Research Paper. S.I. Ahmed 1, M.L. Narsu 3, S.J. Mohan 2 and Y.M. Rao 2 *

Transcription

1 6 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 2 July-September 21 International Journal of Pharmaceutical Sciences and Nanotechnology Research Paper Volume 3 Issue 2 July - September 21 Formulation Study and Evaluation of Matrix and Three-Layer Matrix Tablets Oral Controlled Drug Delivery System Based on Xanthan Gum and Locust Bean Gum S.I. Ahmed 1, M.L. Narsu 3, S.J. Mohan 2 and Y.M. Rao 2 * 1 Jayamukhi College of Pharmacy, Warangal, India. 2 University College of Pharmaceutical Sciences, Warangal, India. 3 JNTU, Hyderabad, India. ABSTRACT: The present study was carried out to develop oral controlled release matrix tablets and three layer matrix tablets of highly water soluble diltiazem HCl using natural polymers Xanthan gum (XG), locust bean gum (LBG) and a mixture XG: LBG in 1:1 ratio as matrix forming agent, and anionic Sodium Carboxyl Methyl Cellulose as release retardant layer on the matrix core, Di calcium Phosphate (DCP) and Micro crystalline Cellulose (MCC) as fillers. Matrix core tablets were prepared with by granulation technique.the characterization of physical mixture of drug and excipeints was performed by infra red spectroscopy. The finding of the study indicated that the matrix tablets prolonged the release, but predominantly in a first order fashion, layering with SCMC granules on the matrix core, provided linear drug release with zero order kinetics. The influence of layers on matrix core and release rate was described by the peppas equation, model independent approach, Mean dissolution time (MDT) and dissolution efficiency (D.E 8%). The addition of SCMC layers on the matrix core could notably influence the dissolution behavior and mechanism of drug release. Increasing the quantity of layers caused decreased values of k and increased n value, in a linear relationship. MDT for matrix tablet (S6) and three layer matrix tablets (S6L3) was found to be 5.16h and 11.97h, D.E 8% was 76.23% and 66.21% respectively. These indicated that the release of drug is slower from the three layer matrix tablets. Type of fillers has a limited effect on the drug release mechanism from matrix tablets. Stability studies revealed that the formulation was stable at 45 ±2 C and 75±5%RH. Hence natural polymer as matrix core and anionic polymer SCMC as retardant layer in the form of three layer matrix tablets provided the zero order release of highly water soluble Diltiazem HCl. KEYWORDS: Hydrophilic polymers, three layer matrix tablets, Diltiazem HCl, oral controlled drug delivery systems Introduction Oral ingestion has long been the most convenient and commonly employed route of drug delivery due to its ease of administration and flexibility in the design of the dosage form. There are many ways to design modified release dosage forms for oral administration and one of them is multi layered matrix tablet. One to three multi layered matrix tablet is a drug delivery device, which comprises a matrix core containing the active solute and one, or more barriers (modulating layers) incorporated during tabletting process (Colombo P et al., 199). The modulating layers delay the interaction of active solute with dissolution * For correspondence: Y.M. Rao, Tel.: ; Fax yamsani 123@gmail.com medium, by limiting the surface available for the solute release and at the same time controlling solvent penetration rate (Conte U et al., 1993, Conte U et al., 1994). In the device, the coat layers prevent the water penetration through the protected core for some duration. After this phase during the subsequent dissolution process, the swollen barriers erode and the surface available for drug release slowly increases. In this way the decrease of delivery rate due to the increase in diffusion path length (saturation effect) is counter balanced by the simultaneous increase of the area available for drug release, (Yihong Qui et al., 1997, Conte U et al., 1996).Thus by combining a time-dependent control of the hydration rate of the device with the reduction of tablet surface exposed to the dissolution medium, it is feasible to achieve a linear release profile. (Krishnaiah Y. S et al 22). 6

