ISSN: 0975-766X Available Online through Research Article www.ijptonline.com DEVELOPMENT OF ORAL MULTI PARTICULATE DRUG DELIVERY SYSTEM OF GALANTAMINE HYDROBROMIDE BY USING EXTRUSION SPHERONIZATION TECHNIQUE T. Jagadeesh *, R. Bala Ramesha Chary # AET Laboratories Pvt. Ltd. Survey No. 42, Gaddapotharam, Kazipally Industrial Area, Medak Dist. Hyderabad - 502 319. India. Email: jaggagouda@yahoo.co.in Received on 10-04-2011 Accepted on 22-05-2011 Abstract: In the present research study an multi unit particulate drug delivery system of Galantamine was developed by the Extrusion/Spheronization followed by sub coating and Prolonged Release coating using combination of Surelease and Hypromellose at 9:1 ratio at different percentage weight gain. The formulation optimized on the basis of invitro release profile in phosphate buffer ph 6.8. In-vitro releases profiles were compared with marketed formulation. The model-dependent and the model-independent methods are the used as analytical methods to compare dissolution profile of optimized formulation. The selected model-dependent methods studied by analysing the dissolution data using kinetic equation like the zero order, the first order, Huguchi square root, and K-peppas equations. The analysis of kinetic equations data that it follows first order kinetics and the release mechanism involves anomalous transport. The model independent method similarity factor (F 2 ) was 73 for optimum formula experiment No. GALC/E-10. The optimized formulation shows no significant changes from stability studies. Keywords: Galantamine Hydrobromide ; Surelease ; Extrusion / Spheronization; Stability; In-vitro dissolution. Introduction: 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. When compared with single-unit dosage forms, oral multiparticulate drug-delivery systems (eg. Pellets, Granules) offer IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2633
biopharmaceutical advantages in terms of a more even and predictable distribution and transportation in the gastrointestinal tract, which is fairly independent of the nutritional state. In contrast to single units, coated pellets can be used to mix incompatible drugs or to tailor the overall release at the delivery system by combining pellets with different release patterns [1]. Pellets are systematically produced, geometrically defined agglomerates of bulk drugs and excipients. They are small, free-flowing, spherical or semi- spherical solid units which are in the size range of 0.5-2.0 mm. Extrusion spheronization is the most commonly used technique for pelletization 2. Extrusionspheronization is a process of wet- extrusion, followed by spheronization, used to produce a wide variety of engineered, controlled release drugs. The excipients for pelletization by extrusion/spheronization are very limited because of the characteristics desired from wet masses. The main desired property for the extrusion process is to form a cohesive plastic mass on wetting 3,4. In the most bead formulations, microcrystalline cellulose (MCC), commercially available as Avicel and Emcocel products, is regarded as a concial diluent and spheronizing aid for successful extrusion and spheronization [5]. Ethylcellulose, dissolved in an organic solvent or solvent mixture, can be used on its own to produce water-insoluble films. Higher-viscosity ethylcellulose grades tend to produce stronger and more durable films. Ethylcellulose films may be modified to alter their solubility, by the addition of Hypromellose or a plasticizer. An aqueous polymer dispersion (or latex) of ethylcellulose such as Aquacoat ECD (FMCBiopolymer) or Surelease (Colorcon) may also be used to produce ethylcellulose films without the need for organic solvents. Drug release through ethylcellulose-coated dosage forms can be controlled by diffusion through the film coating. This can be a slow process unless a large surface area (e.g. pellets or granules compared with tablets) is utilized. In those instances, aqueous ethylcellulose dispersions are generally used to coat granules or pellets. Ethylcellulose-coated beads and granules have also demonstrated the ability to absorb pressure and hence protect the coating from fracture during compression 6. Materials and Methods: Materials: Galantamine hydrobromide was purchased from Johnson Matthey Macctorlan Smith limited, UK. Microcrystalline Cellulose (Avicel PH 102 FMC Biopolymer, USA) purchased from Signet Chemical IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2634
