Physicochemical properties

Solubility

Stability Hydrophilicity LogP pKa Physical state Melting point UV max Storage Other information

Freely soluble in water slightly soluble in alcohol practically insoluble in acetone and in dichloromethane. Protect from light and moisture. Hydrophilic -o.5 12.4 Solid 223-226C 233 nm in water. Store between 15-30 C (59-86 F). Dispense in light resistant container. Hygroscopic nature

Pharmacological Properties
1 2 3 4 Use/Category Bioavailability (%) Protein Binding (%) Main elimination route Antidiabetic,used to treat type-II diabetes Used in treatment of Polycystic ovary syndrome 50-60 % Metformin is negligibly bound to plasma proteins. Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Approximately 90% of the drug is eliminated in 24 hours in those with healthy renal function Renal clearance of metformin is approximately 3.5 times that of creatinine clearance, indicating the tubular secretion is the primary mode of metformin elimination. 2-6 hours. 8-12 hours 1.03 (500 mg) 1.60 (850 mg) 3 hours 6 hours Absolute bioavaibility F= 0.5-0.6 No hepatic metabolism. Metformin's mechanisms of action differ from other classes of oral antihyperglycemic agents. Metformin decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the initial activation by metformin of

5 6 7

Elimination half-life (h) Duration of action (h) Cmax(gml-1)

8 Tmax(h) 9 T1/2(h) 10 Bioavalability (F) 11 First pass metabolism 12 Mechanism of action

13 Side effects

AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. Metformin administration also increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. The rare side effect, lactic acidosis, is thought to be caused by decreased liver uptake of serum lactate, one of the substrates of gluconeogenesis. In those with healthy renal function, the slight excess is simply cleared. However, those with severe renal impairment may accumulate clinically significant serum lactic acid levels. Other conditions that may precipitate lactic acidosis include severe hepatic disease and acute/decompensated heart failure. epigastric discomfort nausea, and vomiting followed by diarrhea drowsiness weakness dizziness malaise and headache might be seen.

Work done on drug

Sr. Dosage form no developed . 1 Orodispersible tablet Polymers used Justification

Sustained release matrix tablet

HPMC and guar gum.

Floating dosage form

Highly porous gastroretentive tablet Response surface optimization of sustained release metforminhydrochloride matrix tablets Sustained release tablet

Psyllium, HPMC K15M and carbopol 940 Polyethelyne oxide(PEO) HPMC K4M and K100M

To develop oro-dispersible tablets of metformin by direct compression method using super disintegrant approach, effervescent approach and sublimation approach To develop an oral sustained-release (SR) metformin tablet prepared by the direct compression method, using hydrophilichydroxylpropylmethylcellulos e(HPMC) and Guar gum polymer alone and in combination at different concentrations. To formulate anti diabetic drug Metformin as a controlled release floating delivery making use of Psyllium as release retardant. To obtain sustained release by swelling and erosion of polymer. To formulate sustained release matrix tablet.

Sustained release taste masked tablet

Eudragit RSPO, gum copal and gum damar Cation exchange resin, indion 244,indion 264 and HPMC K100M

To formulate sustained release matrix tablet.

To formulate sustained release matrix tablet and mask bitter taste of drug.

Effervescent floating tablet

pH controlled delievery(matrix tablet) 10 Floating tablet

HPMC, stearic To develop effervescent floating tablet. acid and sodium bicarbonate PEO and To formulate sustained release matrix eudragit L100 tablet. To formulate sustained release floating tablet.

11

12

13

14 15 16 17

polyvinylpyrro lidone (PVP) tamarind seed gum (TSG) and HPMC. Sustained release Triacylbetacyc tablet lodextrin andHPMC, xanthan gum, chitosan, ethylcellulose , Eudragit L100-55, and Precirol. Gastroretentive NaCMC,Na tablet alginate and Eudragit NE 30 Mucoadhesive HPMC,NaCM pellets C,Carbopol and Na alginate Mucoadhesive HPMC and pellets MCC Non-ionic surfactant vesicles(Niosome) Nano particle Eudragit RSPO/PLGA Microsphere Pectin -

To formulate sustained release matrix tablet.

To formulate sustained release Gastroretentive tablet.

To formulate sustained release mucoadhesive pellets.

To formulate sustained release mucoadhesive pellets. To formulate sustained release niosome. To formulate sustained release nanoparticle. To formulate sustained release microsphere. To formulate floating microspheres in order to increase its residence time at

18 Floating microshere

the site of absorption and thus improve its bioavailability; and to extend the duration of action along with possibilities of dose reduction.

Dose of drug
Adult
Initial dosage is 500 mg two or three times daily or 850 mg once or twice daily with or after meals, gradually increased if necessary, at intervals of at least 1 week, to 2 to 3 g daily For 10 years old children starting dose of 500 mg or 850 mg once daily, or 500 mg twice daily, given with or after a meal. It may be gradually increased if needed, at intervals of at least 1 week, to a maximum of 2 g daily given in 2 or 3 divided doses. As given in adult

Pediatrics

Geriatrics

Marketed product
SNo Brand Name 1 Bigesens (500mg) 2 Bigesens XR(500mg) 3 Bigesens XR (1 gm) Exermet (500mg) Formin(500mg) Manufacturers Zydus Cadila Healthcare Ltd CND (Zydus Cadila Healthcare Ltd) Zydus Medica (Zydus Cadila Healthcare Ltd) Cipla Limited Dosage form Tablet Tablet(extended release)

Tablet(extended release)

4 5 6 7 8

Tablet Tablet Tablet Tablet Tablet

10

11

12 13 14 15 16

Alkem Laboratories Ltd Formin (500 mg) Stadmed Pvt Ltd Formin (850 mg) Alkem Laboratories Ltd Forminal(500mg) Alembic Chemical Works Co Ltd Forminal (850 Alembic mg) Chemical Works Co Ltd Forminal SR Alembic (500mg) Chemical Works Co Ltd Gluformin(500 Abbott mg) Healthcare Pvt Ltd (AHPL) Glumet Cipla Limited Glumet (850mg) Cipla Limited Glumet EXT Cipla Limited Glumet -XR Protec (Cipla Ltd) Insumet Cadila Pharmaceuticals

Tablet

Tablet(sustained release)

Tablet

Tablet Tablet Tablet(extended release) Tablet(extended release) Tablet

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Insumet (850 mg) Insumet SR

18

19

Irmet

20

K -Met SR

21

K -Met SR (1000 mg) M -Forlin

22

23

M -Forlin (850 mg) Riomet

24

Ltd. Cadila Pharmaceuticals Ltd. Cadila Pharmaceuticals Ltd. A.S.V. Laboratories (India) Pvt. Ltd. Blue Cross Laboratories Ltd. Blue Cross Laboratories Ltd. Lincoln Pharmaceuticals Ltd Lincoln Pharmaceuticals Ltd Ranbaxy Laboratories Ltd.

Tablet

Tablet(sustained release)

Tablet

Tablet(sustained release)

Tablet(sustained release)

Tablet

Tablet

Oral Solution

Reference :1. http://www.drugbank.ca/drugs/DB00331 2. http://www.drugs.com/international/metformin.html 3. Martindale, The complete drug reference, 36th edition,Pharmaceutical Press, page no 453. 4. http://www.ncbi.nlm.nih.gov/pubmed 5. http://www.sciencedirect.com/