Formulation and Evaluation of Orodispersible Tablet with an Extended Release Profile

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1 Formulation and Evaluation of Orodispersible Tablet with an Extended Release Profile Chavan Ritesh A.* and Mayee Rahul Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, Rajasthan ABSTRACT Galantamine is a tertiary alkaloid, selective, competitive and reversible inhibitor of acetyl cholinesterase. It is used for symptomatic treatment of mild to moderately severe dementia of the Alzheimer type. Current study was focused on formulation development of orodispersible tablet of Galantamine which disintegrates extended release pellets. Drug coating of drug was done on Celphere CP 203 with the help of Povidone K30 as a binder. Extended release pellets were formulated using wurster process. Extended release coating on drug loaded pellets were done using eudragit NE 30D as a rate limiting polymer. About 30 % extended release coating with eudragit NE 30D showed comparable drug release pattern that of with marketed preparation s pellets of Galantamine ER. Further these pellets were compressed tablets that were dispersed within 30 seconds, releasing extended release pellets. These formulations showed ideal drug release comparable to precompressed pellets. It showed no rupture of extended release pellets that can hamper the drug release pattern. At accelerated stability conditions developed formulations were found to be stable for six month. Keywords Galantamine, Extended release orodispersible tablet, extended release pellets, Eudragit NE 30D, Antialzhimer drug etc. INTRODUCTION Orally disintegrating (dissolving) tablets (ODTs) are solid dosage forms that are placed in the mouth, rapidly disintegrate/dissolve when in contact with the saliva and then easily swallowed without the need for water. The fast disintegrating behavior of the ODT in the mouth limits the active ingredients that can be incorporated to drugs that exhibit good taste, stability in gastric conditions and have long half-life. 1 Bitter tasting drugs can cause discomfort to patients and consequently reduce their compliance, whereas incorporating drugs that suffer from instability in gastric fluids reduces the efficacy of the dosage form (bioavailability). On the other hand, delivering active drugs that have short half-life in ODTs compromise the practicality of the dosage form as more frequent administration is required. To address these issues, a great deal of interest has been directed towards incorporating multiparticulate drug delivery system in *Corresponding Author Chavan Ritesh A 55 P a g e

2 ODT formulations. The multiparticulate drug delivery system comprises of drug particles encapsulated or coated by one or more layers of polymers that control the release of the drug. The polymer can be selected to provide extended, delayed or pulsed drug delivery, allowing the rate of release of the drug to be tailored as required. Moreover, they provide many advantages over single-unit dosage forms because of their multiplicity and small sizes including reduced risk of systemic toxicity, enhanced bioavailability, reduced risk of local irritation and reduced patient to patient variability as a result of their more predictable gastric emptying. Accordingly, the formulation of multiparticulate into ODTs can extend their application to more challenging drugs (e.g. acid sensitive) by overcoming restrictions imposed by the nature of these drugs and combine the benefits of ODTs and multiparticulate drug delivery system 2, 3. The compression of multiparticulate into ODT formulations has attracted substantial attention in both academia and industry and resulted in many scientific publications and patent applications. However, to produce a tablet with good structural integrity, relatively high compression pressures are required. These high pressures can cause damage to the polymer layers of the multiparticulate system, and, as a result, compromise their release controlling properties. Peroral controlled-release multiple unit dosage forms (e.g., pellets, granules or sustained release pellets, microcapsules, microparticles) are becoming more and more important on the pharmaceutical market, as they provide several advantages compared to single-unit dosage forms (e.g., tablets or capsules) 4,5 Galantamine is a tertiary alkaloid, selective, competitive and reversible inhibitor of acetyl cholinesterase. It is used for symptomatic treatment of mild to moderately severe dementia of the Alzheimer type. Currently available formulations for galantamine are in the form of pellets, capsules for extended release and conventional tablets for immediate release 6. By looking at target population for Galantamine, orodispersible tablet with extended release profile could be favorable option that could administer the dosage form easily. The present work led to the formulation of orodispersible tablets for oral administration. The developed formulation which disintegrates disperses in oral cavity in less than 30 seconds without the need of drinking water; had pleasant mouth feel and improved patient compliance particularly for those who have difficulty in swallowing 7. MATERIALS AND METHODS Materials Galantamine Hydrobromide was selected as a model drug candidate for the formulation trials aqueous dispersion of Eudragit NE 30D was used as a rate controlling polymer. Talc was used as an antitacking agent. Celphere CP 203 pellets from Asahi Kasei Excipients were used as a core pellets for drug loading. Water and Methanol (GR grade) was used as solvents. Microcrystalline cellulose of various grades viz. Ceolus KG 802 and KG 1000 (Blanver) were used as a filler which provides good cushioning effect to 56 P a g e

