Metformin hydrochloride, a biguanide, is an effective treatment for type 2 diabetes, lowering both basal and postprandial hyperglycemia either as monotherapy or in combination with other antihyperglycemic drugs (Nathan D, 2009). Metformin hydrochloride in its immediate release form (IR) has been used for decades in the treatment of type 2 diabetes. An IR formulation releases the entire drug within 1–2 h after dosing, resulting in high drug concentrations in the GI (gastrointestinal) tract which may be associated with GI side effects (especially nausea, diarrhea) in 20-30% patients.  This can limit the tolerated dose, reduce adherence and result in discontinuation of therapy (Garber A, 1997; Schwartz L, 2008). In addition, the frequent need to administer metformin two or three times daily may also not support good adherence to therapy (Blonde L, 2004).  

Metformin hydrochloride extended release (ER) formulations have been developed to overcome these problems. Because metformin gets absorbed in the first part of the small intestine, extended release metformin hydrochloride formulations employ various novel gastric-retentive techniques. The polymeric matrix (hydroxyl propyl methyl cellulose) of the extended release metformin tablet is designed to swell in the gastric fluid. As the matrix swells, it becomes resistant to peristalsis and is more easily retained in the stomach. Gastric fluid penetrates the matrix, dissolving the drug which then diffuses out of the matrix in the liquefied form.  Metformin hydrochloride is thus slowly released from the matrix of the tablet and is absorbed when this gastric fluid passes through the small intestine (Foster R, 2006).  The slow release of the drug in the GI tract permits once daily dosing and also reduces the incidence of nausea (6.5%) and diarrhea (9.6%). These factors are particularly relevant for increasing treatment adherence to long term therapies like anti-diabetic medication   (Levy J, 2010; Schwartz L, 2008).

Glimepiride, a new generation sulphonylurea, in doses of 1-8mg/day, is an effective treatment option for NIDDM patients. Oral bioavailability is approximately 100% and the absence of a food interaction guarantees highly reproducible pharmacokinetics with this drug [Prescribing information for Amaryl (glimepiride), 2011]. A combination tablet formulation of sustained release metformin hydrochloride and glimepiride  is beneficial in terms of  convenience of administration and patient compliance.

Metformin hydrochloride extended-release formulation should generally be given once daily with the evening meal. Administration with food increases the bioavailability of metformin hydrochloride.  Food increases the extent of absorption (AUC) of metformin hydrochloride (AUC 13306 ng h/ml with high fat breakfast, AUC 10200 ng h/ml with a low fat breakfast, AUC 7506 ng h/ml in fasting condition) (Schwartz L, 2008). Food can either cause no change  or an increase in C_max of the drug. One study has reported no effect of food on the C_max of metformin [high fat meal (1018 ng/ml), low fat meal (992 ng/ml) and fasting condition (1022 ng/ml)] (Schwartz L, 2008). In contrast, in a healthy volunteer study with Glucophage SR 1000mg, food increased the extent of absorption (AUC) by 77%, peak plasma concentration (C_max) by 26% and prolonged time to peak plasma concentration (T_max) by about 1 hour as compared to the fasting state (MHRA, UKPAR Glucophage SR 1000mg Prolonged-Release Tablets, BE study).

The mechanical stress of the grinding action of the stomach in the fed state could introduce variability if an extended release tablet containing metformin hydrochloride is broken down more rapidly than anticipated. Because food prolongs the gastric retention time, extended release formulations administered with food are exposed to longer duration of mechanical stress in the stomach (Foster R, 2006). The latter raises the possibility of increased release rate (than intended) of the drug from the formulation. This can result in a higher risk of ‘dose dumping’, creating a potential safety risk for patients (Fyhr P, 2011).  Therefore it is clinically important to assess the effect of food on extended release formulations of metformin hydrochloride and metformin hydrochloride/glimepiride.