FORMULATION OF FLOATING MIXED MATRIX TABLETS

J. A. Raval et al / International Research Journal of Pharmaceuticals (2011), Vol. 01, Issue 01

Research Paper

Formulation of Floating Mixed Matrix Tablets Using Low Density Copolymer J. A. Raval1* J. K. Patel2 and Nai-Hong Li3 1

Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat Universiy, Kherva, Gujarat, India. E-mail address: [email protected] 2 Nootan Pharmacy College, Gujarat Technical University, Visnagar, Gujarat, India. 3 Polygenetics, Inc., Los Gatos, CA 95031, USA.

ABSTRACT Drugs with a narrow absorption window in the gastrointestinal tract have poor absorption. Therefore, gastroretentive drug delivery systems (GRDDS) have been developed, which prolong the gastric emptying time. Several techniques such as floating drug delivery system, low density systems, raft systems, mucoadhesive systems, high density systems, superporous hydrogels and magnetic systems, have been employed. Floating drug delivery systems have a bulk density less than gastric fluids and so, remain buoyant in the stomach for a prolonged period of time, releasing the drug slowly at the desired rate from the system. Dosage forms available as gastric floating systems include tablets, capsules, granules and microspheres. This research attempt is to investigate formulation of mixed matrix controlled drug delivery system with all the possible mechanisms used to achieve gastric retention. The tablets were prepared by direct compression technique, using hydrophilic matrixing polymers chitosan and carbopol with or without low density copolymer (used to get buoyancy). Tablets were physically characterized and evaluated for in vitro release characteristics for 8 hours in 0.1N HCl at 37oC. The effect of low density copolymer addition and drug release pattern was also studied. The release rate was modified by varying the concentration of matrix-forming polymers, and the addition of water-soluble or water-insoluble diluents. Variation on the floating lag time was checked with different concentrations of low-density copolymer. In vitro release mechanism was evaluated by kinetic modeling. Similarity factor, floating lag time, and drug release were taken as parameters for the selection of the best batch. The highly porous copolymer provided low density and, thus, excellent in vitro floating behavior of the tablets in the concentration of 17 %w/w. It was concluded that it was possible to formulate a low-density drug delivery system giving prolongation of the drug release patterns. Keywords: Ranitidine hydrochloride; Floating mixed matrix; Chitosan; Carbopol; Low density copolymer.

1. Introduction The gastroretentive drug delivery systems can be retained in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract. These systems help in continuously releasing the drug before it reaches the absorption window, thus ensuring optimal bioavailability. It is also reported that oral treatment of gastric disorders with an H2-receptor antagonist like

ranitidine or famotidine used in combination with antacids promotes local delivery of these drugs to the receptor of the parietal cell wall. Local delivery also increases the stomach wall receptor site bioavailability and increases the efficacy of drugs to reduce acid secretion (Coffin et al., 1995). This principle may be applied for improving systemic as well as local delivery of ranitidine hydrochloride, which would efficiently reduce gastric acid secretion. Several approaches are currently used to prolong gastric retention time. These include floating drug delivery

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systems, also known as hydrodynamically balanced systems, swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, highdensity systems, and other delayed gastric emptying devices (Singh et al, 2000; Chawla et al, 2003). The principle of buoyant preparation offers a simple and practical approach to achieve increased gastric residence time for the dosage form and sustained drug release.

mixed matrix tablets of ranitidine based on low density copolymer that increases its gastric residence time. An orderly approach to the development of gastroretentive ranitidine hydrochloride dosage form was planned.

2. Materials and Methods 2.1. Materials

Ranitidine hydrochloride is a histamine H2-receptor antagonist, widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastroesophageal reflux disease, and erosive esophagitis. The recommended adult oral dosage of ranitidine is 150 mg twice daily or 300 mg once daily. The effective treatment of erosive esophagitis requires administration of 150 mg of ranitidine 4 times a day (Drug Facts and Comparisons, 2002). A conventional dose of 150 mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. An alternative dose of 300 mg leads to plasma fluctuations; thus a sustained release dosage form of ranitidine hydrochloride is desirable (Somade et al, 2002). The short biological half-life of drug (~2.5-3 hours) also favors development of a sustained release formulation.

