International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 2, Suppl 2, 2010 Review Article SULFONYL UREAS FOR ANTIDIABETIC THERAPY, AN OVERVIEW FOR GLIPIZIDE SHAMMI GOYAL1*, JITENDRA KUMAR RAI¹, R.K.NARANG¹, RAJESH K.S¹ 1 Nanotechnology Research Centre, Indo Soviet Friendship College of Pharmacy, Moga­142001, Punjab, India Email: [email protected] Received: 07 Jan 2010, Revised and Accepted: 24 Jan 2010 ABSTRACT Glipizide is a "second generation" sulfonylurea, an oral hypoglycemic agent for the management of non‐insulin dependent diabetes mellitus. Oral delivery of glipizide shows bioavailability problems and causes hypoglycemia with gastric disturbances. To overcome these problems, controlled release formulations as sustained release and controlled release tablets are available. Solubility of glipizide increases with increase in pH. Like any other sulfonylurea, glipizide appears to act principally by stimulating the insulin secretion from pancreatic beta‐cells. Glipizide overdose symptoms include low blood sugar. Keywords: Antidiabetic, Sulfonyl urea, Glipizide INTRODUCTION presumed that this effect is related to an alteration of the tissue plasma membrane, resulting in an increased number of insulin Glipizide is one of the most commonly prescribed drugs for receptors7. Data also suggest that glipizide improves glucose treatment of type II diabetes. It is an oral hypoglycemic drug from utilization not only by promoting pancreatic insulin release but also sulfonylurea group. It is active at very low doses, a characteristic by enhancing extra‐pancreatic availability of insulin and/or the feature of second generation sulfonylureas. Oral therapy with number of insulin receptors8. glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycemia and gastric disturbances. 4) Studies have demonstrated that during long‐term treatment with The physicochemical characteristics of glipizide has been given in sulfonylureas agents, plasma insulin levels either returned to Table 1. Although it is closely related to other sulfonylureas of the pretreatment values or actually decrease9. However, glipizide same therapeutic class such as glibenclamide, blood insulin and (unlike other sulfonylureas agents which result in decreased insulin glucose time courses differ. It also carries much lower risk of levels following long term treatment) maintains an elevated insulin hypoglycemia. secretory response (increased from 100% to 1500% above 7,10 DIABETES untreated values) for periods of 2 to 6 years or longer . These data indicate that glipizide causes a long‐term increase in glucose‐ Diabetes mellitus is a chronic metabolic disorder characterized by stimulated insulin secretion. high blood glucose concentrations (hyperglycemia) caused by insulin deficiency and it is often combined with insulin resistance3. 5) Glipizide has shown to potentiate chronic effects on insulin Non Insulin Dependent Diabetes Mellitus (NIDDM) represents a secretion7. At the same time, other studies utilizing glipizide for heterogeneous group comprising milder form of diabetes that occur periods of over 6 months have not reported tolerance to predominately in adults and a vast majority of diabetic patients hypoglycemic effects10. Stabilization of blood glucose levels were possess NIDDM4. The analytical parameters of glipizide which will reported for at least 4 years with glipizide therapy10. One study prove beneficial to researchers are shown in Table 2. Glipizide has reported that glipizide maintained control for up to 6 years in 70% been in extensive use to treat NIDDM and acts by increasing the of patients7 (cumulative secondary failure rate of approximately release of endogenous insulin as well as its peripheral effectiveness4; 30%). but it has been associated with severe and sometimes fatal 6) Studies by Brogden et al and other researchers has shown that hypoglycemia and gastric disturbances like nausea, vomiting, glipizide improved control of hyperglycemia in patients with poor heartburn, anorexia and increased appetite after oral therapy in results from other sulfonylureas5,10. However, improvement with normal doses. glipizide has been greater in patients who were well‐controlled on MECHANISM OF ACTION AND PHARMACOLOGY previous sulfonylureas therapy, compared to patients who responded poorly. 