164 Original Article ISSN Print Online International Journal Pharmacy Industrial Research 2231 3648 2231 366 A VALID ADVANCE TECHNIQUE DESIGNED FOR GLIBENCLAMIDE AND METFORMIN HCL INTO IMMEDIATE AND EXTENDED RELEASE BILAYERED TABLET *,1 *,1 Aiswarya R, 2Suresh A G, 1Parthiban K G J.K.K.M.M.R.F College Pharmacy, Komarapalayam, Namakkal (dt), TN, India 638 183. 2 C.L.Baid Metha College Pharmacy, Thorapakkam, Chennai, TN, India 600 097. Abstract The present study was to establish Bilayer tablets containing Metformin hydrochloride as extended layer Glibenclamide as immediate layer for treatment type II diabetes mellitus. Extended layer was prepared by wet granulation method using HPMC ethyl cellulose as polymers. Immediate layer were prepared by using super disintegrants such as sodium starch glycolate cross carmellose sodium. The granules were evaluated for bulk density,tapped density, compressibility index, hausner s ratio. The granules showed satisfactory flow properties. The tablets were subjected to weight variation test, hardness test, friability test, drug content test,wetting time water absorption test. All tablets were passed tests. The invitro studies were carried out in phosphate buffer PH 6.8 for 12 hours using USPtype II paddle apparatus. The invitro priles drug from sustained layer could be best expressed by Higuchi s equation as plots showed high linearity (R2> 0.988). The formulations (F12, F27) having immediate layer produces effect within 30 minutes followed by sustained (98.90%) at 12 hours. Keywords: Bilayer tablet, Glibenclamide,Metformin hydrochloride,higuchis equation. most prominent being high dose2 (1.2.0 Introduction Metformin hydrochloride is a highly water g/day), low bioavailability (4060%), short soluble antihyperglycemic agent used in biological halflife (0.92.6 h) which requires treatment type II (noninsulindependent) repeated administrations high doses to diabetes mellitus. It is only agent maintain effective plasma concentrations,3 specifically affecting elevated plasminogen high incidence gastro intestine tract side activator in effects (30% cases) such as abdominal noninsulin discomfort, nausea, diarrhea, may occur (PAI) hypertriglyceridemia levels in both during clinical response metformin hydrochloride absorption metformin is incomplete under suffers from certain drawbacks which, fasting conditions in combination with rapid Author for Correspondence: Aishwarya R, J.K.K.M.M.R.F College Pharmacy, Ethirmedu, B.Komarapalayam, Namakkal Dt, Tamilnadu, India 638 183. Email: ais_sakthi7@yahoo.co.in treatment.4 dependent diabetes.1 In spite its favorable Gastrointestinal
16 elimination 30% an oral dose is multiple immediate preparations, recovered in feces. Bioavailability decreases as to reduce frequent dosing interval drug. dose increases, suggesting some form Therefore, it is an object to produce a bilayer saturable absorption process need for tablet with two different priles with twice to three times a day administration glibenclamide as immediate layer which can also reduce patient compliance metformin hydrochloride as a sustain hinder more successful rapy. layer to provide a desired pharmacokinetic rapeutic action. Glibenclamide is a second generation sulphonyl urea capable stimulating insulin Materials Methods, but are not capable acting on insulin Materials resistance, metformin hydrochloride able Metformin to act on insulin resistance, whereas y are were received as gift samples from Arvind not able to stimulate insulin secretion. 6 Remedies Hydrochloride, ltd. Chennai. Glibenclamide Sodium starch glycolate, Crospovidone, Croscarmellose Rationale for combination glibenclamide sodium were obtained from Sigma Aldrich, with metformin hydrochloride, suggests Bangalore. Hydroxy propyl methyl cellulose use combined formulations medicaments capable finding a remedy for both Reagent. Ethyl cellulose, Povidone (PVP deficiency in insulin secretion insulin K30) were purchased from Lab Chemicals, resistance condition. Reduces incidence Chennai. Microcrystalline cellulose, Colloidal secondary failure mono rapy also Silicon dioxide (Aerosil), Magnesium increases by stearate was obtained from Paxmy specialty 7 administering drug in a single dosage form chemicals, Chennai. Lactose, Talc Manitol mg were purchased from Chemspure, Chennai. All metformin hydrochloride is suitable for or chemicals reagents used were treatment type II diabetes mellitus at any analytical grades purchased from S.d. Fine time progression disease, from its Chemicals ltd, Mumbai patient glibenclamide compliance 00mg purchased from Rolex Laboratory onset to most severe cases. In sudden occurrence hyperglycemia, a dose mg Methods glibenclamide is required to reduce Characterization active pharmaceutical hyperglycemic effect 00mg metformin ingredient polymer using FT IR hydrochloride is required to sustain normal Metformin hydrochloride, Glibenclamide, glycemic level for type II diabetic patient. 8 ir mixture discs were prepared by pressing ir respective drug, polymer The primary goal our work is to produce a superdisintegrant with potassium bromide by sustained more using FT IR Spectrophotometer MB 4 uniform maintenance blood plasma active Boman Canada. Spectrum was observed concentration. between 40001cm to 001cm under preparation Thus, with potentially avoiding undesirable peaks troughs associated with operational conditions.
