# US 2019/0167698 A1 · Methods of Treating Certain Depressive Disorders and Delirium Tremens

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2019/0167698 A1
- Document ID: US20190167698A1
- Status: Published application
- Kind: A1
- Application number: 16/150,782
- Filed: 2018-10-03
- Published: 2019-06-06
- Earliest claimed: 2016-09-09
- Assignees: Marinus Pharmaceuticals
- Applicants: Marinus Pharmaceuticals Inc.
- Inventors: Christopher Cashman; Jaakko Lappalainen; David A. Czekai
- Web page: https://patentgrep.com/patent/US20190167698A1

## CPC

- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/38: Cellulose; Derivatives thereof
- A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)}
- C07J 7/009: {by only one oxygen atom doubly bound}
- C08B 37/0015: {Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes}
- A61K 31/718: Starch or degraded starch, e.g. amylose, amylopectin
- A61K 31/721: Dextrans
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07J: STEROIDS (seco-steroids C07C)
- C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21)

## Abstract

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.

## Claims

### Claim 1

A method of treating a patient having postpartum depression, premenstrual dysphoric disorder, menopausal depression, or delirium tremens comprising administering an effective amount of an neurosteroid formulation to the patient; wherein the neurosteroid formulation is an ganaxolone formulation.

### Claim 2 (depends on 1)

The method of claim 1 wherein the ganaxalone formulation is an intravenous formulation.

### Claim 3 (depends on 2)

The method of claim 2 wherein the intravenous ganaxolone formulation comprises
a) water;
b) sulfobutyl ether-β-cyclodextrin (CAPTISOL) and ganxalone, wherein the ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone wherein weight to weight (w/w) ratio of sulfobutyl ether-β-cyclodextrin is about 52:1 or greater; and
c) a buffer, the formulation having a pH of 6.8 to 7.6.

### Claim 4 (depends on 3)

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.

### Claim 5

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; wherein the formulation comprises
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.

### Claim 6 (depends on 5)

The method of claim 5, wherein the neurosteroid is ganaxolone.

### Claim 7 (depends on 5)

The method of claim 5, wherein the neurosteroid is allopregnanolone.

### Claim 8 (depends on 5)

The method of claim 5, wherein the surface stabilizer is hydroxyethyl starch.

### Claim 9 (depends on 5)

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.

### Claim 10 (depends on 5)

The method of claim 5, wherein
the nanoparticles have a D50 of 10 nm to 300 nm;
the formulation additionally comprises 0.5% to 1.5% weight percent sodium chloride;
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 of the foregoing.

### Claim 11 (depends on 2)

The method of claim 2, wherein the patient is administered 0.1 mg/kg to 200 mg/kg neurosteroid as a single bolus dose.

### Claim 12 (depends on 11)

The method of claim 11, wherein the single bolus dose provides a sufficient amount of ganaxolone to provide a plasma Cmax of ganaxolone of at least 60 ng/mL in the patient.

### Claim 13 (depends on 2)

The method of claim 2, wherein the patient is administered the formulation as an intravenous infusion for 1 hour to 10 consecutive days at a rate of 1 to 10 mg neurosteroid/hr/kg, with or without an initial bolus dose.

### Claim 14 (depends on 2)

The method of claim 2, wherein the intravenous neurosteroid formulation administered to the patient is a ganaxolone infusion administered at the rate of 2 mg/hr to 4 mg/hr.

### Claim 15 (depends on 2)

The method of claim 2, wherein the intravenous neurosteroid formulation administered to the patient is a ganaxolone infusion administered at a rate sufficient to provide a steady state plasma concentration of 50 ng/ml to 100 ng/ml.

### Claim 16 (depends on 14)

The method of claim 14, wherein the intravenous neurosteroid formulation is a ganaxolone formulation which is administered at for 36 hrs to 72 hrs.

### Claim 17 (depends on 1)

The method of claim 1, wherein the patient is a patient having premenstrual dysphoric disorder and the patient is administered a daily oral dose of ganaxolone of 100 mg to 2000 mg administered from day 18-24 of the patients menstrual cycles until day 2-4 of the patient's menstrual cycle.

### Claim 18 (depends on 1)

The method of claim 1, wherein the patient is a patient having menopausal depression and the patient is administered a daily oral dose of ganaxolone of 100 mg to 2000 mg ganaxolone.

### Claim 19 (depends on 18)

The method of claim 18, wherein the patient is administered the ganaxolone in combination with an SSRI or SNRI antidepressant.

### Claim 20 (depends on 1)

The method of claim 1, wherein the patient is a patient having delirium tremens and the patient is administered a ganaxolone intravenous infusion at a rate of 50 mg/hr to 500 mg/hr for 1 to 5 days.

### Claim 21 (depends on 20)

The method of claim 20, wherein the patient is administered the ganaxolone in combination with an intravenous benzodiazepine infusion.