Pharmaceutical Research, Vol. 1, No. 6, 1997 Development of a Novel Controlled- Release System for Gastric Retention Arati A. Deshpande,'?4 Navnit H. Shah,? Christopher . Rhodes," and Waseem Malick* Received December 20, 1996: accepted March ‘Purpose. We report on the development ofa novel conlled-eease asc tention system, which consists of a matrix table, coated with 8 permeable membrane. When immersed in simolated gasti Mui, the tablet expands, The tablet remains expanded for eighteen to twenty hours, during which time the drug is released. The tablet then either disintegrates into fragments oF loses its integrity. ‘Methods. Tabet containing a soluble drug (chlosphenramine maleate, ite, CPM) and & poorly sluble drug (riboflavin 5° phosphate, ic RS'P) were compressed. They were costed witha permeable and elastic polymer (Eudragit®). Dissolution profiles ofthese tables were studied. ‘The changes inthe pH, viscosity, and deformation characteristics asa function of time were measured Results. Carbopol® provided firm stricture to the swollen table, Polyvinyl pyrolidone XL (PVP XL) contributed tothe swelling ofthe tablet. Carbonates provided the intial alkaline microenvironment for Carbopol® to gel and conferred buoyancy to the tablet. Coating ro- vided the support needed for the core to remain intact during drug release and, athe same time t allowed deugreleate due ois perme able nature. During release, the gelling properties of Carbopol® les Sened, resulting in a decrease in the fires of the core. This was evident from the decrease in the viscosity of the core, The energy required at 50% strain also decreased asthe drug release progressed, Conclusions. When histabltis ingested the chances fitselimination| ‘trough the pylorus shouldbe greatly reduced duc to table's expansion, and due to its disintegration of Toss in integrity i should then be cxpelled out of the stomach atthe end ofthe drug release KEY WORDS: controlledvelease, gastric retention; Roaing, swell ings mattix 1997, INTRODUCTION Today more than fifty percent of the drug delivery systems available on the market are administered orally. The inability to restrain and confine these systems to selected regions of ‘gastrointestinal tract has been the principal obstacle tothe devel- ‘opment of oral contolled-release systems, Various approaches hhave been tried to overcome such an obstacle. They include the development of swelling and expanding systems, floating systems and bioadhesive systems. There are various patents describing welling systems (1.2.3) Researchers have used vari ‘ous polymers to develop such systems, They have developed swelling devices having different shapes, such as a ring, a disk, " Dept of Pharmaceuties, University of Rhode Island, Kingston, Rhode Island 02881, USA, * Curent Address: Dept. of Pharmacy University of Geneva, 30, Quai Emest-Ansermet, 211 Geneva 4, Switzerland. * Horinan-La Roche, Nutley, New Jersey 07110, USA. ‘To whom corespondence shouldbe addressed, ais Report a string and many others (4,5.6,7). Various approaches have been used to develop floating systems, Some scientists devel- ‘oped shells of polymers with lower density than that of the gastrointestinal fluid, to enable them to float (8), Some scientists developed a drug and hydrocolloid mixture (9) whereas others developed a gel type matrix (10), a hydrodynamical balanced capsule (11), or a bilayer capsule (12). In onder to develop a bioadhesive system, researchers have studied a broad range of polymers for their bioadhesive properties (13). Some of these polymers have been used to prepare bioadhesive systems (14,15). A matrix tablet has also been evaluated as abioadhesive gastrointestinal retention system (16). It has been suggested that all these different kinds of devices improve bioavailability of those drugs which exhibit a site specific absorption and that they prolong the transit time sufficiently to achieve controlled release allowing a once a day administration, Unfortunately, most of these devices have many drawbacks. For instance, floating systems require the presence of food to delay their gastric emptying. They do not always release the drug at the intended site. For example, when Mazer er al. studied an isradi- pine floating