Corporation, Mumbai, India. Hypromellose (Methocel E-5 Premium LV) purchased from Colorcon Asia Pvt. Ltd., Goa, India. Surelease gift sample from Colorcon Asia Pvt. Ltd., Goa, India. Povidone (Plasdone K-90) purchased from ISP, India. Hard Gelatin Capsule Shell (White/White) was a gift sample from Associated Capsule Pvt. Ltd., India. All other chemicals and reagents used were of analytical grade. Methods: Preparation of core pellets: Core pellets prepared by sifting of all Stage A (Dry mix) mentioned in Table-1 through ASTM 40 mesh and mixed for 5 minutes in Rapid Mixer Granulator (HSMG10 Kevin Process Tech Pvt Ltd. India). The dry mix was granulated with Plasdone K-90 solution and added additional quantity of purified water to get suitable wet mass. The wet mass was extruded using 1.00 mm orifice in Extruder (Extruder 20, Caleva, ENGLAND) and the extrudats were immediately spheronized (Spheronizer 250, Caleva, ENGLAND) at 1000 rpm for 5 minutes. The obtained wet round pellets were dried in Rapid Drier (Restech drier TG 200, Restech, Germany) at 60 C±5 C till to get LOD at 105 C less than 2% m/m. The dried pellets were sifted and the fraction of ASTM 18 mesh passed and ASTM 35 mesh retains were taken for further coating. Coating of Drug-containing pellets: Sub coating: The calculated amount of Hypromellose 5cP (Methocel E5 LV Premium) and Polyethylene glycol 4000 dissolved in purified water to get solids contents 10 % w/w in solution and coated in a fluid bed coater (GPCG 1.1, Wurster Insert Pamm Glatt, India Pvt. Ltd., INDIA). Prolonged release coat: The calculated amount of Hypromellose 5cP (Methocel E5 LV Premium) dissolved in purified water. To this calculated amount of Surelease is added and mixed for 60 minutes. The dispersion made to contains solids of 15 % w/w. The above coating mixture is coated on to sub-coated pellets in Fluid bed coater (GPCG 1.1, Wurster Insert, Pamm Glatt India Pvt., India). The coated pellets were dried in an oven at 60 C for 12 hours. The dried pellets were filled in to capsules and analysed. IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2635
Evaluation of the pellets: T. Jagadeesh * et al. /International Journal Of Pharmacy&Technology In-vitro dissolution studies: The drug release profile from the coated pellets was performed using USP XXVIII dissolution apparatus (VARIAN with Auto Sampler). Media - Phosphate Buffer ph 6.8, Volume 900 ml, Apparatus - Basket at 100 rpm. Samples of 5 ml were withdrawn at predetermined time intervals. Samples were filtered (0.45 millipore filter) and their concentrations were determined using High Performance Liquid Chromatography System (Watters Alliance.2695) using Column XTerra RP 1.8 250 x 4.6 mm, 5 µm or equivalent (Waters) at UV detection at 238 nm. Stability Studies: Stability studies were conducted according to ICH guidelines by using optimized formulation at 40 C/75±5% RH for a period of 6 months. The samples were withdrawn at 1, 3 and 6 month and analyzed for drug content, water, related substances and dissolution study as given in in-vitro release dissolution studies by an HPLC method. Results and Discussion: The core pellets prepared by extrusion and spheronization technique is almost circular and having enough strengths to withstand the further coating processes. From the experiments with different polymeric coating thickness / weights it is evident that increase in polymeric coating thickness / weight there is a decrease in dissolution rate. This can be attributed to the ingestion of dissolution medium in to the core through polymeric film and subsequent dissolution of drug in the medium and further diffusion through polymeric film will depend on polymeric film thickness. The release of Galantamine is inversely proportional to the polymeric thickness on the coated pellets.the release rates of Galantamine from prepared capsules were compared with commercial Prolonged-Release formulation (Reminyl XL capsule 24 mg, manufactured by Janssen-Cilag AB, Germany). The experiment number GALE/C-10 was found to be an optimum formulation in providing controlled drug delivery with similar release profile of Reminyl XL 24 mg capsules as shown in Table-2. IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2636
