Nasal formulations of metoclopramide
Inventors
D'Onofrio, Matthew J. • Gonyer, David A. • Shah, Shirish A. • Madden, Stuart J.
Assignees
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Publication Number
US-8334281-B2
Publication Date
2012-12-18
Expiration Date
Abstract
Nasal formulations of metoclopramide, which remain stable and/or colorless upon storage over a period of time, are provided. Also provided are methods of treating disorders treatable with metoclopramide, comprising administering the nasal solutions to patients in need thereof.
Core Innovation
The invention relates to a pharmaceutical composition of metoclopramide, or a pharmaceutically-acceptable salt thereof, as a nasal solution containing a citrate buffer and benzalkonium chloride. The nasal solution is required to be clear to pale yellow when compared to standard E, 32 USP <631> on storage, and the composition is further characterized by storage at a temperature of 40°C for at least about 4 weeks while maintaining the specified appearance criterion.
A core aspect is that the composition has a citrate concentration of at least about 10 millimolar. The disclosed framework addresses prior nasal metoclopramide solutions that become yellow-to-brown on storage under accelerated conditions, which motivates a formulation that remains substantially clear or colorless over long-term storage while meeting the USP appearance comparison.
The patent also defines additional formulation constraints that support the stability and appearance requirements, including pH above about 4.5 and, in further refinements, quantitative selections for metoclopramide concentration, benzalkonium chloride concentration, and osmolality. In some embodiments, benzyl alcohol is limited to less than about 1% w/v.
Claims Coverage
The independent claims define pharmaceutical nasal solutions comprising metoclopramide (or a pharmaceutically-acceptable salt), with a specified buffer and benzalkonium chloride, constrained to remain clear to pale yellow by Standard E, 32 USP <631> after storage at 40°C for at least about 4 weeks, and with additional independently stated formulation parameters. Across the independent claims, three principal inventive formulation features are emphasized: the citrated buffer plus benzalkonium chloride framework, the appearance/stability criterion against Standard E (USP <631>), and the minimum citrate concentration or pH/benzyl alcohol limitations.
Citrate buffer with benzalkonium chloride for stable nasal appearance
A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, a citrate buffer, and benzalkonium chloride, wherein the composition is a nasal solution that is clear to pale yellow when compared to standard E, 32 USP <631> on storage at a temperature of 40°C for at least about 4 weeks; and wherein the composition has a citrate concentration of at least about 10 millimolar.
pH above about 4.5 with nasal clarity versus Standard E (USP <631>)
A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, a buffer, and benzalkonium chloride; wherein the composition is a nasal solution that is clear to pale yellow when compared to standard E, 32 USP <631> on storage at a temperature of 40°C for at least about 4 weeks; and wherein the composition has a pH of above about 4.5.
Citrate buffer and benzalkonium chloride with limited benzyl alcohol
A pharmaceutical composition comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, a citrate buffer, benzalkonium chloride, and less than about 1% w/v benzyl alcohol; wherein the composition is a nasal solution that is clear to pale yellow when compared to standard E, 32 USP <631> on storage at 40°C for at least about 4 weeks; and wherein the composition has a citrate concentration of at least about 10 millimolar.
The independent claims collectively cover nasal metoclopramide formulations that maintain a clear-to-pale-yellow appearance versus Standard E, 32 USP <631> after storage at 40°C for at least about 4 weeks. They require a citrated buffer framework with benzalkonium chloride and a minimum citrate concentration, and they further require either a pH above about 4.5 or an explicit limitation on benzyl alcohol (less than about 1% w/v) in conjunction with the same appearance criterion.
Stated Advantages
Remains substantially clear or colorless (clear to pale yellow when compared to standard E, 32 USP <631>) on storage at 40°C for at least about 4 weeks.
Has improved stability relative to prior nasal metoclopramide solutions that become yellow-to-brown under accelerated storage conditions.
Maintains the required appearance criterion (clear to pale yellow versus Standard E, 32 USP <631>) during extended storage in refined embodiments (e.g., at least about 8 weeks).
Documented Applications
Intranasal treatment of metoclopramide-treatable disorders including gastroparesis, emesis, delayed emesis, and nausea.
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