Compositions, formulations, and methods of treating neurodegenerative diseases
The present disclosure relates to compositions, formulations, and associated methods for treating neurodegenerative diseases, wherein the compositions include an alpha-1 adrenergic agonist, such as midodrine, and an alpha-2A adrenergic agonist, such as dexmedetomidine. Upon administering to a human subject, the alpha-2A adrenergic agonist crosses the subject's blood-brain barrier thereby acting upon the subject's central nervous system, whereas the alpha-1 adrenergic agonist does not cross the subject's blood-brain barrier. The alpha-1 adrenergic agonist minimizes or eliminates the systemic vascular effects induced by the alpha-2A adrenergic agonist that causes the negative cerebral autoregulatory response, thereby enabling the alpha-2A adrenergic agonist to increase glymphatic flow in the subject's brain.
1 . An orally or parenterally administered pharmaceutical composition comprising
dexmedetomidine, or a pharmaceutically acceptable salt thereof; and
midodrine, or a pharmaceutically acceptable salt thereof.
2 . The orally or parenterally administered pharmaceutical composition of claim 1 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, is 240 micrograms to 2400 micrograms and the midodrine, or the pharmaceutically acceptable salt thereof, is 2 milligrams to 15 milligrams.
3 . The orally or parenterally administered pharmaceutical composition of claim 1 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, is present in an effective amount to achieve a maximum blood concentration in a subject of 100 pg/mL to 2000 pg/mL and the midodrine, or the pharmaceutically acceptable salt thereof, is present in an effective amount to achieve a maximum blood concentration of active metabolite desglymidodrine in the subject of 5 ng/mL to 100 ng/mL.
4 . The orally or parenterally administered pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
5 . The orally or parenterally administered pharmaceutical composition according to claim 1 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are provided as separate components of the pharmaceutical composition.
6 . The orally or parenterally administered pharmaceutical composition according to claim 1 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are provided as integrated components of the pharmaceutical composition.
7 . The orally or parenterally administered pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is provided orally in a dosage form selected from the group consisting of a film, a wafer, a lozenge, a gel, a spray, a tablet, a capsule, a powder, and a liquid drop.
8 . The orally or parenterally administered pharmaceutical composition according to claim 1 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are present in an effective amount to enhance clearance of proteinopathy proteins in a human.
9 . A method comprising
orally or parenterally administering a pharmaceutical composition to a human, the pharmaceutical composition comprising
dexmedetomidine, or a pharmaceutically acceptable salt thereof, and
midodrine, or a pharmaceutically acceptable salt thereof.
10 . The method according to claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are administered to the subject simultaneously.
11 . The method according to claim 9 , wherein the midodrine, or the pharmaceutically acceptable salt thereof, is administered to the human before the dexmedetomidine, or the pharmaceutically acceptable salt thereof, is administered to the human.
12 . The method according to claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, that is administered is 240 micrograms to 2,400 micrograms, and the midodrine, or the pharmaceutically acceptable salt thereof, that is administered is 2 milligrams to 15 milligrams.
13 . The method according to claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, that is administered achieves a maximum blood concentration in the human of 100 pg/mL to 2000 pg/mL and the midodrine, or the pharmaceutically acceptable salt thereof, that is administered achieves a maximum blood concentration of active metabolite desglymidodrine in the human of 5 ng/ml to 100 ng/mL.
14 . The method according to claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are administered as separate components of a pharmaceutical composition.
15 . The method according to claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are administered as integrated components of a pharmaceutical composition.
16 . The method according to claim 9 , wherein the pharmaceutical composition is provided orally in a dosage form selected from the group consisting of a film, a wafer, a lozenge, a gel, a spray, a tablet, a capsule, a powder, and a liquid drop.
17 . An orally or parenterally administered pharmaceutical formulation comprising
dexmedetomidine or a pharmaceutically acceptable salt thereof;
midodrine or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable carrier or pharmaceutically acceptable excipient.
18 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salt forms.
19 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of a diluent, a binder, a dye, a preservative, an antioxidant, a flavoring, and a lubricant.
20 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of a liposome, a polymer matrix, a sugar, a starch, cellulose, a wax, a polyol, a buffering agent, agar, and a saline solution.
21 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the pharmaceutical formulation is provided orally and in a dosage form selected from the group consisting of a film, a wafer, a lozenge, a gel, a spray, a tablet, a capsule, a powder, and a liquid drop.
22 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are present in an effective amount to enhance clearance of proteinopathy proteins in a human.
23 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the pharmaceutical formulation is administered orally, and
wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, is 240 micrograms to 2400 micrograms and
the midodrine, or the pharmaceutically acceptable salt thereof, is 2 milligrams to 15 milligrams.
24 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, is present in an effective amount to achieve a maximum blood concentration in a subject of 100 pg/mL to 2000 pg/mL and the midodrine, or the pharmaceutically acceptable salt thereof, is present in an effective amount to achieve a maximum blood concentration of active metabolite desglymidodrine in the subject of 5 ng/ml to 100 ng/mL.
25 . The orally or parenterally administered pharmaceutical formulation according to claim 17 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, achieves a maximum blood concentration in a subject of 100 pg/mL to 2000 pg/mL at a T max-d time interval and the midodrine, or the pharmaceutically acceptable salt thereof, achieves a maximum blood concentration of active metabolite desglymidodrine in the subject of 5 ng/mL to 100 ng/mL at a T max-m time interval, wherein the T max-d time interval does not diverge from the T-max-m time interval by more than 20%.
26 . The orally or parenterally administered pharmaceutical composition of claim 1 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, achieves a maximum blood concentration in a subject of 100 pg/mL to 2000 pg/mL at a T max-d time interval and the midodrine, or the pharmaceutically acceptable salt thereof, achieves a maximum blood concentration of active metabolite desglymidodrine in the subject of 5 ng/ml to 100 ng/ml at a T max-m time interval, wherein the T max-d time interval does not diverge from the T-max-m time interval by more than 20%.
27 . The method of claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, achieves a maximum blood concentration in the human of 100 pg/mL to 2000 pg/mL at a T max-d time interval and the midodrine, or the pharmaceutically acceptable salt thereof, achieves a maximum blood concentration of active metabolite desglymidodrine in the human of 5 ng/mL to 100 ng/mL at a T max-m time interval, wherein the T max-d time interval does not diverge from the T-max-m time interval by more than 20%.
28 . The method of claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, and the midodrine, or the pharmaceutically acceptable salt thereof, are present in an effective amount to enhance clearance of proteinopathy proteins in the human.
29 . The orally or parenterally administered pharmaceutical composition of claim 1 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, is 40 to 400 micrograms and the midodrine, or the pharmaceutically acceptable salt thereof, is 2 milligrams to 15 milligrams.
30 . The method of claim 9 , wherein the dexmedetomidine, or the pharmaceutically acceptable salt thereof, that is administered is 40 to 400 micrograms, and the midodrine, or the pharmaceutically acceptable salt thereof, that is administered is 2 milligrams to 15 milligrams.