1) Glipizide is a "second generation" sulfonylureas, an oral hypoglycemic agent for the management of non‐insulin dependent 7) At the cellular level, sulfonylureas is known to bind to a diabetes mellitus (type II diabetes; maturity‐onset diabetes). On a sulfonylureas receptor on the pancreatic beta‐cell inhibiting the weight basis, glipizide is 100 times more potent than tolbutamide in adenosine triphosphate‐dependent potassium channel (K‐ATP). animal studies5. Glipizide has a more rapid onset of hypoglycemic Stabilization of potassium efflux causes depolarization and effect than glyburide (glibenclamide) and a shorter duration of activation of the L‐type calcium channel. Influx of calcium stimulates action5. insulin secretion. The effect of sulfonylureas is similar to that of glucose at the cellular level; however, sulfonylureas only stimulates 2) Glipizide reduces blood glucose by stimulating insulin secretion phase I (initial rapid peak) release of insulin and shows no effect on and altering insulin sensitivity; the drug causes a sustained increase phase II (prolonged insulin release). When sulfonylureas treatment in glucose‐stimulated insulin secretion in most patients during is initiated, insulin levels increase and plasma glucose levels prolonged therapy. gradually decrease. As the glucose levels decrease, insulin levels also 3) Like other drugs belonging to the class of sulfonylureas, glipizide decrease but still remain higher than pretreatment levels. appears to act principally by stimulating the insulin secretion from ADVANCES IN DELIVERY SYSTEMS pancreatic beta‐cells6. Glipizide is also reported to exert a major portion of its antidiabetic effect by altering the responsiveness of Some of the recent advancements incorporated for improved insulin‐sensitive tissues, such that the action of insulin is delivery of glipizide but yet to be released into the market is given potentiated5,7, an effect also postulated for chlorpropamide7. It is briefly below: 1 Int J Pharmacy Pharm Sci 1) Ashok V. Bhosale et al. has reported a formulation of glipizide 3) Mutalik, S. et al. has also performed pharmacological evaluation with beta cyclodextrin as a controlled release matrix tablet. of membrane moderated transdermal system of glipizide with The invitro evaluation shows promising results for the drug results which are acceptable for controlling diabetes13. where the release is for an extended period of time with 4) Jain, S, et al, have prepared and studied glipizide loaded constant levels (Ashok V. Bhosale et al.,2009). biodegradable nanoparticles and the influence of variables on 2) Mutalik, S. et al. has prepared and evaluated glipizide matrix transdermal systems for diabetes mellitus. Preclinical studies the formulation to show that it can be the future for diabetic are also completed for this formulation where the results are therapy14. adaptable for comfortable long term therapy13. Table 1: Physico characterstics of Glipizide² Sr. no. Description 1 Molecular formula C21H27N5O4S 2 Molecular weight 445.5 3 Physical state Powder (white) 4 Melting point 205 °C 5 Solubility Soluble Chloroform, dimethylformamide, Insoluble Water, ethanol Sparingly soluble Acetone 6 Dissociation constant pKa5.9 7 Partition coefficient Log P(octanol/water), 1.9 8 Colour test Mercurous Nitrate—black Table 2 Analytical parameters of Glipizide2 Particulars Thin layer chromatography System Rf value TA Rf 87 TB Rf 00 TC Rf 41 TE Rf 07 TL Rf 05 TAE Rf 86 High performance liquid chromatography System RI value HX 478 HY 423 HZ Retention time 4.5 min. HAA Retention time 17.6 min. Ultraviolet spectrum λmax 276 nm Infra‐red spectrum Principal peaks 1528,1690,1650,1159, 1032,900 cm−1 (KBr disk). Mass spectrum Principal ion at m/z 150,121,56,93,39,151,66,94. Table 3: Saturation Solubility of Glipizide at Different pH Sr. no. Medium Ph Saturation solubility(µg/mL) 1 2 1.1 2 4.4 1.3 3 5.22(DI water) 3.9 4 5.8 4.9 5 6.8 26.6 6 8 280.7 7 10 898.9 Fig. 1: pH solubility profile of Glipizide 2 Int J Pharmacy Pharm Sci The solubility is expected to increase by rise in pH. As given, Excretion glipizide shows increased solubility immediately above the pKa A) Through Kidney ‐ Renal Excretion is 63% to 89%. Only 3% to 9% values which is shown in Figure 1 and Table 3. It is recommended to of a dose is eliminated as unchanged drug; the majority of a dose is study the dissolution of glipizide at pH 6.8 buffer for experimental recovered as metabolites5. purposes. B) Other excreation is via feces,11% . CONVENTIONAL AND NOBLE FORMULATIONS OF GLIPIZIDE Elimination half­life Glipizide is available in market mainly in tablet form (2.5mg,5 mg, Elimination half‐life is 2 to 5 hours5,17.The half‐life did NOT differ 10mg). Some of different marketed brands available are shown in between middle‐aged (8.4 hours; mean=46.1 years) and elderly Table 4. patients (10.3 hours; mean=64.8 years). This study differs from earlier ones by using a 2‐ compartment model. The half‐life in obese PHARMACODYNAMICS/KINETICS versus nonobese patients was 5.4 hours and 6.7 hours, respectively, at steady state. This study differs from earlier ones by using a 2‐ Bioavailability compartment model.