Ranitidine hydrochloride (Mann Pharmaceuticals Pvt. Ltd., Mehsana, India), Low Density Powder - Poly (StyreneDivinyl Benzene) Copolymer [PSDVB] (Polygenetics Inc., CA, USA), Chitosan (Central Institute of Fisheries Technology, Cochin.), Carbopol 940, Hydrochloric Acid, Dibasic calcium phosphate, Lactose, Talc, Magnesium Stearate (S. D. Fine Chemicals Ltd., Mumbai, India). 2.2. Preparation of Floating Matrix Tablets Different tablets formulations were prepared by direct compression technique. All the powders were passed through 80 mesh sieve. Required quantity of drug, matrix polymer and low-density copolymer were mixed thoroughly. Talc and magnesium stearate were finally added as glident and lubricant respectively. The blend was compressed (12 mm diameter, flat punches) using multipunch tablet compression machine (Cadmach, Ahmedabad, India). Each tablet contained 336 mg of ranitidine hydrochloride (336 mg equivalent to 300 mg of ranitidine) and other pharmaceutical ingredients as listed in table 1.

A traditional oral sustained release formulation releases most of the drug at the colon, thus the drug should have absorption window either in the colon or throughout the gastrointestinal tract. Ranitidine is absorbed only in the initial part of the small intestine and has 50% absolute bioavailability (Lauritsen, 1990; Grant, 1989). Moreover, colonic metabolism of ranitidine is partly responsible for the poor bioavailability of ranitidine from the colon (Basit et al, 2001). These properties of ranitidine hydrochloride do not favour the traditional approach to sustained release delivery. Hence, clinically acceptable sustained release dosage forms of ranitidine hydrochloride prepared with conventional technology may not be successful.

2.3. In Vitro Buoyancy Studies The in vitro buoyancy was determined by floating lag time method described by Rosa et al (1994). The tablets were placed in 100 ml beaker containing 0.1 N HCl. The time required for the tablets to rise to the surface and float was determined as floating lag time.

The present investigation aimed on formulating floating Table 1 Composition of Ranitidine Batches

Ingredients

A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

RHCl

336

336

336

336

336

336

336

336

336

336

336

336

336

336

Chitosan Carbopol 940 PSDVB Lactose DCP Magnesium Stearate Talc

100 25 -

100 50 -

100 75 -

100 100 -

25 100 -

50 100 -

50 100 30

50 100 50

50 100 70

50 100 100

37.5 75 100 37.5 -

25 50 100 75 -

37.5 75 100 37.5

25 50 100 75

5

5

5

5

5

5

5

5

5

5

5

5

5

5

10

10

10

10

10

10

10

10

10

10

10

10

10

10

* All the quantities are in mg


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2.4. In Vitro Dissolution Studies

2.7. Kinetic Modeling of Drug Release

The release rate ranitidine from floating tablets (n=3) was determined using The United States Pharmacopoeia (USP) XXVI dissolution testing apparatus II (paddle method). The dissolution test was performed using 900 ml of 0.1 N HCl, at 37o C and 75 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus hourly for 8 hours, and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45 membrane filter and diluted to a suitable concentration with 0.1N HCl. Absorbance of these solutions was measured at 315 nm using a Shimadzu UV1601 UV/Vis double beam spectrophotometer. Cumulative percentage of drug release was calculated using the equation obtained from a standard curve.

The dissolution profile of the best batch was fitted to zeroorder, first-order, Higuchi and Hixon-Crowell models to ascertain the kinetic modeling of drug release. The method of Bamba et al. (1979) was adopted for deciding the most appropriate model.

2.5. Comparison of Dissolution Profiles The similarity factor (f2) given by SUPAC guidelines for modified release dosage form was used as a basis to compare dissolution profile. The dissolution profiles are considered to be similar when f2 is between 50 and 100 (Paulo et al., 2001). The dissolution profiles of products were compared using f2. This similarity factor is calculated by following formula: n f2 = 50 x log {[1+(1/n) Σ | Rj – Tj | 2 ] - 0.5 x 100} j=1 Where, n is the number of dissolution time and Rj and Tj are the reference and test dissolution values at time t.

