METHODS AND COMPOSITIONS FOR TREATING CANCER
20230226105 · 2023-07-20
Assignee
Inventors
- Norbert F. VOELKEL (Denver, CO, US)
- Charles MAGOLSKE (Denver, CO, US)
- Stephen DORDUNOO (Halethorpe, MD, US)
- Johannes KHINAST (Graz, AT)
- Erik EGLITE (Lake Forest, IL, US)
Cpc classification
A61B5/4848
HUMAN NECESSITIES
A61K31/205
HUMAN NECESSITIES
International classification
A61B5/00
HUMAN NECESSITIES
A61K31/495
HUMAN NECESSITIES
Abstract
Pharmaceutical compositions containing tetrathiomolybdate (TTM) are disclosed. Pharmaceutical compositions and formulations that contain TTM along with other co-drugs, such as diethylcarbamazine (DEC) and astaxanthin (ATX), are also disclosed. Formulations include a delayed release oral form that releases the TTM in the gastrointestinal tract after the oral form passes the stomach, and an enteric oral form that is not a delayed release form are disclosed. Methods of treating cancer, treating cancer patients as an adjuvant therapy, and treating pulmonary arterial hypertension by administering the pharmaceutical compositions are further disclosed.
Claims
1. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a copper chelator comprising a tetrathiomolybdate (TTM) salt of formula X(MoS.sub.4), and optionally one or more of diethylcarbamazine (DEC) and astaxanthin (ATX), wherein: X is (2Li).sup.+2, (2K).sup.+2, (2Na).sup.+2, Mg.sup.+2, Ca.sup.+2, or {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5), (R.sup.6)(R.sup.7)(R.sup.8)]}; R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroaralkyl, cycloalkyl alkyl, and heterocycloalkyl alkyl; and R.sup.4 and R.sup.8 are absent or independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroaralkyl, cycloalkyl alkyl, and heterocycloalkyl alkyl; wherein when R.sup.4 is absent, R.sup.1 and R.sup.2 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, N, and S; wherein when R.sup.8 is absent, R.sup.5 and R.sup.6 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, NH, and S; wherein R.sup.1 and R.sup.2, R.sup.2 and R.sup.3, or R.sup.2 and R.sup.4, together with N optionally forms an optionally substituted cyclic structure; wherein R.sup.5 and R.sup.6, R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8, together with N optionally forms an optionally substituted cyclic structure; wherein R.sup.4 and R.sup.8 may be joined by a covalent bond; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are each independently optionally substituted with One or more of OH, oxo, alkyl, alkenyl, alkenyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, C═N(OH) or OPO.sub.3H.sub.2, wherein R.sup.9 is each independently alkyl or —C(═O)(O)-alkyl; wherein R.sup.4 and R.sup.8 are each independently optionally substituted with one or more of OH, oxo, alkyl, alkenyl, alkynyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, —C═N(OH), or —.sup.+(R.sup.10).sub.3 wherein is each independently optionally substituted alkyl; and wherein one or more —CH.sub.2— groups in R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 may be replaced with a moiety selected from the group consisting of O, NH, S, S(O), and S(O).sub.2.
2. The method of claim 1, wherein the copper chelator comprises at least one of ammonium tetrathiomolybdate ((NH.sub.4).sub.2MoS.sub.4), Bis-choline tetrathiomolybdate (C.sub.10H.sub.28MoN.sub.2O.sub.2S.sub.4), ammonium trithiomolybdate ((NH.sub.4).sub.2MoOS.sub.3), or a combination thereof.
3. The method of claim 1, wherein the copper chelator is administered orally.
4. The method of claim 1, wherein the copper chelator is administered orally in a delayed release oral preparation that releases the copper chelator in the gastrointestinal tract after the preparation passes the stomach.
5. The method of claim 1, wherein the copper chelator is administered in combination with a therapeutically effective amount of ATX.
6. The method of claim 1, wherein the copper chelator is administered in combination with a therapeutically effective amount of DEC.
7. The method of claim 1, wherein the copper chelator is administered in combination with a therapeutically effective amount of DEC and ATX.
8. The method of claim 1, wherein the copper chelator is administered in combination with a therapeutically effective amount of one or more selected from the group consisting of: LEAPS peptide heteroconjugate, inhibitors of 5-lipoxygenase enzyme, diethylcarbamazine, Zileuton, inhibitors of LTA4 hydrolase, inhibitors of LT receptors, Sulforaphane, Multikine, Bestatin, tert-Butylhydroquinone, Montelukast, inhibitors of leukotriene B4 receptors BLT1 and/or BLT2, LY293111, BAY-u9773, and combinations thereof.
9. The method of claim 1, wherein the patient is administered TTM in a total dosage in a range of 120 mg-300 mg per day.
10. The method of claim 1, further comprising measuring plasma ceruloplasmin level in the patient, and maintaining or adjusting dosage of the TTM in response thereto.
11. The method of claim 10, wherein when the measured ceruloplasmin level is between 15 mg/dL and 18 mg/dL the TTM dosage is administered to the patient at about 180 mg/day.
12. The method of claim 10, wherein when the measured ceruloplasmin level is below 15 mg/dL the TTM dosage is administered to the patient at about 120 mg/day.
13. The method of claim 10, wherein when the measured ceruloplasmin level is above 20 mg/dL the TTM dosage is administered to the patient at about 240 mg/day-300 mg/day.
14. The method of claim 1, wherein the copper chelator comprising TTM is administered to the patient in a first dosage form, and the one or more of DEC and AXT is administered separately in a second dosage form.
15. A pharmaceutical composition comprising a copper chelator comprising: a tetrathiomolybdate (TTM) salt of formula X(MoS.sub.4); and a pharmaceutically acceptable carrier, wherein: X is (2Li).sup.+2, (2K).sup.+2, (2Na).sup.+2, Mg.sup.+2, Ca.sup.+2, or {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5), (R.sup.6)(R.sup.7)(R.sup.8)]}; R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroaralkyl, cycloalkyl alkyl, and heterocycloalkyl alkyl; and R.sup.4 and R.sup.8 are absent or independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroaralkyl, cycloalkyl alkyl, and heterocycloalkyl alkyl; wherein when R.sup.4 is absent, R.sup.1 and R.sup.2 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, N, and S; wherein when R.sup.8 is absent, R.sup.5 and R.sup.6 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, NH, and S; wherein R.sup.1 and R.sup.2, R.sup.2 and R.sup.3, or R.sup.2 and R.sup.4, together with N optionally forms an optionally substituted cyclic structure; wherein R.sup.5 and R.sup.6, R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8, together with N optionally forms an optionally substituted cyclic structure; wherein R.sup.4 and R.sup.8 may be joined by a covalent bond; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are each independently optionally substituted with one or more of OH, oxo, alkyl, alkenyl, alkynyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, —C═N(OH), or OPO.sub.3H.sub.2, wherein R.sup.9 is each independently alkyl or —C(═O)(O)-alkyl; wherein R.sup.4 and R.sup.8 are each independently optionally substituted with one or more of OH, oxo, alkyl, alkenyl, alkynyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, —C═N(OH), or .sup.+(R.sup.10).sub.3, wherein R.sup.10 is each independently optionally substituted alkyl; and wherein one or more —CH.sub.2— groups in R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 may be replaced with a moiety selected from the group consisting of O, NH, S, S(O), and S(O).sub.2, and wherein the composition is in a delayed release oral form that releases the copper chelator in the gastrointestinal tract after the oral form passes the stomach.
16. The pharmaceutical composition of claim 15, wherein the copper chelator comprises at least one of ammonium tetrathiomolybdate ((NH.sub.4).sub.2MoS.sub.4), Bis-choline tetrathiomolybdate (C.sub.10H.sub.28MoN.sub.2O.sub.2S.sub.4), ammonium trithiomolybdate ((NH.sub.4).sub.2MoOS.sub.3), or a combination thereof.
17. The pharmaceutical composition of claim 15, wherein the composition is a long-acting extended-release oral form.
18. The pharmaceutical composition of claim 15, further comprising one or more of diethylcarbamazine (DEC), astaxanthin (ATX), or a combination thereof.
19. The pharmaceutical composition of claim 15, further comprising DEC.
20. The pharmaceutical composition of claim 15, further comprising ATX.
21. The pharmaceutical composition of claim 15, further comprising DEC and ATX.
22. The pharmaceutical composition of claim 18, wherein the copper chelator comprising TTM is in a first dosage form, and the one or more of DEC, ATX, or a combination thereof is in a separate second dosage form.
23. The pharmaceutical composition of claim 15, further comprising at least one other active agent selected from the group consisting of LEAPS peptide heteroconjugate, inhibitors of 5-lipoxygenase enzyme, diethylcarbamazine, Zileuton, inhibitors of LTA4 hydrolase, inhibitors of LT receptors, Sulforaphane, Multikine, Bestatin, tert-Butylhydroquinone, Montelukast, inhibitors of leukotriene B4 receptors BLT1 and/or BLT2, LY293111, BAY-u9773, and combinations thereof.
24. The pharmaceutical composition of claim 15, wherein the copper chelator is encapsulated inside a first capsule and the first capsule is encapsulated inside a larger second capsule.
25. The pharmaceutical composition of claim 24, wherein the larger second capsule contains a filler, and the first capsule inside the second capsule is isolated from the larger second capsule by the filler such that the first capsule is not in contact with the second capsule.
26. The pharmaceutical composition of claim 25, wherein the filler comprises mesoporous dicalcium phosphate, colloidal silicon dioxide, or a combination thereof.
27. The pharmaceutical composition of claim 24, wherein one or more of the first capsule and the second capsule comprises an enteric coating on an outer surface.
28. The pharmaceutical composition of claim 24, wherein the second capsule contains one or more of DEC and ATX.
29. The pharmaceutical composition of claim 15, wherein the copper chelator is encapsulated by a protective coating comprising an antacid.
30. The pharmaceutical composition of claim 29, wherein the antacid comprises one or more of aluminum hydroxide, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium trisilicate, sodium bicarbonate, alginate, or a combination thereof.
31. The pharmaceutical composition of claim 29, further comprising an enteric coating encapsulating the copper chelator and the protective coating.
32. The pharmaceutical composition of claim 18, in a form having a core comprising TTM encapsulated by ATX.
33. The pharmaceutical composition of claim 18, in a form having a core comprising TTM encapsulated by DEC.
34. The pharmaceutical composition of claim 18, in a form having a first core comprising TTM, a second core comprising DEC, the first core and the second core encapsulated by ATX.
35. The pharmaceutical composition of claim 34, wherein the TTM, DEC and ATX are encapsulated by a protective coating comprising an antacid, and further comprising an enteric coating.
36. The pharmaceutical composition of claim 15, further comprising at least one other active agent, a protective coating comprising an antacid encapsulating the copper chelator and the at least one other active agent, and an enteric coating encapsulating the protective coating.
37. The pharmaceutical composition of claim 36, wherein the at least one other active agent is one or more of DEC, ATX, or a combination thereof.
38. The pharmaceutical composition of claim 15, further comprising at least one other active agent, a protective coating comprising an antacid encapsulating the copper chelator, and an enteric coating encapsulating the copper chelator, protective coating, and the at least one other active agent.
39. The pharmaceutical composition of claim 38, wherein the at least one other active agent is one or more of DEC, ATX, or a combination thereof.
40. The pharmaceutical composition of claim 15, wherein the TTM has a dosage in a range of 20-300 mg.
41. The pharmaceutical composition of claim 19, wherein the DEC has a dosage in a range of 100-250 mg.
42. The pharmaceutical composition of claim 20, wherein the ATX has a dosage in a range of 5-30 mg.
43. The pharmaceutical composition of claim 15, wherein at least 50% of the TTM salt has a particle size smaller 44 μm.
44. The pharmaceutical composition of claim 15, wherein at least 90% of the TTM salt has a particle size smaller than 122 μm.
45. The pharmaceutical composition of claim 15, wherein no less than 50% of the TTM salt has a particle size smaller than 122 μm.