166 Thermal analysis for ethanol as a binder solution. Granules were characterizing interaction between drugs excipients dried in hot air oven at 0 C for 30 minutes Differential scanning colorimetry passed through #. Prepared granules Thermograms were obtained for mixture were lubricated with magnesium stearate drugs its excipients were done with aerosil NETZSCH DSC 2 in range from 23.9 C Prepared granules were compressed with to 237.9 C, ir melting point glass round shaped concave punches for initial transition temperature were detected. assessments in an average weight mg previously passes through 60#. per tablet. Analysis excipients compatibility by stability studies The active ingredients Preparation sustained granules metformin Hcl, Metformin hydrochloride, microcrystalline glibenclamide alone mixtures active cellulose HPMC / Ethyl Cellulose ingredients with various excipients in ratio were sifted through 40#. Sifted materials were 1:1 1:0. 1:0.3 were taken in glass vial mixed thoroughly for 1 minutes in a kept at various conditions (40 C / 7%RH porcelain mortar granulated with PVP K30 0 C / 90% RH) studied in open in Isopropyl alcohol as a binder solution. closed vials for a period 1 month. Granules were dried in hot air oven at 0 C for 30 minutes passed through #. Prepared Preparation immediate granules granules were lubricated with magnesium Glibenclamide, lactose, manitol, micro stearate, Talc aerosil previously passes crystalline cellulose, super disintegrant through were sifted through 40#. Sifted materials were compressed mixed thoroughly in a porcelain mortar for 1 punches for initial assessments in an average minutes granulated with PVP K30 in weight mg per tablet. 60#. Prepared with round granules shaped were concave Table no. 1: Formulation glibenclamide immediate layer S. No Ingredients F1 F2 F3 F4 F F6 F7 F8 F9 F F11 F12 1 Glibenclamide 2 Sodium starch glycolate 6 8 12 3 Crospovidone 6 8 12 4 Croscarmellose sodium 6 8 12 Povidone K 30 6 Microcrystalline cellulose 73 73 73 71 71 71 69 69 69 67 67 67 7 Mannitol 0 0 0 0 0 0 0 0 0 0 0 0 8 Lactose 0 0 0 0 0 0 0 0 0 0 0 0 9 Aerosil Magnesium stearate Total
167 Table no. 2: Formulation metformin hydrochloride sustained S.No Ingredients F13 F14 F1 F16 F17 F18 F19 F F21 F22 F23 F24 F2 F26 F27 1 Metformin hydrochloride 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 2 HPMC 12 17 0 3 Ethyl cellulose 12 17 0 4 Microcrystalline cellulose 160 13 1 8 60 160 13 1 8 60 1 1 60 0 PVP K 30 2 30 6 Talc 7 Aerosil 8 Magnesium stearate 9 Isopropyl alcohol Total Preparation bilayer tablet Both immediate sustained layer granules were compressed as a single layer tablets in different formulations ir results were interpreted, optimized chosen Where, for bilayer tablet. Optimal formulation from W = weight powder; both layers was compressed with caplet V0 = initial volume; shaped plain punches in an average weight Vf = final volume 0mg per tablet. Compressibility index Evaluation for immediate granules 9 Angle repose The compressibility index was calculated with following equation, The diameter powder cone was measured angle repose was calculated using following equation Hausner s ratio Hausner s was calculated with following Where, formula h = Height cone; r = Radius surface area pile. Evaluation immediate tablet Bulk density tapped density Bulk density tapped density calculated using formula given below, were Weight variation friability thickness were evaluated. hardness
