Liquid formulations for treatment of diseases or conditions
Diseases and conditions associated with tissues of the body, including but not limited to tissues in the eye, can be effectively treated, prevented, inhibited, onset delayed, or regression caused by administering therapeutic agents to those tissues. Described herein are liquid formulations which deliver a variety of therapeutic agents, including but not limited to rapamycin, to a subject for an extended period of time; liquid formulations which form a non-dispersed mass when placed in an aqueous medium of a subject; non-dispersed mass-forming liquid formulations which form a gel or gel-like substance in an aqueous medium; liquid formulations, comprising a therapeutic agent and a plurality of polymers; and methods for delivering therapeutic agents to a subject for an extended period of time using the liquid formulations. The liquid formulation may be placed in an aqueous medium of a subject, including but not limited to via intraocular or periocular administration, or placement proximate to a site of a disease or condition to be treated in a subject. A method may be used to administer rapamycin to treat or prevent angiogenesis, choroidal neovascularization, or age-related macular degeneration, or wet age-related macular degeneration in a subject. The liquid formulations may comprise rapamycin or other therapeutic agents.
1 . A liquid formulation comprising a therapeutic agent, wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/mg.
2 . A liquid formulation comprising a therapeutic agent, wherein the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 1000 ng/ml.
3 . A liquid formulation comprising a therapeutic agent, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/ml.
4 . A liquid formulation comprising a therapeutic agent, wherein the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.001 ng/mg.
5 . A liquid formulation comprising a therapeutic agent, wherein the liquid formulation forms a non-dispersed mass when injected into the vitreous of a rabbit eye.
6 . The liquid formulation of claim 1 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001, temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of rapamycin; rapamycin arylsulfonates, rapamycin sulfamates, monoesters at positions 31 and 42, diesters at positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs, analogs, salts and esters thereof.
7 . The liquid formulation of claim 6 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof.
8 . The liquid formulation of claim 2 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001, temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of rapamycin; rapamycin arylsulfonates, rapamycin sulfamates, monoesters at positions 31 and 42, diesters at positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs, analogs, salts and esters thereof.
9 . The liquid formulation of claim 8 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof.
10 . The liquid formulation of claim 3 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001, temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of rapamycin; rapamycin arylsulfonates, rapamycin sulfamates, monoesters at positions 31 and 42, diesters at positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs, analogs, salts and esters thereof.
11 . The liquid formulation of claim 10 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof.
12 . The liquid formulation of claim 4 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001, temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of rapamycin; rapamycin arylsulfonates, rapamycin sulfamates, monoesters at positions 31 and 42, diesters at positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs, analogs, salts and esters thereof.
13 . The liquid formulation of claim 12 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof.
14 . The liquid formulation of claim 5 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001, temsirolimus AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin, 2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of rapamycin; rapamycin arylsulfonates, rapamycin sulfamates, monoesters at positions 31 and 42, diesters at positions 31 and 42, 30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs, analogs, salts and esters thereof.
15 . The liquid formulation of claim 14 , wherein the therapeutic agent is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof.
16 . A method for treating wet age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery a volume of the liquid formulation of any of claims 7 , 9 , 11 , 13 , and 15 containing an amount of rapamycin effective to treat wet age-related macular degeneration in the human subject.
17 . A method for preventing wet age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery a volume of the liquid formulation of any of claims 7 , 9 , 11 , 13 , and 15 containing an amount of rapamycin effective to prevent wet age-related macular degeneration in the human subject.
18 . The method of claim 16 , wherein the liquid formulation further comprises polyethylene glycol and wherein the volume of liquid formulation is administered to the human subject by placement in the vitreous and the volume of liquid formulation contains less than 100 μL of polyethylene glycol.
19 . The method of claim 16 , wherein the liquid formulation further comprises polyethylene glycol and wherein the volume of liquid formulation is administered to the human subject by placement between the sclera and conjunctiva and the volume of liquid formulation contains less than 150 μL of polyethylene glycol.
20 . The method of claim 17 , wherein the liquid formulation further comprises polyethylene glycol and wherein the volume of liquid formulation is administered to the human subject by placement between the sclera and conjunctiva and the volume of liquid formulation contains less than 150 μL of polyethylene glycol.
21 . A method for treating wet age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery of a liquid formulation comprising an effective amount of a therapeutic agent selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof; and wherein the liquid formulation has one or more characteristics selected from the group consisting of (1) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/mg; (2) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 1000 ng/ml; (3) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/ml; (4) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.001 ng/mg; and (5) the liquid formulation forms a non-dispersed mass when injected into the vitreous of a rabbit eye.
22 . A method for preventing wet age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery of a liquid formulation comprising an effective amount of a therapeutic agent selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof; and wherein the liquid formulation has one or more characteristic selected from the group consisting of (1) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/mg; (2) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 1000 ng/ml; (3) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/ml; (4) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.001 ng/mg; and (5) the liquid formulation forms a non-dispersed mass when injected into the vitreous of a rabbit eye.
23 . The method of claim 22 , wherein the human subject is identified as being at heightened risk of developing wet age-related macular degeneration in the eye to which the liquid formulation is administered.
24 . The method of claim 23 , wherein the human subject has dry age-related macular degeneration in at least one eye.
25 . The method of claim 23 , wherein the human subject has wet age-related macular degeneration in one eye and the liquid formulation is administered to the eye without wet age-related macular degeneration.
26 . A method for treating dry age-related macular degeneration in a human subject, the method comprising administering to the human subject by intraocular or periocular delivery of a liquid formulation comprising an effective amount of a therapeutic agent selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof; and wherein the liquid formulation has one or more characteristic selected from the group consisting of (1) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/mg; (2) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 1000 ng/ml; (3) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/ml; (4) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.001 ng/mg; and (5) the liquid formulation forms a non-dispersed mass when injected into the vitreous of a rabbit eye.
27 . A method for preventing wet age-related macular degeneration in a human subject having dry age-related macular degeneration, the method comprising administering to a human subject having dry age-related macular degeneration a liquid formulation comprising an effective amount of a therapeutic agent selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically acceptable salts and esters thereof; wherein the liquid formulation is administered by intraocular or periocular delivery; and wherein the liquid formulation has one or more characteristic selected from the group consisting of (1) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/mg; (2) the liquid formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 1000 ng/ml; (3) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the vitreous of the rabbit eye equivalent to a rapamycin concentration of at least 0.01 ng/ml; (4) the liquid formulation when injected between the sclera and conjunctiva of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve, for a period of time of at least 30 days following administration of the liquid formulation, an average concentration of therapeutic agent in the retina choroid tissues of the rabbit eye equivalent to a rapamycin concentration of at least 0.001 ng/mg; and (5) the liquid formulation forms a non-dispersed mass when injected into the vitreous of a rabbit eye.