Extended release tablet formulations of flibanserin and method for manufacturing the same

• US 20080038346A1
• Filed: 08/13/2007
• Published: 02/14/2008
• Est. Priority Date: 08/14/2006
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Friedl, Thomas, Eisenreich, Wolfram
• Granted Patent: US 8,545,886 B2
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• 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 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The invention is directed to a Pharmaceutical extended release system, particularly for oral administration, of a pH-dependent water-soluble active substance, comprising or essentially consisting of a) flibanserin or a pharmaceutically acceptable derivative thereof as active substance; b) one or more pharmaceutically acceptable pH-dependent polymers; c) one or more pharmaceutically acceptable pH-independent polymers; d) one or more pharmaceutically acceptable acids; and e) optionally one or more additives. The present invention provides a release profile of flibanserin which is independent on the pH in the gastrointestinal tract when administered orally resulting in a significantly improved bioavailability.

Claims

1. A pharmaceutical extended release system for a water-soluble active substance, comprising:

a) flibanserin or a pharmaceutically acceptable derivative thereof as active substance;

b) one or more pharmaceutically acceptable pH-dependent polymers;

c) one or more pharmaceutically acceptable pH-independent polymers;

d) one or more pharmaceutically acceptable acids; and

e) optionally one or more additives.

2. The pharmaceutical extended release system according to claim 1, wherein a pH-dependent polymer is selected from the group consisting of acrylic acid polymerisate, methacrylic acid copolymers, alginates, carrageenans, acacia, xanthan gum, chitin derivatives, carmellose sodium, carmellose calcium, phthalate, trimellitate, shellac, and derivatives and mixtures thereof.

3. The pharmaceutical extended release system according to claim 1, wherein a pH-dependent polymer is present in an amount of 0.25-25% by weight.

4. The pharmaceutical extended release system according to claim 1, wherein a pH-independent polymer is selected from the group consisting of alkylcelluloses;

hydroxyalkyl celluloses;

hydroxyalkyl alkylcelluloses;

carboxyalkylcellulose esters;

other natural, semi-synthetic, or synthetic di-, oligo- and polysaccharides;

ammonio methacrylate copolymers;

polyvinylalcohol;

polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate;

combinations of polyvinylalcohol and polyvinylpyrrolidone;

polyalkylene oxides;

copolymers of ethylene oxide and propylene oxide; and

derivatives and mixtures thereof.

5. The pharmaceutical extended release system according to claim 1, wherein a pH-independent polymer is present in an amount of 0.5-75% by weight.

6. The pharmaceutical extended release system according to claim 1, wherein an acid is selected from the group consisting of acetic acid, I-alanine, arginine, asparagines, aspartic acid, benzenesulphonic acid (besylate), benzoic acid, p-bromophenylsulphonic acid, camphorsulphonic acid, carbonic acid, gamma-carboxyglutamic acid, citric acid, cysteine, ethanesulphonic acid, fumaric acid, particularly cis-fumaric acid and/or trans-fumaric acid, gluconic acid, glutamic acid, glutaric acid, I-glutamine, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, isoleucine, lactic acid, I-leucine, lysine, maleic acid, malic acid, malonic acid, mandelic acid, methanesulphonic acid (mesylate), methionine, mucinic acid, nitric acid, ornithine, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, serine, succinic acid, sulphuric acid, tartaric acid, p-toluenesulphonic acid, tyrosine glutamic acid, valine, and derivatives and mixtures thereof.

7. The pharmaceutical extended release system according to claim 1, wherein an acid is selected from the group consisting of succinic acid, fumaric acid, malic acid, tartaric acid and glutaric acid and mixtures thereof.

8. The pharmaceutical extended release system according to claim 1, wherein an acid is in solid or liquid form.

9. The pharmaceutical extended release system according to claim 1, wherein an acid is present in an amount of 0.25-40% by weight.

10. The pharmaceutical extended release system according to claim 1, wherein the extended release system is provided in form of a tablet or bilayer tablet.

