Methods of treating certain depressive disorders and delirium tremens
The disclosure provides a method of treating a patient having postpartum depression, premenstrual dysphoric disorder, menopausal depression, or delirium tremens comprising administering an effective amount of an injectable neurosteroid formulation to the patient. In certain embodiments the injectable neurosteroid formulation is an injectable ganaxolone formulation. Two types of injectable neurosteroid formulations may be used in the disclosed methods. The first such formulation is an injectable formulation containing ganaxolone and sulfobutyl ether β-cyclodextrin in a 1:1 inclusion complex. The second such formulation is an injectable neurosteroid formulation comprising a neurosteroid, preferably ganaxolone, but which may be a neurosteroid selected from allopregnanolone, ganaxolone, alphaxalone, alphadolone, hydroxydione, minaxolone, pregnanolone, tetrahydrocorticosterone, and combinations of the foregoing; a surface stabilizer selected from hydroxyl ethyl starch, dextran, and povidone; and a surfactant.
1. A method of treating a patient with postpartum depression, premenstrual dysphoric disorder, menopausal depression, or delirium tremens comprising administering to a patient in need thereof an effective amount of a ganaxolone formulation.
2. The method of claim 1 , wherein the ganaxolone formulation is an intravenous formulation.
3. The method of claim 2 , wherein the intravenous ganaxolone formulation further comprises:
a) water;
b) sulfobutyl ether-μ-cyclodextrin (CAPTISOL) and ganaxolone, wherein the weight to weight (w/w) ratio of sulfobutyl ether-μ-cyclodextrin to ganaxolone is about 52:1 or greater; and
c) a buffer, the formulation having a pH of 6.0 to 8.0.
4. The method of claim 3 , wherein formulation comprises 0.1 mg/mL to 15 mg/mL ganaxolone and 5.5 mg/mL to 800 mg/ml sulfobutyl ether-β-cyclodextrin.
5. A method of treating a patient having with postpartum depression, premenstrual dysphoric disorder, menopausal depression, or delirium tremens comprising administering to a patient in need thereof an effective amount of an injectable neurosteroid formulation; wherein the formulation comprises a neurosteroid selected from allopregnanolone, ganaxolone, alphaxalone, alphadolone, hydroxydione, minaxolone, pregnanolone, tetrahydrocorticosterone, and combinations thereof; a surface stabilizer selected from hydroxyl ethyl starch, dextran, and povidone; and a surfactant.
6. The method of claim 5 , wherein the neurosteroid is ganaxolone.
7. The method of claim 5 , wherein the neurosteroid is allopregnanolone.
8. The method of claim 5 , wherein the surface stabilizer is hydroxyethyl starch.
9. The method of claim 5 , wherein the (wt:wt) ratio of the neurosteroid to the surface stabilizer is about 4:1 to about 3:1.
10. The method of claim 5 , wherein the injectable neurosteroid formulation further comprises nanoparticles that have a D50 of 10 nm to 300 nm; wherein the formulation additionally comprises 0.5% to 1.5% weight percent sodium chloride; and wherein the formulation additionally comprises a buffer and a preservative selected from benzyl alcohol, chlorbutanol, 2-ethoxyethanol, parabens (including methyl, ethyl, propyl, butyl, and combinations), benzoic acid, sorbic acid, chlorhexidene, phenol, 3-cresol, thimerosal, phenylmercurate salt, and combinations thereof.
11. The method of claim 2 , wherein the patient is administered 0.1 mg/kg to 200 mg/kg of ganaxolone as a single bolus dose.
12. The method of claim 11 , wherein the single bolus dose provides a plasma C max of ganaxolone of at least 60 ng/mL in the patient.
13. The method of claim 2 , wherein the patient in need thereof is administered the formulation as an intravenous infusion for 1 hour to 10 consecutive days at a rate of 1 to 10 mg ganaxolone hr/kg, with or without an initial bolus dose.
14. The method of claim 2 , wherein the intravenous ganaxolone formulation is administered to the patient in need thereof at the rate of 2 mg/hr to 4 mg/hr.
15. The method of claim 2 , wherein the intravenous ganaxolone formulation is administered at a rate sufficient to provide a steady state plasma concentration of 50 ng/ml to 100 ng/ml.
16. The method of claim 14 , wherein the intravenous ganaxolone formulation is administered at for 36 hrs to 72 hrs.
17. The method of claim 1 , wherein the patient in need thereof has premenstrual dysphoric disorder, and is administered a daily oral dose of ganaxolone of 100 mg to 2000 mg from day 18-24 of the patients menstrual cycles until day 2-4 of the patients menstrual cycle.
18. The method of claim 1 , wherein the patient in need thereof has menopausal depression, and is administered a daily oral dose of ganaxolone of 100 mg to 2000 mg.
19. The method of claim 18 , wherein the patient in need thereof is administered the ganaxolone in combination with an SSRI or SNRI antidepressant.
20. The method of claim 1 , wherein the patient in need thereof has delirium tremens and, is administered a ganaxolone intravenous infusion at a rate of 50 mg/hr to 500 mg/hr for 1 to 5 days.
21. The method of claim 20 , wherein the patient in need thereof is administered the ganaxolone in combination with an intravenous benzodiazepine infusion.
22. The method of claim 1 , further comprising administering ganaxolone orally.
23. The method of claim 22 , wherein ganaxolone is administered orally following after administration of the intravenous ganaxolone formulation.