Glyburide and Metformin

GLYBURIDE AND METFORMIN- glyburide and metformin hydrochloride tablet, film coated
Rebel Distributors Corp

DESCRIPTION

Glyburide and metformin hydrochloride tablets USP contain two oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide USP and metformin hydrochloride USP.

Glyburide USP is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glyburide USP is 1-[[p -[2-(5-chloro-o -anisamido)ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide USP is a white to off-white crystalline compound. The glyburide USP used in glyburide and metformin hydrochloride tablets USP has a particle size distribution of 25% undersize value not more than 6 µm, 50% undersize value not more than 7 to 10 µm, and 75% undersize value not more than 21 µm. The structural formula is represented below:

Glyburide Structural Formula
(click image for full-size original)

C23 H28 ClN3 O5 S M.W. 494.01

Metformin hydrochloride USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride USP ( N,N -dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound. Metformin hydrochloride USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin USP is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride USP is 6.68. The structural formula is as shown:

structural formula
(click image for full-size original)

C4 H12 ClN5 (monohydrochloride) M.W. 165.63

Each glyburide and metformin hydrochloride tablet USP, for oral administration, contains 1.25 mg glyburide USP with 250 mg metformin hydrochloride USP, 2.5 mg glyburide USP with 500 mg metformin hydrochloride USP, or 5 mg glyburide USP with 500 mg metformin hydrochloride USP. In addition, each tablet contains the following inactive ingredients: copovidone, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, talc, and titanium dioxide. The 1.25 mg/250 mg strength also contains D&C Yellow #10 aluminum lake and FD&C Red #40 aluminum lake; the 2.5 mg/500 mg strength also contains FD&C Red #40 aluminum lake and FD&C Yellow #6 aluminum lake; and the 5 mg/500 mg strength also contains D&C Yellow #10 aluminum lake and FD&C Yellow #6 aluminum lake.

CLINICAL PHARMACOLOGY

Mechanism of Action

Glyburide and metformin combines two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.

Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacokinetics

Absorption and Bioavailability

Glyburide and metformin

In bioavailability studies of glyburide and metformin 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of the glyburide coadministered with metformin. The glyburide component of glyburide and metformin, therefore, is not bioequivalent to glyburide. The metformin component of glyburide and metformin is bioequivalent to metformin coadministered with glyburide.

Following administration of a single glyburide and metformin 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the Cmax and a relatively small effect of food on the AUC of the glyburide component. The Tmax for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The clinical significance of an earlier Tmax for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.

Glyburide

Single-dose studies with glyburide tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between glyburide and metformin hydrochloride tablets and single ingredient glyburide products.

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.

Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35-minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Glyburide

Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs, such as phenylbutazone, warfarin, and salicylates, displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding results in fewer drug-drug interactions with glyburide tablets in clinical use.

Metformin hydrochloride

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

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