Nanosome formulations of aprepitant and methods and applications thereof
Inventors
Ugwu, Sydney • He, Xin • Fu, Zengli • Teng, Xin • Ji, Ming
Assignees
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Publication Number
US-11260028-B2
Publication Date
2022-03-01
Expiration Date
Abstract
Disclosed herein are pharmaceutical formulations of aprepitant suitable for parenteral administration including intravenous administration. The pharmaceutical formulations are stable and ready-to-use liposomes for the treatment of emesis and are particularly useful for treatment of chemotherapy or surgery-induced nausea and vomiting. Methods of preparation of the aprepitant formulations are also provided.
Core Innovation
The invention is directed to an injectable aprepitant pharmaceutical composition in which aprepitant liposomes are provided as a stable, ready-to-use formulation in water. The aprepitant liposomes comprise aprepitant, a phospholipid selected from DOPC, DMPC, DLPC, soy phosphatidylcholine (SPC), or mixtures of two or more thereof, and tocopherol, with defined wt %:wt % ratios for phospholipid to aprepitant and for tocopherol to phospholipid. The liposomes have an intensity weighted mean particle size of about 50 nm to about 300 nm as determined by dynamic light scattering, and the composition is polysorbate free, oil free, and solvent free.
The formulation is characterized by stability in a glass vial with a stopper when stored at 25 °C or 2–8 °C for four weeks, where the composition shows no visible signs of aprepitant crystals when inspected by microscopy. The aprepitant liposomes can optionally further include cholesterol or cholesteryl sulfate as a bilayer stabilizer, while maintaining the specified liposome size range and the defined composition parameters.
In another aspect, an injectable aprepitant pharmaceutical composition is provided consisting of water, an osmotic agent and/or a lyoprotectant, a pH buffering agent, and aprepitant liposomes. The aprepitant liposomes consist of aprepitant, the specified phospholipid selection, tocopherol, and optionally a bilayer stabilizer selected from cholesterol and cholesteryl sulfate. The pharmaceutical composition has a pH of about 6 to about 8 and shows no visible signs of aprepitant crystals after storage for four weeks at 25 °C or 2–8 °C.
Claims Coverage
The independent claims are clm-00001 and clm-00009. They define two main inventive features: aprepitant liposomes with specified phospholipid and tocopherol composition, defined wt %:wt % ratios, and a liposome particle size range; and an injectable composition with water, an osmotic agent and/or lyoprotectant, a pH buffering agent, and aprepitant liposomes, with pH about 6 to about 8 and crystal-free storage stability.
Injectable aprepitant liposomes with tocopherol-stabilized composition and defined ratios
An injectable aprepitant pharmaceutical composition comprising water and aprepitant liposomes wherein the aprepitant liposomes comprise aprepitant, a phospholipid selected from DOPC, DMPC, DLPC, SPC, and mixtures of two or more thereof, and tocopherol; wherein the wt %:wt % ratio of phospholipid to aprepitant is about 4:1 to about 12:1; the wt:wt ratio of tocopherol to phospholipid is about 1:343.75 to about 1:562.5; and the liposomes have an intensity weighted mean particle size of about 50 nm to about 300 nm as determined by dynamic light scattering.
Polysorbate free, oil free, solvent free injectable aprepitant liposomes with crystal-free storage at 25 °C or 2–8 °C
The composition is polysorbate free, oil free and solvent free and after storage of the composition in a glass vial with a stopper at 25 °C or 2–8 °C for four weeks the composition shows no visible signs of aprepitant crystals when inspected by microscopy.
Optional bilayer stabilizer in injectable aprepitant liposomes
The aprepitant liposomes further include cholesterol or cholesteryl sulfate.
Water plus osmotic/lyoprotectant and pH buffering agent with aprepitant liposomes
An injectable aprepitant pharmaceutical composition consisting of water, an osmotic agent and/or a lyoprotectant, a pH buffering agent, and aprepitant liposomes wherein the aprepitant liposomes consist of aprepitant, a phospholipid selected from DOPC, DMPC, DLPC, SPC, and mixtures of two or more thereof, tocopherol, and optionally a bilayer stabilizer selected from cholesterol and cholesteryl sulfate.
Defined liposome particle size, composition pH, and crystal-free storage
The wt %:wt % ratio of phospholipid to aprepitant is about 4:1 to about 12:1; the wt:wt ratio of tocopherol to phospholipid is about 1:343.75 to about 1:562.5; the liposomes have an intensity weighted mean particle size of about 50 nm to about 300 nm as determined by dynamic light scattering; the pharmaceutical composition has a pH of about 6 to about 8 and after storage of the composition in a glass vial with a stopper at 25 °C or 2–8 °C for four weeks the composition shows no visible signs of aprepitant crystals when inspected by microscopy.
Across the independent claims, the main inventive elements are aprepitant liposomes containing aprepitant, a selected phospholipid, and tocopherol with defined wt %:wt % ratios, a specified DLS intensity weighted mean particle size range, and demonstrated absence of visible aprepitant crystals after storage in a glass vial for four weeks at 25 °C or 2–8 °C; clm-00001 additionally requires polysorbate-free, oil-free, solvent-free composition, while clm-00009 requires water plus osmotic/lyoprotectant and a pH buffering agent and specifies a composition pH of about 6 to about 8.
Stated Advantages
After storage in a glass vial with a stopper at 25 °C or 2–8 °C for four weeks, the composition shows no visible signs of aprepitant crystals when inspected by microscopy.
The composition is polysorbate free, oil free and solvent free.
Documented Applications
Injectable/parenteral antiemetic use described for chemotherapy-induced nausea/vomiting and surgery-induced nausea/vomiting.
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