device, they found that the maximum release of the drug took place in the colon and not in the stomach, as desired (17). Bioadhesive systems adhere to the mucus. This adhesion isa result of electrostatic and hydrogen bond formation at the mucus-polymer boundary. The bond formation is pre- vented by the acidic environment and thick mucus present in the stomach. High turnover of mucus adds to the difficulty of retaining the bioadhesive systems at the site. A gastric retention system overcoming such drawbacks of floating and bioadhesive systems can have significant advantages and could have a trong ‘impact upon improving the therapeutic effect of the drugs. ‘This paper reports on the development of a novel drug delivery system with a prolonged gastric residence time. A. tablet coated with a membrane was designed which, during in vitro studies, expanded to two to four times its original volume. ‘The tablet swelled in about ten to fifteen minutes and drug release occurred for at least fifteen to eighteen hours. At the tnd of the release, the tablet either burst into small fragments ddue to continuous expansion or lost its integrity. A schematic representation of such a delivery system is shown in Figure I MATERIALS AND METHODS ‘The drug delivery system investigated here consisted of (D a core that swelled and of (U1) a permeable coating that provided a shell for the swollen core and allowed drug release fo oceut Materials The core consisted of soluble or poorly soluble drugs. Chlorpheniramine maleate, Le., CPM (Interchem Corp.. CA, USA) was used as an examplary soluble drug and riboftavin ‘5 phosphate, ie., RS’P (Hoffman-La Roche Inc., NJ, USA) ‘was used as an examplary poorly soluble drug. Cazbopol® 934P (BE Goodrich, OH, USA) was used as a pH sensitive polymer. Polyvinyl pyrrolidone XL (PVP XL. from ISP, USA) was used as. aswelling agent. A base such as caleium carbonate (Pharma- carb® from Crompton and Knowles, NJ, USA) or sodium bicar- Donate (Mallinckrodt-Baker Inc., MO, USA) was used to816 <> porous membrane = > Complete drug release (i818 hrs) Nene rupturing Quick Swating (10-45 mins) Loss of Integrity rors o4o ae .@ e Intestine Fig. 1. Schematic representation of a novel gastric retention system, provide an intial alkaline miero-environment and confer buoy: ancy (o the tablet. Magnesium stearate (Hoffman-La Roche Inc., NJ, USA) was added as a lubricant for easy compression of the tablets The membrane consisted of methacrylate co-polymers (Eudragis® from Rohm Pharma Tech Inc., MA, USA), a plasti cizer such as triethyl citrate (TEC) from Morflex Inc., NC, USA, an anti-tacking agent such as tale (Ashland Chemical Dist, OH, USA), and of the ant-foaming agent simethicone (OSI Specialities Ine., WV, USA). Methacrylate co-polymers were used because of their permeability and elasticity. Pasti- Cizer was added (o avoid breaking of the tablet after swelling ‘An anti-tacking agent was added to avoid tablets’ sticking 0 ‘one another during and after coating. Methods Preparation of Tablets In the first step, the drug was mixed with the swelling agent in geometric proportion. In the Second step, other ingredi- {ents were incorporated by blending in a V blender for 30 mins ‘The tablets were compressed on a manually operated tablet press (from Fred S. Carver Inc, WI, USA) at a suitable compres- sion force, using 5/16 * 3/4 inch capsule-shaped punches to ‘obtain tabiets which were about 0.75 in length and 0.25 in Width. Tablet hardness was between 22-25 scu. Coating of Tablets A laboratory coater (Glatt Air Techniques Ine., NI, USA, Model # GC 300) was used to coat these tablets. The coating preparation was a dispersior. It was stirred continuosly in order Deshpande, Shah, Rhodes, and Malick tw ensure uniform dispersion during coating. The coating prepa- ‘ation was sprayed at the rate of 3 m/min on a batch of about 1.5 kg of tablets. The coating pan was rotated atthe speed of 8 rpm. The temperature was maintained around 30°C during coating, to avoid any sticking of the tablets. After coating the tablets were dried in an oven at 30°C for one day and then stored under vacuum, The tablets were coated to different ‘coat- ing levels’. Coating levels indicate the inerease in weight of the tablets