3. Results and Discussion 3.1. Floating Behavior The batches taken were evaluated for the floating behavior by checking the floating time and the floating lag time. It was found that the low density polymer in the formulation highly favoured the floating of the tablets by reducing its density in the release medium. Based on the mass of the tablet, incorporation of 17% w/w of the low-density copolymer powder sufficient in vitro floating behavior for at least 8 hours was achieved. The tablets floated almost immediately upon contact with the release medium and thus showed extremely low lag times in floating (time <10 sec). Extended floating times were achieved as a result of the air entrapped within the low-density powder particles, which is only slowly removed from the system upon contact with the release medium. As expected, tablets without poly (styrene-divinyl benzene) copolymer powder sank to the bottom of the vessel showing no floating behavior. Addition of low-density powder highly reduced the lag times. The pictorial results of in vitro buoyancy study of the optimized batch is shown in fig.1, which clearly depicts the floating lag time, stable and persistent buoyancy characteristic of tablet.

2.6. Drug Excipient Interaction Study 3.2. In Vitro Dissolution Studies The pure drug, ranitidine hydrochloride and a mixture of it with the polymer chitosan-carbopol 940 and PSDVB copolymer powder was mixed separately with IR grade KBr. The powder blends were scanned over a wave number range of 400 to 4000 cm-1 in FTIR 8400S model instrument.

At Initial Time

After 7 Seconds

Various batches were prepared with different concentrations of chitosan and carbopol 940 using 0.1 N HCl at 37o C (900 ml using USP apparatus II at 75 rpm.) The drug release was measured and the formulated batch was evaluated for the in vitro buoyancy test. During this

After 10 Seconds

After 8 Hours

Fig. 1. In vitro buoyancy studies of batch A10


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study low density co-polymer was not added into the formulation. The aim here was to check the drug release from the system and finding the optimized ration of the two polymers for making the mixed matrix for the tablets. Thus the ratios of chitosan and carbopol 940 (4:1, 2:1, 4:3, 1:1 resp.) were taken and the dissolution profiles were obtained. Batch A1 dispersed completely in 5 hours while batches A2 and A3 dispersed completely in 6 hours. At the same time batch A4 dispersed completely in 7 ½ hours. In the batches containing more concentration of chitosan (100 mg) compared to carbopol 940 (25 mg, 50 mg, 75 mg and 100 mg) there was erosion of the tablets because of the chitosan. Then a reverse order was followed i.e. with more concentration of carbopol 940 (100 mg) as compared to chitosan (25 mg and 50 mg) as batches A5 and A6. There was no loss of integrity of the tablets in this case. Thus, it became clear that there was decrease in loss of integrity with the increase in concentration of carbopol 940. This was directly proportional to the drug release from the hydrophilic matrices. The drug release after the first hour, from the formulation batches A5 and A6 was 36.58 %, and 23.35 % respectively while that after 8 hours, was 102.23 %, and 95.66 % respectively. Despite of having the desired first hour release A5 was not considered optimized drug, polymer ratio for further studies since its similarity factor (57.646) was less than that of batch A6 (66.787). To determine the effect of low density copolymer PSDVB on the drug release rate of chitosan-carbopol 940 floating matrix tablets formulation batches having 336 mg of ranitidine hydrochloride, 50 mg of chitosan and 100 mg of carbopol 940 was appropriate because the tablets also maintained its in vitro integrity for more than 24 hours. Once the concentrations chitosan-carbopol 940 were almost optimized the effect of floating by low density copolymer i.e. PSDVB on in vitro buoyancy and drug dissolution profile, different formulation batches containing 30, 50, 70 and 100 mg PSDVB copolymer i.e. approximately 5 %, 10 %, 12 % and 17 % were formulated. The results obtained from in vitro dissolution study revealed that there is no significant change in drug dissolution profile with increase or decrease in PSDVB low density copolymer concentration. The drug release in the first hour for all the four batches A7 to A10 was approximately near to 33 % and that after 8 hours was near to 97 % (> 90%). The similarity factor for batches A7 to A10 in ascending order of batch numbers was 69.489, 68.576, 63.239, and 57.334 respectively. During the in vitro buoyancy test, a significant change was observed in the floating lag time of the formulation with increased amount of PSDVB. No floating of the tablets was achieved in lower concentrations of PSDVB copolymer i.e. upto 12 %. Evaluating all the parameters batch A10 was selected as the optimized batch since it had the minimum concentration of low density copolymer required to float the tablets (FLT: approximately 10 seconds) and similarity factor between 50 and 100.

