INTRODUCTION:

Theophylline is structurally classified as a methylxanthine. THP is a non-specific adenosine antagonist, antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects and some of its anti-asthmatic effects. Bioavailability is 100%. It is excreted unchanged in the urine (up to 10%). It is metabolized extensively in the liver (up to 90%). The protein binding is 40%.The success of THP controlled release as a bronchodilator to treat bronchitis is due to its prolonged release rate.THP, a bronchodilator, relaxes and opens the air passages to the lungs, making it easier to breathe. This drug is used mainly in solid oral dosage forms, particularly slow release forms, and has a narrow therapeutic index, requiring regular monitoring of serum THP concentrations to avoid adverse effects. Although this primary role has now been taken by the β2-adrenoceptor agonist,.The main advantages of these formulations for oral use are improved absorption and fewer gastrointestinal adverse effects. The latter can also be reduced by using slow release formulations and these formulations have also been shown to produce a plasma concentration/time profile with adequate therapeutic concentration for upto 12 hr after a dose, despite the short t1/2 of theophylline.³Hydrophilic polymers are becoming very popular in formulating oral sustained-release tablets.

As the dissolution medium or biological fluid penetrates the dosage form, the polymer material swells and drug molecules begin to move out of the system by diffusion at a rate determined by the nature and composition of the polymer as well as formulation technology. Natural gums are among the most popular hydrophilic polymers because of their cost-effectiveness and regulatory acceptance. Xanthan gum is a natural, biosynthetic, edible gum and an extracellular polysaccharide produced by the bacterium Xanthomonas campestris.⁶Xanthan gum is widely used in oral and topical pharmaceutical formulations, cosmetics, and foods as a suspending and stabilizing agent. It is nontoxic, compatible with most other pharmaceutical ingredients, and has good stability and viscosity properties over a wide pH and temperature range.⁷Sustained release preparations provide an immediate dose required for the normal therapeutic response, followed by the gradual of drug in amounts sufficient to maintain the therapeutic response for a specific extended period of time. The major advantage of this category is that, in addition to the convenience of reduced frequency of administration, it provides blood levels that are devoid of the peak-and-valley effect which are characteristic of the conventional intermittent dosage regimen. Sustained release dosage forms are designed to complement the pharmaceutical activity of the medicament in order to achieve better selectivity and longer duration of action. Among the various types of cellulose ether derivatives, HPMC polymers are popular in controlled release matrices due to their compatibility with numerous drugs HPMC offers the advantage that, although wet massing may be used to conventionally granulate the material direct compression of the drug blended drug with HPMC is easily accomplished The adjustment of the polymer concentration and the viscosity grade and the addition of different types and levels of excipients in the HPMC matrix can modify the drug release rate. The objectives of the present work were to prepare sustained release tablets of THP by direct compression method and to study the effect of different of hydrophilic polymers (hydroxypropylcellulose and Xanthan gum ) on the drug release profile on tablets and evaluate its various parameters like hardness, weight variation, thickness, dissolution test, etc^.2,3,5,6

EXPERIMENATAL METHODOLOGY:

Materials and Methods:

Theophylline was procured from (Vergo, Goa) Xanthan gum, magnesium stearate Lactose monohydrate, hydroxyl propyl methylcellulose K-4M (HPMC K-4M) was purchased from S.D. Fine-chem. Pvt. Ltd, Mumbai. All other chemical used were of analytical grade.

Formulation of theophylline sustain release tablets by direct compression method:

The tablets were made by using two different hydrophilic polymers. Microcrystalline cellulose was used as the filler. Magnesium stearate was used as the lubricant. Tablets weighed 250 mg and measured 1.27 cm in diameter. All the formulation ingredients, except the lubricant, were mixed in a plastic container and shaken by hand for about 15–20 min. The lubricant was added to the powder mixture and mixed for another 2–3 min by hand. The tablets were compressed on a laboratory tablet press from (Remi) fitted with flat faced 1.27 cm punch and die sets and compressed at a force of 2000 lbs.^1,4,5

Evaluation of tablets:

Prepared tablets were evaluated as follows:

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 Analytical balance. Weight control is based on a sample of 10 tablets14.

Dimensions:

The dimensions (diameter and thickness) were then determined to within ± 0.01 mm by using vernier calipers.

Tablet dosage forms assay procedure:

Individually, five reference commercial tablets (Voltaren SR 75) and prepared SR tablets were accurately weight and finely powdered by pestle in a martar. A weighed portion of each powder equivalent to 1 mgml–1 of theo was transferred in to a volumetric flask and completed to the volume with methanol. The contents of the flask were sanicated for 10 min to effect complete dissolution. Then these solutions were filtered using Milipore 0.45 μm filter. Appropriate solutions were prepared by taking suitable aliquots of the clear filtrant and diluting them with mobile phase in order to obtain a final solution

Hardness:

The hardness of the tablets was determined by using a Monsanto Hardness Tester.

