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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                                                                                                           Research Article 

Design, Development and Evaluation of Gastroretentive Drug Delivery System of Antacids

Raj Mohan¹*, Revathi A. Gupta²

¹ PG Scholar, Institute of Pharmacy, Dr. A. P. J. Abdul Kalam University, Indore, MP, 452016 

² Principal, Institute of Pharmacy, Dr. A. P. J. Abdul Kalam University, Indore, MP, 452016 

INTRODUCTION

The major disease of the stomach and duodenum are gastritis, gastric ulcer, duodenitis, and duodenal ulcer, all of which are in some way related to gastritis with injury that is mediated by acid¹. The normal pH of the stomach is 1.2 to 1.8. During most of the day, the food stimulates the acid secretion also neutralizes it, keeping the pH between 3 and 5. However, when the stomach is empty, approximately 2 to 3 hr after eating, then the pH again drop, and ulcer patients tend to suffer pain that is relieved by consuming antacids. In general, pain only occurs when the pH is below 2^1-3. Antacids are used widely for the relief of heartburn and dyspepsia, as well as a large variety of nonspecific gastrointestinal symptoms. The primary role of antacids in the management of peptic acid disorders is to relief pain. Another action of antacids is to prevent the conversion of gastric pepsinogen to pepsin, the active form. This is a proteolytic enzyme thought to mediate tissue injury in ulcer disease³. Conventional dosage form of antacids has a short duration due to the short residence time. Conventional dosage form of antacids is cleared from the empty stomach in 30 minutes due to the regulary gastric emptying. If administered while food is in the stomach, the buffering action will last for 2 hours. An additional dose 3 hours after meals will extend the buffering time by 1 hour^{3, 4}. The ideal antacid should be rapid in onset and provide a continuous buffering action. The duration of buffering action is determined largely by when the antacid is administered. Healing of the peptic acid diseases occurs when the mean 24-h pH is kept above 3 to 4. The pH can be increased by either neutralizing acid (antacids) or inhibiting gastric secretion (H2-reseptor antagonists or proton pump inhibitors) ³. Oral route is considered as the most promising route for drug delivery⁵. Development of oral controlled release systems has been a challenge to formulation scientists because of the difficulty in localizing the system in target areas of the gastrointestinal tract⁶. The real challenge in the development of an oral controlled-release drug delivery system is not just to sustain the drug release but also to prolong the presence of the dosage form within the gastrointestinal tract (GIT) until all the drug is completely released at the desired period of time⁷. One of the novel approaches in the area of oral sustained release drug delivery is gastro retentive drug delivery system⁸. GRDDS 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 bioavailability⁹. Extended-release dosage forms with prolonged residence time in the stomach are highly desirable for drugs with i) narrow absorption windows, ii) stability problems in the intestinal or colonic environment, iii) local action in the stomach and iv) low solubility at high pH values¹⁰. The biphasic system is used mostly when maximum relief needs to be achieved quickly and it is followed by a sustained release phase. It also avoids repeated administration of drug. Coronary vasodilator, antihypertensive, antihistaminic, analgesic, antipyretics and antiallergenic agents are mainly used for this system. Bilayer tablet is new era for developing a combination of two or more active pharmaceutical ingredient in single dosage form, Promoting patient convenience and compliance. Dual release tablet is a unit compressed tablet dosage form intended for oral application. It contains two layers in which one layer having conventional or immediate release part of single or multiple actives; another layer is sustained or controlled release part of single or multiple actives. They are also called as multi-layer matrix tablet. Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose¹¹. The current investigation aims at the development of gastroretentive bilayer floating tablets with different release patterns of Magaldrate. It was further planned to use optimization software for optimization of floating layer. Factorial design was planned to use for optimization. Two level factorial design having three independent and three response variable were selected for the studies.

MATERIALS AND METHODS

Magaldrate was gifted by Aurobindo Pharma Limited, Hyderabad A.P, India. HPMC K4M, Ac-Di-Sol and lactose was obtained from Mapromax, Life sciences Pvt. Ltd. Dehradun. Polyplasdone XL-10 and sodium starch glycolate obtained from Danmed Pharmaceuticals Pvt Ltd, Hyderabad. Sodium bicarbonate, magnesium stearate and Aerosil were obtained from Loba Chemical Pvt Ltd (Mumbai, India). Hydrochloric acid was obtained from S. D. Fine Chem. Ltd., Mumbai. All other chemical were purchased from Hi Media, Mumbai. Double distilled water was prepared freshly and used whenever required. All other chemicals used in this study including those stated were of analytical reagent (A.R.) grade.

