Diabetes Mellitus is the most common of the serious metabolic diseases affecting humans. It has been estimated that there are over 200 million people that have diabetes in the world.
Metabolically, diabetes is characterized by an inappropriate elevation of blood glucose levels. In Type I Diabetes Mellitus, this is due to an absence of insulin in the individual. In Type II Diabetes Mellitus, although there is circulating insulin, its signal is not efficiently transduced via the insulin receptor, giving rise to insulin resistance, where the body responds less and less well to a given amount of insulin. Insulin is a peptide hormone which is produced by the Langerhorn islets in the pancreas. Insulin triggers increased glucose utilization, protein synthesis, and the formation and storage of neutral lipids. The present invention focuses on Type II Diabetes Mellitus, or non-insulin-dependent diabetes.
Diabetes Mellitus is also characterized by long term complications involving the eyes, nerves, kidneys and blood vessels. These diabetic complications include premature atherosclerosis, intercapillary glomerulosclerosis, retinopathy and neuropathy. The major cause of morbidity and mortality among diabetics is coronary heart disease.
The primary goal in the treatment of diabetes is to maintain blood glucose levels as close to normal as possible. For Type II diabetics, the first line of therapy for maintaining blood glucose level is modification of diet and lifestyle. The diabetic diet features restrictions on fat content and an increased intake of dietary fiber. Regular exercise is also emphasized to decrease weight and reduce the degree of insulin resistance.
If diet and lifestyle modifications fail to control glucose levels, oral hypoglycemic therapy or insulin therapy is required to control glucose levels and thus minimize complications related to the disease.
One of the compounds used to treat diabetes is metformin or its pharmaceutically acceptable salts. Metformin is a dimethyl biguanide having the formula: 
The pharmaceutically acceptable salts of the formula in which A is the anion of the non-toxic salt are the preferred medicaments.
U.S. Pat. No. 3,174,921 to Sterne discloses various pharmaceutically acceptable salts of metformin, for example, phosphate, sulfate, hydrochloride, salicylate, maleate, benzoate, ethanedisulfonate, fumarate and glycolate. U.S. Pat. No. 6,031,004 to Timmins, et al. discloses metformin salts of dibasic acids, such as fumarate and succinate, wherein the molar ratio of metformin:dibasic acid is 2:1.
However, the most preferred metformin product is the hydrochloride salt. In fact, the biguanide anti-hyperglycemic agent, metformin, is currently marketed in the U.S. in the form of its hydrochloride salt. (Glucophage®, Bristol-Myers Squibb Company).
Metformin hydrochloride is a cohesive white powder which is highly soluble in water (>300 mg/ml at ambient temperature). The market metformin hydrochloride salt has a pronounced saline, bitter taste. Accordingly, it is usually marketed as a coated tablet wherein its coating is masked or is designed to mask any unpleasant taste.
Unfortunately, as sold, the tablet is very large, making it different to swallow. Moreover, due to its size, this drug cannot be used by children or adults who are not able to swallow tablets. However, the present inventors realize that a liquid formulation would be useful for children and adults who cannot swallow large size tablets or orally intake chewable tablets.
To date, no one has heretofore made a liquid formulation of metformin hydrochloride salt which has masked the unpleasant taste thereof. Moreover, to date, no one has made a liquid formulation of metformin or salt thereof.
The preparation of a liquid formulation for masking the bitter taste of metformin or its salts is not straightforward, as one might think. After all, the skilled artisan would expect that the taste could be masked by adding a sugar. However, since the liquid formulation is being used to treat diabetes, sugar cannot be used. Moreover, in addition to being sugar free, the liquid formulation should contain none or a minimal amount of sodium salt since it detrimental to diabetic patients. Moreover, it should contain little or no alcohol (ethanol) since ethanol is detrimental to diabetic patient. Furthermore, metformin and its salts, especially the hydrochloride salts are so bitter, it has heretofore been difficult to completely mask the taste without the use of sugar, alcohol and sodium salts.
The present inventors have also found a means of making the metformin in the liquid formulation palatable to patients.