Pentaaza macrocyclic ring complexes possessing oral bioavailability
Aspects of the present disclosure relate to compounds which have enhanced oral bioavailability. A transition metal complex includes a transition metal coordinated by a macrocycle comprising the pentaaza 15-membered macrocyclic ring corresponding to Formula A and two axial ligands having the formula —OC(O)X 1 . each of the two axial ligands has the formula —OC(═O)X 1 wherein each X 1 is independently substituted or unsubstituted phenyl or —C(—X 2 )(—X 3 )(—X 4 ); each X 2 is independently substituted or unsubstituted phenyl, or substituted or unsubstituted alkyl; each X 3 is independently hydrogen, hydroxyl, alkyl, amino, —X 5 C(═O)R 13 where X 5 is NH or O, and R 13 is C 1 -C 18 alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl, or —OR 14 , where R 14 is C 1 -C 18 alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl, or together with X 4 is (═O); and each X 4 is independently hydrogen or together with X 3 is (═O).
1. A method of lessening the severity of tissue damage resulting from a cancer treatment in a mammal afflicted with cancer, comprising orally administering a therapeutically effective dose of a pentaaza macrocyclic ring complex to the mammal,
wherein the pentaaza macrocyclic ring complex comprises the following formula:
2. The method according to claim 1 , comprising lessening the severity of oral mucositis resulting from the cancer treatment.
3. The method according to claim 1 , wherein the cancer treatment comprises at least one of radiation therapy and chemotherapy.
4. The method according to claim 3 , comprising administering the pentaaza macrocyclic ring complex prior to or simultaneous with administration of a dose of the cancer treatment.
5. The method according to claim 4 , comprising administering the pentaaza macrocyclic ring complex prior to or simultaneous with a dose of radiation.
6. The method according to claim 5 , comprising administering the pentaaza macrocyclic ring complex on the day before or the day of, but prior to the dose of radiation.
7. The method according to claim 4 , comprising administering the pentaaza macrocyclic ring complex prior to or simultaneous with a dose of chemotherapy.
8. The method according to claim 7 , comprising administering the pentaaza macrocyclic ring complex on the day before or the day of, but prior to the dose of chemotherapy.
9. The method according to claim 1 , wherein the mammal is a human patient.
10. The method according to claim 1 , comprising administering the pentaaza macrocyclic ring complex in a pharmaceutical composition for oral administration having a pharmaceutically acceptable excipient.
11. The method according to claim 10 , wherein the pharmaceutical composition comprises at least one of mono/diglyceride and triglycerides of caprylic/capric acids.
12. The method according to claim 11 , wherein the pharmaceutical composition comprises a mixture of caprylic/capric acid triglycerides.
13. The method according to claim 10 , wherein the pharmaceutical composition is in a solid or semi-solid dosage form.
14. The method according to claim 13 , wherein the pharmaceutical composition comprises an enteric coating layer.
15. The method according to claim 10 , wherein the pharmaceutical composition is in the form of a tablets, gelatin capsules, HPMC capsules, gel or suspension suitable for oral administration.