REASON FOR METFORMIN DRUG TO SHOW ITS SUSTAINED ACTION UPTO 8-12 HRS

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REASON FOR “METFORMIN” DRUG TO SHOW IT’S SUSTAINED ACTION FOR 8-12HRS LITERATURE REVIEW BY K PRASHANTH KUMAR (11U21S0315) M-PHARMACY (PHARMACEUTICS) Sree Dattha Institute of Pharmacy, Hyderabad (under the supervision of) Naresh kshirasagar ( Assit . Prof.) M. PHARM (MBA)

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CONTENTS 1) INTRODUCTION 2) CLASSIFICATION OF DRUGS 3) DRUG PROFILE OF METFORMIN 4) REASONS FOR SUSTAINED ACTION 5) CONCLUSION 6) REFERENCE

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INTRODUCTION INSULIN 2 Insulin is a hormone produced by the β -cells of pancreas which is central to regulating carbohydrate and fat metabolism in the body. It is a polypeptide consisting of about 50 amino acids(A-chain 20 amino acids and B-chain 30 amino acids) Functions: Acting on cell membranes and stimulating uptake and use of glucose by muscles and connective tissue cells. Increasing conversion of glucose to glycogen( glycogenesis ) in liver and muscles. Accelerating uptake of amino acids by cells and synthesis of proteins. Promoting synthesis of fatty acids and storage of fats in adipose tissue ( lipogenesis )

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Decreasing glycogenolysis (breakdown of glycogen into glucose) Preventing the breakdown of proteins and fats gluconeogenesis (formation of new sugars from proteins etc.,) Insulin secretion is increased by increase blood glucose levels and to lesser extent by parasympathetic stimulation, raised blood amino acids, fatty acid levels and gastro intestinal hormones like gastrin , secretin , cholecystokinin . Insulin secretion is decreased by sympathetic stimulation, glucagon, adrenaline, cortisol and somatostatin Mechanism of action:

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B) Diabetes 1 Diabetes Mellitus is a metabolic disorder characterized by hyperglycaemia, glycosuria, hyperlipaemia, negative nitrogen balance and ketonaemia Diabete Insipidus is the condition caused due to hyposecretion of Anti Diuretic Hormone (ADH) due to damage to the hypothalamus. Type 1 is the “Insulin Dependent Diabetes Mellitus(IDDM)” due to β -cell destruction 2 Type 2 is the “Non Insulin Dependent Diabetes Mellitus(NIDDM)” due to insulin resistance

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CLASSIFICATION ANTI DIABETIC DRUGS 1 SULFONYL UREAS 1) First generation: → Tolbutamide → Chlorpropamide 2) Second generation: → Glibenclamide → Glipizide B) Biguanides → Metformin → Phenformin C) Phenyl analine analouges → Repaglinide → Nateglinide

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D) Thaizolidediones → Rosiglitazone → Pioglitazone E) α -Glucosidase Inhibitors → Acarbose → Miglitol

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DRUG PROFILE OF METFORMIN 4 Metformin hydrochloride tablets USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown Metformin hydrochloride is a white to off-white crystalline compound. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of Metformin is 12.4. The pH of a 1% aqueous solution of Metformin hydrochloride is 6.68. Metformin hydrochloride tablets USP contain 500 mg, 850mg, 1000mg of Metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, polyethylene glycol, povidone and titanium dioxide. M.F. C4H11N5•HCl M.W. 165.63

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REASONS FOR SUSTAINED ACTION ASPECTS TO THIS APPROACH: THE SUSTAINED ACTION OF A DRUG DEPENDS ON MAILY 3 ASPECTS A) CHEMISTRY ASPECT 4 B) PHARMACOLOGICAL ASPECT 1 C) PHARMACEUTIC/FORMULATION ASPECT 5

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CHEMISTRY ASPECTS 1. Di methyl amine, 2. 2-cyanoguanidine, 3. Metformin IF THE METHLY CHAIN INCREASES LIPOPHILICITY INCREASES AND IF ANY OTHER FUNCTIONAL GROUP IS REMOVED OR ADDED IT LOSTS ITS PHARMACOLOGICAL ACTIVITY

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PHARMACOLOGICAL ASPECTS MECHANISM OF ACTION:

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Pharmacological properties: Has an oral bioavailability of 50-60% under fasting and absorbed slowly Peak plasma concentration reaches with in 1-3hrs for immediate release and 6-12hrs for sustained release formulations Plasma protein binding is “negligible” due to its high volume of distribution(300-1000 liters after single dose) Steady state concentration reached in 1-2 days Not metabolized and cleared from body by tubular secretion Elimination half life is 6.2hrs Tissue toxicity occurs dude to oversdose (40-120mg/ L in children and 80-200mg/L in adults) overcome by haemodyalysis as the metformin has low molecular weight and less bound to proteins so easily removed Interaction with “cimetidine” and “cefalexin” show competitive mechanism in excretion as both the drugs are cationic in nature

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PHARMACEUTIC/FORMULATION ASPECTS The period between 1950 to 1970 is considered as period of Sustained drug release 7 . The main AIM of preparing sustained release formulation’s was intended to modify and improve the drug performance by Increasing the duration of drug action. Decreasing the frequency of dosing. Decreasing the required dose employed. Providing uniform drug delivery. SRF’s describes the slow release of a drug substance from a dosage form to maintain therapeutic response for extended period (8-12hrs)of time. Time depends on the dosage form. In oral form it is in hours, and in parenteral’s it is in days and months.

