121 P a g e International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 3(6): November-December 2014 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093*** Pharmaceutical Sciences ICV 5.13*** RESEARCH ARTICLE!!! DESIGN AND IN-VITRO EVALUATION OF THE SUSTAINED RELEASE MATRIX TABLETS OF MIGLITOL 1 Y.Raghu *, 1 N.Srinivas, Ajaykumar.B 2 1 Department of Pharmaceutics, Mallareddy Institute of Pharmaceutical Sciences, Maisammaguda, Dulapally, Secundrabad. 2 Project co-ordinator, Richer Pharmaceuticals, prashanthi nagar, Hyderabad. KEYWORDS: Diabetics; Miglitol; Sustained release polymers; Sustained release; Matrix tablets formulation. For Correspondence: Y.Raghu* Address: Department of Pharmaceutics, Mallareddy Institute of Pharmaceutical Sciences, Maisammaguda, Dulapally, Secundrabad. E-mail: raghuy32@gmail.com ABSTRACT Miglitol, an oral alpha-glucosidase inhibitor for use in the management of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the current investigation is to design oral once a daily sustained release matrix tablets of Miglitol 100mg, used for the treatment of NIDDM which can release the drug for 10 to 12 hours. The tablets were prepared by the Wet granulation method using varying concentration of sustained release polymers HPMC (k 15 m, k l00 m, E 5 ) and Xanthan gum. The compatibility of the polymers was ruled out by FT-IR studies and found to be compatible. Total 12 formulations were prepared. The Miglitol powder and the powder-blends of tablets were evaluated for their physical properties like angle of repose, bulk density and compressibility index and found to be good and satisfactory. The manufactured tablets were evaluated for in process and finished product quality control tests including appearance, dimensions, weight variation, hardness, friability, drug content, and in vitro drug release. The dissolution medium used was distilled water. All formulations showed acceptable pharmaco-technical properties and complied with inhouse specifications for tested parameters. The results of dissolution studies indicated all formulations released up to 12hours and formulation containing HPMC k 15 m (8%) i.e. F1 was the most successful formulation with 99.1% drug release at the end of 12 hours. Based on mathematical models the formulation F1 fitted into zero order and korsmeyer- peppas plot with 0.996 and 0.992 regression values respectively and show fickian diffusion mechanism release.
122 P a g e International Standard Serial Number (ISSN): 2319-8141 INTRODUCTION: Sustained release dosage forms are designed to release a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects. 1 The advantages of administering a single dose of a drug that is released over an extended period of time, instead of numerous doses, have been obvious to the Pharmaceutical industry for some time. The desire to maintain a near-constant or uniform blood level of a drug often translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended use. 2 Introduction of matrix tablet as sustained release (SR) has given a new breakthrough for novel drug delivery system (NDDS) in the field of Pharmaceutical technology. It excludes complex production procedures such as coating and pelletization during manufacturing and drug release rate from the dosage form is controlled mainly by the type and proportion of polymer used in the reparations. Hydrophilic polymer matrix is widely used for formulating an SR dosage form. 3,4,5, 6 Because of increased complication and expense involved in marketing of new drug entities, has focused greater attention on development of sustained release or controlled release drug delivery systems 7. Matrix system is widely used for the purpose of sustained release. It is the release system which prolongs and controls the release of the drug that is dissolved or dispersed. In fact, a matrix is defined as a well-mixed composite of one or more drugs with gelling agent i.e. hydrophilic polymers. By the sustained release method therapeutically effective concentration can be achieved in the systemic circulation over an extended period of time, thus achieving better compliance of patients. Numerous SR oral dosage forms such as membrane controlled system, matrices with water soluble/insoluble polymers or waxes and osmotic systems have been developed, intense research has recently focused on the designation of SR systems for poor water soluble drugs. Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to breakdown complex carbohydrates into glucose. It is primarily used in diabetes mellitus type 2 for establishing greater glycemic control by preventing the digestion of carbohydrates (such as disaccharides, oligosaccharides, and polysaccharides) into monosaccharides which can be absorbed by the body. Miglitol inhibits glycoside hydrolase enzymes called alpha-glucosidases. Since miglitol works by preventing digestion of carbohydrates, it lowers the degree of postprandial hyperglycemia. It must be taken at the start of main meals to have maximal effect. Its effect will depend on the amount of non-monosaccharide carbohydrates in a person s diet. It is a white to pale-yellow powder with a molecular weight of 207.2. Miglitol is soluble in water and has a pka of 5.9. Its empirical formula is C 8 H 17 NO 5. 8