Formulation development 

Formulation of immediate release (IR) layer

All the ingredients except Mg stearate and aerosil were passed through the 40-mesh sieve. Mg stearate and aerosil were passed through 80-mesh sieve. Magaldrate and starch 1500 were mixed thoroughly by gentle blending for few minutes. After blending, granulation was done by sufficient quantity of water. Wet masses were first passed through the 10-mesh sieve and then dried in an oven at 50^oC for 2 hour. Then the granules were passed through the 22-mesh sieve and the granule obtained were mixed with superdisintegrant and lubricated with Mg stearate and aerosil and then compressed. Hardness were tried to keep constant Table 1.

Table 1: Optimization bathes of immediate release layer

Optimization of the floating layer using 2³ factorial designs

On the basis of the selection of the 2³ factorial designs and taking a center point gives a total of nine trial batches. Nine trial batches were taken for the studies and evaluation has been done for the each batches. Excipients other than independent variable are kept constant viz. the amount of sodium bicarbonate, Mg stearate and aerosil are kept at 30mg, 10mg, and 3mg respectively Table 2-4.

Table 2: List of independent variable

Table 3: List of dependent or response variable selected for the studies

Table 4: Trial batches and their combination of independent variables

Preparation of bilayer tablets

Immidiate release tablet granules were prepared as above. All the ingredients except Mg stearate and aerosil were passed through the 40-mesh sieve. Mg stearate and aerosil were passed through 80-mesh sieve. Floating layer tablet were prepared by wet mixing magaldrate powder with water and pass through the 20 mesh seive and then dried it in oven for 50^oC for two hours. Then all the ingredients were mixed in geometric proportion. Batches consisting of 50 tablets were prepared by compresion method. All the product and process variable (other than factor chosen for optimisation studies) like amount of sodium bi carbonate, amount of lubricant and glidant, mixing time and hardness were kept as practically constant. Magaldrate and polymer were seived through  80 mesh seive and the magnesium stearate and aerosil were seived through 120 mesh seive prior to use. All the material were accurately weighed and mixed by gentle mixing for 10 minutes and subsequently compressed into tablets using capsule shaped pucnches of size 11^’’´22’’. 

Optimized batch formula

 On the basis of the optimization studies the software gives the optimimum value of independent variable. On the basis of that we prepare a optimum batch and it was evluated for all the studies. The response variable anticipated by the software is cross check to the value obtained by observation Table 5. 

Table 5: Formula for optimum formulation

Evaluation of pre-compression parameter¹² 

Angle of repose (θ)

The angle of repose was determined by using fixed funnel method. The physical mixtures of drug with different excipients were prepared and the accurately weighed drug powder or its physical mixture was taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touches the apex of the heap of the drug powder. The powder was allowed to flow through the funnel freely onto surface. The angle of repose was calculated using the following equation.

θ = tan-1(h/r)

Where, h and r are the height and radius of the powder cone respectively.

Bulk density/tapped density

Both loose bulk density (LBD) and tapped density (TBD) were determined were calculated using the following formulas.

LBD = Powder weight/volume of the packing

TBD = Powder weight /tapped volume of the packing

Compressibility index

 The compressibility index of the granules was determined by Carr’s compressibility index.

Carr’s index (%) = [(TBD – LBD)/TBD] × 100.

Hausner’s ratio

Hausner’s ratio is an indirect index of ease of measuring the powder flow. It was calculated by the following formula [7-9].

Hausner’s ratio = Tapped density/Bulk density

Evaluation of post compression parameter^13-15 

Hardness

For each formulation, the hardness of five tablets was determined using the Monsanto hardness tester (Cadmach) and measured in terms of kg/cm².

Weight variation

Twenty tablets were selected randomly from each formulation and average weight was determined.  The tablets were weighed individually and compared with average weight. The U.S Pharmacopoeia allows a little variation in the weight of a tablet.