after coating (e-g., 10% coating level means tablet weight increased by 10% after coating compared to its origi- nal weight) In Vitro Studies ‘The tablets containing CPM were evaluated forthe follow ing exteria: 1. Swelling of tablets 2. Dissolution profile 3. Changes in viscosity of swollen cores over time 4. Changes in pH of swollen cores over time 5. Deformability of the tablets as a function of time 6. Thermo-mechanical properties of the tablets Swelling of Tablets. Tablets were immersed ina simulated gastric fluid at 37°C, Swelling of tablets was monitored by ‘measuring the weight gain as well as the increase inthe thick= ress and te length ofthe tablets It was measured at equilibrium as well as at various time intervals, Dissolution. USP XXIVNF XVI dissolution method with apparatus II was used to study drug release. Simulated gastric fluid (900 ml, pH 1.2) prepared according to the procedure given in USP XXII at 37°C was used as a dissolution medium. The paddles were rotated atthe speed of 50 rpm. The amount of drug dissolved was measured at various time intervals by using a spectrophotometer with ultraviolet ight source. The amount of CPM dissolved was measured at the wavelength of 274 nm and the amount of RS'P dissolved was measured at the wavelength of 282 nm. Dissolution studies were conducted ‘on twelve tablets from each formulation The frst order dissolu- tion rate constants were calculated for the comparison of the data Viscosity of the Tablet Core. Tablets were immersed in simulated gastric fluid at 37°C for various time intervals such as two, four, eight, twelve and twenty hours. The tablets were removed from simulated gastric fuid and the tablet membranes Were separated from the cores. Viscosity ofthe cores from three tablets was determined using CSL Controlled Stress eheometer (TA Instruments, DE, USA). A parallel plate assembly was used. The diameter of the plate was two em. The temperature was maintained at 37°C. A stress of 12000 dyne/em? was applied, The starting and ending angular frequencies were 0.6283 rad/see and 62.83 rad/see respectively pit of the Tablet Core. Tablets were immersed in simulated gastric luid at 37°C for various time intervals, such as, wo, four, eight and twenty hours. After removing the tablets from simulated gastric Muid, the tablet membranes were separated from the cores and the pH of the cores from three tablets Were measured. A digital pH/millivolt meter 611 from Orion Research Inc., MA, USA was used to measure the pH. Deformability: Tablets were immersed in simulated gastric uid at 37°C for various time intervals, such as, two, four,Controlled-Release System for Gastric Retention eight, twelve and twenty hours. The hardness of tablets was measured immediately after removing them from the simulated {gastric fluid, Hardness, in terms of energy at 50% strain, was measured on three tablets using compression mode on a tensi ‘ometer (Instron Corp., Ma, USA, model # 4301). The tablet was placed on the platform, The upper platform was lowered ‘on the tablet ata speed of 0.5 in/min. The instrument was not ‘equipped to maintain the temperature constant. Thus, all the ‘measurements were made at room temperature. Thermo Mechanical Analysis (TMA). These studies were conducted using 2 thermo-mechanical analyzer (Seiko Instru- ments Ine., CA, USA, Model # 1200). A penetration probe was used, Coated tablets were heated from ~45°C to + 150°C at a rate of 10°C/min, Glass transition temperature (Tx) of three tablets with diferent coating levels and different coating preparations was measured Core Formulation Incase of tablets containing CPM, the principal ingredients for the core consisted of Carbopol®, polyvinyl pyrrolidone XL (PVP XL) and calcium carbonate. The effect of Carbopol® and PVP XL on the swelling time was studied by compressing tablets with different combinations of these ingredients. When Compressing the tableis, the concentration of one ingredient was kept constant and the concentration ofthe other was varied. ‘Carbopol® provided a firm structure forthe swollen tablet due (0 ts adhesive, binding, and gelling properties. It was desirable for the delivery system to swell in ten to fiftee minutes in the gastric fluid to prevent premature gastric