A study of effect of diluents on the release rate of chitosancarbopol 940 floating mixed matrix tablet containing lactose and dicalcium phosphate (DCP) was carried out (batches A11 to A14). The release profile obtained after 8 hours has been shown in figure. The drug release increased when adding the fillers; however no differences were seen between the two different fillers at the investigated filler percent of 25 % and 50 % each. The slight difference in drug release can probably be explained by the less tight hydrogel structures upon swelling. Thus, the polymers, chitosan-carbopol 940 clearly are the dominating compounds controlling the release rate of the drug in the investigated low density matrix tablets. The results of different formulation batches were compared with theoretical dissolution profile by similarity factor f2 test and the floating lag time of each batch. The similarity tests show that among all the batches, batch A10 containing 50 mg chitosan, 100 mg carbopol 940 and 100 mg PSDVB copolymer showed f2 value > 50 indicating closest fit with theoretical dissolution profile. Other criteria for the selection of best batch, was that the formulation should release drug in predictable and controlled manner and have FLT less than 15 sec. and both these parameters were also satisfied by batch A10, and hence it was studied further. 3.3. Drug Interaction Study Drug-excipient interactions play a vital role with respect to release of drug from the formulation amongst others. FTIR techniques have been used here to study the physical and chemical interaction between drug and excipients used. In the present study, it has been observed that there is no chemical interaction between ranitidine hydrochloride and the polymers used. Drug has given peaks due to furan ring, secondary diamine, alkene and two peaks due to nitro functional groups. (Chatwal and Anand, 2005). Form the fig. 3 it was observed that there were no changes in these main peaks in IR spectra of mixture of drug and polymers, which show there were no physical interactions because of some bond formation between drug and polymers. 3.4. Kinetic Modeling of Drug Release The results of F-statistics were used for the selection of the most appropriate model. The goodness of fit test proposed by Bamba and Co-workers was used to determine the kinetics of drug dissolution profile. The release profile of the best batch (A10), which showed highest similarity factor f2, was fitted to Higuchi model (F= 6.81). This superiority is however statistically insignificant with Hixon Crowell model (F = 10.06) while it is significant with Zero order model (F = 106.72) as shown by the goodness of fit test (F-ratio test). But the priority should be given to the model with the least F-value. Thus, it may be concluded that the drug release from gastro retentive


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ranitidine hydrochloride tablet is best explained by Higuchi model. The values of slope and intercept for Higuchi model are 4.655 and – 1.511 respectively. See Fig. 2.

a

b

c

d

e)

Fig. 2. Drug release data of various formulated batches (A1 to A14).

Fig. 3. Infrared spectra of a) ranitidine hydrochloride, b) chitosan, c) carbopol 940, d) Poly (Styrene-divinylbenzene) and e) formulation batch (A10).


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4. Accelerated Stability Optimized Batch

Study

of

the

Gastro retentive tablets of ranitidine hydrochloride formulated in the present study were subjected to accelerated stability studies in Aluminum / Aluminum pouch pack as aluminum strip is considered the best protecting packaging material but in the present study simulation was made using aluminum foil pouch. As the dosage form is formulated for site specific drug delivery to stomach, no change should occur in its floating lag time and drug dissolution profile. Dose dumping and failure of buoyancy are probable effects anticipated during the stability study of such dosage forms. The tablets of batch A12 were packed in aluminum pouch and charged for accelerated stability studies at 40 °C and 75% RH for 3 months in a humidity jar. Floating lag time and drug dissolution profile of exposed sample was carried out. The results of accelerated stability studies are shown in fig. 4.

