Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-08-07
2003-05-06
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S634000
Reexamination Certificate
active
06559187
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a liquid formulation of metformin and salts thereof and to the use thereof in treating hyperglycemia and/or diabetes.
BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
The present invention is directed to a liquid pharmaceutical composition for oral administration to a subject in need thereof which comprises a therapeutically effective amount of metformin or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier.
In a preferred embodiment, the present invention is directed to a liquid formulation of metformin or its pharmaceutically acceptable salts, wherein the formulation comprises a therapeutically effective amount of metformin in a liquid carrier, containing a sweetener or polyhydroxy alcohol. In one preferred embodiment, the liquid carrier contains at least one of the following components: a polyhydroxy alcohol, a sweetener that does not raise the alcohol sugar level when ingested by a mammal, or an alkyl hydroxyethylcellulose. In a more preferred embodiment, the liquid formulation of the present invention contains at least two of the additional components and most preferably all three additional components. It is most preferred, in this embodiment, that the liquid formulation comprises a therapeutically effective amount of metformin or its pharmaceutically acceptable salts, about 40% to about 80% by weight of a sweetener, about 5% to about 55% by weight polyhydroxy alcohol and about 0.01% to about 5% by weight alkyl hydroxyethylcellulose.
In another embodiment, the liquid formulation comprises a therapeutically effective amount of metformin or its pharmaceutically acceptable salt, a sweetener or mixture of sweeteners that do not raise the alcohol sugar level when ingested by a mammal, and a mineral acid and bicarbonate salt, such that the pH of the formulation ranges from about 4 to about 9. In this formulation, the acid and bicarbonate salt are present in an amount sufficient to maintain the formulation in a pH ranging from about 4.0 to about 9.0. In this embodiment, it is preferred that the sweetener is a mixture of a sugar alcohol and non-nutritive sugar.
The present invention is also directed to a method of treating hyperglycemia which comprises administering to a patient in need of treatment an antihyperglycemic effective amount of said liquid formulation. In another embodiment, the present invention is directed to a method for treating Type II diabetes in a patent which comprises administering to a patent in need of treatment an anti-diabetic effective amount of said liquid formulation.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “patient” refers to an animal who is suffering from hyperglycemia or diabetes. The preferred animal is a mammal, such as dogs, cats, horses, cows and humans. It is preferred that the patient is a human.
As described hereinabove, an aspect of the present invention is directed to a liquid formulation comprising a therapeutically effective amount of metformin or its pharmaceutically acceptable salts in association with a liquid carrier.
Metformin and various pharmaceutically acceptable salts are described in U.S. Pat. Nos. 3,174,901 and 6,031,004, the contents of which are incorporated by reference. Examples include mono and dibasic acid salts of metformin, including the hydrochloride salt, the phosphate salts, sulfate salts, hydrobromi
Chandran Ravi
Gogia Ashish
Deshmukh Esq. Jayadeep R.
Ranbaxy Signature LLC
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