INTRODUCTION:

Ambroxol is a metabolite of bromhexine with similar actions and uses. It is chemically described as trans-4- [(2-Amino-3, 5-dibromobenzyl) amino]-cyclohexanol. It is an expectoration improver and a mucolytic agent used in the treatment of acute and chronic disorders characterized by the production of excess or thick mucous. It has been successfully used for decades in the form of its hydrochloride as a secretion-releasing expectorant in a variety of respiratory disorders⁽¹⁾. Its short biological half life (4 h) that calls for frequent daily dosing (2 to 3 times) and therapeutic use in chronic respiratory diseases necessitates its formulation into sustained release dosage form⁽²⁾.

The continual and enormous progress in technology for drug delivery during last three decades has translated many novel concepts, into clinical applications. Apparently there has been an accelerating realization for the need of controlled delivery of drugs. With properly designed or customized systems the concentration of a drug substance in blood plasma pool and the site of action follows an exquisite temporal pattern.⁽³⁾. The current studies were designed with the aim to formulate sustained release tablets of Ambroxol Hydrochloride a mucolytic agent using natural gums- Xanthan, κ Carrageenan and Guar gum. These gums are dominant hydrophilic vehicles used for preparation of oral controlled drug delivery systems. A systematic approach was attempted to develop a twice daily sustained release Ambroxol Hydrochloride tablets.

MATERIALS AND METHODS:

The drug Ambroxol Hydrochloride was procured as a gift sample from Shreya Pharmaceuticals Ltd. Aurangabad. Xanthan, κ Carrageenan and Guar gum were procured from Loba Chemicals.

Formulation of matrices: ^{(4, 5)}

Ambroxol Hydrochloride and the gums were weighed in ratios 1: 1.5, 1: 2, 1: 2.5, screened through stainless steel sieve (mesh no 40) to break the agglomerates if any and the mixture was blended thoroughly by ballooning method in a polybag. Tablets were punched using 8 stations Karnavati Minipress D-II using 8mm flat punches.

Evaluation of matrices :^{( 6- 8)}

Thickness and Diameter- These properties were measured using digital Vernier Calipers using 6 tablets each.

Tablet Hardness- It was measured by Monsanto Hardness tester using 6 tablets each.

Friability- Roche Friabilator was used for testing .20 matrices were accurately weighed and placed in apparatus that revolves at 25 rpm dropping them through 6 inches with each revolution. After 4 mins matrices were reweighed and %loss was determined the following formula:

% loss = Initial weight of matrices- Final weight of matrices X 100

Initial weight of matrices.

Water uptake studies: :^{( 9-10)}

Rate of uptake of test medium was determined by equilibrium weight gain method. Dry matrices were weighed, placed in dissolution baskets and immersed in Phosphate buffer (pH 6.8) maintained at 37± 0.5º C in dissolution vessels. At regular intervals pre-weighed matrices were removed and reweighed. The % uptake was estimated using following Equation:

Water Uptake% = Ws –Wi _{X 100}

Ws: weight of swollen matrix at time t ; Wi: initial weight of the matrix; Wp: weight of the gum in the matrix.

Dissolution studies of the matrices:

The release rate of Ambroxol hydrochloride from the matrices was determined using USP Dissolution test apparatus II (Paddle type) TDT -082-Electrolab using 900 ml of 6.8 buffer at 37 ± 0.5º C and 100 rpm. 5ml was withdrawn hourly for 12 hours and replaced with fresh medium. Absorbance was measured at 248 nm on JASCO V-530. Cumulative drug release was calculated using equation from Standard curve. 6 tablets were used from each batch.

Batches were coded as X1, X2, X3 for Xanthan gum matrices in the ratio of 1:1.5, 1:2,1:2.5, C1, C2 ,C3 for κ Carrageenan matrices in the ratio of drug: κ Carrageenan 1:1.5, 1:2, 1:2.5 and G1, G2, G3 for Guar gum matrices in the ratio 1:1.5, 1:2, 1:2.5. Dose of the drug was 75mg and gum weights in the three different ratios are 112.5 mg, 150 mg and 187.5 mg.

RESULTS:

The results were given in following tables.

Table1 Physical Evaluation of matrices

Batch	Hardness (Kg)	Thickness (mm)	Friability
X1	5.3 ±0.4	2.91± 1.36	0.42
X2	5.8 ±0.9	3.67±1.33	0.61
X3	5.7 ±1.5	4.11± 0.99	0.60
C1	5.3± 0.7	2.96± 1.22	0.65
C2	5.5± 1.5	3.46± 1.56	0.61
C3	5.2± 1.2	4.21± 1.22	0.59
G1	4.3± 1.1	2.99±1.22	0.57
G2	4.3±1.2	3.69±1.1	0.49
G3	4.1±1.1	4.1±1.2	0.67

Mean ± SD for n = 6.