123 P a g e International Standard Serial Number (ISSN): 2319-8141 Sustained release tablets can be prepared by direct compression method using hydrophilic polymers such as HPMC (K 15 M, K 100 M, and E5) and Xanthangum. MATERIALS AND METHODS MATERIALS Miglitol was obtained as a gift sample from Bio Leo Analytical lab, Hyderabad. Hydroxy propyl methyl cellulose and Xanthan gum was obtained as a gift sample from Loba Chem Pvt.Ltd, Mumbai. Microcrystalline cellulose, Ethylcellulose, Isopropyl alcohol, Talc, Magnesium stearate were purchased from S.D.Fine Chem.Ltd., Mumbai. All other chemicals and solvents were purchased from analytical grade. METHODS: Wet Granulation method: The drug and the excipients were passed through sieve no: 40 except lubricant and glidant. Weighed amount of drug and excipients (diluent, binder and sustained release agents) were mixed using Isopropyl alcohol as granulating agent. The blend was subjected to drying at 60 o c for 5hrs, for removal of moisture. After drying the powder is collected and the remaining excipients i.e. Glidant and lubricant were added (perceived through sieve no: 80) and was compressed by using flat faced punches in CADMACH 16 punches tablet punching machine. Round punches measuring 8.7mm diameter were used for compression. Tablet of 200mg was prepared by adjusting hardness and volume screw of compression machine properly. (Figure no: 1) EVALUATION PARAMETERS 1. Bulk density: It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder into a measuring cylinder and the volume was noted. It is expressed in gm/ml. (Table no: 2) Bulk density = Weight of powder / Bulk volume 2. Tapped density: It is the ratio of total mass of powder to the tapped volume of powder. It is determined by placing a graduated cylinder containing known weight of powder, mechanical tapper apparatus operated for fixed number of taps until the powder bed volume has reached a minimum volume. (Table no: 2) Tapped density = Weight of powder / Tapped volume 3. Carr s Index (I): It is measured by using values of bulk density and tapped density. (Table no: 2) Tappeddensity - Bulk density 100 Tappeddensity
124 P a g e International Standard Serial Number (ISSN): 2319-8141 4. Hausner s ratio: Hausner s ratio is the ratio of tapped density to bulk density. (Table no: 2) 5. Angle of Repose: Hausner s Ratio = TappedDensity Bulk Density The frictional forces in a loose powder can be measured by the angle of repose, θ. (Table no: 2) = tan -1 (h/r) Where h=height of the heap r=radius of the heap It is determined by pouring the powder a conical on a level, flat surface, measured the included angle with the horizontal. 6. Hardness: The hardness of the tablet was determined by using a Monsanto hardness tester. It is expressed in Kg / cm 2. 7. Thickness: The thickness of the tablets was measured by Digital Vernier Caliper. It is expressed in mm. 8. Weight Variation: Ten tablets were selected randomly from the lot and weighed individually to check for weight variation. The following %deviation in weight variation is allowed. 9. Friability (F): The friability of the tablet was determined using Roche Friabilator. It is expressed in %. 10 tablets were initially weighed and transferred into the friabilator. The friabilator was operated at 25 rpm for 4 mins. The tablets were weighed again. Friability of tablet should not exceed 1%. 10. Determination of drug content Weigh and powdered 10 tablets in a mortar. From this powder equivalent to 10 mg of Miglitol was taken in a volumetric flask to this 5 ml of methanol was added and then the solution was subjected to sonication for about 10min for complete solubilization of drug and the solution was made up to the mark with methanol, filtered and further appropriate dilutions were made with water and the drug content was estimated by measuring the absorbance at 275nm by using UV-Visible spectrophotometer. 11. Drug-Excipients Interaction Studies This type of interactions was studied with the help of Shimadzu FTIR spectrophotometer, in which KBR pellet method used to determine the interactions.
