Cochleates and methods of using the same to enhance tissue penetration of pharmacologically active agent
A cochleate composition is disclosed. Following oral administration of the cochleate composition, the pharmacologically active agent is found at higher concentrations in the tissue relative to plasma. Oral administration of these cochleate compositions also preferentially targets infected or inflamed tissue as compared to tissue in a healthy subject. The cochleate composition contains a size-regulating agent that reduces cochleate particle size, such as a lipid-anchored polynucleotide, a lipid-anchored sugar, a lipid-anchored polypeptide, or a bile salt (such as oxycholate or deoxycholate). Also disclosed are methods of treatment using the cochleate composition and methods of increasing the concentration of a pharmacologically active agent in an infected tissue relative to the concentration of the pharmacologically active agent in the plasma or the tissue of a healthy subject.
1. A cochleate composition, the composition comprising a plurality of cochleates comprising at least one negatively charged phospholipid, a multivalent cation, a pharmacologically active agent, and a size-regulating agent selected from the group consisting of a lipid-anchored polynucleotide, a lipid-anchored sugar, and a lipid-anchored polypeptide,
wherein the lipid-anchored polynucleotide is a polynucleotide covalently bound to a lipid anchor selected from saturated or unsaturated fatty acids having 12 to 38 carbon atoms, sterols, and vitamins,
wherein the lipid anchor is indirectly linked to the polynucleotide, the sugar, or the polypeptide by a covalently bound spacer consisting of polyethylene glycol.
2. The cochleate composition of claim 1 , wherein the mean particle size of the plurality of cochleates is less than 10 microns.
3. The cochleate composition of claim 2 , wherein the mean particle size of the plurality of cochleates is less than 1 micron.
4. The cochleate composition of claim 3 , wherein the mean particle size of the plurality of cochleates is between 400-800 nm.
5. The cochleate of claim 1 , wherein the mean particle size of the plurality of cochleates is 2-3 times smaller than the mean particle size of cochleates made without the size-regulating agent.
6. The cochleate composition of claim 1 , wherein the tissue level of the pharmacologically active agent in an infected or an inflamed tissue at 24 hours following oral administration of the cochleate composition to the subject is at least 1.5 times higher than the tissue level of the pharmacologically active agent at 24 hours following oral administration to a healthy subject.
7. The cochleate composition of claim 1 , wherein the pharmacologically active agent is selected from the group consisting of an anti-fungal, an anti-bacterial, an anti-viral, an anti-parasitic, anti-protozoal or antihelminthic, a vaccine, an anti-inflammatory agent, a polynucleotide, an immunotherapy, an anti-cancer agent, an anti-dyslipidemia agent, an anti-dementia agent, a nutritional supplement, an herbal product, and a vitamin.
8. The cochleate composition of claim 1 , wherein the multivalent cation is a divalent metal cation.
9. The cochleate composition of claim 8 , wherein the divalent metal cation is calcium.
10. The cochleate composition of claim 1 , wherein the at least one negatively charged phospholipid is present in an amount of about 20%-80% of the total phospholipid content of the cochleate composition.
11. A method of treating a subject in need thereof, the method comprising administering the cochleate composition of claim 1 to the subject.
12. The cochleate composition of claim 7 , wherein the anti-bacterial is a beta-lactamase inhibitor.
13. The cochleate composition of claim 8 , wherein the divalent metal cation is calcium, zinc, magnesium, or barium.
14. The cochleate composition of claim 7 , wherein the polynucleotide is selected from the group consisting of siRNA, iRNA, anti-sense therapy, and gene therapy polynucleotides.
15. The cochleate composition of claim 1 , wherein the size-regulating agent is the lipid-anchored polynucleotide.
16. The cochleate composition of claim 1 , wherein the size-regulating agent comprises a lipid-anchored sugar or a lipid-anchored polypeptide.
17. The cochleate composition of claim 1 , wherein the saturated or unsaturated fatty acid having 12 to 38 carbon atoms is palmitate.