Complexing agent salt formulations of pharmaceutical compounds
Provided herein are pharmaceutical formulations and pharmaceutical compound salts which utilize complexing agents as counterions. Such formulations and salts are useful for treating a variety of disease and disorders.
1. A pharmaceutical composition, comprising:
(i) a pharmaceutical compound, or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof, wherein the pharmaceutical compound comprises a protonated nitrogen atom, wherein the pharmaceutical compound is not ketamine; and
(ii) a complexing agent, wherein the complexing agent is an acid-substituted cyclodextrin comprising a plurality of acidic functional groups, wherein the plurality of acidic functional groups comprise an acidic group which acts as a counterion for the protonated nitrogen atom of the pharmaceutical compound;
wherein the pharmaceutical composition is formulated for subcutaneous or intramuscular administration as an aqueous formulation having a pH of at least about 5.5;
wherein the osmolality of the pharmaceutical composition is lower than an osmolality of a composition comprising an equivalent amount of a freebase form of the pharmaceutical compound encapsulated within a hydrophobic core of a salt of the complexing agent; wherein the composition has a molar ratio of the pharmaceutical compound to the complexing agent of at least 1:1.
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 2 , wherein the cyclodextrin is sulfobutylether-β-cyclodextrin.
4. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is substantially free of excess ions.
5. The pharmaceutical composition of claim 1 , wherein the composition has a molar ratio of complexing agent to the pharmaceutical compound that is from about 1:4 to about 1:10.
6. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition has an osmolality of no more than about 850 mOsm/kg.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition has a pH of about 5.5 to about 8.
8. The pharmaceutical composition of claim 1 , wherein the complexing agent is present in an amount of about 10 mg/mL to about 600 mg/mL.
9. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition further comprises about 0.1 to about 20 molar equivalent of unionized pharmaceutical compound compared to the amount of complexing agent.
10. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a pharmaceutical compound, comprising:
(i) the pharmaceutical compound, or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the pharmaceutical compound comprises a protonated nitrogen atom, wherein the pharmaceutical compound is not ketamine; and
(ii) a conjugate base of a complexing agent comprising a plurality of acidic functional groups, wherein the conjugate base of the complexing agent acts as the counterion of the pharmaceutical compound, wherein the complexing agent is substituted cyclodextrin;
wherein the pharmaceutical composition is formulated for subcutaneous or intramuscular administration as an aqueous formulation having a pH of at least about 5.5;
wherein the osmolality of the pharmaceutical composition is lower than an osmolality of a composition comprising an equivalent amount of a freebase form of the pharmaceutical compound encapsulated within a hydrophobic core of a salt of the complexing agent; wherein the composition has a molar ratio of the pharmaceutical compound to the complexing agent of at least 1:1.
11. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is substantially free of excess ions.
12. The pharmaceutical composition of claim 1 , wherein the pharmaceutical compound is selected from the group consisting of arylcyclo-hexylamine, 1,2-diarylethylamine, β-keto-arylcyclohexylamine, methoxetamine, deschloroketamine, N-ethyl deschloroketamine (eticyclidone), 3-methoxyphencyclidine, methoxieticyclidine, ephenidine, lanicemine, dextromethorphan, dextrorphan, methoxyketamine, a N,N-dimethyltryptamine, a N,N-diethyltryptamine, a N,N-dipropyltryptamine, a N-Methyl-N-propyltryptamine, a N-methyl-N-isopropyltryptamine, a N,N-diallyltryptamine, a N-methyl-N-allyltryptamine, N-methyl-N-ethyltryptamine, a N,N-Diisopropyltryptamine, 4-hydroxy-N-methyl-N-ethyltryptamine, 5-methoxy-N,N-diisopropyltryptamine, O-acetylpsilocin, methylisopropyllysergamide, ethylisopropyllysergamide, 6-allyl-6-nor-LSD, 6-ethyl-6-nor-lysergic acid diethylamide, 1-acetyl-LSD, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-lysergic acid diethylamide, 1-Cyclopropionyl-d-lysergic acid diethylamide, N1-butyryl-lysergic acid diethylamide, 6-propyl-6-nor-Lysergic acid diethylamide, mescaline, 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2-(4-Iodo-2,5-dimethoxyphenyl)ethan-1-amine (2C-I), 2-(4-Chloro-2,5-dimethoxyphenyl)ethan-1-amine (2C-C), 2,5-Dimethoxy-4-iodoamphetamine, 2-[2,5-Dimethoxy-4-(propylsulfanyl)phenyl]ethan-1-amine, 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, racemorphan, levorphanol, racemethorphan, buprenorphine, morphine, loperamide, morphine, codeine, hydrocodone, oxymorphone, buprenorphine, fentanyl, methadone, tramadol, alpha-methyl acetyl fentanyl, alfentanil, butyryl fentanyl, butyrfentanyl, carfentanil, 3-methylcarfentanil, 4-fluorofentanyl, beta-hydroxyfentanyl, alpha-methylfentanyl, cis-3-methylfentanyl, beta-hydroxy-3-methylfentanyl, remifentanil, sufentanil, 3-methylthiofentanyl, naloxone, naltrexone, a cathinone, a 3,4-methylenedioxyamphetamine derivative, an aminoalkyl-substituted benzofuran, a substituted amphetamine, an aminoindane, diphenhydramine, hydroxazine, phenylephrine, dopamine, adrenaline, lidocaine, oxymetazoline, clemastine, chlorpheniramine, and 6-chloro-2-aminotetralin.
13. An pharmaceutical composition comprising a pharmaceutically acceptable salt of a pharmaceutical compound having the formula:
[A] a [B]
wherein:
A is a pharmaceutical compound comprising at least one basic nitrogen atom, wherein the pharmaceutical compound is not ketamine;
B is a complexing agent comprising a plurality of acidic functional groups; and
a is a number from 1-7, wherein the number is selected such that the total number of basic nitrogen atoms of A is equal to the number of acidic functional groups of B,
wherein the complexing agent is cyclodextrin;
wherein the pharmaceutical composition is formulated for subcutaneous or intramuscular administration as an aqueous formulation having a pH of at least about 5.5;
wherein the osmolality of the pharmaceutical composition is lower than an osmolality of a composition comprising an equivalent amount of a freebase form of the pharmaceutical compound encapsulated within a hydrophobic core of a salt of the complexing agent; wherein the composition has a molar ratio of the pharmaceutical compound to the complexing agent of at least 1:1.
14. The pharmaceutical composition of claim 13 , wherein the at least one basic nitrogen atom is comprised in a heterocycle.
15. The pharmaceutical composition of claim 13 , wherein the at least one basic nitrogen atom has a pKa value from about 4 to about 10.
16. The pharmaceutical composition of claim 13 , wherein the pharmaceutical compound comprises only a single basic nitrogen atom.
17. The pharmaceutical composition of claim 13 , wherein a is equal to the number of acidic functional groups.
18. The pharmaceutical composition of claim 13 , wherein the pharmaceutical compound comprises two or more basic nitrogen atoms.