2 Ahmed et al. : Formulation Study and Evaluation of Matrix and Three-Layer Matrix Tablets Oral Controlled 7 The use of naturally occurring biocompatible polymeric materials has been the focus of recent research activity in the design of dosage forms for oral controlled release administration, and hydrophilic polymer matrix systems are widely used because of their flexibility to provide a desirable drug release profile, cost effectiveness, and broad regulatory acceptance (Yeole P.G. et al., 26) Xanthan gum (XG) is soluble, anionic hetro polysaccharide,while Locust Bean Gum (LBG) is a neutral (homo polysaccharide) galactomannan. Both the polymers found to be sensitive to ph and ionic strengths. Synergistic gelation of XG and LBG is independent of ph over the range of 5-1. (V.J Morris 1995) Xanthan gum is a hydrophilic polymer, secreted from Xanthomonas campestris (a Gram-negative, yellowpigmented bacterium). It is used for the fabrication of matrices with uniform drug release characteristics (Talukdar MM et al., 1998, Talukdar MM et al., 1993, Cox PJ et al., 1999, Billa N et al., 2, Munday D L et al., 2). Xanthan gum is the bacterial polysaccharide produced industrially on a large scale. It is a natural carbohydrate commercially produced by fermenting glucose with the appropriate microorganisms. Xanthan gum contains glucose 37%, mannose 43.4%, glucuronic acid 19.5%, acetate 4.5%, and pyruvate 4.4%. Xanthan gum swells in gastric fluid to produce a highly viscous layer around the tablet through which the drug can slowly diffuse. (Tobyn M J et al, 1996). LBG is a plant galactomannan, composed of a 1-4- linked β D mannan backbone with 1-6ά-linked D galactose side groups (I.C.M Dea et al, 1975). The galactose content in galactomannan is strongly influenced by the physico-chemical properties. Galactose with longer side chain produces a stronger synergistic interaction with other polymers and greater functionality (B. Launay et al., 1986). Diltiazem hydrochloride is a calcium channel blocker used for the treatment of chronic stable angina pectoris and for angina pectoris caused by a coronary arterial spasm and systemic hypertension. It is an acidic salt of basic drug having a pka value 7.7 and the molecule is freely soluble in water. Although 9% of an orally administered dose of diltiazem HCl is absorbed, only 4% of the oral dose reaches systemic circulation in an unchanged form. The mean absolute bioavailability of Diltiazem HCl in normal subjects ranged from 33 to 44%. The drug under goes rapid elimination that causes a short half life (3.5h), which dictates dosing three times a day. (Prisant L.M et al., 23) Therefore, diltiazem HCl, with its low oral bioavailability, short half, and multiple daily dosing, is appropriate for a formulation in an extended release, once a day dosage form. This study was carried out to evaluate the affect of the amount of thickness of the retardant layers on the matrix core component containing Xanthan gum (XG), Locust bean gum (LBG), and anionic Sodium Carboxy Methyl Cellulose (SCMC) (higher viscosity) as retardant layers and to develop a constant rate delivery formulation of highly water soluble diltiazem hydrochloride. Materials and Methods Diltiazem hydrochloride was obtained as gift sample from Divis Laboratories Hyderabad, India, Xanthan gum from Raj enterprises Mumbai, India, Locust Bean gum from Lucid gums Mumbai, India, and Sodium Carboxy Methyl Cellulose (SCMC) (high viscosity grade) and Micro Crystalline Cellulose MCC (Avicel PH 11) from Reliance Cellulose Product, Hyderabad, India, was used. Di calcium phosphate (DCP) was procured from (Loba Chime Pvt. Ltd. Mumbai, India). All other materials were of analytical or reagents grade. Calculation of required first order release rate constant kr 1 = Ke (exp (-ke Ti) was the equation used to calculate first order rate constant, (kr 1 ) of diltiazem HCl from tablets formulation, where ke is the elimination rate constant (.198h -1 ) and Ti, crossing time at which the blood level profiles produced by administration of separate loading and maintenance dose intersect, the value of Ti =h-tp (where h is the duration of therapy, i.e.12h in the present study and Tp the time taken for maximum plasma concentration at fourth hour.) This is based on the mean pharmacokinetic parameters of drug in humans and the, first order rate constant was found to be.4h -1. (Lordi N.G et al, 1986). The formulations developed in the study were optimized till the required first order rate constant of diltiazem HCl was obtained. Preparation and Characterization of three layer matrix tablets of Diltiazem Hydrochloride Preparation of Diltiazem hydrochloride matrix core granules The drug and polymers for the matrix tablets and three layer matrix tablets were passed through 18-µm sieve before use in the formulation. The matrix core formulations were prepared as shown in shown in table1. Matrix core granules were prepared by wet granulation technique using starch paste 1% as binding agent. The cohesive mass obtained was passed through a µm sieve, dried at 45 o C for 1hr in a tray dryer. The dried granules were again passed through µm screen to break up agglomerates. The granules were lubricated with a mixture of talc and magnesium stearate.

