Compositions capable of facilitating penetration across a biological barrier

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Compositions capable of facilitating penetration across a biological barrier
Agent: Mintz, Levin, Cohn, Ferris, Glovsky And Popeo, P.C. - Boston, MA, US
Class: 424449000 (USPTO), A61K038/18 (Intl Class)
#20050136103
06/23/05
This invention relates to novel pharmaceutical compositions capable of facilitating penetration of at least one effector across biological barriers. The invention also relates to methods of treating or preventing diseases by administering these compositions to affected subjects.
SUMMARY OF THE INVENTION
[0015] The present invention provides compositions for effectively translocating therapeutically active molecules, i.e., effectors, which are otherwise impermeable to biological barriers, by selectively encapsulating such molecules into a hydrophobic complex. The invention also relates to methods of using a counter ion to the effector to selectively encapsulate and translocate at least one effector across a biological barrier. The counter ion can include a hydrophobic moiety. Specifically, the invention involves a hydrophobic composition sequentially coupled to a therapeutically effective amount of at least one effector, and a counter ion to the at least one effector thereby selectively encapsulating the effector and effectively translocating the effector across a biological barrier. For example, such a compound may be used for transepithelial delivery of at least one effector across a biological barrier.
[0016] "Effective translocation" as used herein means that introduction of the composition to a biological barrier results in at least 5%, but preferably at least 10%, and even more preferably, at least 20% or more, translocation of the effector across the biological barrier. The at least one effector of the composition is selectively encapsulated in such a way that introduction of the composition to a biological barrier results in translocation of the encapsulated effector only, i.e., no other molecules concomitantly administered in a non-encapsulated or free form are translocated across the biological barrier.
[0017] As used herein a "hydrophobic composition" includes any composition that is water insoluble and facilitates the selective encapsulation, or the effective translocation, of a substance, e.g., at least one effector, across a biological barrier utilizing at least one counter ion and at least one pharmaceutically acceptable hydrophobic agent. As used herein, the term "biological barrier" is meant to include biological membranes such as the plasma membrane as well as any biological structures sealed by tight junctions (or occluding junctions) such as the mucosal or vascular epithelia, including, but not limited to, the intestinal or respiratory epithelia, and the blood brain barrier. Moreover, those skilled in the art will recognize that translocation may occur across a biological barrier in a tissue such as epithelial cells or endothelial cells.
[0018] As used herein, the term "encapsulation" refers to the introduction of the at least one effector to the hydrophobic composition. The method of encapsulation can involve complex formation of at least one effector with at least one amphipathic counter ion, and dissolution in water or in an at least partially water soluble solvent. The composition can be further supplemented by a protein stabilizer, a penetrating peptide, and/or one or more pharmaceutically acceptable hydrophobic agents. Any one or more of the components of the composition may be lyophilized at various stages of the encapsulation process.
[0019] A hydrophobic agent can be a single molecule or a combination of hydrophobic molecules, like aliphatic, cyclic, or aromatic molecules. Examples of aliphatic hydrophobic agents include mineral oil, paraffin, fatty acids, mono-, di-, or tri-glycerides, ethers, or esters. Examples of tri-glycerides include long chain triglycerides, medium chain triglycerides, and short chain triglycerides. Specific examples of suitable triglycerides include tributyrin, trihexanoin, trioctanoin, and tricaprin (1,2,3-tridecanoyl glycerol). Examples of cyclic hydrophobic agents include terpenoids, cholesterol, cholesterol derivatives and cholesterol esters of fatty acids. An example of an aromatic hydrophobic agent includes benzyl benzoate.
[0020] At least partially water soluble solvents include, for example, n-butanol, isoamyl(=isopentyl) alcohol, DMF, DMSO, iso-butanol, iso-propanol, propanol, ethanol, ter-butanol, polyols, ethers, amides, esters, or various mixtures thereof.
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