Development and evaluation of Methocel K 15 M based Theophylline floating tablets

Article history: Received on: 12/06/2013 Revised on: 15/07/2013 Accepted on: 05/08/2013 Available online: 18/09/2013 The purpose of the investigation highlights the formulation and optimization of floating tablets containing theophylline as a model drug. Formulations were optimized for different concentrations of cetyl alcohol, citrc acid and methocel K15M by direct compression method. The dissolution study of the tablet matrices of 9 different formulations were carried out in 0.1N HCl as the medium (pH 1.3) for 8 hours using USP type II dissolution apparatus. It was observed the floating lag time for the tablet was 30 seconds and the total floating time was more than 8 hours. The drug release pattern was simulated in different kinetic orders such as Zero Order, First Order, Higuchi, and Korsmeyer release kinetic model. From the study, we observed that Higuchi release kinetics was predominant over other release kinetics and diffusion was the drug release mechanism from the matrices. Korsmeyer-Peppas release kinetics suggests that formulation F3, F4 and F9 followed Fickian type release mechanism whereas formulation F1, F2, F5, F6, F7 and F8 followed Non-Fickian type release mechanism. Thus, it is possible to design theophylline loaded Methocel K15M sustained release matrix tablets with desirable release characteristics by judicious and critical combination of Methocel K15M with other hydrophilic materials.


INTRODUCTION
Theophylline is a methyl xanthine derivative which is effectively used for the treatment of bronchial asthma and bronchospastic reactions.The therapeutic concentration of this drug range from 10 to 20 μg/ml while toxic effect appear at concentration above 20 μg/ml and the fluctuations of its serum concentrations may leads to variable clinical responses (Sarojini et al.,2010;Sundaran et al.,2013).In order to control this problem, short biological half life of drug (8.7 hours) favours development of sustained release formulation (Bosewell-Smith et al.,2006).Sustained release dosage forms are generally used to deliver adequate amount of drug for an extended period to achieve the optimum therapeutic activity of the drug (Sarwar and Hossain, 2012).Such dosage form with prolonged residence times in the stomach are desirable for drugs that are locally active in the * Corresponding Author Dr. Mohammad Safiqul Islam, Associate Professor, Department of Pharmac, Noakhali Science and Technology University Sonapur, Noakhali-3814, Bangladesh. Tel: +88-0321-71483 (Office); + 88-01714165107(Mobile), Fax: +88-0321-62755 stomach, have an absorption window in the stomach or in the upper small intestine, unstable in the intestinal or colonic environment, and/or have low solubility at high pH values.In addition, as the total gastrointestinal transit time of dosage forms is increased by prolonging the gastric residence time (Rathor and Ram 2013), these systems can also be used as sustained release devices with a reduced frequency of administration and therefore, improved patient compliance.Recent approaches to increase the gastric residence time of drug delivery systems include (i) bioadhesive devices (ii) systems that rapidly increase in size upon swallowing and (iii) low density devices that float on the gastric contents (Deshpande et al., 1996;Ingani et al., 1987;Singh and Kim, 2000).But the simplest and possibly the most elegant way to improve drug absorption is to hold a drug delivery system above the absorption window.The properties and type of polymer play very crucial role in release rate, mechanism and floating behaviors in the floating system (Hascicek et al., 2000).The polymers considered as the first category are those which form insoluble or skeleton matrices while the second category represents hydrophobic and water-insoluble materials, which are potentially erodable and the third group exhibits hydrophilic properties (Islam et al., 2009).Methocel K15M is a hydrophilic polymer that become hydrated, swollen and facilitates to diffuse the drug (Bidah and Vernaud, 1991).Drugs that are formulated with such gel forming hydro-colloidal along with carbon dioxide generating agents like citric acid and sodium bicarbonate may swell in the gastric fluid as it gets contact with the aqueous medium.
Generation of carbon-di-oxide and entrapment of this gas into the polymeric gel causes swelling of the dosage form which results in a bulk density of less than 1.It then remains buoyant and floats in the gastric fluid, resulting a prolonged gastric residence time.This floating dosage form is well known as a hydrodynamically balanced system (HBS) (Uzdemir et al., 2000).It has been suggested that an active material should be formulated in the form of an HBS to enhance bioavailability of those drugs having a dissolution or stability problem in the small intestinal fluid, drugs which are being locally effective in the stomach and drugs with a narrow therapeutic window (Jobin et al., 1985).The objective of the present study was to formulate and characterize sutained release floating matrix tablets of theophylline using the hydrophilic cellulose derivatives-Methocel K15.Studies were conducted to determine whether there was any effect of floating agent and rate-retarding agent upon the floating lag time of the tablets.The impact of formulation variables upon the release rate and the mechanism of release were also evaluated with various kinetic model studies.