46. The pharmaceutical composition of claim 15, wherein the composition is in an extended-release form.
47. The pharmaceutical composition of claim 32, further comprising an enteric coating encapsulating the composition.
48. The pharmaceutical composition of claim 33, further comprising an enteric coating encapsulating the composition.
49. The pharmaceutical composition of claim 34, further comprising an enteric coating encapsulating the composition.
50. A method of treating a cancer patient, as adjuvant therapy in patients undergoing or have undergone radiation therapy, chemotherapy, and/or immunotherapy, or otherwise in need thereof, comprising administering to the patient a therapeutically amount of a copper chelator comprising a tetrathiomolybdate (TTM) salt of formula X(MoS.sub.4), and optionally one or more of diethylcarbamazine (DEC) and astaxanthin (ATX), wherein: X is (2Li).sup.+2, (2K).sup.+2, (2Na).sup.+2, Mg.sup.+2, Ca.sup.+2, or {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5), (R.sup.6)(R.sup.7)(R.sup.8)]}; R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroaralkyl, cycloalkyl alkyl, and heterocycloalkyl alkyl; and R.sup.4 and R.sup.8 are absent or independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroalkyl, heteroaralkyl, cycloalkyl alkyl, d heterocycloalkyl alkyl; wherein when R.sup.4 is absent, R.sup.1 and R.sup.2 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, N, and S; wherein when R.sup.8 is absent, R.sup.5 and R.sup.6 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, NH, and S; wherein R.sup.1 and R.sup.2, R.sup.2 and R.sup.3, or R.sup.2 and R.sup.4, together with N optionally forms an optionally substituted cyclic structure; wherein R.sup.5 and R.sup.6, R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8, together with N optionally forms an optionally substituted cyclic structure; wherein R.sup.4 and R.sup.8 may be joined by a covalent bond; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are each independently optionally substituted with one or more of OH, oxo, alkyl, alkenyl, alkynyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, —C≡N(OH), or OPO.sub.3H.sub.2, wherein R.sup.9 is each independently alkyl or —C(═O)(O)-alkyl; wherein R.sup.4 and R.sup.8 are each independently optionally substituted with one or more of OH, oxo, alkyl, alkenyl, alkynyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, —C═N(OH), or .sup.+(R.sup.10).sub.3, wherein R.sup.10 is each independently optionally substituted alkyl; and wherein one or more —CH.sub.2— groups in R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 may be replaced a moiety selected from the group consisting of O, NH, S, S(O), and S(O).sub.2.
51. A method of manufacturing the pharmaceutical composition of claim 15, wherein the TTM is protected from oxidation during manufacture by an inert gas.
52. A method of manufacturing the pharmaceutical composition of claim 25, wherein the second capsule containing filler and the first capsule inside the second capsule are vibrated so that the inner capsule is positioned so that the outer surface of the inner capsule contacts the filler and does not contact the inner surface of the second capsule.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
[0063] Aspects of the present disclosure are provided in the following detailed description directed to specific embodiments. Those skilled in the art will recognize that alternate embodiments may be devised without departing from the spirit or the scope of the disclosure. Additionally, well-known elements of embodiments of the disclosure will not necessarily be described in detail or will be omitted so as not to obscure the relevant details of the disclosure.
[0064] The embodiments described herein are not limiting. The described embodiments herein are not necessarily to be construed as preferred or advantageous over other embodiments. Moreover, the terms “embodiments of the disclosure”, “embodiments” or “disclosure” do not require that all embodiments of the disclosure include the discussed feature, advantage, or mode of operation.
[0065] Copper, due to its Fenton Chemistry, serves as an important cofactor for numerous proteins and enzymes involved in both physiologic and pathological process. The proteins are secreted, intracellular, or transmembraneous. There are more than fifty copper-binding proteins in the various compartments of a cell (membrane, cytoplasm, nucleus, and mitochondria) that function as copper transporters, chaperones, and enzymes. In theory, all these copper-binding proteins may be affected to various degrees by a copper chelator, such as TTM.
[0066] According to various embodiments, the copper chelator is TTM or a salt thereof, which is a highly effective copper-chelator for the purpose of the present disclosure. The terms “tetrathiomolybdate” or “TTM” as used herein refers to a MoS.sub.4 compound, or a (MoS.sub.4).sup.2− anion, or acid forms or salt forms thereof. As used herein, the terms “tetrathiomolybdate” or “TTM” include ammonium tetrathiomolybdate, Bis-choline tetrathiomolybdate, and ATN 224. According to various embodiments, the salt of TTM is according to formula I:
X(MoS.sub.4),
[0067] where X is (2Li).sup.+2, (2K).sup.+2, (2Na).sup.+2, Mg.sup.+2, Ca.sup.+2, or {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6) (R.sup.7)(R.sup.8)]};
[0068] R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroaralkyl, cycloalkyl alkyl, and heterocycloalkyl alkyl; and
[0069] R.sup.4 and R.sup.8 are absent or independently H, or an optionally substituted group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, alkylaralkyl, heteroaralkyl, cycloalkyl alkyl, and heterocycloalkyl alkyl;
[0070] wherein when R.sup.4 is absent, R.sup.1 and R.sup.2 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, N, and S;
[0071] wherein when R.sup.8 is absent, R.sup.5 and R.sup.6 together with N forms an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, NH, and S;
[0072] wherein R.sup.1 and R.sup.2, R.sup.2 and R.sup.3, or R.sup.2 and R.sup.4, together with N optionally forms an optionally substituted cyclic structure;
[0073] wherein R.sup.5 and R.sup.6, R.sup.6 and R.sup.7, or R.sup.7 and R.sup.8, together with N optionally forms an optionally substituted cyclic structure;
[0074] wherein R.sup.4 and R.sup.8 may be joined by a covalent bond;
[0075] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are each independently optionally substituted with one or more of OH, oxo, alkyl, alkenyl, alkynyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, —C═N(OH), or OPO.sub.3H.sub.2, wherein R.sup.9 is each independently alkyl or —C(═O)(O)-alkyl;
[0076] wherein R.sup.4 and R.sup.8 are each independently optionally substituted with one or more of OH, oxo, alkyl, alkenyl, alkynyl, NH.sub.2, NHR.sup.9, N(R.sup.9).sub.2, —C═N(OH), or —.sup.+(R.sup.10).sub.3, wherein R.sup.10 is each independently optionally substituted alkyl; and wherein one or more —CH.sub.2— groups in R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7 and R.sup.8 may be replaced with a moiety selected from the group consisting of O, NH, 5, S(O), and S(O).sub.2.
[0077] In an embodiment, X is [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)] according to formula (II):
##STR00001##
[0078] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)] and [N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)] are the same or different.
[0079] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H or C.sub.1-C.sub.10 alkyl. In another embodiment where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H, C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.6 alkyl. In a further embodiment where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5) (R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.4 and R.sup.8 are independently H or C.sub.1-C.sub.6 alkyl.
[0080] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H, methyl, ethyl or propyl. In a further embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is propyl, and the compound is tetrapropylammoniumtetratinolybdate. In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is methyl, and the compound is tetramethylammoniumtetrathirolybdate. In a further embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is ethyl, and the compound is tetraethiylammoniumtetrathimolybdate.
[0081] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, and R.sup.3 are independently H, methyl, or ethyl and R.sup.4 is H or an optionally substituted alkyl, alkenyl, cycloalkyl alkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl. In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.5, R.sup.6, and R.sup.7 are independently H, methyl, or ethyl and R.sup.8 is H or an optionally substituted alkyl, alkenyl, cycloalkyl alkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, or heteroaryl. In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, the optional substituents for R.sup.4 and/or R.sup.8 are selected from the group consisting of alkyl, OH, NH.sub.2, and oxo. In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, one or more —CH.sub.2— groups of R.sup.4 and/or R.sup.8 is replaced with a moiety selected from O, NH, S, S(O), and S(O).sub.2.
[0082] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently methyl and R.sup.4 and R.sup.8 is each optionally substituted alkyl.
[0083] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, each of R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 is independently methyl and R.sup.4 and R.sup.8 is each optionally substituted ethyl.
[0084] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently methyl and R.sup.4 and R.sup.8 is each substituted ethyl, wherein the substituent is a hydroxyl. In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6) (R.sup.7)(R.sup.8)]}, each of R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 is independently methyl and R.sup.4 and R.sup.8 is each —CH.sub.2CH.sub.2—OH.
[0085] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently methyl, R.sup.4 and R.sup.8 is each optionally substituted alkyl, and the compound is tetramethylammoniumtetrathimolybdate. In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, each of R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 is independently methyl, R.sup.4 and R.sup.8 is each optionally substituted ethyl, and the compound is tetramethylammoniumtetrathimolybdate. In a further embodiment where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3) (R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently methyl, R.sup.4 and R.sup.8 is each substituted ethyl, wherein the substituent is a hydroxyl, and the compound is tetramethylammoniumtetrathimolybdate. In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3) (R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently methyl, R.sup.4 and R.sup.8 is each —CH.sub.2CH.sub.2—OH, and the compound is tetramethylammoniumtetrathimolybdate.
[0086] In another embodiment, the copper chelator compound is bis-choline tetrathiomolybdate.
[0087] In another embodiment, the copper chelator compound according to formula (I) is:
##STR00002##
[0088] Table 1 provides non-limiting embodiments where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5) (R.sup.6)(R.sup.7)(R.sup.8]}
TABLE-US-00001 TABLE 1 R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 R.sup.8 1 H H H H H H H H 2 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 3 ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl 4 propyl propyl propyl propyl propyl propyl propyl propyl 5 butyl butyl butyl butyl butyl butyl butyl butyl 6 pentyl pentyl pentyl pentyl pentyl pentyl pentyl pentyl 7 H H H H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 8 H H H H ethyl ethyl ethyl ethyl 9 H H H H propyl propyl propyl propyl 10 H H H H butyl butyl butyl butyl 11 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 ethyl ethyl ethyl ethyl 12 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 propyl propyl propyl propyl 13 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.2OH CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.2OH
[0089] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, each of [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)] and [N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)] is independently:
##STR00003##
[0090] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8]} at least one of [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)] and [N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)] is:
##STR00004##
[0091] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, both [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)] and [N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8] are:
##STR00005##
[0092] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently H or alkyl. In another embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently H or alkyl.
[0093] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8]}, R.sup.4 and R.sup.8 are joined by a covalent bond. For example, if R.sup.4 and R.sup.8 are both methyl, when R.sup.4 and R.sup.8 are joined by a covalent bond, it can form an ethylene link between the two nitrogen atoms as illustrated below:
##STR00006##
[0094] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.4 and R.sup.8 are both optionally substituted alkyl group joined by a covalent bond.
[0095] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 are independently H, methyl, ethyl or propyl and R.sup.4 and R.sup.8 are joined by a covalent bond. In another embodiment, R.sup.4 and R.sup.8 is each independently an optionally substituted alkyl group. In another embodiment, the optional substituents for R.sup.4 and R.sup.8 is N.sup.+(R.sup.10).sup.3, wherein R.sup.10 is optionally substituted alkyl. In another embodiment, one or more —CH.sub.2— groups of R.sup.4 and R.sup.8 are replaced with a moiety selected from the group consisting of O, NH, S, S(O), and S(O).sub.2.
[0096] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, X is:
##STR00007##
[0097] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1 and R.sup.2 are each independently H, methyl, or ethyl, and R.sup.3 and R.sup.4 are each independently an optionally substituted alkyl, aryl, or aralkyl group. In another embodiment, where X is {[N.sup.+(R.sup.1) (R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.5 and R.sup.6 are each independently H, methyl, ethyl, or propyl, and R.sup.7 and R.sup.8 are each independently an optionally substituted alkyl, aryl, or aralkyl group. In another embodiment, the optional substituents for R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are OH.
[0098] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8]}, [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)] and/or [N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)] is independently:
##STR00008##
[0099] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1 and R.sup.4 are each independently H, methyl, ethyl, or propyl and R.sup.2 and R.sup.3 together with N may form an optionally substituted cyclic structure.
[0100] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.5 and R.sup.8 are each independently H, methyl, ethyl, or propyl, and R.sup.6 and R.sup.7 together with N may form an optionally substituted cyclic structure. In another embodiment, one or more —CH.sub.2— groups in R.sup.2, R.sup.3, R.sup.6, and R.sup.7 is replaced with a moiety selected from the group consisting of O, NH, S, S(O), and S(O).sub.2.
[0101] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8]}, [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)] and/or [N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)] is independently:
##STR00009##
[0102] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.4 and/or R.sup.8 is absent and R.sup.1 and R.sup.2 and/or R.sup.5 and R.sup.6 together with N form an optionally substituted 5- or 6-membered aromatic ring, wherein up to 2 carbon atoms in the ring may be replaced with a heteroatom selected from the group consisting of O, N, and S.
[0103] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, [N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)] and/or [N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]} is independently:
##STR00010##
[0104] In another embodiment, where X is {[N.sup.+(R.sup.1)(R.sup.2)(R.sup.3)(R.sup.4)][N.sup.+(R.sup.5)(R.sup.6)(R.sup.7)(R.sup.8)]}, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each H.
[0105] In another embodiment, the copper chelator compound is ammonium tetrathiomolybdate (NH.sub.4).sub.2MoS.sub.4 (ATTM). In embodiments, ATTM is combined with other copper chelator compounds, such as ammonium trithiomolybdate (NH.sub.4).sub.2MoOS.sub.3.