Friability

A sample of twenty randomly selected tablets were accurately weighed and placed in a Roche friabilator. The friabilator was operated for 4 min at a speed of 25 rpm. The tablets were removed from the friabilator, de-dusted and reweighed. The percent loss in weight due to abrasion and impact was calculated as,

%Friability= (Loss in weight/ Initial weight) x 100

Disintegration test

This test was done for the immediate release tablet. The tablets were taken in a rigid basket rack assembly supporting six cylindrical glass tubes. The glass tubes were 77.5±2.5 mm long, 21.5 mm in internal diameter and with a wall thickness of about 2mm. The assembly was suspended in the liquid medium in a 1000 ml beaker. The volume of the liquid was such that, wire mesh at its lower point was at 25 mm below the surface of the liquid and its lower point was at 25 mm above the bottom of the beaker. The temperature was maintained at 37.0± 2^oC. The average disintegration time was finally recorded. 

Drug content

Twenty tablets were weighed and finely powdered. Accurately weighed portion of the powder; equivalent to about 6 g of Magaldrate was transferred to a 200-ml volumetric flask. 100.0 ml of 2 N hydrochloric acid was added and swirled by mechanical means for 30 minutes. It was diluted with water to volume, mixed, and filtered. 100.0 ml of the filtrate was transferred to a beaker. Excess acid was titrated with 1N sodium hydroxide to a pH of 3.0, the value was potentiometrically determined. Blank determination was performed. Each ml of 2N hydrochloric acid is equivalent to 70.80 mg of Al₅Mg₁₀(OH)₃₁(SO₄) ₂.

Dissolution study

The method was a modification of an RIGO and used USP dissolution test apparatus 2 with a stirring rate of 125 rpm in combination with a burette connected to a peristaltic pump. The test solution was 250 ml 0.02 M HCl. A total of 20 min after addition of an antacid to the test solution titration was started at a constant speed of 2.0 ml/m in 0.1 M HCl. The proposed acceptance criteria was: pH after 4 min not less than 2.5 to ensure a rapid onset of effect, pH after 20 min not exceeding 7.0 to ensure that the pH in the stomach remains within physiological values.

Floating time and floating lag time

These evaluations were part of the dissolution study. Floating time indicates the time for which the tablet remains floating on the surface of the dissolution medium and floating lag time is the time required to reach the surface of the dissolution medium.

RESULTS AND DISCUSSIONS

The powdered blends of different formulations of immediate release layer were evaluated for angle of repose, bulk density (BD), tapped density (TBD) and compressibility index. The results of pre-compression parameter of immediate release layer are summarized in Table 6. The value shows that the powder has compressibility index vary from 11.53 to 13.72 and hausner’s ratio varies from 1.13 to 1.20. This shows good compressibility, whereas angle of repose varies from 31º to 34º which ensure good flow properties of powder. The formulation of immediate release tablet prepared by using the superdisintegrants exhibited the LBD, TBD, angle of repose, compressibility index and Hausner’s ratio of within the range, which shows good flow properties of the powdered blend. The prepared tablets were evaluated for different physico-chemical properties and the results are summarized in Table 7. Results of pre-compression and post-compression parameters of floating layer were given in Table 8&9. The Table 10 trial batches were selected according to the 2³ factorial design of design expert software and their evaluation has been done. The  results obtained were feeded in the software. The Constriants are selected on the basis of the requirement of the formulation in which, the independent variable and dependent variable are kept in the range except the time to maintain pH above 2.5 were maximize. Which shown in the table 11. Table 12 shows that the formulation should not only prolong the action of the antacids but it should kept pH in the physiological range. F1, F3,F5, and F9 shows the case of dose dumping in which the pH after 20 rise above unphysiological pH . Formulation F2, F4, F6, F7, and F8 shows the well control over the rise of pH. All   formulation passes the initial criteria of above pH 2.5 after 4 minutes. The coefficient of polynomial equation generated for the floating time, time to maintain pH above 2.5 and floating lag time and polymer blend were studied . seven coefficients (b_o to b₂₃) were calculated where b_o as the intercept. The coefficients b₁ to b₂₃ were represent various quadratic and interaction terms, but are denoted as such in below equation due to their simplicity. Table 13 shows the  values of coefficient for the polynomial equations for various response variable of the bilayer tablet formulation of magaldrate.