3 8 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 2 July-September 21 Table 1 Composition of Diltiazem HCl Matrix tablets and Three layer matrix tablets. Ingredients Quantity in (mg) present in matrix tablets (S) and release retardant layer (L) of 87%SCMC S1 S2 S3 S4 S5 S6 L1 L2 L3 Diltiazem HCl Xanthan gum LBG SCMC DCP MCC Starch Talc Mg Stearate Total weight Preparation of release retardant layer granules The release retardant layer granules containing anionic polymer of SCMC, were prepared by wet granulation method. The polymer and 1% starch paste were mixed well and the resulting wet mass was passed through µm sieve and dried at 45 C for an hour. The dried polymer granules were passed throughµm screen. The granules were lubricated with talc and magnesium stearate. The composition of Diltiazem HCl, and SCMC release retardant layer granules with their codes are listed in table 1. Characterization of granules Prior to compression, matrix core granules of Diltiazem HCl and release retardant layer granules of SCMC were evaluated for their properties such as tapped density, Carr s index and angle of repose. Carr s index was calculated from the formula: Carr s index = tapped density poured density /tapped density. The bulk and tapped density was measured by using a digital tap density apparatus (Electro lab Ltd, India). Preparation of matrix tablets The composition of formulation used in the study containing 9mg of Diltiazem HCl in each case is shown in table 1. The granules were compressed using a rotary tablet machine. Preparation of three layer matrix tablets Three layer matrix tablets were prepared by using different combinations of drug loaded matrix core granules and release retardant layer granules, the composition of SCMC retardant granules is shown in table I. Initially the volume of die cavity was adjusted equivalent to total weight of three layer matrix tablets. Then pre weighed amount of polymer granules of SCMC equivalent to bottom layer 5mg, 75mg, and mg were taken and placed in the die cavity and uniformally spread. The upper punch was lifted up and 25mg of matrix core granules were placed over the bottom layer of polymer granules in the die cavity and slightly compressed. The remaining volume of die cavity was filled with pre weighed amount of polymer granules equivalent to top layer 5mg, 75mg and mg and finally compressed on a rotary compression machine (Riddhi, Ahmedabad, India). The hardness of matrix tablet and three layer matrix tablets was adjusted to 5-6kg/cm 2. Physical tests for the prepared matrix tablets Ten tablets from each formulation were taken for measurement of diameter and crown thickness with vernier calipers and an average of ten determinations was carried out. Hardness of the matrix tablets and three layer matrix tablets was evaluated by using hardness tester (Pfizer) and weight variation test was performed for twenty tablets from each batch and average values were calculated. Friability of the matrix tablets and three layer matrix tablets was determined by first weighing 1 tablets after dedusting and placing in a friability tester (Roche friabilator, Pharma labs, Ahmedabad, India), which was rotated for 4min at 25rpm. After dedusting, the total remaining weight of the tablets was recorded and the percent friability was calculated. In-vitro drug release studies In vitro dissolution studies for the prepared matrix tablet and three layer matrix tablets were conducted for a period of 12h using a six station (1) USP XXII type II apparatus (Lab India Disso 2 system, India.) at 37±.5 o C and 5 rpm speed. The dissolution studies were carried out in triplicate for 2h in ph 1.2 medium (9ml) as the average gastric emptying time is about 2h.Then the dissolution media was replaced with ph 7.4 phosphate buffer (9ml). At different time intervals, 5ml of the sample was withdrawn with a pre-filter and replaced with 5ml of ph 7.4 phosphate buffer under sink conditions and the experiment was continued for another 1h. After suitable dilution, samples were analyzed at 237 nm using UV spectrophotometer (SL-15, Elico, India).The amount of drug present in the samples were calculated with the help