[0106] In another embodiment, the copper chelator compound is Bis-choline tetrathiomolybdate C.sub.10H.sub.30MoN.sub.2O.sub.2S.sub.4 (sometimes referred to as ATN 224) that substitutes for the ATTM, or is combined with the ATTM, or is combined with other copper chelator compounds, such as ammonium trithiomolybdate (NH.sub.4).sub.2MoOS.sub.3.
[0107] In further embodiments, cancer and/or PAH in a patient is treated by administering a therapeutically effective amount of TTM or a salt thereof. In some embodiments, the copper chelator includes ATTM, and in some embodiments the copper chelator further includes ammonium trithiomolybdate (NH.sub.4).sub.2MoOS.sub.3. In various embodiments, the amount of TTM delivered to the patient is individualized. In an embodiment, the therapeutically effective amount of the copper chelator delivered to the patient is between 20 mg and 300 mg of TTM/day. In various embodiments, the amount of TTM is adjusted according to the level of ceruloplasmin in the plasma. An effective copper chelation is achieved when the plasma ceruloplasmin level approaches about 50% of the normal level; i.e. about 15-17 mg/dl.
[0108] “Administering” has its customary and ordinary meaning as understood by one of skill in the art in view of this disclosure. It refers to providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administration.
[0109] An “effective amount” of a drug, compound, or composition containing such compound, refers to the amount sufficient to achieve a desired biological and/or pharmacological effect according to a selected administration form, route, and/or schedule. The phrases “effective amount” and “therapeutically effective amount” are used interchangeably. Those of ordinary skill in the art will further understand that an “effective amount” may be administered to a subject in a single dose, or through use of multiple doses, in various embodiments.
[0110] “The terms “subject” or “patient” as used herein are used interchangeably and mean all members of the animal kingdom (e.g. humans).
[0111] According to various embodiments, dosing of TTM for treating cancer, for cancer adjuvant therapy, and/or for treating PAH is as follows:
[0112] if the ceruloplasmin level is between 15 mg/dL and 18 mg/dL, then the TTM dose will be stable at 60 mg TTM given three times a day for a total of 180 mg per day;
[0113] if the ceruloplasmin level falls below 15 mg/dL, then the TTM dose will be a total of 120 mg per day and further reduced if needed;
[0114] if the ceruloplasmin level is above 20 mg/dL, then the TTM dose will be a total of 240 mg per day, and up to 300 mg per day if needed.
[0115] According to various embodiments, the copper chelator is administered in a composition containing pharmaceutically acceptable carriers and/or excipients. In embodiments, the composition is administered in an oral form, such as a tablet, a microtablet, a capsule, or a sachet. In some embodiments, the copper chelator is in a composition as an oral form with specific carriers, matrix compounds, and/or excipients that provide a delayed release of the copper chelator in the gastrointestinal tract after passage through the stomach. In general, the carriers, matrix, and/or other excipients are selected to facilitate extended and controlled release of the copper chelator, enabling optimal intestinal uptake and absorption, guarantee stability for storage, and minimizing risk of alcohol-related dose dumping. Moreover, the carriers, matrix, and/or excipients are selected such that destruction by gastric acid is removed or avoided. For this objective, suitable coating materials for enteric coating are applied. For example, various embodiments of the oral forms of the composition include an enteric coating of the tablet, micro-tablet, capsule, or individual pellets and beads in the capsule. Also, in some embodiments, multiple coating layers are applied, e.g., a coating layer for enteric coating and an extended-release coating layer. In some embodiments, a layer is added to avoid burst release. Also, in various embodiments, different dosage forms are combined, such as capsules in capsules, or mini-tablets in capsules. In some embodiments, capsules or mini-tablets are combined with a filler and an adsorbent which can be an antacid, between the TTM and the enteric coating to minimize exposure to liquid water and stomach acid as enteric coating do not seal and the TTM degrades quickly when exposed to any stomach acid that can seep through the enteric coating. By the absorbent including an antacid compound, any acid that seeps through the enteric coating will be neutralized and protect the TTM from degradation.
[0116] The term “pharmaceutically acceptable” as used herein refers to drugs, compounds, compositions, and dosage forms which are suitable for use in human beings and animals and without excessive toxicity, irritation, allergic response, or any other problem or complication.
[0117] The term “oral dose,” “oral dosage,” or “oral formulation” as used herein means a dosage form that is administered by mouth, for absorption through the mucous membranes of the mouth and/or, after swallowing, through the gastrointestinal tract. Such oral dosage forms include but are not limited to solutions, syrups, suspensions, emulsions, gels, powders, granules, capsules, tablets, buccal dosage forms and sublingual dosage forms.
[0118] As used herein, “enteric coating” has its customary and ordinary meaning as understood by one of skill in the art in view of this disclosure. An enteric coating is a barrier applied to oral medication that prevents dissolution or disintegration in the gastric environment. This protects drugs from the acidity of the stomach and helps to release the drug in a desired portion of the gastrointestinal tract, for example the upper tract of the intestine. Many enteric coatings work by presenting a surface that is stable at the intensely acidic pH found in the stomach, but breaks down rapidly at a higher pH (alkaline pH). For example, they will not dissolve in the gastric acids of the stomach (pH ˜3), but they will in the alkaline (pH 7-9) environment present in the small intestine.
[0119] In embodiments, the filler or absorbent is an antacid, and the antacid is one or more of aluminum hydroxide, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium trisilicate, sodium bicarbonate, alginate, or a combination thereof.
[0120] According to various embodiments, the oral coating layer is an extended-release coating, whereby the extended-release coating creates a stable administration of the TTM, whereby it is released over a period of time, creating a long- or extended-release of TTM and reducing or eliminating the need for taking several dosages over a given time period. Such extended release coatings are based on different natural or man-made polymers, such as, but not limited to, ethyl celluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxyethylcelluloses, and sodium carboxy-methylcellulose.
[0121] The term “extended-release” as used herein refers to pharmaceutical compositions that are designed to slowly release an active ingredient, medication, or drug in the body over an extended period of time. An extended-release formulation of a pharmaceutical composition helps maintain a consistent level of the active ingredient, medication, or drug in the body. It also allows for reduced dosing frequency, increases compliance as the patient has less pills a day to consume, and helps lower the risk of side effects.
[0122] Embodiments of enteric coatings and extended release coatings layers are external and/or internal to the tablets, beads, or pellets and in some embodiments are combined to protect from acidic stomach content and/or to create a controlled release profile over an extended amount of time.
[0123] According to various embodiments, an extended release formulation is designed as matrix tablets or pellets in a capsule where either a hydrophilic, hydrophobic, or lipophilic polymer is used as carrier or a lipid matrix
[0124] In embodiments of the hydrophilic matrix system, TTM is dispersed throughout a polymer matrix of hydrophilic material. The rate of drug release is controlled by both diffusion and erosion. When water is absorbed by the matrix, the matrix swells, and the polymer on the surface of the tablet hydrates. TTM dissolves and is released by a combination of diffusion out of the matrix, through the gel layer, and as a result of the erosion of the matrix itself. In embodiments, formulations of the matrix system are enterically coated to inhibit destruction of the copper chelator by stomach acid. Alternatively, the matrix based system is put in an enteric capsule, where the capsule is either made from an enteric material, or is coated and sealed enterically and includes a barrier of antacid to prevent acid that seeps through the enteric coating for interacting with the TTM.
[0125] In embodiments of the hydrophobic matrix system, TTM is dispersed throughout a polymer matrix of inert hydrophobic material, e.g., polymer or lipid. In this embodiment, the hydrophobic matrix undergoes no or minimal swelling on contact with water. When water enters the matrix, TTM dissolves and is predominately released by diffusion out of the matrix. In embodiments, formulations of the matrix system are enterically coated to inhibit destruction of the copper chelator by stomach acid. Alternatively, the matrix based system is put in an enteric capsule, where the capsule is either made from an enteric material, or is coated and sealed enterically. As enteric coatings not seal, the TTM is isolated from the inside of an enteric coating to avoid the stomach acid that initially seeps through the enteric coating from contacting the TTM.
[0126] In another embodiment, suitable polymers, lipid carriers, or a combination of both, are used for a hot-melt extrusion process to make an extended-release material that can further be processed into tablets, micro-tablets, pellets, or beads. In embodiments, a coating layer(s) for enteric coating and/or controlled release adds enteric protection and helps avoid burst release. In some embodiments, another barrier is coated onto the delivery form, either on top or below the enteric coating. This barrier layer is designed such as to improve resistance to diffusion of moisture through the enteric film, i.e., from reaching the copper chelator as the enteric coating starts to dissolve. The barrier agent layer is such that it either absorbs water, neutralizes the acid that seeps through the enteric coating, prevents the TTM from being in contact with the acid, or slowly dissolves (e.g., a functional controlled-release polymer), or is a lipophilic (hydrophobic) coating substance, e.g., lipids and other hydrophobic excipients, or provides antacid properties.
[0127] According to various embodiments, the TTM is packaged in an extended-release system that includes a reservoir system, whereby a core containing TTM is surrounded by an insoluble polymer membrane of suitable extended release polymers. In embodiments, the TTM is contained in a single core, but some embodiments also include additional subunits, such as beads, pellets, or mini-tablets, containing the drug. Some embodiments include a coating layer to add enteric protection and to help avoid burst release.
[0128] In embodiments, TTM is packaged in a capsule with multiple different subunits, such as microtablets, pellets, or beads, with different release characteristics allowing for a multimodal IR (immediate release) plus extended release (ER). In embodiments, the capsule is enterically coated or the subunits are enterically coated. In embodiments, an additional moisture-diffusion-limiting barrier layer minimizes acid-related destruction of the copper chelator from the stomach acid that would otherwise leak through the enteric barrier.
[0129] According to various embodiments the TTM or copper chelator is packaged in an extended-release system using an osmotic-release system that includes a drug-containing core surrounded by an insoluble but semipermeable membrane capsule or coating. This membrane contains an orifice through which the soluble drug is forced by osmotic pressure that builds up inside the capsule on contact with water. In various embodiments, the semipermeable membrane is made of polymeric materials, such as, but not limited to, cellulose acetate polymers, cellulose esters, cellulose ethers, agar acetates, amylose triacetates, betaglucan acetates, poly(vinylmethyl)ether copolymers, poly(orthoesters), polyacetals and selectively permeable poly(glycolic acid), poly(lactic acid) derivatives, as well as Eudragits. In embodiments, this delivery system is enterically coated to ensure that no copper chelator is released in the stomach and that the stomach acid cannot leak through the enteric coating and contact the TTM.
[0130] Some embodiments of the manufacturing of the extended-release systems disclosed herein include a need to prevent oxidation of TTM in the manufacturing process, and embodiments of methods to prevent this oxidation include processing in an inert gas or in an oil or solvent or other non-oxidative material that prevents the TTM from being exposed to oxygen. In embodiments, the inert gas is Argon or Nitrogen. Also in some embodiments, processes with a short residence time in the system are used to minimize exposure of TTM to air where the product is immediately collected and stored under inert gas. Embodiments of the manufacturing process are water free and do not expose TTM to water and hydrolysis. Thus, for these manufacturing processes, solvents other than water are used.
[0131] In another embodiment of the manufacturing process, direct compaction is used to manufacture the tablets. Whereby in this process a mixture of TTM and suitable excipients are fed directly or individually to a tablet press, using standard extended-release excipients (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) and/or more advanced excipients including polymer mixtures. In some embodiments, other excipients for lubrication, stabilization, coloring, taste-masking, or for use as fillers and binders are added in the powder mixture. Such excipients include, but are not limited to, metal soaps such as magnesium stearate, sodium stearyl fumarate, croscarmellose sodium, modified starches, modified lactoses, dextrins, glucose, sucrose, sorbitol dicalcium phosphates, vitamins, colorants, sugar alcohols, crospovidone, polymers and copolymers, silica compounds, silicone or alginates, microcrystalline cellulose, hydroxypropylcellulose. Good flowability of the powder and low tendency for segregation of the powder mixture are desired. Embodiments of the process are carried out in batch or in continuous mode.
[0132] In another embodiment, roller compaction followed by milling and screening is applied to make granules which are then mixed with lubricants and other excipients for tableting. Standard extended-release excipients are used (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) or more advanced excipients including polymer mixtures. In some embodiments, other excipients for stabilization, coloring, taste-masking, or for use as fillers and binders added in the powder mixture. Embodiments of the process are carried out in batch or in continuous mode.