Table 2 Water uptake studies (Swelling Index %)

Batch	2hrs	4hrs	6hrs	8hrs
X1	96.94	209.71	221.31	240.44
X2	168.45	267.99	264.08	246.26
X3	188.54	287.23	295.59	320.47
C1	69.56	162.15	162.49	170.73
C2	70.7	160.18	143.6	160
C3	80.5	151.5	140.7	164.8
G1	21.19	47.06	73.82	93.36
G2	26.95	52.58	74.78	103.38
G3	29.47	54.91	82.64	111.73

Table3 Dissolution studies (%Release)

Batch	1hr	6hr	12hrs
X1	19.94±1.2	55.5±2.27	75±2.2
X2	17.2±1.64	52.7±1.2	70±1.35
X3	15.4±1.54	42.3±2.1	60±1.2
C1	20±1.2	55.25±2.1	75.51±1.35
C2	13±1.43	45.7±2.4	69.7±2.3
C3	12±1.56	39±2.1	66.7±2.27
G1	43.97±2.36	88.54±1.20	---
G2	30.42±2.39	68.08±1.20	90.41±3.17
G3	28.73±2.11	60.45±1.21	85.38±2.19

Mean ± S.D for n = 6.

DISCUSSION: ⁽¹¹⁾

Water uptake studies for the matrices shows that maximum swelling occurs in Xanthan gum matrices. In case of κ Carrageenan matrices high initial swelling is seen due to its high hydration ability. Guar gum on the other hand does not swell rapidly as in the case of Xanthan gum. Guar gum swells slowly initially and hence there is initial burst release of drug from the guar gum matrices. Hence a more quantity of polymer is required to achieve sustained release of drug from guar gum matrices as compared to Xanthan Gum and Carrageenan matrices. The present studies show that greater the amount of Xanthan Gum greater is the retarding effect. At lower concentration Xanthan Gum shows a rapid swelling of matrices with less tight hydrogel structure resulting in higher initial drug release. Conversely at higher gum concentration initial drug release was diminished. κ Carrageenan also showed similar results. As the gum concentration in the matrices increased the dissolution rate decreased. The drug release from guar gum matrices is by water penetration, gelatinization and diffusion. The retarding effect is less as compared to the other two gums which may be due to its slow swelling rate initially. Xanthan and κ-Carrageenan are better retardants than guar gum.

REFERENCES:

1. Tripathi K.D, Respiratory system drugs in Essentials of Medical Pharmacology, Jaypee brothers Medical Publishers, 2003, 5^th ed, pp 195-200.

2. Robinson J.R, Lee V.H.L, Controlled Drug Delivery: Fundamentals and Applications, Marcel Dekker Inc, 2009, 2^nd ed vol 20.

3. Santos H, Veiga F, Pina M.E, Sousa J.J, Compaction, compression and drug release characteristics of xanthan gum pellets of different compositions, Eur. J. Pharm. Sci., 2004 21, 271–281.

4. Chien Y .W, Fundamentals in rate controlled drug delivery in Novel Drug Delivery Systems, 2005, Marcel Dekker, Inc, New York, vol 50, 2^nd ed, pp 41-115.

5. Banker G.S, Anderson N.R, Pharmaceutical Dosage Forms: Tablets in The Theory and Practice of Industrial Pharmacy, edited by Lachman L, Lieberman H.A, Kanig J.L, 1986, Varghese Publishing House, Mumbai, 3^rd ed, pp 293-345.

6. Roy D.S, Rohera B.D, Comparative evaluation of rate of hydration and matrix erosion of HEC and HPC and study of drug release from their matrices, European Journal of Pharmaceutical Sciences 2002, 16,193–199.

7. Conti S, Maggia L, Segalea L, Matrices containing NaCMC and HPMC, Swelling and release mechanism study, International Journal of Pharmaceutics, 2007, 333,143–151.

8. Nerurkar H.W, Jun, Controlled-release matrix tablets of ibuprofen using cellulose ethers and carrageenans: effect of formulation factors on dissolution rates, European Journal of Pharmaceutics and Biopharmaceutics, 2005, 61, 56–68.

9. Hayashi T, Kanbea H, Okada M, Formulation study and drug release mechanism of a new theophylline sustained-release preparation, International Journal of Pharmaceutics, 2005, 304, 91–101.

10. Gupta V. K, Hariharan, M, Controlled-release tablets from carrageenans: effect of Formulation, storage and dissolution factors, European Journal of Pharmaceutics and Biopharmaceutics, 2001, 51, 241-248.

11. Idus H, Lordi N.G, Some factors affecting the release of water soluble drug from a compressed hydrophilic matrix, Journal of Pharmaceutical sciences, 1998, 55, 840-843.

Received on 27.07.2009 Modified on 23.09.2009

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 882-883