The model-dependent and the model-independent methods are the two most widely used analytical methods to compare dissolution profiles. In the model independent method, the dissolution data are fitted into relevant selected mathematical models, characterized by suitable mathematical functions. The dissolution profiles are then evaluated in terms of the derived model parameters. Mathematical models used in dissolution data analysis include the zeroorder rate equation, which describes the systems where the release rate is independent of concentration of the dissolved species [7]. The first order equation describes the release from systems where dissolution rates dependent on the concentration of the dissolving species [8]. The Huguchi square root equation describes the release from systems where the solid drug is dispersed in an insoluble matrix and the rate of drug release is related to the rate of drug diffusion [9,10]. To gain some insight into the drug release mechanism, where n=0.5 indicating diffusional controlled drug release, and n=1.0 indicating swelling controlled drug release and values n between 0.5 and 1.0 can be regarded as indicating the superposition of both phenomena (anomalous transport) [10]. The applicability of all of these equations was tested in this work. The model independent method compares dissolution data directly and does not rely on the choice of mathematical model which may be unrealistic at times. In this method, graphical representation of the dissolution profiles is performed as a preliminary step to illustrate non-quantitative differences and their evolution along the profile. The dissolution data are subjected to further analysis, using time-point or pairwise approaches to determine similarity (F 2 ) between dissolution curves. The dissolution data was subjected for determining F 2 values by using the formula: F 2 = 50 x log{1+1/n) E τ=1 n (R t T t ) 2 } -0.5 x 100 [11]. The dissolution data of optimized formulation in phosphate buffer ph 6.8 plotted in accordance with the zero-order equation is percent dissolved as a function of time (Fig.1). It is evident from the figure that the plots are curvilinear, suggesting that the release process is not zero-order in nature. The dissolution data of optimized formulation in phosphate buffer ph 6.8 plotted in accordance with first order equation in the logarithm of the percent remained as a function of time (Fig.2). It is evident from Fig.2 and Table-3 that linear relationship was obtained with r values close to unity and higher than r obtained from zero-order IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2637
equation for all formulations, showing that the release is an apparent first-order process. This indicates that the release is proportional to the amount of Galantamine Hydrobromide remaining in the dosage form. The dissolution results plotted accordingly to the Higuchi square root equation (Fig.3). The obtained r values are lesser than r obtained from first-order equation. The dissolution results were also plotted according to K-peppas model (fig.-4), the values were found to between 0.5 and 1.0. It suggests that release mechanism was due to anomalous transport. The similarity factor is 73 for formulation of GALE/C-10 compared to other experiments. Stability studies stored at 40 C/75% RH for 6 months showed in Table-4 and Fig.-5 all the tested parameters were showed that there were no significant changes. This shows the stable formulation. CONCLUSION: The analysis of the dissolution data for Galantamine multiparticulate drug delivery system shows that it follows first-order kinetics and active release mechanism process involves anomalous transport. The optimized formula of batch No. GALE/C-10 gives similarity factor (F 2 ) of 73 when compared to marketed formulation Reminyl XL 24 mg capsules and very stable from accelerated stability study. From this study can be concluded that Galantamine can be formulated as MUPS (Prolonged Release) with the combination of Ethylcellulose (Surelease ) and Hypromellose. Table: 1 Composition of different formulation. S.No. Ingredients Stage-A (Dry mix) 1 Galantamine Hydrobromide equivalent to Galantamine GALE/C- 06 GALE/C- 07 GALE/C- 08 GALE/C- 09 GALE/C- 10 30.80 30.80 30.80 30.80 30.80 2 Microcrystalline cellulose 142.00 142.00 142.00 142.00 142.00 Stage-B (Binder solution) 1 Povidone K-90 7.20 7.20 7.20 7.20 7.20 2 Purified water q.s q.s q.s q.s q.s Core pellets weight 180.00 180.00 180.00 180.00 180.00 Stage- C (Sub coating) 1 Hypromellose 5 cp 8.00 8.00 8.00 8.00 8.00 2 Polyethylene Glycol 4000 1.00 1.00 1.00 1.00 1.00 3 Purified water q.s q.s q.s q.s q.s Stage-D (Prolonged Release coating) 1 Surelease 9.00 18.00 27.00 22.5 24.30 2 Hypromellose 5 cp 1.00 2.00 3.00 2.5 2.7 IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2638