[0133] In another embodiment, wet granulation, e.g., via massing and screening or high-shear wet granulation or twin-screw wet granulation, with solvents that do not destroy TTM are used to make granules, followed by a drying process (e.g., via tray drying, fluid bed drying, conveyer belt drying and other methods) to produce dry granules which are used for tableting. In some embodiments, the solvents used do not contain water. Standard extended-release excipients are used (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) or more advanced excipients including polymer mixtures. In some embodiments, other excipients for stabilization, coloring, taste-masking, or for use as fillers and binders are added in the powder mixture. Embodiments of the process are carried out in batch or in continuous mode. In various embodiments, granules are filled in capsules and sachets, or are used for tableting if mixed with an external phase, such as lubricants or binders.
[0134] In another embodiment, granules are produced via wet granulation in extruders where a suitable solvent is added and matrix materials and TTM are added either separately or as a premix.
[0135] Extruders include twin-screw extruders, radial screw extruders, roll extruders or Koller press extruders. Subsequently to extrusion, granules are dried via methods as described herein. Materials are selected based on required formulation and biopharmaceutical requirements as described herein. In various embodiments granules are filled in capsules and sachets, or are used for tableting if mixed with an external phase, such as lubricants or binders.
[0136] In another embodiment, hot-melt extrusion is applied where powders or powder mixtures containing TTM, a matrix material for extended release, and other excipients are fed to a hot-melt extruder. The extruded strand is cooled and milled, or is directly processed into pellets and beads or to tablets via calandering. In embodiments, milled material is mixed with suitable excipients and is tableted on a tableting machine. Embodiments of the process are carried out in batch or in continuous mode.
[0137] In yet another embodiment, additive manufacturing technology, also known as 3D printing, is applied to make tablets of a desired release profile. For some embodiment of such a process, filaments are manufactured that contain the TTM and delayed-release matrix materials as described herein. These filaments are made by extrusions process as described herein using different types of extruders including single-screw, double-screw or ram extruders. Filaments are then used to print tablets via thermal technique, such as fused deposition modeling. Alternatively, melt from extruders are directly used to cast tablets via additive manufacturing technology. In embodiments, other additive manufacturing technologies are applied such as powder bed printing, inject printing, VAT polymerization, direct-wise printing, and others. Materials for printing include delayed-release artificial and natural polymers, starches, lactoses, hydroalcohols, lipids, and other natural products.
[0138] For coating the tablets, in various embodiments, standard or advanced drum coaters are used that also can be used to carry out multiple coating steps. For coating of micro-tablets, pellets, and beads, in various embodiments, fluidized bed coaters are used. Sprayed solutions or suspensions contain the required polymers for enteric coating, or extended release and suitable colors, pigments, surfactants, plasticizers, and other components. Alternatively, in embodiments, spray congealing or dip coating is applied.
[0139] According to various embodiments, the extended-release system contains TTM from a minimum of 20 mg to up to 300 mg with an approximate release period of up to about 24-hours.
[0140] According to various embodiments, the extended release tablet further contains DEC as a co-drug. Embodiments of suitable formulations that minimize chemical interaction between DEC and TTM are disclosed.
[0141] According to various embodiments, the extended-release tablet further contains AXT as a co-drug. Embodiments of suitable formulations that minimize chemical interaction between AXT and TTM are disclosed.
[0142] According to various embodiments, the extended-release tablet contains TTM, ATX, and DEC and/or another co-drug.
[0143] Various embodiments of the present disclosure for cancer and/or PAH therapy combine TTM in an extended release tablet design of TTM alone or combined as a multi drug form with one or more co-drugs such as 5-lipoxygenase inhibitors, such as DEC or Zileuton, or inhibitors of the enzyme leukotriene A4 [LTA4]-hydrolase such as Bestatin, or inhibitors of the leukotriene C4 receptor such as Montelukast, or inhibitors of leukotriene B4 receptors (BLT1, BLT2) such as LY293111, BAY-u9773, or the inclusion of SFN, or AXT or MK, or LEAPS peptide heteroconjugates, with tart-butylhydroquinone, as pre-treatment. Both DEC or Zileuton or the other inhibitors of the leukotriene producing enzymes or leukotriene receptor inhibitors mentioned above provide multiple benefits that include inhibition of the synthesis of the leukotrienes LTB4 and LTC4 which are mediators of inflammation, and inhibition of the synthesis of the highly chemotactic LTB4 addressing inhibition of chemotaxis of inflammatory cells.
[0144] In various embodiments, the copper chelator compound is ammonium tetrathiomolybdate [NH.sub.4]2MoS.sub.4 (ATTM). In some embodiments, ATTM is combined with other copper chelator compounds, such as ammonium trithiomolybdate [NH.sub.4]2MoOS.sub.3 or ATN 224.
[0145] According to various embodiments, cancer and/or PAH in a patient is treated by administering a therapeutically effective amount of a copper chelator TTM, ATTM, or ATN 224, or a salt thereof. In an embodiment, the copper chelator includes ATTM, and in some embodiments the copper chelator further includes ammonium trithiomolybdate [NH.sub.4]2MoOS.sub.3. The amount of TTM delivered is individualized. In an various embodiments, the therapeutically effective amount of the copper chelator delivered to the patient is between 20 mg and 300 mg of TTM/day. In embodiments, the amount of TTM is adjusted according to the level of the ceruloplasmin in plasma. An effective copper chelation is achieved when the plasma ceruloplasmin level approaches 50% of the normal level; i.e., about 15-17 mg/dl.
[0146] According to various embodiments, the copper chelator is administered in a composition containing pharmaceutically acceptable carriers and/or excipients. The composition is administered in an oral form, such as a tablet, a microtablet, a capsule filled with pellets or powder, or a sachet. In some embodiments, the copper chelator is in composition of an oral form with specific carriers, matrix compounds, and/or excipients that provide a delayed release of the copper chelator in the gastrointestinal tract after passage through the stomach. Such matrix materials can be, but are not limited to, hydroxypropyl methylcellulose (HMPC), gums, alginates, lipids of various compositions, polyvinyl acetates, polyvinylpyrrolidones, methacrylate copolymers, polyethylene glycols (PEG)/polyethylene oxides (PEO), and others. In general, the carriers, matrix, and/or other excipients are selected to facilitate extended (sustained) and controlled release of the copper chelator, enabling optimal intestinal uptake and absorption, to guarantee stability for storage, and possibly minimizing risk of alcohol-related dose dumping. Moreover, the carriers, matrix, and/or excipients are selected such that destruction by gastric acid is avoided. For this objective, suitable coating materials for enteric coating are applied. In embodiments, such a coating is applied externally on the tablet or on drug-containing pellets individually. For example, embodiments of oral forms of the composition include an enteric coating of the tablet, micro-tablet, capsule, or of individual pellets and beads in the capsule. Also, in embodiments, multiple coating layers are applied, e.g., a coating layer for enteric coating and an extended release coating layer. Also, in embodiments, a layer is added to avoid burst release and prevent acid that leaks through the enteric costing from interacting with the TTM, such layers provide antiacid characteristics. Enteric coatings contain typically pH-sensitive polymers or particles, such as, but not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, shellacs, polyvinyl acetate phthalate, hydroxy-propylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, poly-methacrylic acids, poly-ethyl acrylates, or poly-methacrylates at various mixtures, amylose starches and other starches, dextrins, plant proteins (e.g., zein and others), fatty acids, lipids including modified lipids, waxes and other.
[0147] In another embodiment, suitable polymers or lipid carriers or a combination of both are used for a hot-melt extrusion process to make the extended-release material which can further be processed into tablets, micro tablets, or pellets and beads. In embodiments, coating layer(s) for enteric coating and controlled release coating add enteric protection and help avoid burst release. In some embodiments, another barrier is coated onto the delivery form, either on top or below the enteric coating. This barrier layer is designed such as to improve resistance to diffusion of moisture through the enteric film, i.e., from reaching the copper chelator as the enteric coating starts to dissolve. The barrier agent layer is such that it either absorbs water, neutralizes the acid that seeps through the enteric coating or slowly dissolves (e.g., a functional controlled-release polymer) or may be a lipophilic (hydrophobic) coating substance, e.g., lipids and other hydrophobic excipients.
[0148] According to various embodiments, the extended-release system contains TTM from a minimum of 20 mg to up to 300 mg with a TTM in an approximate release period of about 24-hours.
[0149] According to various embodiments, the extended release system also contains DEC or ATX as co-drugs. In various embodiments, suitable formulations that minimize chemical interaction between DEC and TTM and ATX are designed. In some embodiments, this means to create mixtures of the drug and co-drugs and to investigate chemical stability and to choose formulations based on the outcome. Should a chemical interaction occur, embodiments of the formulation techniques will separate the two chemicals spatially. In some embodiments, this is achieved by making multi-layer tablets with layer 1 containing TTM, and a layer 2 and a layer 3 containing a co-drug. In other embodiments, pellets of two types are made with the methods described herein, with pellet (or bead) type 1 containing TTM, and pellet (or bead) type 2 containing the co-drug. Both pellet (or bead) types can be processed in different ways, e.g., by compressing them into one tablet, or coating them separately and embedding them in a matrix material, called multi-unit pellet system (MUPS). In embodiments, the produced tablets are coated enterically or with extended release coating. In embodiments, the matrix material of the MUPS is made of extended release matrix materials as described herein. Another embodiment is to prepare multilayer coating of an inert bead, having different APIs in different coating layers. Thereafter, the beads are filled in capsules with release modifiers. In another embodiment, TTM loaded particles (pellets) are prepared as per the methods described herein and thereafter are coated with polymers/excipients having other API. Thereafter, the coated particles are delivered as tablets with excipients or filled in capsules with release modifiers and excipients. Another embodiment is to use an active coating of the co-drug. In this case, TTM is contained in the core of the tablet and a suspension or solution containing the co-drug is sprayed on the tablets via a conventional coating process. The tablet can still be enterically coated or coated with an extended release polymer.
[0150] Embodiments of the present disclosure include methods for cancer and/or PAH treatment in a patient that includes administering TTM alone, or at least one other active agent, or co-drug, in combination with TTM.
[0151] Copper is highly angiogenic, and TTM enhanced by DEC is anti-angiogenic. The combination of TTM with ATX, or TTM, DEC, and ATX provides a more effective inhibition of NF-kappaB activation and therefore inhibition of production of inflammatory mediators. While DEC inhibits the synthesis of leukotrienes, AXT, via inhibition of MAPK, inhibits the action of leukotrienes. Moreover, by using the combination of TTM and DEC, or TTM, DEC, and ATX, the present inventors are employing strategies that (1) inhibit chemotaxis of inflammatory cells, (2) decrease vascular permeability and leak, (3) decrease the activity of the master inflammatory mediator transcription factor NF-kappaB, and (4) decrease VEGF production and action, vital to combating cancer. The summary mechanisms of action for DEC are inhibition of the enzyme 5-lipoxygenase, inhibition of oxidants, and inhibition of NF-kappaB-dependent gene transcription. In the aggregate, by such molecular mechanisms, DEC inhibits chemotaxis and preserves normal endothelial cell function, i.e., it also decreases vascular leak. Note that vascular permeability (vascular leak), plays a role in PAH and cancer and it is part of the inflammatory process. To summarize the mechanisms of actions of ATX: this non-toxic and bioavailable carotene acts as a powerful antioxidant via upregulation of the expression of Nrf2, it is an antiprotease, it stabilizes mitochondrial metabolism, protects against DNA damage, it is anti-inflammatory and anti-fibrotic, protects endothelial cells against damage and it has properties shown to inhibit cancer cell growth,
[0152] A supporting reason for using TTM to curtail cancer and/or PAH includes the fact that the molybdenum in TTM binds with a very high affinity to the copper atoms in the catalytic centers of at least 54 copper-containing proteins, many of which are involved in angiogenesis and cell growth. This particular affinity of molybdenum is independent of the copper chelation property of TTM. The combination of two drugs with different mechanisms of action (a 5-lipoxygenase inhibitor like DEC or Zileuton) plus TTM are primary drivers to fight cancer and/or PAH. ATX adds mechanisms of action explained by upregulation of Nrf2 resulting in a normalization of the tissue and cell oxidant/anti-oxidant balance, inhibition of protease-induced cell damage and DNA damage-not provided by the actions of TTM.
[0153] A supporting reason for using TTM and DEC or other co-drugs, such as ATX and others disclosed herein to disrupt cancer and/or PAH includes the fact that TTM decreases the activity of two very important transcription factors: HIF-1-alpha, which is needed for the production of the highly angiogenic VEGF and plays a role in cancer, and the transcription factor NF-kappaB, which is a switchboard for the production of a very large number of inflammatory mediators. This dampening of transcription factors is therapeutically important because it will reduce angiogenic cell growth and inflammation found in human patients.