almost immediately upon contact with the release medium, showing no lag times in floating behavior because low density is provided from the beginning (t ≤ 10 seconds). Extended floating times are achieved due to the air entrapped within the low density copolymer particles, which is only slowly removed from the system upon contact with the release medium. As expected, tablets without low density copolymer (e.g. consisting of 50 mg chitosan, 100 mg carbopol 940 and 336 mg ranitidine hydrochloride first sank before floating, showing no floating lag times. Adding only 17% w/w (based on the mass of the tablet) of the PSDVB copolymer reduced the lag times to 10 seconds. The other most important thing that can be concluded from the study was that the formulation and process variables play sole role in the release behavior of the matrices. Faster release of the drug from the hydrophilic matrix was probably due to faster dissolution of the highly water-soluble drug from the core and its diffusion out of the matrix forming the pores for entry of solvent molecules. So, we can obtain a formulation that has desired release profile by adjusting different parameters that ultimately effect release behavior of the matrices.

Acknowledgements Dr. James R. Benson and Dr. Nai-Hong Li of Polygenetics, Inc., (USA) are acknowledged for kind support in the research work.

References Fig. 4. Comparison of dissolution profile before and after stability studies of batch A10

The similarity factor was calculated for comparison of dissolution profile before and after stability studies. The f2 value was found more than 50 (76.117) that indicate a good similarity between both the dissolution profiles. Similarly, no significant difference was observed in the floating lag time after stability studies. Hence, the results of stability studies reveal that the developed formulation has good stability.

5. Conclusion The present investigation shows that the chitosan-carbopol 940 mixed matrices can be used to modify release rates in hydrophilic matrix tablets prepared by direct compression. Incorporation of the highly porous low density copolymer in the matrix tablets provides densities that are lower than the density of the release medium. 17% w/w low density copolymer (based on the mass of the tablet) was sufficient to achieve proper in vitro floating behavior for at least 8 hours. In contrast to most conventional floating systems (including gas-generating ones), these tablets floated

Bamba, M., Puisieux, F., Marty, J. P., Carstensen, J.T. (1979). Release mechanisms in gel forming sustained release preparation. Int. J. Pharm. 2, 307–315. Basit, A. W., Lacey Larry, L. (2001). Colonic metabolism of ranitidine: implications for its delivery and absorption. Int. J. Pharm. Sci. 227, 157 – 165. Chatwal, G. R., Anand, S. K. (2005). Instrumental Methods of Chemical Analysis (Analytical chemistry). 5th revised and enlarged ed., Himalaya Publishing House: 2.29-2.82. Chawla, G., Bansal, A. (2003). A means to address regional variability in intestinal drug absorption. Pharm. Tech. 27, 50-68. Coffin, M. D., Parr, A. F. (1995). Ranitidine Solid Dosage Form. US Patent: 5,407,687. Grant, S. (1989). Ranitidine: an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in peptic ulcer and other allied diseases. Drugs. 37, 801-870.


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Histamine H2 antagonists. In: Drug Facts and Comparisons. (2002). 56th ed. St Louis, MO: Wolters Kluwer Co. 1192-1197. Lauritsen, K. (1990). Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases. Clinical Pharmacokinetics. 19, 11-31, 94-125. Paulo, C., Jose, M., Sousa, L. (2001) . Modeling and comparison of dissolution profiles. Eur. J. Pharm. Sci. 13, 123-133. Rosa, M., Zia, H., Rhodes, T. (1994). Dosing and testing in-vitro of a bioadhesive and floating drug delivery system for oral application. Int. J. Pharm. 105, 65-70. Singh, B.N., Kim, K.H. (2000). Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J. Control Release. 63, 235–259. Somade, S., Singh, K. (2002). Comparative evaluation of wet granulation and direct compression methods for preparation of controlled release Ranitidine HCL tablets. Indian J. Pharm Sci. 64, 285. The United States Pharmacopoeia, 26 /The National Formulary 21, Ranitidine Hydrochloride, United States Pharmacopeial Convention, Inc. 1615-1619.


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FORMULATION OF FLOATING MIXED MATRIX TABLETS

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