3 the pellets. Crosspovidone XL 10 (ISP chemicals) was used as a disintegrant. Glyceryl Stearate was used a waxy agent to promote easy flow of pellets. Flavour (firmenich) was used as a flavour. Aspartame as a sweetener. Magnesium Stearate was used as a lubricant. METHODS Formulation Development Drug loading Procedure:- Refer the table no. 1 for the formula. Galantamine Hydrobromide was dissolved in purified water under continuous stirring until it gets completely dissolved then Povidone K30 was added slowly under continuous stirring in vertex. Stirring was continued until clear solution obtained. Finally above drug loading solution so formed was then subjected for drug loading over Celphere CP 203 pellets in Fluidized Bed Equipment (Pam Glatt) with bottom spray attachment of 1.0 mm spray gun having fixed column height. After drug loading, drug loaded pellets were then dried at 50 0 C until LOD achieved NMT 1.5 % w/w. and then sifted through ASTM mesh # 60. Process parameters were set as in table no.2. Extended Release Coating Procedure:- Refer the table no. 3 for the formula.talc was dispersed in purified water under continuous stirring for 30 min, then Eudragit NE 30 D was added under continuous stirring and Stirred for another 30 minutes more. Finally above extended release coating solution was then subjected for enteric coating over drug loaded pellets of Galantamine in Fluidized Bed Equipment (Pam Glatt) with bottom spray attachment of 1.0 mm spray gun having fixed column height. During the process samples of extended release coated pellets each at 10, 20, 30, 40 and 50 % extended release coating, was removed periodically and subjected for curing in oven at 50 0 c for 1 hr. Withdrawn samples were then passed through ASTM mesh #30 and 50 and retained pellets on ASTM mesh # 50 were subjected for dissolution and subsequently for further study. Process parameters were set as in table no.4. From the in vitro drug release patterns and curing effects of extended release pellets of appropriate coating that matches to in vitro drug release profile of marketed preparation, were selected for further evaluation and subsequently compression process. Compression of Pellets Procedure Refer the table no. 5 for the formula.ceolus KG 1000 and 802, Crospovidone XL 10, Aspartame and flavor were passed through mesh # 30 separately. Magnesium Stearate was passed through mesh # 60.All ingredients except magnesium Stearate was blended with extended release pellets were blended in polybag for 5 minutes. Magnesium Stearate was then lubricated with the above blend for 2 minutes and subjected for compression with 13 mm biconvex round shaped punch.compressed tablets were evaluated for Appearance and dimensions, Thickness, Hardness, Friability, Disintegration, in vitro drug release and stability studies 8, P a g e

4 Evaluation of Lubricated Blend and Pellets Angle of repose The powder mixture was allowed to pass through the funnel fixed to a stand at definite height. The angle of repose was then calculated by measuring the height and radius of the heap of powder formed. Then angle of repose had been calculated from below formula θ = tan -1 (h/r) Where: θ = Angle of repose h = Height of pile in cm r = radius in cm. Bulk Density Accurately weighed quantity of sample, and carefully poured into graduated cylinder. Then after pouring the powder into the graduated cylinder the powder bed was made uniform without disturbing. Then the volume was measured directly from the graduation marks on the cylinder as ml. The volume measure was called as the bulk volume and the bulk density is calculated by following formula: Bulk density = Weight of powder /Bulk volume Tapped Density After measuring the bulk volume the same measuring cylinder was set into tap density apparatus. The tap density apparatus was set to 100 taps drop and operated for 50 taps. Volume was noted as (Va) and again tapped for 50 times and volume was noted as (Vb). If the difference between Va and Vb not greater than 2% then Vb is consider as final tapped volume. The tapped density is calculated by the following Formula: Tapped Density = Va / Vb Where Va = weight of the powder Vb = tapped volume of the packing Compressibility index and Hausner ratio:- Compressibility index and Hausner ratio were calculated from bulk and tapped density of the sample. These parameters show the flow properties of sample. Compressibility index = [(D T - D B )/ D T ] x 100 Hausner ratio = D T / D B D T =Tapped density D B = Bulk density Friability test Roche Friabilator was used to measure the friability of the pellets. It was rotated at a rate of 25 RPM. 5 g pellets were weighed collectively and placed in the chamber of the friabilator. After 100 rotations (4 minutes), the pellets were taken out from the friabilator and intact pellets were again weighed collectively after removing fines using ASTM sieve # 60 sieve. Permitted percentage friability limit is 0.8%. The percent friability was determined using the following formula. % friability = [(W 1 W 2 ) / W 1 ] x 100 Where W 1 = weight of the pellets before test. W 2 = weight of the pellets after test. 58 P a g e