168 Invitro disintegration test Six immediate glibenclamide tablets were selected romly from each formulation Where, for disintegration test. The test was carried out Wa = weight after water absorption; in 0.1N hydrochloric acid buffer at 37 ± 0. C Wb = weight before water absorption for 3 minutes at 24 to 26 C. The complete disintegration tablet with no palpable Evaluation sustained tablet mass in apparatus was measured in Precompresssion parameters such as angle seconds. repose, bulk density, tapped density, compressibility index, Hausners ratio Drug content11 physical parameters such as weight variation, Twenty tablets were triturated. Weighed friability, accurately a quantity powder containing evaluated as it was evaluated in immediate mg glibenclamide shaken with 40ml tablet. 0.1M methanolic hydrochloric acid, heated hardness thickness were gently centrifuged. To extract 0.1M Drug content13 methanolic hydrochloric acid was added to Twenty tablets were triturated. Weighed produce ml measured absorbance accurately a quantity powder containing at 300nm. 0.1gm metformin hydrochloride, shaken with 70ml water for 1 minutes, diluted to Invitro dissolution test ml with water filtered. To ml Dissolution studies were carried out by USP filtrate ml water was added for dilution. type II method at 37 ± 0. C, taking 900ml From this diluted solution ml was furr ph 1.2 hydrochloric acid buffer at 0 rpm. The diluted with ml water measured test sample ml was withdrawn at specific absorbance at 232nm. interval (,, 1,, 30minutes) replaced with fresh dissolution medium. The test sample was filtered concentration dissolved drug was determined using UV spectrophotometer at 300nm. Six tablets were selected for this test ir mean ± stard deviation was calculated. In vitro dissolution studies were carried out using USP type II apparatus at 0 rpm. The dissolution medium consisted 900ml ph 1.2 hydrochloric acid buffer for first two hours n it was replaced with 900ml 6.8 phosphate buffer maintained at 37 ± 0. C. Wetting time water absorption ratio (R)12 A tablet was placed on wet tissue paper placed in a dish containing 6ml water, time for complete wetting was measured water absorption ratio was calculated using formula. In vitro dissolution test Withdrawn suitable volume medium it was replaced with fresh buffer, absorbance was measured at 233nm. Kinetic analysis dissolution data The rate mechanism drug were analyzed by fitting dissolution data into zero order equation,
169 Withdrawn suitable volume medium it was replaced with fresh buffer at specific Where, is zero order rate constant expressed in units concentration/time t is time in hours. intervals absorbance was measured at 300nm for glibenclamide 233nm for metformin hydrochloride. Results discussion For first order, Characterization active pharmaceutical ingredient polymer Where, Glibenclamide metformin hydrochloride C0 is initial concentration drug, K is first order constant, t is time. ir respective mixtures were analyzed under IR spectra ir results confirm identification sample which is compared with For Higuchi s model, reference stard. Where, K is constant reflecting design variables system t is time in hours. Thermal analysis for characterizing interaction between drug excipients DSC was done for mixture drug excipients. Result showed re were presence For Korsmeyer equation, an exormic peak at 170 C this attributes to presence glibenclamide rmal curve for metformin hydrochloride exhibited a Where, sharp endormic effect, at 221.6 C. The amount drug d at time t, is amount drug after infinite time, K is a rate constant n is diffusional exponent. DSC priles for ethyl cellulose, hydroxypropyl methyl cellulose K, were typical amorphous substances, showing dehydration b in 134.2 137.8 C Evaluation bilayer tablet between 160 C temperature range when Bilayer tablets were evaluated for weight compared with stard indicates no variation, friability, hardness, thickness. changes observed between drug Drug content both drugs in bilayer tablet excipients. was measured by separating both layer Analysis Drug Excipient compatibility bilayer tablet measured individually. studies Invitro dissolution test In vitro dissolution studies were carried out using USP type II apparatus at 0 rpm. The dissolution medium consisted 900ml ph 1.2 hydrochloric acid buffer for first two hours n it was replaced with 900ml 6.8 phosphate buffer maintained at 37 ± 0. C. The drugexcipient compatibility studies were determined in different ratios under humidity cabinet at different temperature humidity for period four weeks results showed that re was no physical change in state, colour odour.