Y= b_o+b₁X₁+ b₂X₂+ b₃X₃+b₁₂X₁ X₂+b₁₃X₁ X₃+b₂₃X₂X₃

Figure 1(A) depicts a quite linear increasing trend in the values of floating time with increase in the amount of HPMC. Whereas increasing the amount of croscarmellose the floating time decreases. Here the effect of HPMC is more prominent than croscarmellose. Figure1 (B) reveals that the increase in amount of HPMC and lactose leads to increase in floating time. But the influence of HPMC is more prominent than lactose. Figure 1(C) depicts that the floating time is increase by decrease in croscarmellose whereas floating time increase by increasing amount of lactose but the effect of lactose is more prominent than lactose. Figure 2(A) depicts a quite linear increasing trend in the values of time to maintain pH above 2.5 with increase in the amount of HPMC. Whereas increasing the amount of croscarmellose the time to maintain pH above 2.5 is decreases. Here the effect of HPMC is more prominent than croscarmellose. Also increase in lactose leads to decrease in floating time. Figure 2(B) reveals that the increase in amount of HPMC and lactose leads to increase in time to maintain pH above 2.5. But the influence of HPMC is more prominent than lactose. Figure 2(C) depicts that the time to maintain pH above 2.5 is increase by decrease in croscarmellose whereas “time to maintain pH above 2.5” increase by increasing amount of lactose but the influence of lactose is more prominent than croscarmellose. Figure 3(A) depicts a quite linear increasing trend in the values of floating lag time with increase in the amount of HPMC and croscarmellose. Here the influence of HPMC is more prominent than croscarmellose.  Figure 3(B) reveal that the increase in amount of HPMC and lactose leads to increase in floating lag time. But the influence of HPMC is more prominent than lactose. Figure 3(C) depicts that the floating lag time is increase by increase in croscarmellose and lactose. But the effect of croscarmellose is more prominent than lactose. The three batch of optimum formula were prepared and their powder and tablet were evaluated. Their evaluations were shown in table 14. It was found that the all batches have good compressibility as well good flow properties. The tablets were passes the weight variation and friability test. The drug content was found to be satisfactory. Further responses of three optimum batches were taken and it shown in table 15. Here it shows a good correlation between the observed responses with that of the anticipated value predicted by software hence the optimization method was validated the optimization tool. Table 16 list the dissolution parameter of marketed formulation studied viz. Ulgel (Dabur), containing 400mg of Magaldrate. The results of table shows that the developed formulation is long acting in comparison to existing normal dose of marketed products and also when the dose of marketed formulation is increased then the pH after 20 minutes rises above the physiological pH. Hence the prepared formulation is long acting as well as safe and effective.

Table 6: Result of pre-compression properties of immediate release layer

Table 7: Results of post-compression parameters of immediate release layer

Table 8: Result of pre-compression properties of floating layer

Table 9: Results of post-compression parameters of Magaldrate floating tablets

Table 10: Optimization trial batches and their responses

Table 11: Constriants given to the system

Table 12: Dissolution data of optimization batches

Table 13: Polynomial coefficient values for response variables

Table 14: Powder and tablet evaluation of optimum batches

Table 15: Responses of the optimized batch

Table 16: Dissolution parameter for optimized batch and popular marketed batch

(A)                                                                                     (B)

(C)

Figure 1: Response surface plot  (A) showing the influence of HPMC K4M and Ac-Di-Sol, (B) HPMC K4M and Lactose, (C) Lactose and Ac-Di-Sol on the floating time

(A)                                                                    (B)

(C)

Figure 2: Response surface plot  (A) showing the influence of HPMC K4M and Ac-Di-Sol, (B) HPMC K4M and Lactose, (C) Lactose and Ac-Di-Sol on the time to maintain pH above 2.5

(A)                                                                       (B)

(C)

Figure 3: Response surface plot  (A) showing the influence of HPMC K4M and Ac-Di-Sol, (B) HPMC K4M and Lactose, (C) Lactose and Ac-Di-Sol on floating lag time of tablet

CONCLUSION

In present study we developed a bilayer formulation having one layer as immidiate release and other layer as floating layer which gives the long duration action of antacids. Hence for the optimisation of the floating layer  2 level factorial design has been selected. The design expert software 7.2.3 version has been used. A very good correlation between the observed value of optimized batch and the anticipated value of software was found. Also formulation was compared with the marketed product and it was found that the present formulation is safe and effective as well as long acting.