125 P a g e International Standard Serial Number (ISSN): 2319-8141 12. In vitro dissolution studies The dissolution studies were performed using USP 24 type II paddle apparatus, employing paddle stirrer rotating at 75 rpm, 900 ml of distilled water as a dissolution medium at 37 ± 0.5ºC. 5 ml aliquots of dissolution medium was withdrawn at specified time intervals and the volume of the dissolution medium was maintained by adding the same volume of fresh dissolution medium. The absorbance of the withdrawn samples was measured spectrophotometrically at 275nm. (Table no: 4) 13. Stability studies The stability studies were conducted for satisfactory formulation as ICH guidelines. The satisfactory formulation sealed in aluminum packaging and kept in humidity chamber containing 30±2 C with 65±5% RH for 2months.Samples were analyzed for drug content and in vitro drug release profile. (Table no: 5) 14. Drug release kinetics To analyze the mechanism of drug release from the tablets, the results of in vitro release data were plotted in various kinetic models like zero order, Higuchi model and Korsmeyer- peppas. (Table no: 6) RESULTS AND DISCUSSION Evaluation parameters Tablets of different formulations were subjected to various physicochemical evaluation parameters such as weight variation, hardness, friability, thickness, drug content, and diameter. The results of these studies were found to be within the limits and given in Table no.3 Compatibility studies The standard spectrum of Miglitol shown in fig.7 was compared by FTIR spectrum of physical mixture fig 8. FTIR studies proved that the drug is compatible with excipients. In vitro dissolution studies Dissolution is carried out in USP 2 type apparatus at 75rpm in the volume of 900ml dissolution media (distilled water) for 12hours. The dissolution rate was found to decrease linearly with increasing concentration of Sustained release agent. Formulations F1, F2, F3 and F4 which contained HPMC k 15 m shows % drug release of 99.1%, 86.9%, 71.69% and 66% Formulations F5, F6 and F7 which contained HPMC (K 15 m and K 100 m) shows % drug release of 75.21%, 76.45%, and 91.45% respectively. Formulations F8-F12 which contained HPMC and Xanthan gum shows % drug release of 101.27%, 105.41%, 106.66% 93.21% and 93.52% respectively with in the 3 hours. The % drug release of formulations table (4) comparative release profile in fig.2.
126 P a g e International Standard Serial Number (ISSN): 2319-8141 Release kinetics Different models like zero order, first order, higuchi's, and peppas plots were drawn for formulation F-1. The regression coefficient (r2) value for zero order, first order, higuchi's, and peppas plots (figures no: 3-6) for formulation F-1 was found to be 0.996, 0.73, 0.966, and 0.992 respectively. The formulation F-1 follows zero order release and peppas plot. Since the regression coefficient of peppas was 0.999 and slope n value is less than 0.5 which confirms that the drug release through the matrix was fickian diffusion. Stability studies F1 formulation was subjected to stability studies. It was suggested that there was no significant change physical parameters such as weight variation, hardness, friability, thickness; drug content. This is shown in table no 5. Conclusion Results of present research work demonstrate that the individual and combination of hydrophilic polymers was successfully employed for formulation of miglitol sustained release tablets. It is observed that 8% of polymer (HPMC k 15 m) produces a more drug release from matrix tablets. The oral sustained release tablets of miglitol and that can be shows upto 12 hours drug release. In all the formulations, drug release rate is decreases if we increase the polymer ratio. From this study, it is possible to design promising oral sustained release matrix tablets containing miglitol for the treatment of type-ii diabetes mellitus diseases with more efficacy and better patient compliance. REFERENCES 1. Lieberman HA, Lachman L and Schwartz JB., Pharmaceutical Dosage Forms: Tablets, Volume 3, 2nd edition, 199-287. 2. Kuno Y, Kojima M, Ando S, Nakagami H, Evaluation of rapidly disintegrating tablets manufactured by phase transition of sugar alcohols, J Control Release, 105, 2005, 16-22. 3. Vidyadhara S, Rao PR., Prasad JA., Indian J. Pharm Sci, 66, 188-192 (2004). 4. Reddy KR., Mutalik S, Reddy S, AAPS Pharm. Sci. Tech., 4, 1-9, (2003) 5. Mohammed AD., James LF., Michael HR., John EH., Rajabi-Siahboomi AR., Phar. Dev. Tech., 4, 313-324 (1999). 6. Lee BJ, Ryu SG, Cui JH, Drug Dev. Ind. Pharm., 25, 493-501 (1999). 7. Gwen MJ and Joseph RR, In Banker GS and Rhodes CT, Eds., Modern Pharmaceutics, 3 rd Edn, Vol. 72, Marcel Dekker Inc. New York, 1996, 575. 8. http://www.drugbank.ca/drugs/ DB00491.