170 Evaluation immediate granules The bulk tapped density formulations F1 F12. Hausner s ratio in formulations F1 F12 in immediate range 1.12 1.18 shows good flow granules, ranged from 0.3 to 0.329 properties, formulations F1, F2, F, 0.341 0.367 respectively. Angle repose F6, F7 depicts result 1.12, 1.13, 1.13, formulations (F1 F12) was found to be 1.12, between limit 2 30 showing excellent formulations F3, F4, F8, F9, F, F11, flow character. The % carr s index was F12 produced a result 1.11, 1.11, 1.09, 1., found to be 6.26 11.74%, indicating an 1.09, 1.06, 1.06 respectively which excellent flow character for immediate showed an excellent flow character. 1.13 respectively. And Table no. 3: Evaluation immediate layer granules Formulation Bulk density (g/ml) Tapped density (g/ml) Carr s index (%) Hausner s ratio Angle repose ( ) F1 F2 F3 F4 F F6 F7 F8 F9 F F11 F12 0.323 0.32 0.334 0.333 0.3 0.312 0.314 0.324 0.3 0.314 0.327 0.329 0.362 0.367 0.373 0.372 0.349 0.30 0.3 0.36 0.341 0.34 0.349 0.31.77 11.44.4.48 11.74.8 11.4 8.98 9.09 8.98 6.30 6.26 1.12 1.13 1.11 1.11 1.13 1.12 1.13 1.09 1. 1.09 1.06 1.06 30.2 28.30 29.42 29.29 28.21 28.70 27.12 27.14 26.6 27.64 27.69 26.00 Evaluation immediate layer tablet In immediate formulations wetting The weight variation tablets in time water absorption ratio for F1, F4, F7, immediate formulation F1 F12 was F containing sodium starch glycolate < observed to be within limit ± %. Friability F2, crospovidone < F3, F6, F9, F12 prepared immediate formulations were F, F8, prepared with depicts friability is within passes limit observation croscarmellose sodium provides which is not more than 1% w/w, indicating less wetting time water absorption ratio sufficient mechanical integrity strength compared with sodium starch glycolate prepared tablets. Hardness about 3 4 crospovidone due to fibrous structure kg/cm is optimum for immediate sodium. From with ranging from 0.26 0.94% w/w, values 2 croscarmellose F11 this croscarmellose sodium. tablet. Hardness for formulations F1 F12 ranges from 3.90 4. kg/cm2 which are very The disintegration times for formulation F1 much in limit. All formulations in F12 immediate layer tablets passes limit formulation F12 containing croscarmellose sodium 12mg disintegrated fastest with no produced necessary hardness. The thickness for F1 F12 ranges from 4.93 was compared that indicates mass left had good hardness..21mm variations were found less than %.
percentage 171 Drug content lies between 93.40 3.80%. cumulative ir Results show all formulation containing drugs respective formulations. From dissolution were within limit (90 1%). results obtained F3, F6, F9, F12 prepared with croscarmellose sodium d drug Invitro dissolution immediate faster than or formulations as layer glibenclamide concentration superdisintegrants increases The dissolution study immediate re was an increase in percentage layer drug. formulation F1 F12 revealed Table no. 4: Evaluation parameters immediate layer tablets Weight Formulation variation (mg) ± s.d Friability Hardness Thickness (%) (kg/cm2) (mm) Wetting Water time absorption (sec) ratio Disintegration time (sec) F1 1.6±0.7 0.26 4.23±0.1 4.94±0.12 121 71.42 348±1.00 F2 1.3±0.7 0.43 4.13±0..00±0.07 3 61.90 92.3±2.1 F3 2.0±1.00 0.7 4.00±0..01±0.24 49 2.38 47.6±1.3 F4 1.3±1.2 0.86 4.16±0.21.19±0.06 91 70.00 191.3±1.3 F 1.3±1.2 0.31 4.00±0..17±0.0 49 60.00 80.3±0.8 F6 1.0±1.73 0.4 4.±0.17.±0.19 47 2.38 46.3±1.3 F7 199.3±3.1 0.81 4.16±0.06.17±0.06 9 68.42 180±1.00 F8 197.6±3.21 0.94 4.±0.17.17±0.0 48 7.14 79.3±4.0 F9 199.6±1.2 0.33 4.±0..01±0. 4 4.00 29.3±0.8 F 1.3±1.1 0.4 3.96±0.21 4.93±0.03 7 6.00 1.6±1.3 F11 199.3±2.1 0.63 4.06±0.1.12±0.09 46.00 76.3±1.3 F12.0±3.00 0.87 4.±0..21±0. 36 3.00 26±1.00 Graph 1 Graph 2