3 Purified water q.s q.s q.s q.s q.s Coated Pellets weight 198.00 209.00 219.00 214.00 216.00 Stage-E (Capsule Filling) 1 Hard Gelatin capsule (white/white) Size 3 Size 3 Size 3 Size 3 Size 3 Table: 2 In-vitro dissolution results and similarity factor results. Time in hour Reminyl 24 mg GALE/C-06 GALE/C-07 GALE/C-08 GALE/C-09 GALE/C-10 1 28 91 50 15 33 28 2 40 99 85 28 44 36 4 60 99 95 45 65 55 6 74 101 100 55 76 70 8 81 102 99 65 81 77 12 89 102 100 77 85 88 24 100 99 101 80 92 99 Similarity Factor (F2) 21 29 40 66 73 Table: 3 In-vitro dissolution release kinetic results Formula no. Zero - Order First - Order Huguchi Model Korsmeyer-Peppas R R R N GALE/C-10 0.7702 0.9966 0.9172 0.536 Reminyl XL 24 mg 0.7307 0.9964 0.8922 0.5086 R correlation coefficient. N Diffusion exponent Table-4: Summery of stability Data of Galantamine Prolonged Release Capsules 24 mg at 40 C / 75% RH S.No. Test Initial 1 Month 3 Month 6 Month 1 Assay (%) 100.1 99.3 98.9 99.7 2 Water (by Kf) (%) 3.30 2.86 2.56 2.55 3 Related Substances (%) Highest Individual 0.20 0.19 0.19 0.19 Total 0.22 0.23 0.23 0.22 4 Dissolution Profile (%) Time (hr) Reminyl XL 24 mg 1 28 28 26 25 27 2 40 42 40 38 41 4 60 61 59 61 63 6 74 74 71 77 76 8 81 83 79 83 83 12 89 95 92 93 91 24 100 104 99 100 99 F 2 77 83 79 84 Pack : PVC-PE-PVDC/Aluminium blister (10 S) IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2639
120 Cumulative % of Labeled Amount Dissolved 100 80 60 40 20 Reminyl 24 mg GALE/C-10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (Hour) Figure-1: Comparative In-vitro dissolution of Galantamine mups by Zero-Order Release model. 2.500 2.000 Log % remained 1.500 1.000 Reminyl 24 mg GALE/C-10 0.500 0.000 0 5 10 15 20 25 Time(Hour) Figure-2: Comparative In-vitro dissolution of Galantamine mups by First-Order Release model. IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2640
120 Cumulative % of Labeled Amount Dissolved 100 80 60 40 20 Reminyl 24 mg GALE/C-10 0 0.000 1.000 2.000 3.000 4.000 5.000 6.000 Sq. Rt of time (Hour) Figure-3: Comparative In-vitro dissolution of Galantamine mups by Huguchi Release model. 0.00 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6-0.10 Log Fraction drug release -0.20-0.30-0.40 Reminyl 24 mg GALE/C-10-0.50-0.60 Log Time(Hr) Figure-4: Comparative In-vitro dissolution of Galantamine mups by Korsmeyr-Peppas Release model. IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2641
120 Cumulative % of Labeled Amount Dissolved 100 80 60 40 20 Reminyl XL 24 mg Initial 1 Month 3 Month 6 Month 0 0 5 10 15 20 25 30 Time (Hour) Figure-5: Comparative In-vitro dissolution stability Data of Galantamine Prolonged Release Capsules 24 mg at 40 C/75% RH. References: 1. Christoph Schmidt and Ronald Bodmeier., A multiparticulate drug delivery system based on pellets incorporated in to congealable polyethylene glycol carrier materials, International Journal of Pharmaceutics, 216, 2001, 9 16. 2. Kandukuri J.M., Allenki V., Eaga C.M., Keshetty V., Jannu K.K., Pelletization techniques for oral drug delivery, International Journal of Pharmaceutical Sciences and Drug Research, 1(2), 2009, 63-70. 3. Chatlapalli R., Rohera Bhagwan D., Physical characterization of HPMC and HEC and investigation of their use as pelletization aids, Int. J. Pharm., 161, 1998, 179-193. 4. Podzeck F., Knight P.E., Newton J.M., The evaluation of modified microcrystalline cellulose for the preparation of pellets with high drug loading by extrusion/spheronization, Int. J. Pharm., 350, 2008, 145-154. IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2642
5. Matthew A. Howard., Steven H. Neau and Marvin J. Sack., PEO and MPEG in high drug load extruded and spheronized beads that is devoid of MCC, International Journal of Pharmaceutics, 306, 2006, 66 76. 6. Raymond C. Rowe., Paul J. Sheskey and Marian E. Quinn., Handbook of Pharmaceutical Excipients, sixth edition Pharmaceutical Press and American Pharmacists Association, Washington, 2009, 262-267. 7. Shan-Yang Lin., Effect of excipients on tablet properties and dissolution behavior of theophylline-tableted microcapsules under different compression forces, Journal of Pharmaceutical Sciences, 77, 1988, 229-232. 8. Ranga Rao K.V., Padmalatha Devi K. and Buri P.K., Cellulose Matrices for Zero-Order Release of Soluble Drugs, Drug development and industrial Pharmacy, 14, 1988, 2299-2320. 9. Baveja S. K., Ranga Rao K.V. and Buri P.K., Zero-order release hydrophilic matrix tablets of β-adrenergic blockers, International Journal of Pharmaceutics, 39, 1987, 39-45. 10. Reena Singh., Poddar S. S. and Amit Chivate., Sintering of Wax for Controlling Release From Pellets, AAPS PharmSciTech, 8(3), 2007. 11. Schwartz J. B., Simonelli A. P. and Higuchi W.J., Drug release from wax matrices. I. Analysis of data with first-order kinetics and with the diffusion-controlled model. Journal of Pharmaceutical Sciences, 57, 1968, 274-277. 12. Nappinnai M. and Kishore V.S., Formulation and Evaluation of Microspheres of Diltiazem Hydrochloride. Indian journal of pharmaceutical Sciences, July-August, 2007, 511-514. Corresponding Author: T. Jagadeesh* E-mail: jaggagouda@yahoo.co.in IJPT June-2011 Vol. 3 Issue No.2 2633-2643 Page 2643