127 P a g e International Standard Serial Number (ISSN): 2319-8141 TABLES: Table No 1: Formulation of Different Batches Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 Miglitol 100 100 100 100 100 100 100 100 100 100 100 100 HPMC k15m 16 24 30 36-6 16 - - - - - HPMC k100m - - - - 16 10 8 - - - - - HPMC E5 - - - - - - - 24 30 - - 12 Xanthangum - - - - - - - - - 24 30 12 MCCP ph 101 65 57 51 45 65 65 57 57 51 57 51 57 EC-N-20 10 10 10 10 10 10 10 10 10 10 10 10 IPA q.s q.s q.s q.s q.s q.s q.s q.s qs qs qs qs Magnesium stearate 6 6 6 6 6 6 6 6 6 6 6 6 Talc 3 3 3 3 3 3 3 3 3 3 3 3 tablet weight 200 200 200 200 200 200 200 200 200 200 200 200 Table No 2: Pre-compression studies of the blend Formulation code Bulk density (gm /ml) Tapped density (gm/ml) Hausner s ratio Carr s index (%) Angle of repose (θ) F1 0.317 0.376 1.18 15.69 26.38 F2 0.291 0.331 1.19 12.11 27.14 F3 0.307 0.347 1.13 12.26 26.85 F4 0.326 0.384 1.17 15.1 29.12 F5 0.286 0.342 1.19 16.37 28.47 F6 0.301 0.35 1.16 14 26.96 F7 0.298 0.344 1.15 13.33 25.72 F8 0.307 0.356 1.15 13.76 26.38 F9 0.314 0.361 1.14 13 26.54 F10 0.294 0.351 1.19 16.23 26.45 F11 0.305 0.359 1.17 15.04 27.64 F12 0.307 0.364 1.18 15.65 27.58
128 P a g e International Standard Serial Number (ISSN): 2319-8141 Table No 3: Post compression studies of Miglitol Sustained Release tablets Formulation code Weight variation Thickness (mm) Hardness kg/cm2 Friability (%) Content uniformity (%) F1 197 2.1 5.5 0.254 99.54 F2 201 2.15 6 0.364 98.4 F3 200 2.11 6.1 0.354 97.6 F4 201 2.14 6.4 0.258 98.1 F5 203 2.15 6 0.364 98.36 F6 198 2.1 5.8 0.487 98 F7 199 2.15 5.9 0.658 98.36 F8 198 2.11 5.5 0.874 98.14 F9 197 2.12 5.6 0.648 99.45 F10 199 2.14 5.9 0.24 97.14 F11 201 2.1 6 0.569 101.2 F12 200 2.1 6.1 0.647 100.36 Table No 4: Dissolution tables of formulations in water media Time in hours F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 1 13.034 8.79 10.66 8.28 7.86 11.59 6.31 99.72 99.21 100.8 88.76 87.31 2 20.6 11.28 15.1 12.31 13.76 17.49 11.69 108 103.76 101.7 86.69 88.24 3 29.59 17.59 20.69 17.59 20.6 24.41 15.62 101.27 105.41 106.66 93.21 93.52 4 34.66 23.28 24.2 19.55 23.9 25.66 22.03 5 43.45 28.14 29.59 26.17 29.17 32.38 30.31 6 49.76 34.03 36.41 28.86 31.55 36.41 37.03 7 59.49 40.03 41.59 33 37.86 43.86 45.83 8 66.93 49.03 46.86 36.31 43.76 49.55 57.62 9 73.03 60.93 52.14 41.07 49.45 53.48 64.76 10 84.62 70.03 59.28 47.79 55.76 62.17 74.69 11 93.83 78.21 63.31 57.8 63.62 70.03 82.76 12 99.1 86.9 71.69 66 75.21 76.45 91.45 STABILITY STUDIES Table No.5 Stability studies: Drug content Formulation Initial amount 30±2 o c/65 ± 5%RH after1month 30±2 o c/65 ± 5%RH after2 nd month F1 99.1 98.9 98.5
129 P a g e International Standard Serial Number (ISSN): 2319-8141 Table no: 6 Kinetic Model Fitting for Formulation F1 Time in min SQRT of time Log time %CDR Log %CDR Log Cu % Drug remain 0 0 0 0 0 2 1 1 0.301 13.034 1.115 1.939 2 1.414 0.447 20.6 1.313 1.899 3 1.732 0.602 29.59 1.471 1.847 4 2 0.698 34.66 1.539 1.815 5 2.236 0.778 43.45 1.637 1.752 6 2.449 0.845 49.76 1.696 1.701 7 2.645 0.903 59.49 1.774 1.607 8 2.828 0.954 66.93 1.825 1.519 9 3 1 73.03 1.863 1.43 10 3.162 1.041 84.62 1.927 1.186 11 3.316 1.079 93.83 1.972 0.79 12 3.464 0.301 99.1 1.996-0.045
130 P a g e International Standard Serial Number (ISSN): 2319-8141 FIGURES Figure no: 1 Representation of Wet granulation Technique for design of sustained release tablet Figure no.2 Drug Release of All Miglitol SR Formulations
131 P a g e International Standard Serial Number (ISSN): 2319-8141 Figure no: 3 In vitro release profile of Miglitol from tablets of F1 fitted in zero order release Figure no: 4 In vitro release profile of Miglitol from tablets of F1 fitted in first order release Figure no: 5 in vitro release profile of Miglitol from tablets of F1 fitted in Higuchi plot
132 P a g e International Standard Serial Number (ISSN): 2319-8141 Figure no: 6 In vitro release profile of miglitol from tablets of F1 fitted in Korsmeyer-Peppas plot Figure no: 7 FT-IR Spectra of Miglitol Figure no: 8 FT-IR Spectra of All ingredients.