REFERENCES

1. Gregory MC. Disease: Manifestations and Pathophysiology. In: Gennaro AR, (Editor). Remington: The Science and Practice of Pharmacy, 20th Edition, Volume II, Lippincott Williams & Wilkins, London, 2000, pp. 1084-1085.
2. Perigard CJ. Clinical Analysis, Gastric Analysis. In: Gennaro   AR, (Editor), Remington: The Science and Practice of Pharmacy, 20th Edition, Volume I. Lippincott Williams & Wilkins, London, 2000, pp. 580-581.
3. Tolman KG. Gastrointestinal and Liver. In: Gennaro AR, (Editor), Remington: The Science and Practice of Pharmacy, 20th Edition. Volume II, Lippincott Williams & Wilkins, London, 2000, pp. 1219-1220.
4. Wallace JL, Keith AS. Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease, Chapter 45, In: Brunton LL, Chabner BA, Knollmann BC. (Eds.), Goodmann and Gilman's the Pharmacological Basis of Therapeutics, Twelfth Edition, MC Graw Hill Medical, New York, 2011, pp. 1315-1320.
5. Santhanalakshmi G, Elango K, Kumar RK, Farheen F. Formulation and evaluation of bilayer floating tablets of trimetazidine hydrochloride and metoprolol succinate. Indian journal of Pharmaceutical education and research. 2012; 46(3):259-64.
6. Gahiwade HP, Patil MV, Tekade BW, Thakare VM, Patil VR. Formulation and in-vitro evaluation of trifluoperazine hydrochloride bi-layer floating tablet. IJPBS. 2012; 2(1):166-72.
7. Tadros MI. Controlled-release effervescent floating matrix tablets of ciprofloxacin hydrochloride: Development, optimization and in vitro–in vivo evaluation in healthy human volunteers, Eur J Pharm and Biopharm. 2010; 74:332–33. https://doi.org/10.1016/j.ejpb.2009.11.010
8. Sarfaraz M, Ch PK, Udupi RH, Doddayya H. Formulation and in-vitro evaluation of bilayer floating tablets of tramadol hydrochloride. International Journal of Drug Development and Research. 2012; 4(3):335-347.
9. Guguloth M, Bomma R, Veerabrahma K. Development of sustained release floating drug delivery. PDA J. Pharm Sci Technol. 2011; 65:198-206. https://doi.org/10.5731/pdajpst.2011.00685
10. Streubel A, Siepmann J, Bodmeier R. Floating matrix tablets based on low density foam powder: effects of formulation and processing parameters on drug release. European journal of pharmaceutical sciences. 2003 Jan 1; 18(1):37-45. https://doi.org/10.1016/S0928-0987(02)00223-3
11. Sheth PR, Tossounian J. The hydrodynamically balanced system (HBS™): a novel drug delivery system for oral use. Drug Development and Industrial Pharmacy. 1984; 10(2):313-39. https://doi.org/10.3109/03639048409064653
12. Jain P, Nair S, Jain N, Jain DK, Jain S. Formulation and evaluation of solid dispersion of lomefloxacin hydrochloride. International Journal of Research in Pharmaceutical Sciences. 2012; 3(4):604-608.
13. Pandey SP, Khan MA, Dhote V, Dhote K, Jain DK. Formulation development of sustained release matrix tablet containing metformin hydrochloride and study of various factors affecting dissolution rate. Scholars Academic Journal of Pharmacy. 2019; 8(3):57-73.
14. Patel AK, Rai JP, Jain DK, Banweer JI. Formulation, development and evaluation of cefaclor extended release matrix tablet. International Journal of Pharmacy and Pharmaceutical Sciences. 2012; 4(4):355-7.
15. Gautam SP, Rai JP, Billshaiya U, Jain N, Vikram P, Jain DK. Formulation and evaluation of mouth dissolving tablet of loperamide. International Journal of Pharmaceutical Sciences and Research. 2013; 4(5):1782.