5 Drug content (Assay calculation) This practice was done for the pellets obtained after drug coating to check the entrapment of the drug in the drug loaded pellets. Drug loaded pellets equivalent to 24 mg of pellets had been dissolved in diluents, from this solution 1ml was pipette out in to 10ml volumetric flask and volume was made up to with methanol 10. In vitro drug release In vitro drug release of pellets was carried out after functional coating to check drug release pattern of the extended release pellets prior to the compression and on to the compressed tablets. Invitro drug release/ dissolution studies were carried out using following dissolution conditions. Dissolution Conditions:- Dissolution Apparatus = USP type II (Paddle type). Dissolution medium = Phosphate buffer ph 6.8 Temperature = 37 ± 0.5 o C Paddle rpm = 100. Time Points = 1,2,3,4,6,8,10,12,14,16,18,20,22,24 hrs. Accurately weighed pellets were placed in each flask of dissolution apparatus. The apparatus was allowed to run for 24 hours. Samples measuring 5 ml were withdrawn. Then samples were filtered through 0.45 Millipore filter and their concentrations were determined using High Performance Liquid Chromatography System 11 Curing effect: The pellets were cured in a hot air oven for 24 hours to check the effect of curing on drug release; the cured pellets are subjected for in vitro release studies 12. EVALUATION OF COMPRESSED TABLETS:- Appearance and Dimensions:- The thickness and diameter of the tablets was determined using a Vernier calliper. Five tablets from each type of formulation were used and average values were calculated. It is expressed in mm. Weight variation test:- Twenty tablets were selected randomly from each formulation, weighed individually and the average weight and % variation of weight was calculated. Hardness For each formulation, the hardness of 3 tablets was determined using the Monsanto hardness tester. The tablet was held along its oblong axis in between the two jaws of the tester. Then constant force was applied by rotating the knob until the tablet fractured. The value at this point was noted. Friability For each formulation, the friability of 20 tablets was determined using the Roche friabilator. A sample of preweighed 20 tablets was placed in Roche friabilator, which was then operated for 25 RPM for 4 minutes. A loss of less than 1% in weigh in generally considered acceptable. Percent friability (% F) was calculated as follows, % friability = [(W 1 W 2 ) / W 1 ] x 100 Whereas W 1 = weight of tablets before test. W 2 = weight of the tablets after test. In vitro disintegration test The process of breakdown of a tablet into smaller particles is called as disintegration. The in-vitro disintegration time of a tablet 59 P a g e

6 was determined using disintegration apparatus as per USP specifications. In vitro drug release Same as in vitro drug release testing of pellets. Stability Studies Stability studies were conducted according to ICH guidelines by using optimized formulation at 40 C/75±5% RH or a period of 6 months. The samples were withdrawn at 1, 3 and 6 month and analyzed for drug content, and dissolution study as given in in-vitro release dissolution studies by an HPLC method. Drug content (Assay calculation) Twenty tablets were weighed and powdered. The blend equivalent to 24 mg of Galantamine was weighed and dissolved in sufficient quantity of PH 6.8 phosphate buffer. The solution was filtered through Whatmann filter paper (no.41), suitably diluted with ph 6.8 phosphate buffer and assayed. RESULT AND DISCUSSION Drug loading Drug solution of Galantamine hydro bromide was loaded on Celphere CP 203 pellets Due to low viscous solution drug loading process was done without any process issues. Further drug loaded pellets were evaluated. Moisture Content Loss on drying was measured using moisture analyzer at c and was found to be 1.13 %w/w. Assay content 130 mg of drug loaded Pellets equivalent to 24 mg of Galantamine was subjected for assay determination by HPLC which was found to be % which shows effective drug loading on inert pellets. Friability Friability of drug loaded pellets was found to be which showed enough strength to withstand any pellets breaking issues during pelletisation. EXTENDED RELEASE COATING Extended release coating was done on drug loaded pellets. Due to low glass transition temperature of eudragit NE 30D, process was done using slow rate of spray rate. Also it was found that increasing spray rate triggers the sticking of pellets which was not ideal condition for rate controlling issue. Parameters observed during extended release coating were as below. Samples were withdrawn at different coating levels and then subjected for curing at 50 0 c for 1 hr. Cured pellets were then passed through ASTM mesh # 30 and 50. Pellets retained on ASTM mesh #50 was subjected for dissolution to check drug release pattern of the extended release pellets and drug release was found to be as in table no. 6 and graph no.1. It was found that coated 30% extended release coated pellets were found to be comparable with marketed extended release pellets. So these were chosen for further studies as below. Moisture Content:- Loss on drying was measured using moisture analyzer at c and was found to be 0.89 %w/w. Friability Friability of extended release pellets was found to be at 300 RPM which showed enough strength to withstand any 60 P a g e