4 Ahmed et al. : Formulation Study and Evaluation of Matrix and Three-Layer Matrix Tablets Oral Controlled 9 of appropriate calibration curves constructed from reference standards. During the drug release studies, the formulations were observed for physical integrity at different time intervals. Analysis of release data The dissolution parameters used for comparing the different formulations was MDT and DE 8 %. The following equation was used to calculate the mean dissolution time (MDT) from the mean dissolution data: MDT = Σ t M M i= n i= 1 mid i= n Σi= 1 Where i is the dissolution sample number, n is the number of dissolution sample time, t mid is the time at the midpoint between i and i-1 and M is the additional amount of drug dissolved between i and i-1 (Gohel et al, 22). MDT, which is calculated from the amount of drug released to the total cumulative drug. MDT is a measure of the rate of the dissolution process: the higher the MDT, the slower the release rate. Dissolution efficiency (DE) (Banakar, 1992) after 8hr of release test was used to compare the results of dissolution tests of different formulations: t y dt DR8% = y t [2] FT-IR study Infrared spectrum was taken (FT-IR, Spectrum RX1, Perkin Elmer Ltd, Switzerland) by scanning the sample in Potassium bromide discs. The samples of pure drug and formulated tablets were scanned individually. Stability studies Stability studies were conducted for the optimized formulations S5L3 and S6L3. To assess their stability with respect to their physical appearance, drug content and drug release characteristics after storing at 4 C/75% RH for 6months. (B.R. Mathews, 1999) was seen. Results and Discussion The present study was carried out to develop oral controlled release tablet dosage form for highly water soluble drug diltiazem HCl in the form of matrix and three layer matrix tablets. The bulk densities for the matrix core granules and release retardant granules of various formulations ranged from.81 ±.11 and 2.39 ±.32 with good packaging characters. The compressibility indices of all the formulations were found to be less than 15 indicating desirable properties of bulk density and compression indices. The angle of repose for all matrix and three layer matrix granules; ranged between 21.33±.45 to 23.56±.21 and 2.31 to 23.2 respectively, these values [1] indicated good flow property. The physical parameters such as hardness, thickness, friability and weight variation of the matrix tablets and three layer matrix tablets was shown in table 2. All the values were found to be within the limits indicating that the tablets were of sufficient strength and drug content uniformity ranged from 98.3± 2.6% to 13.2± 2.65%. FT-IR spectrum reveals the principal absorption peaks of Diltiazem hydrochloride at 2837 (O-CH 3 stretch), 1679 (Lactam C= O stretch), 839 (O-substituted aromatic C-H out of plane deformation) and 781cms -1 (P-substituted aromatic C-H out of plane deformation) were obtained in the spectra of the pure drug as well as three layer matrix tablets S5L3 and S6L3 as shown in fig1. Indicating that no chemical interaction occurred between the diltiazem HCl and the excipeints used in the study. Matrix tablets with different excipeints after 12h of dissolution study dissolved either completely or near to completion forming a very loose porous mass, sticking to the bottom of the beaker. XG was used along with diltiazem HCl in the ratio of 1:1 as the matrix core. Diltiazem HCl (S1 and S2) released completely with in 12h. It might be due to high water solubility of both diltiazem HCl and XG. LBG and diltiazem HCl in the ratio of 1:1 as the matrix core, the formulations (S3 and S4) showed rapid rate of drug release when compared to the formulations (S1 and S2). It might be due to degradation of LBG at high ph. The release of diltiazem HCl was slower from the formulations (S5 and S6) with XG: LBG in 1:1 ratio, when compared to X and LBG matrices alone. (S1 to S4).The XG: LBG matrix core formulations retarded the release of highly water soluble diltiazem HCl, than XG and LBG alone. The effect may be due to synergistic interaction between two hydrophilic polymers to produce a strong and elastic gel around the core of the matrices in the presences of fillers DCP and MCC. LBG structure contains long stretches of bare mannose back bone which is responsible for synergistic interaction with Xanthan gum (Morris et al 199). The effect of changing filler from DCP to MCC on diltiazem HCl release, from Fig 2, decreased the release by 5-7% (after 4h). Since diltiazem HCl is highly water soluble, its release from the matrix core get entrapped in the insoluble fillers. MCC changes the release profile to a small extent due to a change in the rate of swelling at the tablet surface. The presences of insoluble fillers (15%) does n t affect its integrity. Based on the prepared formulations, it may be concluded that filler swelling has a limited effect on diltiazem HCl release from the hydrophilic matrix tablet. Therefore the formulations (S5 and S6) prolonged the release rate. The percentage in-vitro drug release (fig 2) from xanthan gum as matrix component (S1 and S2) ranged from 99.7± 2.12% to 98.95± 1.32%, similarly from LBG as matrix component (S3 and S4) ranges from 97.15±1.56 %, 98.95±2.5%. The drug release was slower from the matrix tablets of (XG: LBG): diltiazem HCl in 1:1 ratio ranged from

