Type II diabetes mellitus (T2DM) is a progressive metabolic disorder with diverse pathologic manifestations and is often associated with lipid metabolism and glycometabolic disorders. The long-term effects of diabetes result from its vascular complications, e.g., the microvascular complications of retinopathy, neuropathy and nephropathy, and the macrovascular complications of cardiovascular, cerebrovascular and peripheral vascular diseases. Initially, diet and exercise is the mainstay of treatment of type II diabetes. However, this is often followed by administration of oral hypoglycemic agents. Exemplary drugs useful for managing type II diabetes and its precursor syndromes such as insulin resistance include classes of compounds, such as, biguanides, glitazones, sulfonylureas, thiazolidinediones α-glycosidase inhibitors, meglitinides and dipeptidyl peptidase IV inhibitors (DPP4 inhibitors).
Presently, dipeptidyl peptidase IV inhibitors, biguanides, glitazones and sulfonylureas are commercially available in the form of tablets of the individual drugs, either in immediate release (IR) formulations or in controlled release (CR) formulations. These are usually administered orally to patients in need thereof, using protocols calling for the administration of the individual ingredient.
Insulin resistance and reduced insulin secretion are two abnormalities that can occur in type 2 diabetic patients. Therefore, reducing insulin resistance or increasing insulin sensitivity and augmenting insulin secretion from the pancreatic beta cells are two major treatment approaches. The tissues most commonly resistant to actions of insulin are liver, skeletal muscles, and adipose tissues. Therefore, combination treatment strategies directed towards improving the insulin sensitivity of these major tissues can help in overall enhancement of insulin sensitivity.
In some cases, physicians have been initiating therapy for T2DM using at least two drugs to obviate the mono-therapy difficulties that can accompany prolonged use of metformin. Metformin mono-therapy typically has been used as a first line treatment in diabetic patients. This treatment may be supplemented with other drugs if secondary failure of the therapy arises. The addition of a second drug, e.g., dipeptidyl peptidase IV inhibitor, glitazones or a sulfonylurea to the concurrent treatment can provide a balance of stimulated release of insulin while ameliorating insulin resistance. This may provide an optimal level of glycemic control that is currently unattainable using either medication alone. However, requiring a patient to take multiple medications such as these for the prophylaxis or treatment of diseases can result in patient inconvenience and lead to non-compliance of the prescribed dosage regimen. The ease of using single composition for multiple medications as opposed to separate administration of the individual medications has long been recognized in the practice of medicine. Such a composition can provide a therapeutic advantage for the benefit of the patient and the clinician. Further, such a composition can provide both increased convenience and improved patient compliance resulting form the avoidance of missed doses through patient forgetfulness.
Pharmaceutical dosage forms containing combinations of anti-diabetic drugs are known from for example, EPO 0 749 751 discloses pharmaceutical compositions comprising an insulin sensitivity enhancer, such as a thiazolidinedione compound, in combination with other anti-diabetic compounds. More specifically, EPO 0 749 751 discloses pioglitazone as a insulin sensitivity enhancer, which can be combined with other anti-diabetics such as metformin, phenformin or buformin, and further that these drugs can be associated (mixed or coated) with conventional excipients to provide taste masking or provide a sustained or slow release. U.S. Pat. No. 6,011,049 discloses a combination of antihyperglycemic drugs and thiazolidinedione derivatives. This patent discloses a pharmaceutical composition having pioglitazone or trolitazone and metformin in slow release forms such as osmotic pumps or skin patches. Other combinations of antihyperglycemic drugs and thiazolidinedione derivatives can be found in U.S. Pat. Nos. 6,524,621; 6,475,521; 6,451,342 and 6,153,632 and PCT patent applications WO 01/3594 and WO 01/3594. U.S. Pat. No. 7,125,873 describes pharmaceutical composition comprising a dipeptidyl peptidase IV inhibitor like Sitagliptin with other anti-diabetic drugs such as biguanide and PPAR agonists. U.S. Pat. Application No. 2009/0105265 discloses pharmaceutical compositions comprising fixed-dose combinations of a dipeptidyl peptidase-4 inhibitor and metformin, methods of preparing such pharmaceutical compositions, and methods of treating Type 2 diabetes with such pharmaceutical compositions.
There is a need for pharmaceutical compositions comprising a dipeptidyl peptidase IV inhibitor and a slow release biguanide. Further the invention provides a method of administering the combination of a slow release biguanide and a dipeptidyl peptidase IV inhibitor that provides the advantages discussed above. It is an additional object of the present invention to provide a dosage form that can provide delivery of a DPP inhibitor and a biguanide wherein the peak plasma levels of the biguanide compound is approximately 8-12 hours after administration and peak plasma levels of a DPP IV inhibitor is approximately 1-4 hours after dosing. DPP IV inhibitor and Metformin combinations have been reported to cause diarrhea; gas; headache; indigestion; nausea; sore throat; stomach upset; stuffy or runny nose; vomiting; weakness. The extent of common adverse drug reactions reported include diarrhea (2.4%); gas (3.2%), stomach upset (2.6%), hypoglycemia (0.6% to 12.2%), headache (1.1% to 5.9%), nasopharyngitis (5.2% to 6.3%), upper respiratory infection (4.5% to 6.3%), etc. Thus there is a need for pharmaceutical compositions that alleviate or minimize these side effects.