Formulations for ocular treatment
Diseases and conditions associated with tissues of the body, including tissues in the eye, can be effectively treated by administering therapeutic agents to those tissues. Described herein are self-emulsifying formulations and methods for delivering therapeutic agents to such tissues. A self-emulsifying formulation may be delivered to an aqueous medium of a subject, including but not limited to the vitreous. A method may, for instance, be used to administer rapamycin or related compounds to treat or prevent choroidal neovascularization associated with age-related macular degeneration, or to treat dry AMD. A self-emulsifying formulation may also be administered systemically, such as orally, to treat transplant rejection in a subject. A self-emulsifying formulation may comprise rapamycin, related compounds, or other therapeutic agents.
1 . A method for treating age-related macular degeneration in a human, the method comprising administering to an eye of a subject a self-emulsifying formulation comprising a therapeutic agent in an amount effective to treat age-related macular degeneration.
2 . The method of claim 1 , wherein the self-emulsifying formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve an average concentration of therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least about 0.001 ng/ml for a period of time of at least about 7 days following administration of the self-emulsifying formulation to the rabbit eye.
3 . The method of claim 2 , wherein the self-emulsifying formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve an average concentration of therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least about 0.01 ng/ml for a period of time of at least about 7 days following administration of the self-emulsifying formulation to the rabbit eye.
4 . The method of claim 3 , wherein the self-emulsifying formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve an average concentration of therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least about 0.1 ng/ml for a period of time of at least about 7 days following administration of the self-emulsifying formulation to the rabbit eye.
5 . The method of claim 2 , wherein the self-emulsifying formulation when injected into the vitreous of a rabbit eye delivers an amount of the therapeutic agent sufficient to achieve an average concentration of therapeutic agent in the retina choroid of the rabbit eye equivalent to a rapamycin concentration of at least about 1 ng/ml for a period of time of at least about 7 days following administration of the self-emulsifying formulation to the rabbit eye.
6 . The method of claim 1 , wherein the therapeutic agent is an immunophilin binding compound.
7 . The method 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, and analogs, salts and esters thereof.
8 . The method of claim 7 , wherein the therapeutic agent is rapamycin.
9 . The method of claim 1 , wherein the self-emulsifying formulation is placed in an aqueous medium of the eye of the subject.
10 . The method of claim 9 , wherein the self-emulsifying formulation is placed into the vitreous of an eye of the subject.
11 . The method of claim 9 , wherein the self-emulsifying formulation is placed between the sclera and conjunctiva of an eye of the subject.
12 . The method of claim 1 , wherein the self-emulsifying formulation further comprises a solvent.
13 . The method of claim 12 , wherein the self-emulsifying formulation further comprises a surfactant.
14 . The method of claim 13 , wherein the surfactant is a nonionic surfactant.
15 . The method of claim 14 , wherein the nonionic surfactant has an HLB value greater than about 10.
16 . The method of claim 15 , wherein, wherein the nonionic surfactant is Cremophor EL.
17 . The method of claim 12 , wherein the solvent is a fatty acid.
18 . The method of claim 12 , wherein the solvent is selected from the group consisting of oleic acid, Imwitor 742, Softigen 767, or Capmuls PG8.
19 . A method for treating a disease or disorder in a human, the method comprising administering to an eye of a human subject a self-emulsifying formulation comprising rapamycin in an amount effective to treat one or more of choroidal neovascularization, iris neovascularization, macular degeneration, wet AMD, dry AMD, uveitis, allergic conjunctivitis, dry eye, glaucoma, retinitis pigmentosa, central retinal vein occlusive diseases, macular edema, diabetic retinopathy, and corneal graft disease.
20 . The method of claim 19 , wherein the rapamycin is present in an amount effective to treat wet AMD.
21 . The method of claim 19 , wherein the rapamycin is present in an amount effective to prevent wet AMD.
22 . The method of either of claims 20 or 21 , wherein the self-emulsifying formulation is placed in the vitreous of the subject's eye.
23 . The method of either of claims 20 or 21 , wherein the self-emulsifying formulation is placed between the sclera and conjunctiva of the subject's eye.
24 . The method of claim 22 , wherein the self-emulsifying formulation contains between about 20 μg and about 4 mg.
25 . The method of claim 23 , wherein the self-emulsifying formulation contains between about 20 μg and about 4 mg.
26 . The method of either of claims 24 or 25 , wherein the self-emulsifying formulation contains between about 20 μg and about 2 mg.
27 . A self-emulsifying formulation comprising an amount of an immunophilin binding compound effective to treat wet AME, dry AMD, or CNV; a solvent; and a surfactant, wherein the self-emulsifying formulation is formulated for placement in an aqueous medium of an eye of a subject.
28 . A self-emulsifying formulation comprising an amount of an immunophilin binding compound effective to prevent wet AMD; a solvent; and a surfactant, wherein the self-emulsifying formulation is formulated for placement in an aqueous medium of an eye of a subject.
29 . The self-emulsifying formulation of claim 28 , wherein the compound is selected from the group consisting of rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, and analogs, salts and esters thereof.
30 . The self-emulsifying formulation of claim 29 , wherein the compound is rapamycin.
31 . The self-emulsifying formulation of claim 30 , wherein the self-emulsifying formulation when administered to a subject delivers an amount of rapamycin effective to treat choroidal neovascularization in the subject.
32 . The self-emulsifying formulation of claim 30 , wherein the self-emulsifying formulation when administered to a subject delivers an amount of rapamycin effective to treat wet age-related macular degeneration in the subject.
33 . The self-emulsifying formulation of claim 30 , wherein the self-emulsifying formulation when administered to a subject delivers an amount of rapamycin effective to prevent wet age-related macular degeneration in the subject.
34 . The self-emulsifying formulation of claim 30 , wherein the surfactant is nonionic.
35 . The self-emulsifying formulation of claim 30 , wherein the surfactant has an HLB value greater than about 10.
36 . The self-emulsifying formulation of claim 30 , wherein the solvent is a fatty acid.
37 . The self-emulsifying formulation of claim 30 , wherein the solvent is selected from the group consisting of oleic acid, Imwitor 742, Softigen 767, or Capmuls PG8.
38 . The self-emulsifying formulation of claim 34 , wherein the nonionic surfactant is Cremophor EL.
39 . The self-emulsifying formulation of claim 34 , wherein the self-emulsifying formulation contains between 0.1 to 5% w/w rapamycin; between about 40 to 50% w/w solvent; and between 40 to 50% w/w non-ionic surfactant.
40 . The self-emulsifying formulation of claim 39 , further comprising ethanol.