[0154] TTM can also induce apoptotic cell death of apoptosis-resistant abnormal vascular cells—another favorable anti-cancer and anti-PAH treatment effect.
[0155] A supporting reason for using TTM to assist in combating cancer and/or PAH includes the fact that TTM can “teach” pluripotent stem cells to behave and turn them back into normal vascular wall cells, instead of endlessly proliferating. Research has shown that progressive adaptation of human embryonic self-renewing stem cells to their culture conditions does occur, and we expect the conditions created from TTM will turn these stem cells back into normal vascular wall cells.
[0156] Various embodiments of the present disclosure include methods for cancer and/or PAH therapy, which utilize TTM in an extended release design as TTM alone, or TTM combined with ATX or a 5-lipoxygenase inhibitor such as DEC or Zileuton, with or without ATX, or inclusion of LEAPS peptide heteroconjugates, tart-butylhydroquinone, or SFN. Embodiments also include a cytokine mixture in a method for pre-sensitizing cancer prior to a therapeutic treatment with TTM and DEC or Zileuton. In embodiments, the cytokine mixture is a serum-free and mitogen-free mixture containing specific ratios of cytokines such as IL-10, TNF-α, IFN-γ, and GM-CSF to Interleukin 2 (IL-2), which is effective in inducing cancerous cells to enter a proliferative cell cycle phase thereby increasing their vulnerability to TTM and DEC or Zileuton therapy. One such cytokine mixture is Leukocyte Interlukin Injection (LI) or MULTIKINE®, which is used with the TTM and DEC combination or Zileuton. In further embodiments, treating patients with TTM and DEC when pre-sensitized with SFN allows for isolating a cell population during its vulnerable cell cycle phase where cells are specifically vulnerable to damage. Unlike chemotherapy, applying TTM and DEC (which are not toxic drugs and have far fewer side effects) makes this therapy ideal for treating cancer and/or PAH. According to various embodiments, the co-drugs to TTM are in an extended release formulation, or TTM is the only drug that is extended release and the co-drugs are not in an extended release formulation.
[0157] In addition to TTM alone, in some embodiments the therapy contains at least one other active agent, or co-drug, in combination with TTM.
[0158] For example, possible co-drugs include inhibitors of the 5-lipoxygenase enzyme (5-LO), which drives inflammation and controls cell growth, such as DEC and zileuton. The 5-LO protein is expressed more in the tumor tissue and in metastases in patients with cancer which has cell growth that has a similarity to cancer.
[0159] Thus, in various embodiments, TTM and a 5-LO inhibitor or a LTA4 inhibitor work synergistically for cancer and PAH. In various embodiments, ATX works synergistically for cancer and PAH as well. While a TTM salt is expected to induce anoikis (inducing death of tumor vessel endothelial cells), inhibition of 5-LO is expected to decrease inflammation and inhibit 5-LO-dependent cell growth. The 5-LO enzyme acts as an activator of gene expression. 5-LO leads to the production of leukotriene C4, which is the first and well-established action of 5-LO. Thus, inhibiting 5-LO would also inhibit leukotriene C4 synthesis. A second action of 5-LO is a non-enzymatic function of binding to the 5-LO activating protein (FLAP) on the envelope of the cell nucleus. Fitzpatrick and Lepley showed in 1998 that 5-LO co-precipitated with a subunit of the transcription factor NF-kappaB when they examined nuclear extracts (Archives of Biochemistry and Biophysics, 1998, 356(1) 71-76). NF-kappaB controls the expression of genes encoding several LTB4 inflammatory mediators. Thus, 5-LO, by binding to NF-kappaB in the cell nucleus, could activate transcription of a number of genes in control of cell growth and genes encoding inflammatory mediators such as IL-1beta and IL-6—and also VEGF. As a result of 5-LO inhibitor treatment, there would be a reduction in vascular inflammation and perhaps stem cell reprogramming leading to halting of tumor growth and metastatic dissemination and assist disease arrest. LTB4 is another important chemotactic leukotriene that is a product of the enzyme leukotriene A4 hydrolase—which is downstream from 5-LO. Because effective inhibition of the 5-LO would also block LTB4 production, it is expected that 5-LO inhibitors in the treatment of cancers would also target LTB4-dependent pathomechanisms. By adding ATX in combination with DEC, the activity of NF-kappaB is decreased to a greater extent than achieved with TTM or DEC, and via the blockade of MAPK, the action of leukotrienes is inhibited.
[0160] In some embodiments, cancer in a patient, or a patient with PAH, is treated with a therapeutically effective amount of TTM in an enteric oral formulation dose with or without an extended-release formulation.
[0161] In some embodiments, cancer in a patient, or a patient with PAH, is treated with a therapeutically effective amount of a combination of TTM in an extended-release formulation and at least one 5-LO inhibitor. In some embodiments, cancer and/or PAH treatment includes the administration of a therapeutically effective amount of ATX and one or more of the 5-LO inhibitors DEC or zileuton, in combination with a therapeutically effective amount of TTM. In various embodiments, these 5-LO inhibitors and ATX are or are not in an extended release formulation.
[0162] In some embodiments, cancer and/or PAH treatment includes the administration of a therapeutically effective amount of ATX and one or more of the 5-LO inhibitors DEC or zileuton, in combination with a therapeutically effective amount of TTM. In various embodiments, these 5-LO inhibitors and ATX are or are in an oral dose, in either and tablet or capsule form that is enterically coated.
[0163] In some embodiments, cancer in a patient, or a patient with PAH, is treated with a therapeutically effective amount of a combination of TTM, in an enteric coated tablet, and at least one 5-LO inhibitor. In some embodiments, cancer and/or PAH treatment includes the administration of a therapeutically effective amount of one of the 5-LO inhibitors DEC or zileuton in combination with a therapeutically effective amount of TTM.
[0164] In some embodiments, cancer in a patient, or a patient with PAH, is treated with a therapeutically effective amount of a combination of TTM, and with or without at least one 5-LO inhibitor and SFN.
[0165] In some embodiments, a patient with cancer and/or PAH is treated with a therapeutically effective amount of a combination of TTM, and with or without at least one 5-LO inhibitor and ATX.
[0166] In some embodiments, a patient with cancer and/or PAH is treated with a therapeutically effective amount of a combination of TTM, either in an extended release formulation or without an extended release formulation, and administered together with one or more of the following: a 5-lipoxygenase inhibitor, a leukotriene receptor blocker such as Montelukast, LY29311, SFN, or tert-butylhydroquinone.
[0167] In terms of administration, some embodiments concerning the administration of both the TTM and the co-drug is in a single dose form or composition, and in other embodiments the TTM and co-drugs are administered in separate compositions. In some embodiments, the TTM, with or without a co-drug, is administered to the patient at a dose of 20 mg to 300 mg/day. In embodiments, the dose is adjusted to produce a target ceruloplasmin level in the patient of 50% of its normal value. According to embodiments, this target ceruloplasmin level is 15-17 mg/dl of plasma.
[0168] According to various embodiments, the compositions contain pharmaceutically acceptable carriers and/or excipients. In various embodiments, the compositions are in an intravenous form or an oral form, such as a tablet, a microtablet, or a capsule. In some embodiments, the TTM is in a composition of an oral form, and the co-drug is in a composition of an intravenous or inhalable form. For compositions containing TTM, with or without the co-drugs, in some embodiments specific carriers and/or excipients are added to provide a delayed release of the TTM in the gastrointestinal tract after passage through the stomach. Specifically, the carriers and/or excipients are selected to facilitate protection of the TTM against destruction by gastric acid and enabling optimal intestinal uptake and absorption. For example, in some embodiments the oral forms of the composition include an enteric coating of the tablet or capsule or include a delayed release formulation and composition.
Examples: Embodiments of Enteric Capsules
[0169] TTM degrades rapidly in stomach acid and dosing patients to date in various drug trials over the years with TTM has always involved administering a proton pump inhibitor (PPI) in advance of swallowing a TTM pill. This is due to the well-known fact that the stomach acid breaks down the TTM quite rapidly before it can reach the intestinal tract and be absorbed by the body.
[0170] The concept of administering TTM in this manner is that the stomach acid has been somewhat reduced by the proton pump inhibitor and the TTM can then pass on to the intestine without losing potency, thereby insuring TTM's bio-availability. The first problem with this method is that each person is different; the PPIs have a half-life and the timing of controlling the acidity of the stomach varies for each person. The TTM therefore will degrade differently in each person, accounting for a variable bioactivity of the TTM from patient to patient. Further, compliance to a regime of taking a PPI in advance of the TTM is difficult for some patients, and often such treatment protocols are not followed. Note that TTM degrades substantially in a lower pH acidic solution yet less so in higher pH solution. The second problem with this method is the TTM dissolves in the stomach and gives off sulfur smelling gas. This is known as “sulfur burp” and patients do not enjoy this side effect, discouraging the use of this drug.
[0171] PPIs inhibit the gastric H,K-ATPase by covalent binding, so the duration of their effect is longer than expected from their levels in the blood. However, PPIs cannot inhibit all gastric acid pumps with oral dosing because not all pumps are active during the 90-minute half-life of the PPI in the blood. Because PPIs have a short half-life, only 70% of the pump enzymes are inhibited. It takes about 2 to 3 days to reach steady state inhibition of acid secretion. The pump protein has a half-life of about 54 hours in the rat (and probably in humans). Thus, about 20% of pumps are newly synthesized over a 24-hour period, and there may be greater pump synthesis at night than during the day. In addition, bedtime administration of PPIs will not add to inhibition of nocturnal acid breakthrough, because the drug will have disappeared by the time nighttime acid secretion is evident. Assuming that about 70% of pumps are activated by breakfast and that the PPI is given 30 to 60 minutes beforehand, it can be calculated that steady state inhibition on once-a-day dosing is about 66% of maximal acid output. Increasing the dose has virtually no effect once optimal dosage has been reached. Increasing the dose frequency does have some effect; a morning dose and an evening dose before meals results in about 80% inhibition of maximal acid output.
[0172] In the manufacture of TTM, the initial TTM particles are larger crystals, so large sometimes, that they are crushed and screened to assure that TTM will flow properly for filling capsules and that the bioavailability is high enough (large particles dissolve slowly). This crushing process creates very small sizes that will degrade quickly in acid, and depending on the ratio of TTM to water, will dissolve quickly in water. These small sizes are vulnerable to destruction and are one explanation of why some patients medicated with TTM do not respond to the TTM therapy or do not respond to the degree required. This is simply because not all of the acid is neutralized and since many of the TTM particles are small and susceptible to immediate destruction, they are not therapeutically active.
[0173] To optimize bioavailability is important, and thus, small particles must survive the environment of the stomach and dissolve in the intestine. We propose that differences in treatment outcomes can to some extent be explained by the differences in bioavailability that can be shown by measuring serum ceruloplasmin. TTM is a copper chelator, and if the TTM is bioavailable and copper levels have been lowered, the ceruloplasmin serum levels decrease. In some clinical studies the treatment success correlated with the achieved low ceruloplasmin levels. For one study, lowering serum ceruloplasmin levels (ideally to 50% of normal) was not achieved in a number of patients. One explanation for the failure to lower serum ceruloplasmin levels can be a lack of bioavailability due to TTM destruction by stomach acid. Further, as TTM dissolves in water, and even in an acid reduced stomach (higher pH) there is enough water to dissolve TTM, creating the potential to destroy the TTM by the remaining acidity, especially for the very small particles that dissolve easily.
[0174] There have been attempts to address this problem other than adding a proton pump inhibitor, and one study showed that smaller TTM crystals were destroyed immediately by the stomach acid and much larger TTM crystals have a higher level of survival, as some percentage of each crystal is destroyed, but due to the lower specific surface area of a larger size of a TTM crystal, there is a remaining portion of the crystal passed from the stomach to the intestine for the body to absorb this remaining TTM.
[0175] Some literature has discussed the use of an enteric coating for administering TTM, however nothing describes how such an enteric coating for TTM is supposed to work and no commercial enterically coated TTM capsules have been developed or offered commercially for delivering TTM in an enteric coating that is not destroyed while in the stomach. Empty enteric capsules to be filled with Active Pharmaceutical Ingredients (API) are common and are commercially available, however, they are not effective in preventing the stomach's acid from attacking and destroying the TTM as enteric capsules are designed to slowly dissolve, delaying the release of the API, however as they dissolve, the TTM is subjected to acid that degrades the TTM. The inventors experimented also with liquid spray on coatings applied to enteric and non-enteric capsules and found the seepage of acid to the TTM was also present. The same occurred to enteric coatings applied to a non-enteric tablet.
