through # 30 mesh.

Ø The above material were loaded into the RMG and mixed at slow speed impeller for 15 minutes.

Ø The PVPK-30 binder solution was added slowly into the RMG at slow speed impeller and chopper off.

Ø The mixing was continued at fast speed impeller and with chopper for 2 minutes until end point is reached.

Ø The wet mass was passed through 7.00 mm screen.

Ø The wet mass was loaded in Fluidized Bed Dryer and then dried at 55-60°C until LOD was not more than 3.5%.

Ø The dried material was sifted through # 20 sieve using vibratory sifter.

Ø At last lubrication was done.

Amlodipine Part:

Ø Amlodipine besilate was mixed with microcrystalline cellulose in polybag manually and passed through # 40 mesh.

Ø Then colour sunset yellow (Aluminium Lake) was mixed with anhydrous calcium hydrogen phosphate and croscarmellose sodium in geometric proportion in poly bag manually and passed through #100 sieve.

Ø The above blend was loaded into RMG and mixed it for approximately 15 minutes.

Ø The binder solution was prepared by adding the starch slurry to hot water (100°C) slowly with continuous stirring.

Ø Binder solution was added into RMG at slow speed.

Ø The binder vessel was rinsed with sufficient quantity of purified water and added to RMG. It was mixed at slow speed for 3 minutes.

Ø The mixing was continued at fast speed for approximately 2 minutes, till the granulation end point was reached.

Ø The wet mass was then passed through 7.00 mm screen.

Ø The wet mass was loaded in Fluidized Bed Dryer and then dried at 55-60°C until LOD was not more than 3.5%.

Ø The dried material was sifted through # 20 sieve using vibratory sifter.

Ø At last lubrication was done.

Fig. – Bilayer Tablets of Metoprolol Succinate ER and Amlodipine Besilate.

RESULT-

The Formulation of Metoprolol Succinate ER and Amlodipine Besilate were prepared by using different polymer (Hpmc, Methocel, Carbapol) with different diluents (MCC, Cellulose Phosphate, Starch, Croscarmalose Sodium) and then evaluated.

Table No. 3 – Post- compression study of Bilayer Tablet

Specifications	Unit	Trial No.
Specifications	Unit	1	2	3	4	5	6	7	8
Thick ness	Mm	3.92	3.86	3.94	3.90	3.80	3.90	3.85	3.90
Hard ness	Kg/ cm2	8	8.5	8	9	8.5	8.5	8	8
Friabi lity	%	0.12	0.14	0.22	0.20	0.11	0.14	0.15	0.16
Uniformity of weight (mg)	Mg	340.0	343.0	340.0	345.0	344.0	343.0	342.0	344.0

In-Vitro Dissolution Study of Bilayer Tablet -

Table No. 4 - Comparative dissolution profile of bilayer Tablets containing Metoprolol succinate

Sr. No.		Time (Hrs)		% of Drug Release
				Marketed Product (%)		Trial Batches
						1		2		3		4		5		6		7		8
1.		1		18.7		14		10.9		40		33		27.3		24.5		16.2		13.1
2.		4		35.4		57.4		25.3		66.2		61.2		55		50.6		42.3		32.5
	3.	8	54.3		73.8		44.7		71.3		77.4		74.1		71.3		55.7		51.4
	4.	20	83		78		73.1		75.9		79		75		77.1		73.2		80.1

Table No. 5 - Comparative dissolution profile of bilayer Tablets containing Amlodipine Besilate

Sr. No.	Time (min)	% of Drug Release
		Marketed Product (%)	Trial Batches
		Marketed Product (%)	1	2	7	8
1.	10	22.3	19.3	24.3	16.2	23.9
2.	20	48.2	38.2	46.5	42.3	46.7
3.	30	74.6	66	79.5	55.7	77.8
4.	45	98	80	98.8	73.2	99.2

Kinetic Study –

Table No.6- Kinetic study

Time	Cumulative % Release	Cumulative % of drug remaining	Log cumulative % of drug remaining	Square root of Time
1	13.1	86.9	1.94	1
4	32.5	67.5	1.83	2
8	51.4	48.6	1.69	2.83
20	80.1	19.9	1.3	4.47

Figure 1- Zero order release kinetics of Trial VIII

Figure 2- First order Kinetics of Trial VIII

Figure 3 - Higuchi (square root) kinetic (Cumulative percent drug released vs square root of time). SQRT indicates square root.

Drug Release Kinetics:

The zero-order rate describes the systems where the drug release rate is independent of its concentration. Figure 1 shows the cumulative amount of drug release vs time for zero-order kinetics. The first order, which describes the release from systems where the release rate is concentration dependent, is illustrated by Figure 2, which shows the log cumulative percent drug remaining vs time. Higuchi’s model describes the release of drugs from an insoluble matrix as a square root of a time-dependent process based on Fickian diffusion. Figure 3 illustrates the Higuchi square root kinetics, showing the cumulative percent drug release vs the square root of time³³. The release constant was calculated from the slope of the appropriate plots, and the regression coefficient (r²) was determined (Table 6). It was found that the in vitro drug release of Metoprolol succinate ER was best explained by first order (r² =0. 9994), as the plots showed the highest linearity, followed by Higuchi’s equation (r² = 0.9974) and zero-order (r² = 0.9471).

DISCUSSION:-

The Formulation of Metoprolol Succinate ER and Amlodipine Besilate were prepared and then evaluated. The prepared tablets were checked for the quality of the tablet under uniform condition of manufacturing process. the values were found to be thickness- 4.0mm ±0.2mm, diameter-9.5, hardness-8-9kg/cm^2, and friability less than 1 % and found to be within the limits prescribed. The prepared tablets were checked for invitro drug released study using 0.1 N HCL as dissolution medium for amlodipine besilate and ph 6.8 phosphate buffer as dissolution medium for metoprolol succinate.

The comparative study were done for drug with marketed preparation and shown in figure. Thus it can be concluded that a stable bilayer tablet of metoprolol succinate ER and amlodipine besilate can be prepared by using hpmc k 15 m and carbomer as a polymer with optimum concentration as shown in trial viii. It was found that the in vitro drug release of Metoprolol Succinate ER was best explained by first order (r² =0. 9994), as the plots showed the highest linearity, followed by higuchi’s equation (r² = 0.9974) and zero-order (r² = 0.9471).

ACKNOWLEDGEMENTS:-

I respectfully acknowledge this project work to my Parents and Family Members who made me genius in field of education and allowed me to do post graduation in Pharmacy with love and all the pains they have taken for me.

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Received on 09.02.2010 Modified on 02.03.2010

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1291-1294