172 Graph 3 Evaluation sustained granules Bulk density was ranged from 0.143 to 0.160, tapped density ranges from 0.14 to 0.190 for F13 F27. Angle repose for F13 F27 produced an excellent flow character except F16, F17, F22, which depicts a good flow character (31 3 ). Compressibility index for sustained formulations F13 F27 was founded in range 0.62 9.3% which has an excellent flow character except, formulations F16, F17, F, F21, F22. Hausners ratio F13 F17 showed an excellent flow character except F16, F21, F17 F22. Table no. : Evaluation sustained layer granules Formulation Bulk Density (g/ml) Tapped density(g/ml) Carr s index (%) Hausner s ratio Angle repose ( ) F13 F14 F1 F16 F17 F18 F19 F F21 F22 F23 F24 0.160 0.19 0.18 0.144 0.143 0.19 0.13 0.19 0.14 0.1 0.12 0.14 0.164 0.169 0.174 0.181 0.190 0.160 0.163 0.179 0.18 0.196 0.14 0.19 2.43.91 9.19.44 24.73 0.62 6.13 11.17 16.7.91 1.29 3.14 1. 1.06 1. 1.2 1.32 1.00 1.06 1.12 1. 1.26 1.01 1.03 2.94 26.6 28.81 32.7 34.43 2.46 27.7 29.89 30.2 33.69 2.34 2.40 Evaluation sustained layer tablet decreases in eir polymers. Hence The dissolution study data sustained use single polymer could not able to sustain formulation F13 F27 demonstrates drug for 12 hours in different ratios, percentage drug in 12 hours time combination period. Formulations F13, F14, F1, F16, hydrophobic polymer were used to retard F17 prepared with HPMC K alone could metformin not able to sustain not more than 7 Formulation F23, F24, F2 were prepared hours; F17 d 99.81% metformin with combination hydrophilic HPMC K hydrochloride. And formulations F18, F19, hydrophobic ethyl cellulose at different F, F21, F22 prepared with ethyl polymer ratios, drug was cellulose could not able to sustain drug sustained for 12 hours. Formulation F23, F24, for not more than 8 hours; F22 d F2 d 99.8, 99.88, 99.69% 99.8% metformin hydrochloride. From metformin above observation, as concentration respectively. polymer formulations F2, F26 F27 on varying increases, drug both hydrochloride hydrochloride hydrophilic for at 12 12th hours. hour It was observed from
173 concentration PVP K30 re is variation in increasing binding hardness properties drug. Sustained layer tablet. 1:1 polymer ratio HPMC K formulation F2, F26 F27 prepared with, 2, 30 mg PVP K30 polymer in concentration ratio 1:1 d 99.69, 99.46 hydrochloride which sustains drug 98.90% drug. From data obtained, PVP for 12 hours. And results were K 30 shows an effect on drug. In tabulated in tables results are plotted in increase in concentration PVP K 30 graphs. ethyl cellulose for was retarding drug from tablet is decreased by Table no. 6 : Evaluation parameters sustained layer tablets Formulation Weight variation (mg) ± S.D Friability (%) Hardness (Kg/cm2) Thickness (mm) F13.3±0.9 1. 3.3±0.06 6.23±0.03 F14.6±1.3 1.07 3.70±0. 6.±0. F1 799.6±0.8 0.96 3.96±0.1 6.01±0.01 F16 799.3±0.8 0.91 4.±0. 6.±0.01 F17 801.6±2.31 0.7 4.33±0.17.99±0.01 F18 801.3±0.8 1.03 4.00±0.00 6.21±0.01 F19 799.6±1.1 1.00 3.93±0.1 6.07±0. F 8.0±1.73 0.87 4.±0. 6.±0. F21 799.3±2. 0.64 4.3±0.0 6.±0.01 F22 799.6±2.1 0.37.±0. 6.±0. F23.3±1.3 0.87 4.23±0.1 6.07±0. F24.6±0.8 0.71 4.80±0..98±0.12 F2 803.3±2.1 0.63.03±0.0 6.19±0.01 F26 803.0±3.46 0.66.30±0. 6.±0. F27 799.3±0.8 0.9.43±0.06 6.±0.01 Graph 4 Graph optimum metformin