[0176] Enteric capsules, such as VCAPS® provided by Lonza for any drug manufacture to fill with their API, meet the requirement of an industry standard enteric coating and show a diffusion rate of 0.5% for each 15 minutes, with an accelerated diffusion increase as time passes. For many drug products added to these enteric capsule products, during the first 120 minutes, the capsule body does not seal 100% and the drug slowly escapes from the capsule, as this is the design of such capsules. While for some drugs, such as Acetaminophen, this is an acceptable solution, this is not the case for TTM that is highly stomach acid sensitive.
[0177] The present inventors have determined that while the designed disintegration properties of an enteric capsule remain stable for 2 hours and the designed enteric capsule may have a diffusion rate below 7.5% in the first two hours, the inventors research confirmed in fact stomach acid or moisture from the stomach does enter the capsule, and the enteric interior capsule walls become wet, thereby subjecting the TTM to the acid or moisture, causing rapid degradation of the enteric capsule from the chemical reaction with the moistened TTM.
[0178] The present inventors have determined that the TTM releases H.sub.2S gas when a small amount of stomach acid or moisture enters the enteric capsule, not only causing degradation of the TTM, but also the moisture seeping through the capsule causes TTM to release H.sub.2S as part of the degradation process, which then comes in contact with the inside of the enteric capsule. This dissolves the enteric capsule from inside the capsule and leads to a catastrophic capsule failure within 15 to 30 minutes.
[0179] The present inventors attempted to prevent this failure by applying additional enteric coatings, and even with additional coating, after one hour it was found that the TTM was still leaking out, providing evidence that while an enteric capsule with additional enteric coatings applied will remain intact, stomach acid and moisture will still get through an enteric coating. This is not a preferred solution as the TTM is getting wet inside the capsule and degrading, creating the problem of not knowing how much TTM will be left to be absorbed by the patient after the tablet leaves the stomach. Such a reaction reduces the amount of drug being available to the patient, thereby reducing the drugs intended effect due to less TTM available.
[0180] The present inventors undertook a study to determine the size of the TTM particles after a crushing and screening process using a 70-mesh screen that would allow a maximum particle size of 210 micrometers. The size range was as follows: 10% under 13.3 μm; 50% under 44.5 μm; 90% under 122 μm.
[0181] Using this data set, the present inventors studied solubility in water and found that 60 mg in 300 ml dissolved fully over time, whereas 160 mg in 300 ml of water did not fully dissolve and a clump remained. This is not unsurprising, as saturation will occur in fluids as a known principle and does illustrate enough fluid is required to be available to dissolve the administered TTM to create optimal bioavailability. Further, larger particles with larger surface area would be expected to remain after the smaller particles dissolve.
[0182] This result, when applied to the intestine, knowing that the intestine does not have a larger content of water at any one spot, and contracts to mash, mix, and move contents contained within it through a process called peristalsis, creating wave-like movements that push the contents of the canal forward, means that initially upon entering the intestine, not all the TTM will dissolve and be bio-available.
[0183] As TTM is a water-soluble crystal, smaller particles have higher specific surface area and thus have faster bioavailability than larger crystals.
[0184] As the intestine eventually will process the TTM dose as it releases from the tablet or capsule with enough water content to dissolve all the TTM in time, having a portion of small particles to create a high bio-availability is important for faster delivery after the tablet or capsule is ingested, and is highly desirable in certain disease states where delivery time to blood is critical. For this reason, ideally 50% of the TTM particles are under 44 μm, for the first immediate dissolution as the enteric capsule dissolves in the intestine.
[0185] An aspect to solving this problem of TTM destruction in the stomach acid is to realize that the enteric capsules and coatings will absorb some moisture and while enteric capsules and coatings are designed to prevent the drug release in the stomach, some moisture can seep through an enteric capsule or enteric tablet, through an enteric coating, to then be in contact with the TTM, causing a chemical reaction that destroys the enteric protection from within the tablet or capsule.
[0186] Another aspect to enhance bioavailability of the TTM is to assure that small particles of TTM survive to be released in the intestine, ideally over 90% of the molecules are smaller than 122 μm, and no less than 50% smaller than 122 μm, when the enteric capsule releases into the intestine.
[0187] According to various embodiments of the disclosure, to solve the stomach acid destruction of the TTM in an enteric capsule, the TTM is isolated from the inside surfaces of the enteric capsule or tablet design and moisture is prevented from contacting the TTM and thereby destroying the integrity of the enteric capsule from the inside. This protection only has to last for a long enough time for the TTM to pass from the stomach to the intestine, generally about 2 hours.
[0188] According to various embodiments, the TTM is encapsulated inside a first capsule, and the first capsule in encapsulated inside a second capsule. In one embodiment, illustrated in
[0189] According to embodiments, one criterion of the smaller capsule inside the larger capsule is that the smaller capsule is of low water content so as not to react with the TTM and slowly dissolve with a minor amount of moisture, where enough of the capsule remains intact for at least two or more hours when subjected to stomach acid, to prevent the moisture that is entering the enteric capsule from destroying the capsule. This result of “enough of the capsule” remaining intact, is a criterion as this is a measurement of the maximum amount of liquid entering through the outer enteric capsule.
[0190] According to embodiments, another criterion of filling TTM in the smaller capsule is that any excipients needed to enhance flow and/or fully fill the capsule when the dosage of TTM is not enough to fill the capsule, the excipient must be of very low or no water content to avoid a reaction with TTM. The inventors determined that while mannitol could be used as a filler, in some embodiments, blending mannitol with colloidal silicon dioxide enhances the ability to absorb moisture, and that colloidal silicon dioxide allowed very good flow into the smaller capsule.
[0191] According to various embodiments for filling a capsule, TTM is blended with only colloidal silicon dioxide, as colloidal silicon dioxide provides a needed benefit of flow enhancement into the capsule and moisture uptake that will increase the stability of the TTM.
[0192] Moisture adsorbs on the surface of colloidal silicon dioxide by the formation of siloxane bonds (≡Si—O—Si—) and silanol groups (≡Si—OH), which are capable of forming numerous hydrogen bonds, thus affecting the collective forces between individual particles, improving the prevention of moisture that can otherwise react to the TTM. The prevention of such moisture or acid ensures the stability of the TTM.
[0193] Gelatin capsules are by design made with 13% to 16% water content and dissolve quickly in moisture and are thus less suitable for encapsulating the TTM, whereas hydroxypropyl methylcellulose (HMPC) capsules are available with a low moisture content of 2 to 3.5%. HPMC capsules have an inherently low moisture content which allows for the encapsulation of ingredients that are sensitive to moisture and are hygroscopic in nature or react to moisture, such as TTM.
[0194] There are two classes of HPMC capsules—the standard HPMC with a water content of 3% to 8%, and low moisture-content HPMC with a water content of 2% to 3.5%. In various embodiments, the low moisture content HPMC capsules will not easily impart moisture to the TTM that would cause H.sub.2S to be released and these HPMC low water content capsules absorb the initial moisture that passes though the enteric capsule and then eventually penetrates the HPMC capsule.
[0195] Note that while any acid that reaches the TTM will start a degradation process and release of H.sub.2S, the degradation of TTM is fast when exposed to acid. For this reason, the TTM must remain dry while in the stomach. The present inventors analyzed several manufacturers of enteric capsules and determined an ideal capsule was one that provided a minimal amount of moisture seepage, because a low level of moisture seepage, when achieved, did not dissolve the HPMC capsule in a rapid fashion, and prevented most of acid from reaching the TTM.
[0196] This innovation is an enteric capsule that limits the moisture contacting the internal capsule to an amount that does not dissolve an HPMC capsule. Not all enteric capsules allow the same amount of acid to seep inside and the enteric capsule selected is designed to be intact for two hours when subjected to stomach acid.
[0197] The present inventors also determined that the smaller HPMC capsule would still start to dissolve and wet the TTM earlier than desired when a surface of the inside smaller HPMC capsule was in direct contact with the inside wall of the larger enteric capsule. To isolate the inside HPMC capsule from the inner wall of the enteric larger capsule, a filler in powder form was added prior to closing the enteric capsule with the HPMC TTM filled capsule inside.
[0198] As shown in
[0199] Another selection criterion for the size of the outer enteric capsule and the inner capsule is that the size differential between the two capsules is enough such that an adequate filler barrier can be placed between the two capsules to assure that the wetness from the outer capsule, when such capsule absorbs water or stomach acid, making the inside of this enteric capsule wet, significantly reduces contact with the inner capsule. In some embodiments, one size that is effective is a size 00 outer enteric capsule with a size 4 inner capsule. Other embodiments utilize a size 000 outer enteric capsule. Some embodiments utilize a size 0-size 5 inner capsule.
[0200] Another innovation of the present disclosure is the vibration of the capsule after assembly that allows the inner capsule to float within the filler and no part of the inner capsule contacts directly the inner wall of the larger enteric capsule. The present inventors found that without such vibration, for some of the filled capsules, the inner capsule still contacted directly the inner surface of the outer enteric capsule, whereby the inner capsule started softening and transferred stomach acid to the TTM, with about 30%-50% of the TTM becoming wet and starting to degrade when submersed in simulated stomach acid for two hours.
[0201] Another innovation of the present disclosure is the selection of a powder or filler or adsorbent, based on silica, that had two key properties. One property is to absorb moisture or acid as this moisture or acid seeps through the outer layer. A second property is to allow the inner capsule to move away from the wall of the outer capsule and “float” while being vibrated to a position where all sides of the inner capsule contact the filler and not the inner wall of the larger enteric capsule. Note that it is important to select non-swelling materials for the filler as otherwise the outer capsules might be destroyed.
[0202] Another innovation of the present disclosure is the selection of a powder or filler, and that while colloidal silicon dioxide may be an ideal moisture absorbent, in some embodiments it is too light to flow well and does not easily fill the capsules. In some embodiments, mesoporous dicalcium phosphate is blended with colloidal silicon dioxide, and an ideal result of preventing the inner capsule to stay dry for at least two hours or more was achieved. In formulations that use solely mesoporous dicalcium phosphate, the absorption properties of mesoporous dicalcium phosphate are not enough to prevent the inner capsule containing the TTM from becoming in contact with the acid that was seeping through the enteric capsule.
[0203] The foregoing disclosure is a design to assure that the TTM has at least two hours before becoming wet, as the human stomach generally passes food to the intestine between 30 minutes to two hours.
[0204] The present inventors were also able to substitute the larger outer capsule with an outer HMPC capsule, such HMPC capsule being either a standard capsule (i.e., 3-8% water content) or a low water capsule (2-3.5% water content), and applying enteric coatings and seals to this larger non-enteric capsule, thereby creating an enteric capsule, and found this could be made to work.
[0205] One alternative embodiment to using the internal HMPC capsule—isolated from the inside of the larger outer capsule with powder added to isolate the internal capsule or tablet—is to replace the internal HMPC capsule with an enteric capsule. This will slow the transfer of moisture and provide more time for the TTM to leave the stomach dry.
[0206] Another alternative embodiment is to replace the inner HMPC capsule with an oil filled capsule. In this embodiment, the TTM is inside of this inner capsule in an oil. A benefit of this approach is that the TTM is then protected from oxidation when suspended in oil and should any water seep in through the wall of the inner capsule, the oil protects the TTM from the water or acid. In some embodiments, ATX is optimally provided in oil, such as olive oil. ATX in oil, between the inner capsule and the outside enteric capsule serves to isolate the internal capsule containing TTM.
[0207] In another embodiment of the oil filled capsule that replaces the HMPC capsule, an enteric coating is applied to the outside of the inner capsule to protect the TTM from any water that seeps into this capsule.
[0208] In another embodiment, the powder inserted between the inner capsule and outer capsule is a mixture of different components, e.g., a co-drug and fillers and/or absorbents. In some embodiments, the co-drug is DEC. In embodiments, the DEC is up to a dose of 300 mg, or less, and can be mixed with adsorbent, such as silica, magnesium oxide/carbonate, kaolin/bentonite or other adsorbing materials or with non-swelling fillers, such as di-calcium phosphate, lactose, sugar-alcohols (such as sorbitol, xylitol and mannitol) and others. In embodiments, the DEC is substituted with ATX. In embodiments, the DEC and ATX are combined together as a substitute for DEC. In various embodiments, SFN is also included in the formulation with DEC or DEC and ATX or alone.
[0209] In some embodiments, the internal capsule is substituted with enterically coated mini-tablets mixed with adsorbent and placed in the outer capsule. In some embodiments, a compressed TTM tablet is enterically coated and placed inside the larger enteric coated capsule.
