Ketamine formulation for subcutaneous injection
Provided herein are subcutaneous formulations of ketamine that are useful for treating a variety of disease and disorders. The subcutaneous ketamine formulations provided herein reduce injection site irritation and pain.
1. A pharmaceutical composition, comprising:
(i) a compound of structural Formula (I):
or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and
(ii) at least one pharmaceutically acceptable excipient; and
(iii) a complexing agent comprising a substituted cyclodextrin comprising a plurality of acidic functional groups, wherein at least two of the plurality of acidic functional groups are deprotonated counter-anions for a protonated form of a plurality of the compound of structural Formula (I), wherein the pharmaceutical composition has a reduced osmolality relative to a composition comprising a salt of the complexing agent and a salt of the compound of structural Formula (I).
2. The pharmaceutical composition of claim 1 , wherein the cyclodextrin is substituted with 3 to 8 acidic functional groups.
3. The pharmaceutical composition of claim 1 , wherein the substituted cyclodextrin is sulfobutyl-ether-beta-cyclodextrin (SBEBCD).
4. The pharmaceutical composition of claim 1 , wherein the composition has a ratio of the complexing agent to the compound of Formula (I) that is from about 1:4 to about 1:10.
5. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition has an osmolality of no more than about 600 mOsm/kg.
6. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition has a pH of about 4.5 to about 7.
7. The pharmaceutical composition of claim 1 , wherein the compound of Formula (I) or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or solvate or hydrate thereof, has a concentration at least about 20 mg/mL.
8. A pharmaceutical composition, comprising:
(i) a compound of structural Formula (I):
or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof;
wherein at least about 75% of the compound of structural Formula (I) is ionized and has a structure of Formula (I-A):
wherein X − is a substituted cyclodextrin comprising a plurality of acidic functional groups that are deprotonated counter-anions for a plurality of the compound of structural Formula (I-A), wherein the pharmaceutical composition has a reduced osmolality relative to a composition comprising a salt of the complexing agent and a salt of the compound of structural Formula (I).
9. The pharmaceutical composition of claim 8 , wherein the substituted cyclodextrin is substituted with 3 to 8 acidic functional groups.
10. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition has a molar ratio of the substituted cyclodextrin to the compound of structural Formula (I) that is from about 1:4 to about 1:10.
11. The pharmaceutical composition of claim 8 , wherein the substituted cyclodextrin is SBEBCD.
12. The pharmaceutical composition of claim 8 , wherein the substituted cyclodextrin is present in an amount of about 50 mg/mL to about 600 mg/mL.
13. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition has an osmolality of no more than about 600 mOsm/kg.
14. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition has a pH of about 4.5 to about 7.
15. The pharmaceutical composition of claim 8 , wherein the compound of Formula (I) or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or solvate or hydrate thereof, has a concentration at least about 20 mg/mL.
16. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition further comprises a preservative.
17. A method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of structural Formula (I):
or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and
a complexing agent comprising a substituted cyclodextrin comprising a plurality of acidic functional groups that are deprotonated counter-anions for a plurality of the compound of structural Formula (I);
wherein the pharmaceutical composition is administered by subcutaneous or intramuscular injection, wherein the pharmaceutical composition has a pH from 4.5 to 7 and a reduced osmolality relative to a composition comprising a salt of the complexing agent and a salt of the compound of structural Formula (I).
18. The pharmaceutical composition of claim 2 , wherein the 3 to 8 acidic functional groups comprise carboxylic acids, sulfonic acids, or both.
19. The pharmaceutical composition of claim 9 , wherein the 3 to 8 acidic functional groups comprise carboxylic acids, sulfonic acids, or both.
20. The pharmaceutical composition of claim 17 , wherein the cyclodextrin is substituted with 3 to 8 acidic functional groups comprising carboxylic acids, sulfonic acids, or both.