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The Goals of SRDF’s is to obtain Zero order release from the dosage form. Zero order release is a release which is independent of the amount of drug present in the dosage form. Usually SRDF’s do not follow zero order release but they try to mimic zero order release by releasing the drug in a slow first order fashion. Pharmacological action is seen as long as the drug is in therapeutic range, problems occur when drug concentration is above/below therapeutic range. ADVANTAGES OF SDRF’s: Improved patient compliance Decreased local and systemic side effects Better drug utilization Improved efficiency in treatment Disadvantages of SDRF’s: Dose dumping Stability problems Reduction in systemic availability

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TECHNIQUES FOR PREPARING SR FORMULATIONS 8 a ) BASED ON DRUG MODIFICATION: COMPLEX FORMATION DRUG-ADSORBATE PREPARATION . PRO DRUG SYNTHESIS. ION EXCHANGE RESINS. b) BASED ON DOSAGE FORM MODIFICATION: Microencapsulation Barrier coating Matrix embedding

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BASED ON DRUG MODIFICATION: Complex formation : The rate of dissolution of solid complex in biological fluids and rate of dissociation of complex in the solution are considered and they depend upon pH and composition of gastric and intestinal fluids. Drug- adsorbate preparation : In this product is insoluble. Drug availability is determined by rate of disabsorption. Pro drug synthesis : They are inactive and need enzymatic hydrolysis for regeneration. Solubility, absorption rate of prodrug must be lower than parent drug. Ion exchange resins : They are water insoluble, cross linked polymers containing salt forming groups. The drug is bound to the resin by using chromatographic column or by prolonged contact. Drug release from this complex depends on pH & property of resin. Drug that is attached to the resin is released by exchanging with the ions present in the GIT Resin + -Drug - +X - Resin + - X - + Drug -

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BASED ON DOSAGE FORM MODIFICATION . Microencapsulation : It’s a process in which tiny particles are surrounded by uniform coating (microcapsule) or held in a matrix of polymer (microsphere.) Spray drying is used which involves rapid evaporation of the solvent from the drug surface. Barrier coating : In this one quarter of the granules are in non sustained form for sudden drug release, remaining part are coated for sustained release. Both these granules are filled in hard gelatin capsule or compressed in a tablet, and the release mechanism is by diffusion. Coating material used are fats, waxes. Matrix embedding : Drug is dispersed in a matrix of retardant material which may be encapsulated or compressed in a tablet.

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METHODOLOGY 5 HPMC K100M : METFORMIN 1:1 IN SODIUM BICARBONATE SHOWS SUSTAINED ACTION UPTO 8hrs HPMC K100M : METFORMIN IN SODIUM BICARBONATE AND CITRIC ACID SHOWS SUSTAINED ACTION UPTO 10hrs METFORMIN WITH XANTHAN AND LOCUST BEAN GUM IN 1:0.5, 1:0.75, 1:1 WITH SODIUM BICARBONATE AND CITRIC ACID SHOWS SUSTAINED ACTION UPTO 12hrs METFORMIN : HYDROGENATED CASTOR OIL WITH GLYCERLY MANOSTERATE 1:1 RATIO METFORMIN : HYDROGENATED CASTOR OIN WITH GLYCERL MONO PALMITATE SHOWS 10% MORE SUSTAINED ACTION COMPARED TO MONOSTERATE.

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CONCLUSION BASED ON THE CHEMISTRY ASPECT THERE IS NO SIGNIFICANT EFFECT ON SUSTAINED ACTION ON METFORMIN DRUG RATHER ON STRUCTURAL MODIFICATION IT LEADS TO TOXICITY BASED ON PHARMACOLOGICAL ACTIVITY AS THE PROTEIN BINDING IS NEGLIGEBLE THIS IS ALSO HAS NO SIGNIFICANT EFFECT ON SUSTAINED ACTION, BUT WHEN CIMETIDINE AND CEFALEXIN ARE USED THE DURATION OF ACTION MAY INCREASED BUT NOT PREFERABLE BASED ON PHARMACEUTIC ASPECT IT WAS CLEAR THAT THE SUSTAINED ACTION OF METFORMIN DRUG IS DUE TO NOVEL FORMULATIONS

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REFERENCES 1.ESSENTIALS OF MEDICAL PHARMACOLOGY,6 th EDITION BY K.D.TRIPATHI 2. ROSS AND WILSON ANOTAMY AND PHYSIOLOGY IN HEALTH AND ILLNESS 3. ESSENTIALS OF CLINICAL PHARMACY BY RAMESH GOYAL 4. en.wikipedia.org/wiki/metformin 5. THEORY AND PRACTICE OF INDUSTRIAL PHARMACY BY LACHMANN AND LIBERMANN 6. Google images 7. Development and in vitro evaluation of gas generating floating tablets of metformin hydrochloride P.S. Salve* Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Mahatma Fuley Shaikshanik Parisar, Amravati Road, Nagpur – 440 033 (MS) *Corresponding Author E-mail: pramodsalve77@yahoo.com 8. Formulations of sustained release metformin hydrochloride tablet using combination of lipophilic waxes by melt granulation technique Kamlesh Jayantilal Wadher1*, Rajendra Baliram Kakde2 and Milind Janrao Umekar1 1Department of Pharmaceutical Technology, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, 441002, India. University Department of Pharmaceutical Sciences, R. T. M. Nagpur University Nagpur, 440033 India. Accepted 22 August, 2010 9. www.google.co.in/images

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Any queries???? “ The inferior physician treats the disease once it occurs. The mediocre physician prevents the disease from coming back. The superior physician prevents the disease from ever occurring.” Old Chinese Proverb