[0210] In an embodiment of an enterically coated TTM tablet or mini-tablet, the TTM is compressed with a non-reactive binder or compression aid, and is then coated with an enteric coating layer, and potentially, with a barrier-agent layer. Coating occurs via drum or fluid bed spray coating, dip coating, or spray congealing, or other coating approaches. The barrier-agent layer improves resistance to diffusion of moisture through the enteric film, i.e., from reaching the TTM as the enteric coating starts to dissolve. The barrier-agent layer is such that it either absorbs water, or slowly dissolves (e.g., a functional controlled-release polymer), or may be a lipophilic (hydrophobic) coating substance, e.g., lipids and other hydrophobic excipients, preventing water or stomach acid from reaching the TTM for 2 hours. In some embodiments, the barrier layer also contains a co-drug, such as DEC, or ATC, or both ATC and DEC, or another co-drug.
[0211] In another embodiment, the TTM is packaged alone in an enteric tablet or capsule of a design described herein to protect the TTM from acid seeping through the enteric tablet or capsule, and the DEC and/or ATX is packaged in a separate tablet or capsule. In some embodiments, both the DEC and the ATX are enclosed in an enteric tablet or capsule. It is known that DEC is a citrate salt, and as such, large doses can cause nausea. By administering in an enteric tablet or capsule, this nausea is avoided. ATX is highly lipophilic, and presently ATX is being sold as a gel capsule that contains ATX combined with olive oil or other vegetable oils. This combination results in a greater stability of the ATX compound and also in better bioavailability. It has been recommended to take this capsule together with a fat-containing meal to increase bioavailability, largely because ATX, being lipophilic, combines or dissolves in lipids or fats, which protects ATX from the stomach acids. By providing ATX in an enteric capsule, the bioavailability increases. In an embodiment of a DEC and ATX pill, tablet, or capsule, both drugs are combined in an enteric capsule.
[0212] In one embodiment, the DEC is in an internal tablet or capsule, ideally in an enteric capsule or tablet form, surrounded by ATX in oil, and the ATX is filled and captured by an outer capsule or gel cap that, such outer capsule or gel cap that may or may not be enterically coated. In this embodiment, the DEC will not release until after the ATX releases.
[0213] In another embodiment the DEC and ATX are combined in one capsule that may or may not be enterically coated.
[0214] In another embodiment, an outer and larger enteric capsule contains a smaller capsule that contains ATX, the smaller internal capsule with ATX is filled with oil to increase the bio-availability, and this smaller internal capsule with ATX is inserted into a larger capsule. The larger capsule is filled with DEC in a powder form, with or without suitable excipients that may be needed to assure a full fill and adequate flow, between the outer enteric capsule and the ATX internal capsule. The benefit of this design of an ATX/DEC capsule is that the ATX is protected from the stomach acids and the DEC is protected as well, released after the stomach, to avoid the nausea that is a known side effect of DEC in larger doses.
[0215] In some embodiments, a combination tablet of DEC and ATX is administered in a composition containing pharmaceutically acceptable carriers and/or excipients. In embodiments, the compositions are administered in an oral form, such as a tablet, a microtablet, a capsule, or a sachet. In some embodiments, the combination is a composition of an oral form with specific carriers, matrix compounds, and/or excipients that provide a delayed release of the two drugs in the gastrointestinal tract after passage through the stomach. In general, the carriers, matrix compounds, and/or other excipients are selected to facilitate extended and controlled release of the DEC and ATX, enabling optimal intestinal uptake and absorption, guaranteeing stability for storage, and possibly minimizing risk of alcohol-related dose dumping. Moreover, the carriers, matrix compounds, and/or excipients are selected such that destruction by gastric acid is avoided. For this objective, suitable coating materials for enteric coating are applied. In some embodiments, the oral forms of the composition include an enteric coating of the tablet, micro-tablet, capsule, or of individual pellets and beads in the capsule. Also, in some embodiments, multiple coating layers are applied, e.g., a coating layer for enteric coating and an extended release coating layer. Also, in some embodiments, a layer is added to avoid burst release. Also, in some embodiments, different dosage forms are combined, such as capsules in capsules, or mini-tablets in capsules. In embodiments, the capsules and mini-tablets are combined with a filler and an adsorbent to minimize exposure to liquid water and stomach acid.
[0216] In various embodiments, the oral coating is an extended-release coating, whereby the extended-release coating creates a stable administration of the DEC/ATX tablet combination whereby it is released over a period of time creating a long- or extended-release of TTM and eliminating the need for taking several tablets over a given time period.
[0217] In embodiments, the extended release is designed as matrix tablets or pellets in a capsule where either a hydrophilic or lipophilic polymer is used as carrier or a lipid matrix.
[0218] In various hydrophilic matrix system embodiments, DEC and ATX are dispersed throughout a polymer matrix of hydrophilic material. The rate of drug release is controlled by both diffusion and erosion. When water is absorbed by the matrix, the matrix swells and the polymer on the surface of the tablet hydrates. DEC and ATX dissolves and is released by a combination of diffusion out of the matrix, through the gel layer, and as a result of the erosion of the matrix itself. In various embodiments, the matrix system is enterically coated to inhibit destruction of the copper chelator by stomach acid. Alternatively, in some embodiments, the matrix based system is put in an enteric capsule, where the capsule is either made from an enteric material, or is coated and sealed enterically.
[0219] In various hydrophobic matrix system embodiments, DEC and ATX are dispersed throughout a polymer matrix of inert hydrophobic material, either polymer or lipid. In embodiments, the hydrophobic matrix undergoes no or minimal swelling on contact with water. When water enters the matrix, DEC and ATX dissolves and is predominately released by diffusion out of the matrix. In various embodiments, the matrix system is enterically coated to inhibit destruction of the copper chelator by stomach acid. Alternatively, in some embodiments, the matrix based system is put in an enteric capsule, where the capsule is either made from an enteric material, or is coated and sealed enterically.
[0220] In another embodiment, suitable polymers or lipid carriers are used for a hot-melt extrusion process to make the extended-release material, which can further be processed into tablets, micro-tablets, pellets, or beads. One or more coating layer(s) adds enteric protection and avoids burst release. In embodiments, another barrier is coated onto the delivery form (either on top or below the enteric coating). This barrier layer is designed such as to improve resistance to diffusion of moisture through the enteric film, i.e., from reaching the copper chelator as the enteric coating starts to dissolve. The barrier agent layer is such that it either absorbs water, or slowly dissolves (e.g., a functional controlled-release polymer), or is a lipophilic (hydrophobic) coating substance, e.g., lipids and other hydrophobic excipients.
[0221] In various embodiments, the DEC/ATX combination is packaged in an extended release system by designing a reservoir system, whereby a core containing DEC or ATX is surrounded by an insoluble polymer membrane of suitable extended release polymers. In embodiments, the DEC/ATX combo is contained in a single core. In embodiments, the DEC/ATX combo is subunits, such as beads, pellets, or mini-tablets, containing the drug. In embodiments, a coating layer adds enteric protection and avoids burst release.
[0222] In embodiments, DEC and ATX are packaged in a capsule with multiple different subunits, such as micro-tablets, pellets, or beads, with different release characteristics allowing for a multimodal IR (immediate release) plus extended release (ER). The capsule is enterically coated or the subunits are enterically coated. In embodiments, an additional moisture-diffusion-limiting barrier layer minimizes acid-related destruction of the ATX and nausea caused by DEC otherwise releasing in the stomach.
[0223] According to various embodiments, the DEC or ATX is packaged in an extended-release system using an osmotic-release system of a drug-containing core surrounded by an insoluble but semipermeable membrane capsule or coating. This membrane contains an orifice through which the soluble drug is forced by osmotic pressure that builds up inside the capsule on contact with water. This delivery system is enterically coated to ensure that no DEC or ATX is released in the stomach.
[0224]
[0225] In
[0226] In
[0227] In
[0228] In
[0229] In
[0230] In
[0231] In
[0232] In
[0233] In
[0234] In
[0235] In various embodiments of the TTM formulations in
[0236] According to various embodiments of the manufacturing process, direct compaction is used to manufacture the tablets. In some embodiments, a combination of DEC and suitable excipients and ATX and suitable excipients are fed directly to a tablet press, producing a tablet with each drug using standard extended-release excipients (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) and/or more advanced excipients including polymer mixtures. Moreover, other excipients for lubrication, stabilization, coloring, taste-masking, or for use as fillers and binders may be added in the powder mixture. Good flowability of the powder and low tendency for segregation of the powder mixture are desired. The process can be carried out in batch or in continuous mode.
[0237] In another embodiment, roller compaction followed by milling and screening is applied to make granules which are then mixed with lubricants and other excipients for tableting. In an embodiment, DEC and ATX is combined and standard extended-release excipients are used (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) and/or more advanced excipients including polymer mixtures. Moreover, other excipients for stabilization, coloring, taste-masking or for use as fillers and binders may be added in the powder mixture. The process can be carried out in batch or in continuous mode.
[0238] In another embodiment, wet granulation, e.g., via massing and screening or high-shear wet granulation or twin-screw wet granulation, with solvents that do not react to or otherwise degrade the ATX or DEC can be used to make granules, followed by a drying process to produce dry granules which are used for tableting. The solvents used cannot contain water. Standard extended-release excipients may be used (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) and/or more advanced excipients including polymer mixtures. Moreover, other excipients for stabilization, coloring, taste-masking or for use as fillers and binders may be added in the powder mixture. The process can be carried out in batch or in continuous mode.
[0239] In another embodiment, hot-melt extrusion is applied where powders or powder mixtures containing ATX and DEC, a matrix material for extended release, and other excipients are fed to a hot-melt extruder. The extruded strand is cooled and milled, or is directly processed into pellets and beads or to tablets via calandering. In embodiments, milled material is mixed with suitable excipients and is tableted on a tableting machine. The process can be carried out in batch or in continuous mode.
[0240] In embodiments, for coating the DEC/ATX tablets, standard or advanced drum coaters are used that also can be used to carry out multiple coating steps. In embodiments, for coating of micro-tablets, pellets, and beads, fluidized bed coaters are used. Sprayed solutions or suspensions contain the required polymers for enteric coating, or extended release and suitable colors, pigments, surfactants, plasticizers and other components. Alternatively, spray congealing or dip coating is applied.
[0241] In some embodiments, cancer and/or PAH in a patient is treated by administering TTM with a therapeutically effective amount of DEC and ATX. The amount of DEC and ATX administered to the patient is individualized. According to various embodiments, the therapeutically effective amount of the ATX is in a range of about 5 mg to 30 mg of ATX/day.
[0242] The amount of ATX is adjusted according to the level of decrease in oxidative stress markers (e.g., malondialdehyde and isoprostane) and the decrease in markers of inflammation (e.g., CRP and IL-1). According to various embodiments, the amount of DEC administered to the patient is in a range of about 100 mg to 250 mg per dose up to about 1,000 mg per day.
[0243] According to various embodiments, the DEC and ATX are administered in a composition containing pharmaceutically acceptable carriers and/or excipients. In embodiments, the compositions is administered in an oral form, such as a tablet, a microtablet, a capsule filled with pellets or powder, or a sachet. In some embodiments, the DEC and ATX are in a composition of an oral form with specific carriers, matrix compounds, and/or excipients that provide a delayed release of DEC and ATX in the gastrointestinal tract after passage through the stomach. Such matrix materials include, but are not limited to, hydroxypropyl methylcellulose (HMPC), gums, alginates, lipids of various compositions, polyvinyl acetates, polyvinylpyrrolidones, methacrylate copolymers, polyethylene glycols (PEG)/polyethylene oxides (PEO), combinations thereof, and others. In general, the carriers, matrix, and/or other excipients are selected to facilitate extended (sustained) and controlled release of the copper chelator, enabling optimal intestinal uptake and absorption, to guarantee stability for storage and possibly minimizing risk of alcohol-related dose dumping. Moreover, the carriers, matrix and/or excipients are selected such that destruction by gastric acid is avoided. For this objective, suitable coating materials for enteric coating are applied. In embodiments, such a coating is applied externally on the tablet or on drug-containing pellets individually. For example, in some embodiments, the oral forms of the composition include an enteric coating of the tablet, micro-tablet, capsule, or of individual pellets and beads in the capsule. Also, in embodiments, multiple coating layers are applied, e.g., a coating layer for enteric coating and an extended release coating layer. Also, in embodiments, a layer is added to avoid burst release. In embodiments, enteric coatings contain typically pH-sensitive polymers or particles, such as, but not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, shellacs, polyvinyl acetate phthalate, hydroxy-propylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, poly-methacrylic acids, poly-ethyl acrylates, or poly-methacrylates at various mixtures, amylose starches and other starches, dextrins, plant proteins (e.g., zein and others), fatty acids, lipids including modified lipids, waxes, combinations thereof, and other.