7 pellets breaking issues during compression. Effect of Curing on extended release pellets. The pellets were cured in a hot air oven for 24 hours at 60 o c to check the effect of curing on drug release. Periodically pellets were sampled and then subjected for in vitro drug release studies and compared with previous initial results. It had been found that there is no drastic effect on drug release after curing for long time. This shows the promising stability of extended release coating. In vitro drug release was found to be as in table no.7 and graph no.2. Further Extended release pellets were evaluated for precompression parameters as Angle of Repose, Bulk density, Tapped density, Compressibility index, Hausner ratio as below which showed good flow property as statedin table no.8. Further these pellets were subjected for blending and lubrication with extragranular ingredients Compression Lubricated blend was then subjected for preformulation studies to check flowability and compressibility properties as stated in table no. 10. Then lubricated blend was compressed into tablets by using 13.0 mm biconvex round shaped punch. In process compression parameters as followed in table no. 11. Since disintegration was achieved on the above parameters hence tablets were compressed and subjected for dissolution to check that if there was any chance of rupturing extended release pellets during the compression, as in table no. 12. It had been observed that there was no impact on dissolution profile of compressed tablets and extended release pellets, also on this hardness there was no rupture of pellets during compression with enough tablet friability. Stability study Stability studies were conducted according to ICH guidelines by using optimized formulation at 40 C/75±5% RH or a period of 6 months. The samples were withdrawn at 1,3 and 6 month and analyzed for drug content, and dissolution study as given in in-vitro release dissolution studies by an HPLC method as in Table no. 13,14 and graph no. 4. REFERENCES 1. Akbari B.V., Dholakiya R.B., Shiyani B.G., Lodhiya D.J. Design, development and characterization of mouth dissolving tablets of cinnarizine using superdisintegrants. International journal of pharmtech research. Vol.2, no.1, pp Jan-Mar Aulton, M.E.,Khan, K.A., The strength and compaction of millispheres. The design of a controlled-release drug delivery system for ibuprofen in the form of a tablet comprising compacted polymer-coated millispheres. Drug Dev. Ind. Pharm., 20, , Bechgaard H., Nielsen G.H. Controlled-Release Multiple-Units and Single-Unit Doses a Literature Review. Drug Development and Industrial Pharmacy 4, 53 67, P a g e

8 4. Bodmeier, R., Tableting of pellets. European Journal of Pharmaceutics and Biopharmaceutics Dashevsky, A., Kolter, K., Bodmeier, R., Compression of pellets coated with various aqueous polymer dispersions. Int. J. Pharm. 279 (1-2), Johansson, B., Nicklasson, F., Alderborn, G., Effect of pellet size on degree of deformation and densification during compression and on compactability of microcrystalline cellulose pellets. Int. J. Pharm., 163, Johansson, B., Wikberg, M., Ek, R., Alderborn, G., Compression behaviour and compactability of microcrystalline cellulose pellets in relationship to their pore structure and mechanical properties. Int. J. Pharm., 117, Juslin, M., Turakka, L., Puumalainen, P., Controlled release tablets. Part 1: The use of pellets coated with a retarding acrylate plastic in tabletting. Pharm. Ind., 42, , Satyakala Ganti. Development of HPLC Methods For Pharmaceutically Relevant Molecules; Method Transfer To UPLC. Comparing Methods Statistically For Equivalence. Temple University Graduate Board. January T. Jagadeesh, R. Bala Ramesha Chary. Development of Oral Multi Particulate Drug Delivery System of Galantamine Hydrobromide by Using Extrusion Spheronization technique. International Journal of Pharmacy & Technology. IJPT June-2011 Vol. 3 Issue No Korber, M., V. Hoffart, et al. (2010). "Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD." Drug Development and Industrial Pharmacy 36(2): P a g e