empty: ing. The effect ofthe concentration of Carbopol® on the swelling time of the tablet is shown in Figure 2. High concentrations of| ‘Carbopol® provided slower diffusion of gastric fluid into the ‘matrix which resulted in an increase inthe swelling time, ‘Carbopol® concentrations of 10% resulted in swelling time of ‘one hour or more. It was necessary to use a concentration of Carbopol® that would not hinder the swelling and at the same time would confer adequate gelling properties for imparting the required firmness to the tablet. Even a small concentration (such as 2.0%) of Carbopol® was enough to obtain this effet. ‘The concentration of PVP XL also affected the swelling time. A high concentration of PVP XL was used to enkance swelling (not for its disintegrating properties). Figure 2 shows wi 1 eeeeezegs ee (un) Fig. 2 Effect of Carbopol® and PVP XA. on swelling time of tables after immersing them in simulated gastric ud at 37°C; [A] = Concen uation of PVP XL held constant at 2.0%. Tw (an a7 the effect of PVP XL concentration on the swelling time, Based. ‘on this data, PVP XL was used at concentrations of 25 to 354% in the final formulation. Calcium carbonate provided a faster rate of expansion for the core and initial alkaline miero-environment for Carbopol® to gel. It also provided buoyancy to the tablet in simulated gastric fluid. It was observed thatthe particle size, method of precipitation, and concentration of other ingredients such as Starch or maltodexttin present in the calcium carbonate used, affected the time taken by tablets to swell significantly. In this experiment, the primary purpose was to minimize the time taken by the tablets to swell after they were immersed in simu- lated gastric Muid. It was required that the tablets swell in about fifteen minutes, Calcium carbonate (Pharma-Carb?) satisfied these requirements and hence was used for further studies, Pharma-Carb® is a natural calcium carbonate which meets all USP XXII specifications. According to the data shoet provided with the sample, the mean particle size of calcium carbonate was 12 Coating Formulation ‘The coating provided the support needed by the core to ‘remain intact during the release. It also provided a permeable membrane for the release of the drug, Tensile strength and c’longation properties of the membrane were very important in ensuring this behavior. Eudragit® RL 30 D was used for its Permeability. However, its elongation properties were insuffi Cent in withstanding the pressure of expansion. TEC was added to increase the elasticity. It improved the elasticity, but did not prevent disintegration, Eudragit® NE 30 D was added to the Eudragit® RL 30 D and TEC combination, to improve the clasticity and firmness of the membrane. When Eudragit® RL 30 D was alone, the drug was released quickly due to the high permeability of Eudragit® RL 30 D. The addition of Eudragie® NE 30 D contributed in slowing down the release, as it is less permeable than Eudragit® RL 30 D. The sclection of the final Tormulation of the coating solution was based on the time taken by the tablets to swell, the release characteristics of the drug during dissolution, and the ability of the film to prevent disinte~ gration of the tablet until complete drug release had occurred, Three ratios of Eudragit® RL 30 D and Eudragit® NE 30 D were investigated. They were 80:20, 70:30 and 60:40 (Eudragie® RL 30 D:Eudragit® NE 30 D). The ratio of 80:20 (Eudragit® RL 30 D-Budragit® NE 30 D) resulted in a brite film whereas the ratio of 60:40 (Eudragit® RL. 30 D:Eudragit® NE 30 D) resulted in a film that was 100 elastic. The ratio of 70:30 (Eudragit® RL 30 D:Eudragit® NE 30 D) was optimum for the drug release as well as for imparting the elasticity to the film needed to withstand the swelling pressure of the core. In Vitro Studies ‘When tablets were immersed in simulated gastric fluid at 37°C, they swelled 10 to three times their original volume. Dissolution studies were conducted in simulated gastric fluid at 37°C. The effects of three ratios of Eudragit® RL 30 D and Eudragit® NE 30 D in membranes at different coating levels are shown in Table I and Figure 3. The rate of release of the drug followed first order reaction kinetics, since