174 Graph 6 Graph 7: Higuchi diffusion kinetics Mechanism drug Graph 8: Korsmeyer peppas equation In optimized sustained formulation (F27), calculated regression coefficients for zero order, first order higuchi model were 0.932, 0.782, 0.998 respectively. Therefore seems to fit higuchi model. To explore pattern, results Invitro dissolution data were fitted to korsmeyerpeppas equation, which characterizes transport mechanism. The value exponent for optimized formulation was 0. indicated governed by anomalous transport (nonfickian) diffusion. Release kinetics values are given in table ir graphs were given in graphs. Optimization bilayer tablet water absorption ratio it d 99.91% Bilayer tablet was compressed by selecting a glibenclamide at 30 minutes which is faster formulation from immediate sustained than or formulations immediate layer tablet with aid data layer tablet. Sustained layer was gared from evaluation both layers optimized was friability dissolution data. The formulation optimized by comparing ir disintegration, F27 prepared with 1:1 polymers ratio showed a wetting time, water absorption ratio with suitable hardness friability sustained dissolution data. In this, formulations F12 has metformin hydrochloride (98.90%) for a least disintegration time, wetting time period 12 hours rest tablet. Immediate layer by comparing ir hardness,
17 formulation fails to sustain. By above data F28 was showed 99.94% formulation F12 for immediate glibenclamide in 30 minutes as immediate formulation F27 for sustained was optimized for compression bilayer hydrochloride in 12 hours as sustained. tablet. Bilayer tablet values graph are shown in 99.28% metformin table graph respectively. Evaluation optimized bilayer tablet F28 Weight bilayer tablets was 1.3 ± Graph 9: Dissolution for formulation F28 2 0.0 gm, hardness was 6. ± 0. kg/cm, thickness was 6.13 ± 0.03mm, friability was found to be 0.4%. Values hardness friability indicated good hling properties prepared bilayer tablet. The drug content in bilayer matrix for glibenclamide metformin hydrochloride was found to be 99.60%. Invitro dissolution for formulation References response surface methodology, Yakugaku 1. zasshi, 127, (7), p. 12811290. Andrew J. Krenz, Clifford J. Bailey (Ed.), Type 2 Diabetes: in Practices, 2 nd 2. limited, London,, p. 11 12. invivo evaluation sustained Ritu B. Dixit, Rajat R. Gupta, Harsha V. metformin hydrochloride pellets, Eur. J. Patel, Pradeep S. Patel, Fromulation Pharm. Biopharm. 64, (6), p. 18192. matrix 4. Lian Dong Hu, Yang Liu, Xing Tang, Qian Zhang, Preparation invitro/ characterization sustained 3.. ed. Royal society medicine press metformin Hcl, 6. Andrew J. Krenz, Clifford J. Bailey International (Ed.), Type 2 Diabetes: in Practices, 2 nd Journal Pharma Recent Research, 1, ed. Royal society medicine press (9), p. 493. limited, London,, p. 141. Giovanna Corti, Marzia Cirri, Francesca 7. Stephen M. Setter, Jason L. Iltz, Jason Maestrelli, Natascia Mennini, Paola Thams, Mura, Sustained matrix tablet Metformin hydrochloride in treatment metformin hydrochloride in combination type 2 diabetes mellitus: A clinical with J. review with a focus on dual rapy, Pharm. Biopharm. 68, (8), p. 303309. Clinical rapeutics, 2, (3), p. 2991 Uttam Mal, Veeran Gowda, Animesh 36. triacetylβcyclodextrin, Eur. Ghosh, Senthamil Selvan, Sam Solomon, 8. R. Keith Campbell, Barbara G. Wells, Joseph T. Dipiro, Terryl Tapan Kumar Pal, Formulation L. Schwinghammer, Cecily V. Dipiro optimization sustained matrix (Ed.), Pharmacorapy hbook, 7th ed. tablet metformin Hcl 00 mg using The McGraw Hill companies, New York, 9, p. 188.
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