Friability:

The friability of the tablets was measured in a Roche friabilator (Camp-bell Electronics, Mumbai). Tablets of a known weight (W0) or a sample of 10 tablets are dedusted in a drum for a fixed time (100revolutions) and weighed (W) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 %.

% Friability= W0- W/W0 X100

Dissolution study:

The dissolution study was carried out in a USP dissolution test apparatus using paddle method. The dissolution of drug was conducted in a medium of changing pH after a tablet was placed in 900 ml 0.1N HCl for 2 hrs. Then medium replaced with 900 ml phosphate buffer pH 6.8.The stirring speed was set at 100 rpm,and the temperature was maintained at 370C+-0.50C.The samples were withdrawn at 15, 30,45 upto 120 in HCl and then 30,60 upto 480 min in phosphate buffer and replenished with fresh dissolution medium. The samples were filtered and analyzed by UV spectrophotometer at 268nm.

RESULT AND DISCUSSION:

The results of the in vitro release study for all the formulations are shown in figure-1. At the end of 8th hours the cumulative percentage drug release for the formulations B1-B5 was found to be, 0.22 + 0.77; 38.2 + 0.96; 51.5 + 1.25; 32.8 + 0.49; 29.2 + 0.77 and 64.6 + 1.66 respectively. Among the six formulations, B5 showed prolonged drug release. An increase in the compression force increases the hardness and the apparent density of the tablet, thereby reducing the matrix porosity in the tablet. The release rate decreases with increase in compression force16. The drug release was found to be faster at lower compression force than at higher ones because of the relatively larger matrix porosity of the tablet, which allowed greater penetration of dissolution fluid into the matrix, thus enhancing polymer disentanglement and drug dissolution. The controlled drug release may also be due to increased proportion of polymer. The release rate kinetic data for all formulations is shown in table-2&3. When the data were plotted according to zero order, the formulations showed a high linearity with regression co-efficient values (R2) between 0.9748– 0.9895. It showed that the drug release follows zero order. Diffusion is related to transport of drug from the matrix tablets into the dissolution medium depends upon the concentration. This is explained by Higuchi’s equation. When the data were plotted according to Higuchi’s equations, the regression co-efficient values (R2) were between 0.9630–0.9879.By using Korsmeyer model, the mechanism of drug release was determined. If n = < 0.45, it is Fickian diffusion and if n= 0.45 – 0.89, it is non-fickian diffusion transport The results of all the formulations showed that the n values are between 0.6739 – 0.6901. It proved that all formulations followed non-fickian transport mechanism both diffusion and erosion.^17-19

Formulation Table For Sustain Tablet By Direct Compression Method:

Batch No	Theo phylline	HPMC	Xanthan gum	Avicel	Magnesium stearate	Total weight
B1	75	12.5	_	160	2.5	250
B2	75	25	_	147.5	2.5	250
B3	75	37.5	_	135	2.5	250
B4	75	50	_	122.5	2.5	250
B5	75	62.5	_	110	2.5	250
B6	75	_	12.5	160	2.5	250
B7	75	_	25	147.5	2.5	250
B8	75	_	37.5	135	2.5	250
B9	75	_	50	122.5	2.5	250
B10	75	_	62.5	110	2.5	250

Evaluation Test of tablet:-

Parameter	Theophylline : HPMC K100M			Theophylline : HPMC K100M
	5 kg/cm2			5 kg/cm2
	B1	B2	B3	B4	B5	B6
Hardness (kg/cm2)	5.02 + 0.21	4.96 + 0.34	6.03 + 0.13	6.01 + 0.19	7.03 + 0.24	6.98 + 0.37
Uniformity of weight (mg)	73.8 + 5.2	75.5 + 5.7	74.1+ 3.5	75.2 + 6.2	73.5 + 6.6	74.6 + 7.6
Friability (%)	0.29 + 0.04	0.24 + 0.03	0.20 + 0.07	0.38 + 0.05	0.20 + 0.06	0.11 + 0.05
Drug content (%)	95.8 + 0.41	96.8 + 0.60	97.0 + 0.33	97.4 + 0.22	96.0 + 0.14	97.0 + 0.29
Thickness (mm)	4.2 + 0.00	4.2 + 0.04	4.1 + 0.03	4.1 + 0.05	4.1 + 0.02	4.1 + 0.00
Diameter (mm)	12.6 + 0.01	12.5 + 0.03	12.5 + 0.05	12.6 + 0.04	12.6 + 0.02	12.6 + 0.03

Fig:- Dissolution Study for Theophylline Tablet of Batch B3 And B5

Fig:-In dissolution medium1.2 N HCl for 2 hrs (A) 4hrs (B) 8hrs(C)

CONCLUSION:

In formulation Theophylline Sustained Release tablet, direct compression employed for preparation of tablets possessing optimized characteristics (batches B3 and B5). The amount of HPMC and Xanthan gum were calculated and selected for optimize batch. Results of the present study confirmed that the hydrophilic polymers and hardness plays a major role in drug release. As the hydrophilic polymers and hardness of the tablets increased the drug release was prolonged.

