Methods
The disclosure provides the use of particular substituted heterocycle fused gamma-carboline compounds as pharmaceuticals for the treatment of residual symptoms of psychosis or schizophrenia. The disclosure also provides novel long acting injectable formulations of particular substituted heterocycle fused gamma-carboline compounds and use of such long acting injectable formulations for the treatment of residual symptoms of psychosis or schizophrenia.
1. A long-acting injectable composition comprising polymeric microspheres comprising a PLGA matrix with either carboxylic acid or carboxylic ester end groups, and an effective amount of a Compound of Formula I, the Compound of Formula I being dispersed, dissolved or encapsulated in the polymer matrix of the microsphere:
wherein:
X is —O—, —NH— or —N(CH 3 )—;
Y is —O—, —C(R 2 )(OH)—, —C(R 3 )(OR 1 ) or —C(O)—; and
R 1 is —C 1-6 alkyl or —C(O)—C 1-21 alkyl, optionally saturated or unsaturated and optionally substituted with one or more hydroxyl or C 1-22 alkoxy groups, wherein such compound hydrolyzes to form the residue of a natural or unnatural, saturated or unsaturated fatty acid;
R 2 is H or —C 1-6 alkyl; and
R 3 is H or —C 1-6 alkyl;
in free or pharmaceutically acceptable salt form;
wherein the composition further comprises an antioxidant in an amount effective to inhibit or reduce oxidation of the Compound of Formula I.
2. The long-acting injectable composition according to claim 1 , wherein the amount of the Compound of Formula I is dispersed, dissolved or encapsulated in each microsphere, on average, is from about 5% by weight to about 50% by weight of each microsphere.
3. The long-acting injectable composition of claim 1 , wherein the compound of Formula I is a compound wherein:
X is —O—, —NH— or —N(CH 3 )—;
Y is —O—, —C(H)(OH)—, —C(H)(OR 1 ) or —C(O)—; and
R 1 is —C(O)—C 1-21 alkyl, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C 1-22 alkoxy wherein such compound hydrolyzes to form the residue of a natural or unnatural, saturated or unsaturated fatty acid,
in free or pharmaceutically acceptable salt form.
4. The long-acting injectable composition of claim 1 , wherein the compound of Formula I is selected from a group consisting of compounds of formula I wherein:
X is —O— and Y is —C(H)(OH)—,
X is —NH— and Y is —C(H)(OH)—,
X is —N(CH 3 )— and Y is —C(H)(OH)—,
X is —O— and Y is —C(O)—,
X is —O— and Y is —O—,
X is —N(CH 3 )— and Y is —C(O)—,
X is —N(CH 3 )— and Y is —O—,
X is —NH— and Y is —C(O)—,
X is —NH— and Y is —O—,
X is —N(CH 3 )— and Y is —C(H)(OR 1 ),
X is —NH— and Y is —C(H)(OR 1 ), or
X is —O— and Y is —C(H)(OR 1 );
X is —O— and Y is —C(CH 3 )(OH)—,
X is —NH— and Y is C(CH 3 )(OH)—, and
X is —N(CH 3 )— and Y is C(CH 3 )(OH)—,
each in free or pharmaceutically acceptable salt form.
5. The long-acting injectable composition of claim 1 , wherein the compound of Formula I is a compound wherein X is —N(CH 3 )— and Y is —C(O)— or —C(H)(OH), in free pharmaceutically acceptable salt form.
6. The long-acting injectable composition of claim 1 , wherein the composition completely degrades and releases the Compound of Formula I within less than 6 months.
7. The long-acting injectable composition of claim 1 , wherein said composition completely degrades and releases the Compound of Formula I within less than 4 months.
8. The long-acting injectable composition of claim 1 , wherein the composition completely degrades and releases the Compound of Formula I within less than 3 months.
9. The long-acting injectable composition of claim 1 , wherein the composition completely degrades and releases the Compound of Formula I within less than 2 months.
10. The long-acting injectable composition of claim 1 , wherein the composition completely degrades and releases the Compound of Formula I within less than 1 month.
11. The long-acting injectable composition of claim 1 , wherein the composition is formulated for intramuscular, intraperitoneal, intrathecal, epidural or subcutaneous injection.
12. The long-acting injectable composition of claim 11 , wherein the composition is formulated for intramuscular or subcutaneous injection.
13. The long-acting injectable composition of claim 1 , wherein antioxidant is selected from butylated hydroxytoluene and butylated hydroxyanisole.
14. The long-acting injectable composition according to claim 1 wherein the effective amount of the compound of Formula I is from 100 mg to 600 mg per month.
15. The long-acting injectable composition according to claim 1 wherein the effective amount of the compound of Formula I is from 150 mg to 300 mg per month.
16. The long-acting injectable composition of claim 1 , wherein the Compound of Formula I is a compound wherein X is —N(CH 3 )— and Y is —C(O)—, in free or pharmaceutically acceptable salt form.
17. The long-acting injectable composition of claim 1 , wherein the Compound of Formula I is in free form.
18. The long-acting injectable composition of claim 1 , wherein the Compound of Formula I is in pharmaceutically acceptable salt form.
19. The long-acting injectable composition of claim 18 , wherein the pharmaceutically acceptable sale form is toluene sulfonic acid addition salt form.
20. The long-acting injectable composition of claim 1 , wherein the Compound of Formula I is a compound wherein X is —N(CH 3 )— and Y is —C(O)—, in free form.