9 Table No. 1 Formula for drug loading Sr. No. Ingredients % w/w 1 Galantamine Hydrobromide (Eq. to 24 mg of Galantamine) Polyvinyl Pyrrolidone (Povidone K30) Celphere CP Purified water Table No. 2 Set Parameters of drug loading. Parameters Set value Inlet temperature ( 0 C) 50 Product temperature ( 0 C) 45 Exhaust temperature ( 0 C) 45 Atomisation Air (bar) Fan speed Peristaltic Pump Speed (RPM) 1-10 Table No. 3 Formula for extended release coating. Sr. No. Ingredients % w/w 1 Eudragit NE 30 D * Talc Purified water q.s. *Solid content. Table No. 4 Set Parameters of drug loading. Parameters Set values Inlet temperature ( 0 C) 25 Product temperature ( 0 C) Exhaust temperature ( 0 C) Atomisation Air (bar) Fan speed Peristaltic Pump Speed (RPM) P a g e

10 Table No. 5 Formula for blending and lubrication of extended release pellets. Sr. No. Ingredients % w/w 1 Extended Release Pellets Ceolus KG 1000* Ceolus KG Glyceryl Stearate Crospovidone XL Orange Flavor Aspartame Magnesium Stearate 1.25 Tablet weight mg *To be adjusted in accordance with extended release pellets weight Table- 6 In vitro drug release profile of extended release pellets at different coating levels. Time (Hours) Marketed sample Percentage of drug released 10 % 20 % 30 % ERC ERC ERC 40 % ERC 50 % ERC F2 Value ERC= Extended release coating 64 P a g e

11 Table-7 In vitro drug release profile of cured extended release pellets at different time intervals Percentage of drug released Time Cured pellets Cured pellets Cured pellets (Hours) (Initial) for 12 hrs. for 24 hrs F2 Value Table No 8 Precompression parameters of extended release pellets Sr. No. Parameters Results Remark 1 Bulk Density g/ml 2 Tapped Density g/ml 3 Hausners ratio 1.12 Good flow 4 Compressibility index % Good flow 5 Angle of repose o Good flow 65 P a g e

12 Table No. 9 Formula for blending and lubrication of extended release pellets Sr. No. Ingredients % w/w 1 Extended Release Pellets Ceolus KG 1000* Ceolus KG Glyceryl Stearate Crospovidone XL Flavor Aspartame Magnesium Stearate 1.25 Tablet weight Table No.10 Preformulation parameters of lubricated blend. Sr. No. Parameters Results Remark 1 Bulk Density g/ml 2 Tapped Density g/ml 3 Hausners ratio 1.15 Good flow 4 Compressibility index % Good flow 5 Angle of repose o Good flow Table No. 11 In process compression parameters Sr. No. Parameters Results Remark 1 Uniformity of weight ( mg) Weight variation 2.25 % deviation Within Limit 3 Thickness (mm) 2.50±0.16 mm 4 Hardness (kp) Friability ( for 100 revolutions) Within Limit 6 In-vitro disintegration time (sec) Within Limit 66 P a g e

13 Table No. 12 Comparative dissolution profile of Extended release pellets and compressed tablets. Time (Hours) Percentage of drug released Extended Release Pellets Compressed tablets F2 Value Table No. 13 Drug content according to stability conditions. Sr.No. Stability Conditions Drug content 1 Initial % 2 40 o c/75% RH, 1 month o c/75% RH, 2 month o c/75% RH, 3 month P a g e

14 % Drug released Table No. 14 In vitro drug release pattern of stabilised formulations. Time (Hours) Initial Percentage of drug released 40 o C/75% RH, 1 month 40 o C/75% RH 2 month 40 o C/75% RH, 3 month F2 values Marketed sample 10 % Extended release coating 20 % Extended release coating 30 % Extended release coating 40 % Extended release coating 50 % Extended release coating Time (Hours) Graph-1 In vitro drug release profile of extended release pellets at different coating levels 68 P a g e

15 % Drug released % Drug released Time (Hours) Cured pellets (Initial) Cured pellets for 12 hrs. Cured pellets for 24 hrs. Graph -2 In vitro drug release profile of cured extended release pellets at different time intervals Time (Hours) Extended Release Pellets Compressed tablets Graph - 3 Comparative dissolution profile of Extended release pellets and compressed tablets. 69 P a g e

16 % Drug released Time (Hours) Initial 40oc/75% RH, 1 month. 40oc/75% RH, 3month. 40oc/75% RH, 6 month. Graph - 4 In vitro drug release data of stabilised formulation 70 P a g e