5 11 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 2 July-September ±1.96%, 91.95±2.9% (S5 and S6). The results from (fig 2) indicated that the XG: LBG matrix core tablets exhibit good controlled release by the utilization of synergetic interaction between two polymers so that together they make a thick gel. There by combination of XG: LBG shows precise control over the drug release. Table 2 Physical Parameters of Diltiazem HCl matrix tablets and three layer matrix tablets (Mean ± SD). Formulation Average wt of Hardness Thickness code tablets (mg) n=1 kg/cm 2 n=1 (mm)n=1 Friability (%) Assay % (n=3) S ± ±.1 3.2±.1.84± ±2.25 S2 25. ±.1 6.1±.2 3.1±.1.781±.3 11.±.32 S ± ±.5 3.1±.1.727± ± 2.6 S4 25. ±.1 6.5±.3 3.1±.1 Capping.3±.91 S ± ±.3 3.1±.1.251±.2 11.±.52 S6 25. ±.1 6.1±.6 3.1±.1.365± ± 3.6 S5L1 351.± ±.3 4.1±.2.62±. 13.2± 2.65 S5L2 41.6± ± ±.1.868±.1 13.± 2.5 S5L3 451.± ±.1 6.2±.2.42±.2 ± 1.97 S6L1 351.± ±.3 4.1±.2.87± ± 2.6 S6L2 41.6± ± ±.1.534±. 98.5± 2.5 S6L3 45.± ±.2 6.2±.2.562± ±.76 Fig. 1 FT IR spectra of pure Diltiazem HCl (A), powdered sample of matrix tablets S5L3 (B) and powdered sample of three layer matrix tablets S6L3 (C).

6 Ahmed et al. : Formulation Study and Evaluation of Matrix and Three-Layer Matrix Tablets Oral Controlled % Drug Released S1 S2 S3 S4 S5 S6 Fig 2 Dissolution profiles of Diltiazem HCl from matrix tablets containing different formulations conducted in ph 1.2 for 2 hrs and in ph 7.4 phosphate buffers remaining 1 hrs. a) S1 to S6.Each point represent the mean SD, (n=3). The description of dissolution profiles has been attempted using different release models. The data were evaluated according to the following equations. Zero order: M t = M o + K o t First order: ln M t = ln M o + K 1 t Higuchi model: M t = K H t Korsmeyer Peppas model: M t /M o = K k t n Where M t is the amount of drug dissolved in time t, M o the initial amount of drug, K 1 is the first order release constant, K the zero order release constant, K H the Higuchi rate constant, K k the release constant and n is the diffusional release exponent indicative of the operating release mechanism. The mean correlation coefficient obtained with all matrix tablets for the first order release kinetics were higher (r 2 =.987 to.91), when compared to those of zero order kinetics indicated that the drug release from all the matrix tablets followed first order kinetics and is shown in table 2. When a matrix tablet is placed in the dissolution medium, the initial drug release occurs from the tablet superficial layer and consequently, the release rate is relatively fast. In order to retard the drug release from the surface matrix core anionic SCMC layers were applied to delay the interaction of core with dissolution medium and also by limiting the dissolution media penetrating rate. In initial phase, coating barrier of SCMC on both the surfaces of the matrix core (XG- LBG: diltiazem HCl in 1:1 ratio) are able to delay the interaction of the core with the dissolution medium by reducing the surface area available for the drug release and by limiting the dissolution media penetration rate. Thus, in the three layer matrix tablet the burst effect is controlled and area available for drug release is maintained relatively at constant level. However, depending on the formulation excipeints used, a changed mechanism of drug release is observed, when the matrix core is layered with anionic SCMC on both the surfaces. Modulating layers were incorporated during the tabletting process. The modulating layers delay the interaction of active drug with dissolution medium, by limiting the surface available for the diltiazem HCl release, and at the same time controlling dissolution media penetration rate (Colombo. P et al 199). The coating barriers prevent the dissolution media penetration through the protected core for some duration. As the dissolution process proceeds the swollen barriers (SCMC), erosion will dominate and the surface available for diltiazem HCl release slowly increase. In case of three layer matrix tablets, the percentage invitro drug release of formulations S5L1 to S5L3 ranged from 91.3±1.56% to 63.27±1.23%, where as in case of S6L1 to S6L3 ranged from 9.95±1.12% to 64.6±2.13%. Three layer matrix tablets (S5L3 and S6L3) showed the calculated first order rate constant (.4h -1 ). Hence the formulations were optimized. Anionic polymer SCMC showed rapid hydration and forms a viscous gel layer that slows down further seeping-in of dissolution fluids toward the matrix core (Carstensen. J.T, 1987). The strength of viscous gel layer around the core of the matrix tablets generally depend on the viscosity of the polymer used. Earlier it was reported from our laboratory that, SCMC shows rapid hydration and less erosion than other cellulose derivates. (Syed, I. A et al 29). Thus, in this system the burst effect is controlled and the area available for drug release is maintained relatively at constant level. Thus on the basis of drug release data, it is evident that as thickness

