Liquid formulations of compounds active at sulfonylurea receptors
Inventors
Jacobson, Sven • Clarke, Gillian • Matharu, Rajinder
Assignees
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Publication Number
US-10688111-B2
Publication Date
2020-06-23
Expiration Date
Abstract
The invention provides liquid formulations of compounds that act at sulfonylurea receptors that are suitable for intravenous and intra-arterial infusion. Compounds active at a sulfonylurea receptor include glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, and glimepiride. Liquid formulations may be concentrated solutions suitable for storage; may be diluted (e.g., dilution of 1:1 or 1:1.2) suitable for bolus injections, and may be further diluted (e.g., dilution of 1:10 or 1:20 or more) for intravenous and intra-arterial infusion over an extended period of time. For example, a liquid formulation may include at least about 0.05 mg/ml glibenclamide in a water-based solution including 40% polyethylene glycol 300, 10% Ethanol, 50% water, at about pH 9. The solution may include a buffer, and is suitable for storage in refrigerator or at room temperature. This solution may be diluted 1:1, or more (e.g., 1:20) without precipitation of the glibenclamide.
Core Innovation
The invention relates to a stable liquid formulation suitable for parenteral administration to a patient. The formulation comprises glibenclamide or a pharmaceutically acceptable salt thereof in a concentration of about 0.5 mg/ml to about 1 mg/ml, 10 mM to 50 mM meglumine, and a pharmaceutically acceptable infusion solution comprising water, a pharmaceutically acceptable base, and a sugar alcohol.
The formulation is characterized by a pH of about pH 9 or higher. The glibenclamide or pharmaceutically acceptable salt is provided with stability and solubility properties such that it does not precipitate out of the solution during or following dilution or when frozen or refrigerated.
The liquid formulation has stability and solubility properties enabling storage stability for six months. The formulation remains free from visible particles upon storage for at least one month.
Claims Coverage
The independent claim is directed to a stable liquid parenteral formulation of glibenclamide with four inventive features, including a defined excipient system, a high pH, anti-precipitation properties, and explicit storage performance criteria.
Stable liquid parenteral formulation with meglumine and glibenclamide
A stable liquid formulation suitable for parenteral administration comprising 10 mM to 50 mM meglumine and glibenclamide or a pharmaceutically acceptable salt thereof at about 0.5 mg/ml to about 1 mg/ml.
Infusion solution of water, pharmaceutically acceptable base, and sugar alcohol
A pharmaceutically acceptable infusion solution comprising water, a pharmaceutically acceptable base, and a sugar alcohol.
High-pH formulation without precipitation during dilution or freeze/refrigeration
The liquid formulation has a pH of about pH 9 or higher and the glibenclamide or pharmaceutically acceptable salt does not precipitate out of the solution during or following dilution or when frozen or refrigerated.
Storage stability for six months and freedom from visible particles
The formulation is stable upon storage for six months and remains free from visible particles upon storage for at least one month.
Overall, the claim coverage centers on a high-pH meglumine-containing liquid infusion system for glibenclamide that prevents precipitation during dilution and after freeze/refrigeration, while meeting explicit storage stability and visible-particle control criteria.
Stated Advantages
Stable upon storage for six months.
Remains free from visible particles upon storage for at least one month.
Does not precipitate out of the solution during or following dilution.
Does not precipitate out of the solution when frozen or refrigerated.
Documented Applications
Parenteral administration to a patient, including formulations formulated for intravenous or intra-arterial delivery.
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