Methods for co-encapsulation of combination drugs and co-encapsulated combination drug product
Inventors
Assignees
Publication Number
US-8637074-B2
Publication Date
2014-01-28
Expiration Date
2029-03-31
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Abstract
This invention is for an improved process to co-encapsulate hydrophobic drugs and hydrophilic drugs in phospholipid liposomes. Non-toxic supercritical or near-critical fluids with/without polar cosolvents are utilized to solubilize phospholipid materials and hydrophobic drugs, and form uniform liposomes to encapsulate hydrophobic drugs and hydrophilic drugs.
Core Innovation
The invention is a method for co-encapsulating hydrophobic and hydrophilic drugs in phospholipid liposomes using supercritical, critical, or near-critical fluids (SCCNC fluids) with or without polar cosolvents. These fluids enable the solubilization of phospholipid materials and hydrophobic drugs and the formation of uniform liposomes that encapsulate both types of drugs. The process specifically allows hydrophobic drugs, such as camptothecins, to be packaged in the lipid bilayer and hydrophilic drugs, such as tetracycline and neomycin, to be packaged in the aqueous core of nanosomes.
The problem addressed by the invention is the lack of available technologies for the scalable, single-step co-encapsulation of hydrophobic and hydrophilic drugs in phospholipid nanosomes. Conventional processes require multiple steps, substantial amounts of organic solvents, are time-consuming and costly, and result in liposomes with a wide dispersion of particle sizes. Additionally, such processes may expose therapeutic agents to conditions that affect product integrity and compromise sterility.
The disclosed methods lead to the creation of liposomes with a narrow and controlled size range, especially in the submicron domain (e.g., 0.1 to 1.0 microns). The approach also allows incorporation of targeting antibodies or ligands for specific cancers, use of pegylated phospholipids for increased residence time, and the formulation of smart drug delivery systems aimed at enhancing efficacy and reducing toxicities of combination therapies.
Claims Coverage
There are two independent claims in this patent: one for a method of making phospholipid liposomes co-encapsulating hydrophilic and hydrophobic drugs, and one for a therapeutic drug product comprising such liposomes.
Method of making phospholipid liposomes co-encapsulating hydrophobic and hydrophilic drugs
This inventive feature describes a method consisting of: 1. Providing a phospholipid material, a hydrophobic drug, and a first fluid that is a supercritical, critical, or near-critical fluid, and forming a hydrophobic drug solution of these components. 2. Providing an aqueous solution containing a hydrophilic drug, forming a hydrophilic drug solution. 3. Depressurizing the hydrophobic drug solution in the presence of the hydrophilic drug solution as it exits one or more orifices, leading to the formation of phospholipid liposomes having an average diameter between 0.01 and 10.0 microns, with removal of the first fluid during depressurization.
Therapeutic drug product comprising co-encapsulated hydrophobic and hydrophilic drugs in phospholipid spheres
This inventive feature covers a therapeutic drug product comprising: - A plurality of spheres with an average diameter of 0.1 to 1.0 microns. - Spheres have a phospholipid surface. - Spheres contain a hydrophobic drug selected from the group consisting of topoisomerase 1 inhibitors. - Spheres also contain a hydrophilic drug selected from the group consisting of tyrosyl-DNA phosphodiesterase (Tdp 1) inhibitors.
The inventive features focus on a unique method for producing uniform, size-controlled phospholipid liposomes encapsulating both hydrophobic and hydrophilic drugs using supercritical fluid technology, and on the resulting therapeutic drug product comprising such co-encapsulated drug-loaded liposomes.
Stated Advantages
The methods require reduced processing steps, time, and preparation costs.
The process allows formation of liposomes with a narrow range of diameters, particularly between 0.1 and 1.0 microns.
Reduced systemic toxicity of the co-encapsulated drugs due to masking of cytotoxic effects.
Improved stability of labile drug structures, such as lactone rings, by protection within the liposomes.
Increased residence time of drugs in the circulatory system, thus enhancing therapeutic efficacy.
Ability to use pegylated phospholipids and targeting ligands or antibodies to increase specificity and residence time, further improving efficacy and reducing toxicities.
Documented Applications
Use in combination therapy for cancers and other medical diseases requiring delivery of both hydrophilic and hydrophobic therapeutic drugs.
Providing more effective and less toxic combination drugs for cancers, such as colon, lung, brain, or ovary, by targeting using specific antibodies or ligands.
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