7 112 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 2 July-September 21 of the SCMC layer is increased the rate of drug release was found to be decreased. The geometrical characteristics/ structure of the tablets as well as the thickness of the retardant layers considerably influences the rate of drug release and the release mechanism. Mathematical analysis of kinetic data obtained revealed that drug release from matrix tablets was mainly attributed to Fickian diffusion. While three layer matrix tablets shows either non- Fickian diffusion or super case type-ii mechanism (table 3). The r 2 values; signifying that the developed three layer matrix tablets showed zero order or case II release. The values of the kinetics constant (k) were in accordance with the values of n, the diffusional exponent; with k having lower values when the transport mechanism was case II and higher values for matrix tables that released the drug by Fickian diffusion. To compare dissolution profiles, model independent methods, MDT and DE 8 % were calculated. MDT of three layer matrix tablets is higher than matrix tablets and is shown in table 2. It also indicated that MDT is increased, while DE 8 % decreased, while increasing the polymer layer on the matrix core. MDT and DE 8 % values of S5, S6, S5L3 and S6L3 formulations were found to be 3.7h, 5.16h, 12.17h, 11.97h and 84.56%, 76.23% 68.31% and 66.21% respectively (table 3). The results indicated that the release of drug is slower from three layer matrix tablets. Release rate profiles in this study clearly demonstrated that both zero order/linear kinetics can be easily achieved using XG-LBG: diltiazem HCl in 1:1 ratio as matrix core, and mg of SCMC as retardant layers on both the surfaces. The three layer matrix tablets S5L3 and S6L3, after storing at 4±2 C /75±5% RH for six months showed no changes either in physical appearance, drug content, and in dissolution profile as shown in (fig 5 a and b). Table 3 In-vitro dissolution kinetics, MDT and DE 8 % of Diltiazem HCl release from matrix tablet and Three layer matrix tablets (n=3). Zero order First order rate Higuchi Release Formulation release rate constant type exponent MDT Order of release code (h) DE 8% mgh -1 r 2 h -1 r 2 r 2 n k S Fickian S Fickian S Fickian S Fickian S Fickian S Fickian S5L Non Fickian S5L Non Fickian S5L Super case type II S6L Non Fickian S6L Non Fickian S6L Super case type II % Drug Released S5L3 before storage S5L3 after storage %Drug Released S6L3 before storage S6L3 after storage (a) (b) Fig. 5 Dissolution profiles of Diltiazem HCl from three layer matrix tablets (S5L3 and S6L3) conducted in ph 1.2 for 2 hrs and in ph 7.4 phosphate buffers remaining 1 hrs, after storage at 4±2 C /75±5% RH for 6months.

8 Ahmed et al. : Formulation Study and Evaluation of Matrix and Three-Layer Matrix Tablets Oral Controlled 113 Conclusion The hydrophilic matrix tablets of Xanthan gum (XG) and Locust bean gum (LBG) alone could not prolong the diltiazem HCl release effectively. The results indicated that a combination of XG:LBG as matrix core and SCMC as layer in the form of three layer matrix tablets is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as diltiazem HCl for once daily administration. Acknowledgements The authors are thankful to Divis laboratories, Hyderabad, India, Raj Enterprises, Mumbai, India, Lucid gums Mumbai, India and Reliance cellulose products, Hyderabad, India for generously giving the samples of Diltiazem hydrochloride, Xanthan gum, Locust bean gum and Sodium Carboxy Methyl Cellulose respectively. 8 % Drug Released S5 S5L1 S5L2 S5L3 Fig. 3 Dissolution profiles of Diltiazem HCl from matrix tablets and three layer matrix tablets conducted in ph 1.2 for 2 hrs and in ph 7.4 phosphate buffers remaining 1 hrs. S5, S5L1, S5L2 and S5L3.Each point represent the mean SD, (n=3). 8 %Drug Released S6 S6L1 S6L2 S6L Fig. 4 Dissolution profiles of Diltiazem HCl from matrix tablets and three layer matrix tablets conducted in ph 1.2 for 2 hrs and in ph 7.4 phosphate buffers remaining 1 hrs. S6, S6L1, S6L2 and S6L3. Each point represent the mean SD, (n=3).

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