REFERENCES:

1. T. Raja Sekharan,S. Palanichamy, Et Al Formulation And Evaluation of Theophylline Controlled Release Matrix Tablets Using Xanthan Gum Scholars Research Library Der Pharmacia Lettre1 (2), 2009: 93-101

2. Gudsoorkar VR, Rambhau D. Sustained release of drugs. The Eastern Pharmacist(4), 1993:17-22.

3. Pandey VP, Manavalan R, Rajan TS, Ganesh KS. Formulation and release characteristics of sustained release diltiazem hydrochloride tablet. Indian J Pharm Sci 1:44-2003:65

4. Rakesh Patel ,Ashok Baria1 Development And Process Optimization Of Theophylline Sustained Release Matrix Tablet Ijpps Vol 2 (1); 2009:43-56

5. Sanghavi NM, Kamath PR, Amin DS. Sustained release tablets of theophylline. Drug Dev. Ind. Pharm.; 16: 1990:1843-48.

6. Ceballos A, Cirri M, Maestrelli F, Corti G, Mura P. Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets. IL Farmaco. 2005: 60; 913-18.

7. Ford J, Rubinstain MH, Hogan JE, Edgar AJ. Importance of drug type, tablet shape, added diluents on drug release from hydropropylmethylcellulose matrix tablets. Int. J. Pharm. 401987:223-34.

8. Raja Sekharan T, Palanichamy S et al Formulation and Evaluation of Theophylline Controlled Release Matrix Tablets using Guar gum, ARS Pharmaceutica, V, Vol. 2009: 50 ; 205-214.

9. P.G. Welling, M.R. Dobrinska, in: J.R. Robinson (Ed.), Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker Inc., New York, 1978.

10. E.A. Hosny, A.R.M. Al-Helw, M.A. Al-Dardiri, Comparative study of in-vitro release diclofenac sodium from certain hydrophilic polymers and commercial tablets in beagle dogs, Pharmaceutica Acta Helveti 1997:72 ;159–164

11. Y.M. El-Sayed, E.M. Niazy, S.-H. Khidr, In-vivo evaluation of sustained-release microspheres of metoclopramide hydrochloride in beagle dogs, Int. J. Pharm. 1995123 113–118.

12. Y. El-Said, F. Hashem, In-vitro evaluation of sustained-release dyphylline tablets, Drug Dev. Ind. Pharm. 17 1991: 281–293.

13. J.L. Cohen, B.B. Hubert, C.T. Rhodes, et al., The development of USP dissolution and drug release standards, Pharm. Res. 1990: 7 (10) (983–987.

14. T. Higuchi, Mechanism of sustained action medication, J. Pharm. Sci. 1963:52 ;1145–1149.

15. Ayhan Savas¸ Er, Yalçın Özkan, As¸ Kın isoımer preparation and in vitro evaluation of sustained release tablet formulations of diclofenac sodium. 2005:60 ;171–177.

16. Pandit JK, Singh S and Muthu MS. Controlled release formulation in neurology practice. Annual of Ind Academy of Neurolgy Dec – 2006; 207 – 216.

17. Yeole PG, Galgatte, Babla IB and Nkhat D. Design and evaluation of xanthan gum – based sustained release matrix tablets of diclofenac sodium. Ind J Pharm Sci 2006; 68: 185-189.

18. Manthena VS Varma, Aditya M. Kaushal, Alka Garg and Sanjay Garg. Factors affecting mechanism and kinetics of drug release from matrix-based oral controlled drug delivery systems. Am J Drug Deliv 2004; 2:43-57.

19. Evelyn Ojoe, Edna Mitie Miyauchi, Telma Mary Kaneko, Maria Valéria Rolbes Velasco and Vladi Olga Consiglieri. Influence of cellulose polymers type on in vitro controlled release tablets containing theophylline. Brazilian J Pharm Sci 2007; 43: 571-579.

20. Prafulla Kumar Nandi. Invitro evaluation of theophylline – SR tablets. The Eastern Pharmacist oct-1997; 149-150.

21. United States of Pharmacopeia-National Formulary. USP 30 – NF 25. The Unit States Pharmacopeial Convention, Rockville, MD, 2007, Vol. 1, 226.

22. Pharmacopoeia of India. Ministry of health and family welfare. Govt. of India, Controller of publications, New Delhi, 2007; vol. II, 1795. Pathra CH.N, Bhanoji Rao MK, Yadav KS and Prakash K. Influence of some cellulose ethers on the release of propranolol hydrochloride from guar gum matrix tablets. Ind J Pharm Sci 2004; 66:

Received on 22.11.2012 Modified on 18.12.2012

Research J. Pharm. and Tech 6(6): June 2013; Page 637-640