Materials
Theophylline was used as a model drug which was obtained as a gift sample from Square Pharmaceuticals Limited, Bangladesh.Methocel K15M was purchased from BASF, Germany while citric acid anhydrous and sodium bi-carbonate was obtained from Loba Cheme Pvt. Ltd., India.Avicel, magnesium stearate, cetyl alcohol and talc were sourced from BASF, Germany.All other chemicals and reagents used were of analytical and pharmaceutical grade.

Preparation of floating tablets of theophylline
Tablets containing theophyline as a pure drug were prepared by direct compression method.The active ingredient (theophylline) and other excipients were accurately weighted for twenty seven tablets according to the formulations (table 1).The respective powders (drug, polymers, and fillers) and optional additives were blended thoroughly with a mortar and pestle.Particular attention was given to ensure thorough mixing and phase homogenization.Finally powder blends were compressed using a Perkin-Elmer laboratory hydraulic press.Before compression, the surfaces of the die and punch were lubricated with magnesium stearate to minimize friction during ejection.All the preparations were stored in airtight containers at room temperature for further study.

Floating behavior (buoyancy) of the tablets
The tablets were immersed in 900 ml of 0.1N HCl buffer in USP type II apparatus at 37 ± 0.5º C for 8 hours.The in vitro buoyancy was determined by floating lag time which is the time that is required to reach the tablet from the bottom to the top surface of the dissolution apparatus.The time for which the tablet constantly floats on the surface of the medium (Total floating time) was also measured (Rosa et al., 1994;Abubkar and Jun 2000;Ali et al., 2004)).

In vitro drug release studies
The in vitro drug release studies were carried in USP type II apparatus at 75 rpm maintained 37 ± 0.5º C containing 0.1N HCl (pH 1.3).Then 10 ml of aliquots was withdrawn from the dissolution medium at specific time intervals and replaced with equivalent volume of fresh medium to maintain the volume constant.Collected dissolution samples were filtered and diluted to a suitable concentration with 0.1 N HCl solution.The absorbances of the solutions were measured at 271 nm for theophylline by using UV spectrophotometer (Shimadzu UV 1201, Japan).

Kinetic analysis of the dissolution data
In order to study the exact mechanism of drug release from the matrix floating tablets, the in vitro dissolution data were fitted to various mathematical models like zero order, first order, Higuchi, and Korsmeyer-Peppas models (Varelas et al., 1995;Mulye and Turco, 1996;Higuchi, 1961;Korsmeyer et al., 1983).Zero-order Model: F = K 0 t, where F represents the fraction of drug released in time t, and K 0 is the apparent release rate constant or zero-order release constant.First-order Model: ln (F) = -K 1 t, where F represents the fraction of drug released in time t, and K 1 is the first order release constant.Higuchi Model: F = K H t, where F represents the fraction of drug released in time t, and K H is the Higuchi dissolution constant.Korsmeyer-Peppas Model: F = K P t n , where F represents the fraction of drug released in time t, K P is the rate constant and n is the release exponent, this indicates the drug release mechanism.For cylindrical shaped tablets, n value below 0.45 indicates Fickian diffusion whereas n value between 0.45 and 0.89 indicate non-fickian or anomalous transport.When the n values are 0.89 or above, the release can be characterized by case II and super case II transport (Ritger and Peppas, 1987).

