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Publication Number
US-9815777-B2
Publication Date
2017-11-14
Expiration Date
Abstract
Metformin salts of 2,4-thiazolidinediones are described for the treatment of diabetes mellitus Type2, gestational diabetes, polycystic ovary syndrome, non-alcoholic fatty liver disease, coronary artery disease, pancreatic cancer, premature puberty, and other diseases which manifest insulin resistance.
Core Innovation
The invention relates to metformin salts formed with 2,4-thiazolidinedione and to compounds captured by Formula (A), with a proviso that a neutral compound of Formula (A) is obtained. A 1:1 metformin-2,4-thiazolidinedione salt (Met.TZ; Formula I) is crystallographically characterized, including a described single-crystal X-ray structure and a hydrogen-bond network.
The disclosure addresses analytical characterization for the metformin-2,4-thiazolidinedione salt, including reported yield, melting point, HPLC purity, CHN, and NMR. It also introduces metforminates of rosiglitazone and pioglitazone (Formulas VI and VII), and reports their stoichiometric relationship with Met.TZ. Single-crystal X-ray structure determination is also reported for pioglitazone metforminate (Formula VII).
The patent content also reports in vivo anti-hyperglycemic evaluation of Met.TZ in db/db mice. Fasting blood glucose and oral glucose tolerance testing are used to compare Met.TZ with metformin hydrochloride as a positive control, with results indicating stronger glucose lowering and improved glucose tolerance versus equivalent metformin dosing, with some differences reaching statistical significance versus vehicle.
Claims Coverage
The provided claim material identifies one independent claim directed to a compound of Formula (A) with a neutral compound proviso, and dependent claims refine formulation composition, specific rosiglitazone/metformin salt and metformin-thiazolidinedione composition relationships, dosage forms, and patient treatment conditions including dosing frequency.
Compound of formula (A) with neutral proviso
A compound of Formula (A) comprising n and R1 wherein, when n is 1, R1 is —NH2; Q is an anion as defined; with the proviso that a neutral compound of Formula (A) is obtained.
Pharmaceutical formulation with specified formulation component categories
A pharmaceutical formulation comprising an active ingredient that is a compound of Formula (A) together with one or more pharmaceutically acceptable adjuvants and additional formulation components including hinders, desiccants, diluents, excipients, buffers, and preservatives.
Mono metformin salt combination and dosage ratio
A pharmaceutical formulation includes rosiglitazone and metformin salt (Formula VI) as active ingredients combined with a metformin-thiazolidinedione composition (Formula I) in a 1:1 ratio, using 2 mg of Formula VI together with 500 mg of Formula I.
Pharmaceutical formulation in specified dosage forms
A pharmaceutical formulation according to claim 3, provided in one of several specified oral and injectable dosage forms.
Treating specified cardiovascular and metabolic/endocrine conditions with daily dosing
A method for treating patients with specified cardiovascular and metabolic/endocrine conditions by administering a pharmaceutical formulation of claim 3 once or twice per day.
The claim coverage centers on the defined Formula (A) metformin-associated salt compound family with a neutral compound proviso. Dependent claims then refine pharmaceutically acceptable formulation components, specify a rosiglitazone/metformin salt combination and a 1:1 metformin-thiazolidinedione relationship, and further narrow to particular oral and injectable dosage forms and to treating specified cardiovascular and metabolic/endocrine conditions with a once or twice per day administration regimen.
Stated Advantages
Stronger glucose lowering and improved glucose tolerance versus equivalent metformin dosing in db/db mice.
Some differences are statistically significant versus vehicle in the in vivo evaluation.
Documented Applications
In vivo anti-hyperglycemic evaluation of Met.TZ in db/db mice using fasting blood glucose and oral glucose tolerance testing, compared to metformin hydrochloride as a positive control.
Treatment of patients with cardiovascular diseases and metabolic/endocrine conditions including type 2 diabetes, gestational diabetes, polycystic ovary syndrome, non-alcoholic fatty liver disease, and premature puberty, using a pharmaceutical formulation once or twice per day.
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