Liposomes for pulmonary administration
Inventors
Gessler, Tobias • Schmehl, Thomas • Rieger, Monika
Assignees
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Publication Number
US-10258570-B2
Publication Date
2019-04-16
Expiration Date
Abstract
The invention relates to liposomes for pulmonary application, advantageously comprising at least one first and at least one second phospholipid, cholesterol, and at least one active substance and/or colorant, wherein the first phospholipid is a phosphatidylcholine, preferably DSPC, and the second phospholipid is a phosphatidylcholine or an ethanolamine, preferably selected from the group DMPC, DPPC, DPPE. It is thereby advantageous if the first and the second phospholipid are present at a molar ratio of 0.5:1 to 10:1, preferably at a ratio of 6:1 to 2:1, in particular preferably at a ratio of 3:1. It is further advantageous if the molar ratio between phospholipids and cholesterol is between 10:1 and 1:1, preferably between 6:1 and 3:1, in particular preferably 4:1. The second phospholipid is further preferably DMPC or DPPE, in particular preferably DPPE. The size of the liposomes is advantageously between 0.05 μm and 5 μm, preferably between 0.2 μm and 2.0 μm, and the median aerodynamic mass diameter of aerosol particles comprising the liposomes is between 1 μm and 6 μm, preferably between 1.5 μm and 5 μm, in particular preferably between 2 μm and 4.5 μm. It is further in particular advantageous if the liposomes comprise an atomization stability of greater than 50%, preferably greater than 75%, in particular preferably greater than 80%, and if the transition temperature is greater than 37° C., preferably greater than 45° C., in particular preferably greater than 50° C.
Core Innovation
The invention relates to a method of pulmonary administration in which liposomes are administered to a subject by inhalation after nebulization. The liposomes comprise disteaorylphosphatidylcholine as a first phospholipid, a second phospholipid selected from dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and dipalmitoylphosphatidylethanolamine, and cholesterol. The liposomes further encapsulate an aqueous solution comprising at least one of an active agent and a dye.
A defining feature is that the molar ratio between the first phospholipid and the second phospholipid in the liposomes is from 2:1 to 6:1, and the molar ratio between the first and the second phospholipids and cholesterol is from 3:1 to 6:1. The administering comprises inhalation of the liposomal formulation after nebulization, and the stability of the liposomes upon nebulization is at least 80%.
The disclosed approach addresses delivering an inhalable liposomal formulation with maintained nebulization robustness and the ability to encapsulate an aqueous active agent and/or dye within the liposomes for pulmonary delivery.
Claims Coverage
The independent claim covers a pulmonary administration method delivering by inhalation after nebulization a liposomal formulation with a defined phospholipid/cholesterol composition, encapsulated aqueous active agent and/or dye, constrained molar ratios, and a minimum nebulization stability of at least 80%. Only one independent claim is explicitly provided in the partial content, so the claim coverage focuses on the single core method and its stated formulation and stability features.
Nebulization followed inhalation of robust phospholipid/cholesterol liposomes
Administering to a subject via inhalation a liposomal formulation after nebulization, where the liposomes comprise disteaorylphosphatidylcholine as a first phospholipid, a second phospholipid selected from dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and dipalmitoylphosphatidylethanolamine, and cholesterol; the aqueous solution comprising at least one active agent and/or a dye is encapsulated inside the liposomes; and the administering comprises inhalation after nebulization with liposome stability upon nebulization of at least 80%.
Defined molar ratios of first phospholipid, second phospholipid, and cholesterol
Setting the molar ratio between the first phospholipid and the second phospholipid to be from 2:1 to 6:1 and setting the molar ratio between the first and the second phospholipids and cholesterol to be from 3:1 to 6:1 in the liposomes that are administered by inhalation after nebulization.
Overall, the provided independent claim ties pulmonary inhalation delivery to a specifically defined liposomal composition (disteaorylphosphatidylcholine, a selected second phospholipid, and cholesterol), encapsulation of an aqueous active agent and/or dye, constrained molar ratios between components, and a minimum liposome stability upon nebulization of at least 80%.
Stated Advantages
At least 80% stability of the liposomes upon nebulization.
Documented Applications
Pulmonary administration to a subject via inhalation after nebulization for lung disease indications explicitly listed in the partial content, including pulmonary hypertension, COPD, asthma, and pneumonia.
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