RESULTS AND DISCUSSION
Tablets from formulations were evaluated for in vitro buoyancy study where they exhibited floating lag times below 1 minute (Table 2).The tablets were constantly floated on dissolution medium for more than 8 hours.It was observed that citric acid content significantly controls the floating lag times.Floating lag time was reduced due to increase of amount of floating agent.Increased amount of floating agent caused rapid formation as well as entrapment of CO 2 gas into the hydrophilic polymeric gel which eventually resulted in reduction of floating lag time (Khan et al., 2009).The three formulations (F1, F4, and F7) in the experiment contain no citric acid.The observation showed that after 8 hours of dissolution formulation F7 containing highest amount of cetyl alcohol (51 mg) released only 51.5% of drug while formulations F1 and F4 which contains no cetyl alcohol 0% and 6% cetyl alcohol respectively; showed a drug release of 48.2% and 47.8% respectively.Similarly, percent drug release from formulations F2, F5, F8 after 8 hours of dissolution is 47.1, 49 and 53% respectively as the amount of cetyl alcohol decreases.Percent drug release from F3, F6, F9 formulations after 8 hours of dissolution is 53.1, 51.5 and 55.8 % respectively.On the other hand, formulations F1, F6 and F8 contain 0% cetyl alcohol whereas 0, 4 and 2% of citric acid.After 8 hour of dissolution drug release from these formulations is 48.2, 51.5 and 53.0%respectively.After 8 hour of dissolution, drug release from formulations F2, F4, F9 is 47.1, 47.8 and 55.8% respectively.While, after 8 hour of dissolution drug release from formulations F3, F5, F7 is 53.1, 49 and 51.5% respectively.Increased drug release from latter formulation may be attributed to decreased amount of cetyl alcohol.It was observed that at low level of cetyl alcohol content (0%), increment of citric acid significantly increased drug release.On the other hand at higher level of cetyl alcohol content (3-6%), the effect of citric acid was reduced to some extent.In the experiment major determinant is found to be polymer concentration.In all cases, it was found that higher polymer concentration retarded the drug release.
The regression co-efficient (R 2 ) values of all the formulations for different kinetic model are indicated in Table 2. From the R 2 values, it was clearly found that all the formulations followed Higuchi release kinetics (Figure 1) other than the zero order or other release kinetics.On the other hand, analysis of release mechanism explored that formulation F3, F4 and F9 followed Fickian type release mechanism whereas formulation F1, F2, F5, F6, F7 and F8 followed Non-Fickian type release mechanism (Table 3).The rate and extent of drug release increased from the matrices with increasing the amount of citric acid in the formulation which is similar findings to previous study (Khan et al., 2009).
From the data, it is clear that T 25% , T 50% and T 80% values were changed due to the change of amount of citric acid and cetyl alcohol in the matrix tablets (Table 4).In all these formulations the values of T 25% , T 50% and T 80% are larger for those formulations which contain higher quantities of citric acid and lowest quantities of cetyl alcohol.If we consider formulation F-1, F-6 and F-8 which contains 0% of cetyl alcohol and 0, 4 and 2% of citric acid, it is seen that highest values correspond to F6 which contains highest citric acid and no cetyl alcohol.Second highest values go to F1 which contains neither citric acid nor cetyl alcohol.Lowest values correspond to F8 possessing intermediate amount of citric acid and no cetyl alcohol.The similar observation is true for the F3-F6-F9, F2-F5-F8, F1-F4-F7, F2-F4-F9, and F3-F5-F7 groups.

CONCLUSION
The approach of the present study was to develop a sustained release theophylline matrix tablet with Methocel K15M.The study reveals that, it is possible to design theophylline loaded Methocel K15M sustained release matrix tablets with desirable release characteristics by judicious and critical combination of Methocel K15M with other hydrophilic materials.Commercial availability of Methocel K15M and its direct compression characteristics will reduce the unit cost of product by decreasing processing steps; the presence of citric acid in the matrix will modulate the drug release to an acceptable pharmacokinetic profile.The Korsmeyer release rate along with Higuchi release rate and T 50 % data clearly manifests the necessity of combining a hydrophilic matrix system with Methocel K15M.However, further studies in this context should be carried out to evaluate stability and reproducibility of this dosage form.In vitro-In vivo correlation should also be performed to assess the efficacy of Methocel K15M based matrix tablets in in vivo environment.

Table . 1
: Formulation of the sustained release matrix tablet of theophylline.
*All the amounts are expressed in gm.