the release depended on the concentration of the drug. According818 Table L Etfect of Coating Level on Release of CPM tables Rio of Eudagie® RL 30D Costing level Dissolution rate (o Eudragit® NE 30 D (%) constant (min) ‘50:80 1000008 = So*10" 150 0.004 + 55*10* 7030 100 0.003 = S010 130 00S = 55*10* 80:20 1000005 = 6.010" 150 0.006 = 6.0*10" to student t test at 95% confidence level, the rate of release increased significantly with the increase in the coating level when Eudragit® RL 30 D and Eudragit® NE 30 D were used in the ratio of 70:30 and 80:20. However, the rate of drug release showed no change with changes in the coating level when Eudragit® RL 30 D and Eudragit® NE 30 D were used in the ratio of 60:40, Such an unusual increase in the rate of release was contrary to the general behavior of a drug when it diffuses from tablets coated with a membrane. ‘To elucidate the possible mechanism associated with this behaviour, two studies were conducted: 1. Thermo Mechanical Analysis (TMA) on the tablets, 2, ‘Time taken by the cores to form a gel TMA results of the three coating preparations are shown in Figure 4. These studies were not very helpful in explaining. the unusual drug release from the tablets. The TMA studies showed that when Eudragit® RL 30 D and Eudragit® NE 30 were used in the ratio of 70:30 and 80:20, the Ty decreased. ina statistically significant manner (student t test at 95% confi- dence level) as coating level increased but not when Eudragit® RL. 30 D and Eudragit® NE 30 D were used in the ratio of 60:40. The study did not provide any indication aso the reasons behind this behaviour. It is known that Tg influences many physical properties such as elasticity, viscosity, solvent release and permeability of coating polymers. Lower Tg results in Cumulative drug released [%] Ss 0 7m wm mm @ a mm OD Tne[ Min} Fig. 3. Effet of coating level on cumulative in vito release of CPM. (S% wh from coated tablets in 900 mi of simulated gastric fluid at pH 12 at 37°C, n = 12, Endragit® RL 30 D: Eudragit® NE 30 “1:30. (0) 10% coating level; (2) 15% coating level Deshpande, Shah, Rhodes, and Malick 8 Po 3 F Be eaea e 2 LEP TS Glass transition temperature [°C] ao m0 a kag LSD: Estat NED [w Fig. 4. Glass tanstion temperature of coated tables containing CPM; 1 = 6 (2) 10% coating level; (@) 15% coating level increased permeability and increased release rate. As the mem- brane at a higher coating level attained its Tg point ata lower temperature than that of a lower coating level, the drug was released faster. Another possiblity, that of relating drug release rate to the gel formation time of the core, was explored, Tablets coated with Eudragit® RL 30 D and NE 30 D (70:30) were selected. Gel formation time of the core at 10% and 15% coating level ‘was found to be two hours and four hours, respectively. This indicates a correlation between shorter gel formation time and slower drug release, and vice versa, Hence the following mecha- nism can be deduced, As the core of the tablet absorbs gastric fluid, gel formation occurs. The faster the gel formation, the fascer the drug entrapment and slower the release. Dissolution studies were also conducted in dissolution ‘media with pH2.0and3. inorder account for individual varia- tionsin stomach pH. The dataindicated that theswelling occurred in ess than fifteen minutes. The data showed thatthe release rate was somewhat slower with an increase in pH. This could be due to the differing solubility of CPM at various pH values. ‘oillustrate that this tablet can also be used for the delivery of poorly soluble drugs, RS'P was selected as a model drug. Dissolution studies were conducted on these tablets using the same method a5 in case of tablets containing CPM as @ model drug. Initially, the composition ofthe core and that of the mem: brane were Kept the same as in the case of tablets containing. ‘CPM and CPM alone was replaced with RS'P. When dissolution studies were conducted on these tablets, the membrane and the ccore used for CPM tablets were not adequate and resulted in an incomplete release of RS'P. To overcome this problem, it was necessary to change either the core or the membrane, oF both. First, attempts were made to modify the membrane in ‘order to achieve complete drug release. Since the drug was poorly soluble, it was necessary to use a highly permeable membrane. However, at the same time, the membrane was requited tobe elastic enough to withstand the pressure of swell 18. The core was modified in order to achieve quick swellingControlled-Release System for Gastric Retention of tablets, Calcium carbonate in the core was replaced with sodium bicarbonate which ensured a faster swelling. Thus, by changing both the core and the membrane, fast swelling as Well as complete drug release were achieved for the tablets containing RS'P as a model drug of poorly soluble drugs. VALIDITY OF THE HYPOTHESIS In order to fully verify the validity of the concept of a gastric retention system that can swell in ten to fifteen minutes, allow the drug release to occur in fifteen to eighteen hours, and, at the end of the release, either disintegrate or loose its integrity in order to be expelled from the stomach, the change in the pHi, viscosity, and deformation characteristics as a func tion of time were measured. It was observed that during the release, the gelling properties of Cazbopol® were reduced due to penetration of gastric fluid into the tablet, resulting in a decrease in the firmness of the core during the release, This was evident from the decrease in the viscosity of the core. Figures 5 shows the change in pH and viscosity of the swollen core as a function of time. They show that a decrease in the pH of the core resulted in a reduction in the viscosity of the core. The reduction inthe core viscosity was duc tothe decrease in the viscosity of Carbopol® with the decrease in the pH. In addition, deformation studies ofthe tablets indicated that energy required at 50% strain decreased as the release of the drug. progressed (Figure 6). Strain energy is a measure of the energy absorption characteristics ofa material under load up to fracture, It is ¢ measure of the toughness of a material. This decrease in the required energy at 50% strain will result in the loss of firmness and integrity of the core matrix. This reduction inthe firmness due to the decrease in the viscosity will enable the tablet to be squeezed out ofthe stomach atthe end of the release if it remained intact atthe end of the release, This satisies one ‘of the major criteria that this delivery system should disintegrate ‘or be squeezed out at the end of the release period. CONCLUSIONS ‘This study has shown that there is the potential to develop ‘tablet dasage form which remains in the stomach for a long time. This tablet will release the drug in the desired time and then either disintegrate into small fragments or will ose its integrity so that itcan be expelled from the stomach. This study has also shown that such a tablet can be used for soluble as well as for poorly soluble drugs. Coating solution and core formulation can be modified to achieve the release rate required { =| i [ies @ Fig. 5. Changes in pH and viscosity of cores separated from mem branes after immersing in simulated gastric fui at 37°C for diferent time intervals. Eudragie® RL 30 D: Eudragit® NE 30 D = 70:30, a = 6, 0) pHs (@) viscosity a9 —— ot ° 4 3s 2 6 Time [Hrs] Fig. 6. Changes in energy required to achieve 50% stain on coated tablets with CPM after immersing in simulated gastric fluid at 37°C for various time intervals, n = 6 (©) 10% coating level; (@) 15% coating level Energy to achieve 50% strain (1b in) aaa by the nature ofthe drug. This tablet provides ideal attributes of gastric retention system and overcomes some ofthe drawbacks associated with presently available systems. ACKNOWLEDGMENTS ‘The authors are thankful to Hoffman-La Roche, Nut [New Jersey for financial support and for allowing the use of their research facilities to conduct this work. REFERENCES RH, Johnson and B. L. Rowe, US Patent # 3574820, 1971 2 RG. Mamajek and E. 8. Moyer. US Patent # 4207890, 1980, 3. J. Urquhart and F. Theeuwes. US Patent # 4434183, 1984 4 L,1 Caldwel, C. Ro Gardner, and R. C. Cargill. US. Patent # 473380, 1988, 5. L.J-Caldwell,C. R. Gardner, RC. Cargill, and T. Higuchi. US. alent #4758836, 1988 6. L. J. Caldwell, C. R. Gardner, and R. C. Cargil. US. 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