[0244] According to various embodiments, the oral coating is an extended-release coating, whereby the extended-release coating creates a stable administration of the DEC and ATX, whereby it is released over a period of time creating a long- or extended-release of DEC and ATX and eliminating the need for taking several dosages over a given time period. Such extended-release coatings are based on different natural or man-made polymers, such as, but not limited to, ethyl celluloses, hydroxypropylmethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxyethylcelluloses, and sodium carboxy-methylcellulose.
[0245] In various embodiments, enteric coatings and extended release coatings layers are external and/or internal to the tablets, beads or pellets and can be combined to protect from acidic stomach content and to create a controlled release profile over an extended amount of time.
[0246] In various embodiments, the extended release system is designed as matrix tablets or pellets in a capsule where either a hydrophilic or lipophilic polymer is used as carrier or a lipid matrix.
[0247] In embodiments of the hydrophilic matrix system, DEC and ATX is dispersed throughout a polymer matrix of hydrophilic materials which have been described above. The rate of drug release is controlled by both diffusion and erosion. When water is absorbed by the matrix, the matrix swells and the polymer on the surface of the tablet hydrates. DEC and ATX dissolves and is released by a combination of diffusion out of the matrix, through the gel layer, and as a result of the erosion of the matrix itself. In formulations, the matrix system is enterically coated to inhibit destruction of the copper chelator by stomach acid. Alternatively, the matrix based system is put in an enteric capsule, where the capsule is either made from an enteric material, or is coated and sealed enterically.
[0248] In embodiments of the hydrophobic matrix system, DEC and ATX is dispersed throughout a polymer matrix of inert hydrophobic materials, either polymer or lipid, as discussed above. In this embodiment, the hydrophobic matrix undergoes no or minimal swelling on contact with water. When water enters the matrix, DEC and ATX dissolves and is predominately released by diffusion out of the matrix. In formulations, the matrix system is enterically coated to inhibit destruction of ATX by stomach acid. Alternatively, the matrix based system is put in an enteric capsule, where the capsule is either made from an enteric material, or is coated and sealed enterically.
[0249] In another embodiment, suitable polymers or lipid carriers or a combination of both are used for a hot-melt extrusion process to make the extended-release material which can further be processed into tablets, micro-tablets, pellets, and beads. In some embodiments, coating layer(s) for enteric coating and controlled release coating add enteric protection and help avoid burst release. In embodiments, another barrier is coated onto the delivery form (either on top or below the enteric coating). This barrier layer is designed such as to improve resistance to diffusion of moisture through the enteric film, i.e., from reaching ATX as well as the copper chelator as the enteric coating starts to dissolve. The barrier agent layer is such that it either absorbs water, or slowly dissolves (e.g., a functional controlled-release polymer), or is a lipophilic (hydrophobic) coating substance, e.g., lipids and other hydrophobic excipients.
[0250] In another embodiment, the DEC and ATX are packaged in an extended release system by designing a reservoir system, whereby a core containing DEC and ATX is surrounded by an insoluble polymer membrane of suitable extended release polymers. In such an embodiment, the DEC and ATX are contained in a single core. In another embodiment, the DEC and ATX are subunits, such as beads, pellets, or mini-tablets, containing the drug. In embodiments, an enteric coating layer adds enteric protection and avoids burst release.
[0251] In embodiments, DEC and ATX is packaged in a capsule with multiple different subunits, such as micro-tablets, pellets, or beads, with different release characteristics allowing for a multimodal IR (immediate release) plus extended release (ER). In embodiments, the capsule is enterically coated or the subunits are enterically coated. In embodiments, an additional moisture-diffusion-limiting barrier layer minimizes acid-related destruction of the copper chelator.
[0252] In embodiments, the DEC and ATX are packaged in an extended-release system using an osmotic-release system including a drug-containing core surrounded by an insoluble but semipermeable membrane capsule or coating. This membrane contains an orifice through which the soluble drug is forced by osmotic pressure that builds up inside the capsule on contact with water. In embodiments, the semipermeable membrane is made of polymeric materials, such as, but not limited to, cellulose acetate polymers, cellulose esters, cellulose ethers, agar acetates, amylose triacetates, betaglucan acetates, poly(vinylmethyl)ether copolymers, poly(orthoesters), polyacetals and selectively permeable poly(glycolic acid), poly(lactic acid) derivatives, as well as Eudragits. Embodiments of this delivery system are enterically coated to ensure that no copper chelator or ATX or DEC is released in the stomach.
[0253] In an embodiment of the manufacturing process, direct compaction is used to manufacture the tablets. In this process, a mixture of DEC and ATX and suitable excipients are fed directly or individually to a tablet press, using standard extended-release excipients (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) and/or more advanced excipients including polymer mixtures. In some embodiments, other excipients for lubrication, stabilization, coloring, taste-masking, or for use as fillers and binders are added in the powder mixture. Such excipients include, but are not limited to, metal soaps such as magnesium stearate, sodium stearyl fumarate, croscarmellose sodium, modified starches, modified lactoses, dextrins, glucose, sucrose, sorbitol dicalcium phosphates, vitamins, colorants, sugar alcohols, crospovidone, polymers and copolymers, silica compounds, silicone or alginates, microcrystalline cellulose, and hydroxypropylcellulose. Good flowability of the powder and low tendency for segregation of the powder mixture are advantageous. Embodiments of the process are carried out in batch or in continuous mode.
[0254] In another embodiment, roller compaction followed by milling and screening is applied to make granules, which are then mixed with lubricants and other excipients for tableting. In embodiments, standard extended-release excipients are used (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) and/or more advanced excipients including polymer mixtures. In some embodiments, other excipients for stabilization, coloring, taste-masking or for use as fillers and binders are added in the powder mixture. Embodiments of the process are carried out in batch or in continuous mode.
[0255] In another embodiment, wet granulation, e.g., via massing and screening or high-shear wet granulation or twin-screw wet granulation, with solvents that do not to destroy DEC and ATX are used to make granules, followed by a drying process (e.g., via tray drying, fluid bed drying, conveyer belt drying and other methods) to produce dry granules which are used for tableting. In embodiments, standard extended-release excipients are used (such as a HPMC, PEO or Eudragit RL, RS, cross-linked PVA) and/or more advanced excipients including polymer mixtures. In some embodiments, other excipients for stabilization, coloring, taste-masking or for use as fillers and binders are added in the powder mixture. Embodiments of the process are carried out in batch or in continuous mode. In some embodiments, granules are filled in capsules and sachets, or are used for tableting if mixed with an external phase, such as lubricants or binders.
[0256] In another embodiment, granules are produced via wet granulation in extruders where a suitable solvent is added and matrix materials and DEC and ATX are added either separately or as a premix. Extruders include twin-screw extruders, radial screw extruders, roll extruders or Koller press extruders. Subsequently to extrusion, granules are dried via methods as described herein. Materials are selected based on required formulation and biopharmaceutical requirements as described herein. In some embodiments, granules are filled in capsules and sachets, or are used for tableting if mixed with an external phase, such as lubricants or binders.
[0257] In another embodiment, hot-melt extrusion is applied where powders or powder mixtures containing DEC and ATX, a matrix material for extended release and other excipients are fed to a hot-melt extruder. The extruded strand is cooled and milled, or is directly processed into pellets and beads or to tablets via calandering. In embodiments, milled material is mixed with suitable excipients and is tableted on a tableting machine. Embodiments of the process are carried out in batch or in continuous mode.
[0258] In another embodiment, additive manufacturing technology, also known as 3D printing, is applied to make tablets of a desired release profile. For such a process, filaments are manufactured that contain the DEC and ATX and delayed-release matrix materials as described herein. In embodiments, these filaments are made by extrusions process as described herein using different types of extruders including single-screw, double-screw or ram extruders. Filaments are then used to print tablets via thermal technique, such as fused deposition modeling. Alternatively, melt from extruders is directly used to cast tablets via additive manufacturing technology. In embodiments, other additive manufacturing technologies are applied such as powder bed printing, inject printing, VAT polymerization, direct-wise printing, and others. Materials for printing include delayed-release artificial and natural polymers, starches, lactoses, hydroalcohols, lipids, and other natural products.
[0259] According to various embodiments for coating the tablets, standard or advanced drum coaters are used, and in some embodiments, also are used to carry out multiple coating steps. In embodiments for coating of micro-tablets, pellets and beads fluidized bed coaters are used. Sprayed solutions or suspensions contain the required polymers for enteric coating, or extended release coatings, and suitable colors, pigments, surfactants, plasticizers, and other components.
[0260] According to various embodiments, an extended release tablet contains DEC and/or ATX as co-drugs. Such embodiments contain suitable formulations that minimize chemical interaction between DEC and TTM and ATX. According to various embodiments, formulation techniques are used that separate the chemicals spatially. In some embodiments, this is achieved by making multi-layer tablets with layer 1 containing DEC and layer 2 containing ATX. In some embodiments, pellets of two types are made with methods described herein, with pellet (or bead) type 1 containing DEC and pellet (or bead) type 2 containing ATX. In various embodiments, the pellet (or bead) types are processed in different ways, e.g., by compressing them into one tablet, or coating them separately and embedding them in a matrix material, called multi-unit pellet system (MUPS). In some embodiments, the produced tablets are coated enterically or with extended release coating. In some embodiments, the matrix material of the MUPS is made of extended release matrix materials as described herein. Another embodiment is to prepare multilayer coating of inert bead, having different APIs in different coating layers. Thereafter the beads are filled in capsules with release modifiers. In another embodiment, the DEC and the ATX loaded particles (pellets) are prepared as per the methods mentioned herein and thereafter are coated with polymers/excipients having other API. Thereafter, the coated particles are delivered as tablets with excipients or filled in capsules with release modifiers and excipients. Another embodiment uses an active coating of the co-drug. In this case, DEC is contained in the core of the tablet and a suspension or solution containing the ATX is sprayed on the tablets via a conventional coating process. In further embodiments, the tablet is enterically coated or coated with an extended release polymer. Alternatively, the ATX is contained in the core of the tablet and a suspension or solution containing the DEC is sprayed on the tablets via a conventional coating process. In further embodiments, the tablet is enterically coated or coated with an extended release polymer
[0261] In embodiments, the DEC is at a dose of 100 mg to 250 mg in an enteric capsule that is encapsulated in a larger capsule containing ATX and olive oil or another oil, where the outer capsule is or is not enteric coated and may be a hard capsule or a gel capsule. DEC in higher doses is known to create nausea and the benefit of an enteric coating is to prevent the DEC from releasing in the stomach and reduce or eliminate the nausea side effect.
[0262] The foregoing description and accompanying figures illustrate the principles, embodiments, and modes of operation of the present disclosure. However, the present disclosure should not be construed as being limited to the particular embodiments discussed herein. Additional variations of the embodiments discussed herein will be appreciated by those skilled in the art.
[0263] Therefore, the embodiments described herein should be regarded as illustrative rather than restrictive. Accordingly, it should be appreciated that variations to those embodiments may be made by those skilled in the art without departing from the scope of the disclosure as defined by the following claims.
[0264] It is to be understood that where the claims or specification refer to “a” or “an” element, such reference is not to be construed that there is only one of the element. If the specification or claims refer to “an additional” element, that does not preclude there being more than one of the additional element.
[0265] For purposes of the disclosure, the term “at least” followed by a number is used herein to denote the start of a range beginning with that number (which may be a range having an upper limit or no upper limit, depending on the variable being defined). For example, “at least 1” means 1 or more than 1. Terms of approximation, such as “about,” should be interpreted according to their ordinary and customary meanings as used in the associated art unless indicated otherwise. Absent a specific definition and absent ordinary and customary usage in the associated art, such terms should be interpreted to be ±10% of the base value.
[0266] When a range is given as “(a first number) to (a second number)” or “(a first number)-(a second number)” this means a range whose lower limit is the first number and whose upper limit is the second number. For example, 25 to 100 or 25-100 should be interpreted to mean a range whose lower limit is 25 and whose upper limit is 100. Additionally, it should be noted that where a range is given, every possible subrange or interval within that range is also specifically intended unless the context indicates to the contrary. For example, if the specification indicates a range of 25 to 100 such range is also intended to include subranges such as 26-100, 27-100, etc., 25-99, 25-98, etc., as well as any other possible combination of lower and upper values within the stated range, e.g., 33-47, 60-97, 41-45, 28-96, etc. Note that integer range values have been used in this paragraph for purposes of illustration only and decimal and fractional values (e.g., 46.7-91.3) should also be understood to be intended as possible subrange endpoints unless specifically excluded.
[0267] While inventive concepts have been described and illustrated herein by reference to certain embodiments, various changes and further modifications may be made by those of ordinary skill in the art without departing from the spirit of the inventive concept, the scope of which is to be determined by the following claims.