Stabilized formulations of CNS compounds

• US 10,149,853 B2
• Filed: 04/25/2014
• Issued: 12/11/2018
• Est. Priority Date: 03/31/2010
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Chang, Rong-Kun, Vieira, Michael L., Liang, Likan, Bhatt, Padmanabh P., Huang, Austin B., Patel, Sachin V.
• Primary Examiner(s): Soroush, Ali
• Application Number:
  US14/261,709
• Publication Number:
  US 20150086629A1
• Time in Patent Office: 1,691 Days
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives

Abstract

Formulations of molindone having superior stability and methods of administering same are provided. The formulations may be immediate, modified, or otherwise delayed release formulations of molindone.

Claims

1. A pharmaceutical formulation comprising molindone as a single active pharmaceutical ingredient and having:

(a) a modified-release formulation comprising;

(i) molindone,

(ii) at least one release controlling polymer, wherein the release controlling polymer (1) consists of one or more pH-dependent polymers selected from the group consisting of poly (methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly (methacrylic acid-co-methyl methacrylate), methacrylic acid-ethyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer dispersion, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and zein and (2) does not comprise non-pH-dependent polymers, and

(iii) at least one stabilizer selected from the group consisting of acidifying agents and hydrophobizing agents; and

, optionally,

(b) an additional formulation comprising molindone in an immediate release, extended release, or delayed release formulation.

2. The formulation of claim 1, wherein the modified release formulation is an extended release formulation.

3. The formulation of claim 1, for once-a-day or twice-a-day administration.

4. The formulation of claim 1, comprising from 0.1 mg to 200 mg of molindone.

5. The formulation of claim 2, comprising 5% to 95% by weight of a pH-dependent polymer.

6. The formulation of claim 2, wherein the modified release formulation comprises a plurality of the delayed release molindone-containing pellets, and the additional formulation comprises a plurality of the molindone-containing pellets.

7. The formulation of claim 2, wherein the additional formulation is an immediate release formulation.

8. The formulation of claim 1, as an osmotic formulation.

9. The formulation of claim 1, comprising an acidifying agent as the stabilizer.

10. The formulation of claim 9, wherein the acidifying agent is selected from the group consisting of fumaric acid, citric acid, malic acid, tartaric acid, ascorbic acid, edetic acid, aspartic acid, adipic acid, alginic acid, benzoic acid, butandioic acid, erythorbic acid, lactic acid, malic acid, maleic acid, glutamic acid, sorbic acid, succinic acid, hydrochloric acid (dilute) nitric acid (dilute), phosphoric acid (dilute), sulfuric acid (dilute), acacia, aluminum phosphate, aluminum sulfate, ammonium alum, ammonium chloride, carbomers, edetate calcium disodium, edetate disodium, methacrylic acid copolymers, poly(methyl acrylate-comethyl methacrylate-co-methacrylic acid), polycarbophils, polydextrose, potassium alum, potassium phosphate monobasic, sodium metabisulfite, sodium phosphate monobasic, sodium starch glycolate, zinc acetate, zinc sulfate and pharmaceutical grade ion exchange resins.

11. The formulation of claim 1, comprising a hydrophobizing agent.

12. The formulation of claim 11, wherein the hydrophobizing agent is selected from the group consisting of magnesium stearate, stearic acid, glyceryl behenate, and glyceryl stearate, glyceryl palmitostearate, waxes and hydrogenated vegetable oils.

13. The formulation of claim 1, further comprising a pharmaceutically acceptable excipient selected from the group consisting of bulking agents, fillers, lubricants, wetting and solubility enhancing agents and dispersants.

14. The formulation of claim 1, wherein molindone is a racemic mixture of (+)-enantiomer and (−

)-enantiomer.

15. The formulation of claim 1, wherein molindone is in the form of (+)-enantiomer.

16. The formulation of claim 1 wherein molindone is in the form of (−

)-enantiomer.

17. The formulation of claim 1, comprising stabilizer and molindone, respectively, in a weight ratio of 0.1:

1 to 50;

1.

18. The formulation of claim 1, comprising stabilizer and molindone, respectively, in a weight ratio of 0.25:

1 to 40;

1.

19. The formulation of claim 1, in a dosage form selected from tablets, osmotic tablets, matrix tablets, mini tablets, capsules, beads, granules, powders, caplets, troches, sachets, cachets, pouches, gums, sprinkles, solutions and suspensions.

20. A method of treating impulsive aggression, aggression, or other conduct disorder comprising administering to a subject in need thereof an effective amount of the formulation of claim 1.

21. The method of claim 20, wherein the subject is a human being.

22. The formulation of claim 1, comprising a pH-dependent polymer selected from the group consisting of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer dispersion, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and zein.