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-11628150-B2
Publication Date
2023-04-18
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 formulated for intranasal administration comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, and having a pH of above about 4.5. The composition is defined to maintain color and clarity during storage, including under conditions of 40°C and 75% relative humidity, and to address yellow-to-brown discoloration and loss of a substantially clear or colorless appearance using a specified buffering system and stability criteria.
The pharmaceutical composition uses a citric acid buffer comprising a combination of citric acid monohydrate and sodium citrate dihydrate, wherein the combination provides a citrate concentration of at least 10 millimolar. The citric acid monohydrate is present at a concentration of up to 50 millimolar, and the stability of the formulation is characterized by limits on the average change in percent optical density (O.D.) per week and by requirements that the composition does not discolor over storage at 40°C.
The invention also characterizes the formulation as substantially free of color/clear and stable according to specified O.D.-based criteria and comparisons using USP color standards and USP iodine standards. In the disclosed embodiments, formulations are engineered so that they do not discolor when stored at 40°C for at least about 4 weeks, and they show less than about 2% average change in percent optical density (O.D.) per week per 200 mg/mL of metoclopramide when stored at 40°C and 75% relative humidity.
Claims Coverage
The independent claim set includes two independent pharmaceutical composition claims that define intranasal metoclopramide formulations with stability to discoloration using a citric acid buffer system and O.D.-based criteria. The main inventive features are the citric buffer composition with constrained citrate and citric acid monohydrate concentrations, pH above about 4.5, and storage-stability requirements quantified by percent optical density changes and/or no discoloration after storage at 40°C.
Intranasal metoclopramide with pH above 4.5 and citric buffer citrate ≥10 millimolar
A pharmaceutical composition formulated for intranasal administration comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, having a pH of above about 4.5, and comprising a citric acid buffer comprising a combination of citric acid monohydrate and sodium citrate dihydrate, wherein the combination provides a citrate concentration of at least 10 millimolar, and wherein the citric acid monohydrate is at a concentration of up to 50 millimolar.
Optical density stability at 40°C/75% RH
Providing less than about 2% average change in percent optical density (O.D.) per week per 200 mg/mL of metoclopramide when stored at a temperature of 40°C and 75% relative humidity.
Intranasal metoclopramide with citric buffer and no discoloration after 40°C storage
A pharmaceutical composition formulated for intranasal administration comprising metoclopramide, or a pharmaceutically-acceptable salt thereof, and a citric acid buffer comprising a combination of citric acid monohydrate and sodium citrate dihydrate, wherein the combination provides a citrate concentration of at least 10 millimolar, and wherein the citric acid monohydrate is at a concentration of up to 50 millimolar, wherein the pharmaceutical composition does not discolor when stored at a temperature of 40°C for at least about 4 weeks.
Overall, the independent claim coverage is directed to intranasal metoclopramide compositions that remain stable with reduced discoloration during storage. The inventive features are the citric acid buffer composition defined by citrate concentration and citric acid monohydrate concentration limits, a pH above about 4.5, and quantified optical-density stability and/or no-discoloration requirements after storage at 40°C.
Stated Advantages
Less than about 2% average change in percent optical density (O.D.) per week per 200 mg/mL of metoclopramide when stored at 40°C and 75% relative humidity.
The pharmaceutical composition does not discolor when stored at 40°C for at least about 4 weeks.
Provides stability characterized by being substantially free of color/clear and stable according to O.D.-based criteria using USP color standards and USP iodine standards.
Documented Applications
Treatment of disorders treatable with metoclopramide, including gastroparesis, emesis, delayed emesis, and nausea, using intranasal spray dosing regimens.
A clinical study design for diabetic gastroparesis comparing intranasal metoclopramide versus oral tablets.
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