11. The pharmaceutical extended release system according to one claim 1, wherein the extended release system consists of

flibanserin 5-50% by weight pH-dependent polymer(s) 0.25-25% by weight pH-independent polymer(s) 0.5-75% by weight organic acid(s) 0.25-40% by weight lubricant(s) 0.1-4% by weight additional additives ad 100% by weight

12. The pharmaceutical extended release system according to claim 1, wherein one or more additives are present that are selected from the group consisting of lubricants, glidants, agents to improve flowability, granulating agents, anti-caking agents, agglomeration inhibitors, antiadherents, anti-tacking agent, anti-sticking agent, flavors, aromatiziers, dyes or colorants, preservatives, plastizers, solubilizers, wetting agents, sweeteners, chelating agents, stabilizers, antioxidants, diluents, fillers and mixtures thereof.

13. The pharmaceutical extended release system according to claim 12, wherein a lubricant is present in an amount of 0.1-4% by weight.

14. The pharmaceutical extended release system according to claim 12, wherein the lubricants or glidants are selected from the group consisting of boric acid, cellulose, silicon dioxide, glyceride, stearic acid as well as salts thereof, DL-leucine, magnesium silicate, calcium silicate, magnesium trisilicate, talc, starch, tribasic calcium phosphate, magnesium oxide, mineral oil, poloxamer, polyvinyl alcohol, hydrogenated oils, kaolin, (light) mineral oil, canola oil, triglycerides, myristic acid, palmitic acid, polyethylene glycols, tribasic calcium phosphate, benzoate, sodium chloride, sodium lauryl sulfate, magnesium lauryl sulphate, sodium acetate, fumaric acid and fumarate, sodium oleate, waxes and derivatives and mixtures thereof.

15. The pharmaceutical extended release system according to claim 14, wherein the lubricant or glidant is selected from stearic acid or a salts thereof, polyethylene glycols, fumaric acid, glyceride and derivatives and mixtures thereof.

16. The pharmaceutical extended release system according to claim 14, characterized in that the lubricant or glidant is selected from colloidal silicon dioxide, talc and derivatives and mixtures thereof.

17. The process for preparing a pharmaceutical extended release system according to claim 1, containing flibanserin or a pharmaceutically acceptable derivative thereof, comprising a step selected from the group consisting of wet granulation, direct compression, and roller compaction process.

18. A capsule comprising a pharmaceutical extended release system of claim 1 wherein the pharmaceutical extended release system in form of granules.

19. A method of treating a condition comprising administering the pharmaceutical extended release system of claim 1 to a mammal in need thereof wherein the condition is selected from the group consisting of central nervous system disorders, affective disorders, anxiety, sleep and sexual disorders (Hyposexual Desire Disorder, premenstrual disorders like premenstrual dysphoria, premenstrual syndrome, premenstrual dysphoric disorder;

sexual aversion disorder, sexual arousal disorder, orgasmic disorder, sexual pain disorders like dyspareunia, vaginismus, noncoital sexual pain disorder;

sexual dysfunction due to a general medical condition and substance-induced sexual dysfunction), psychosis, schizophrenia, personality disorders, mental organic disorders, mental disorders in childhood, aggressiveness, age associated memory impairment, neuroprotection, neurodegenerative diseases, cerebral ischaemia of various origins, anorexia nervosa, Attention Deficit Hyperactivity Disorder (ADHD), obesity, urinary incontinence, chronic pain and Valvular Heart Disease.

20. The method according to claim 19, wherein the flibanserin is administered in a dosage range between 0.1 to 400 mg per day.

21. The method according to claim 19, wherein the pharmaceutical extended release system is administered once or twice daily consecutively over a period of time.

22. The method according to claim 19, wherein the pharmaceutical extended release system is administered in the morning and the evening consecutively over a period of time.

23. The method according to claim 19, wherein the pharmaceutical extended release system is administered once in the evening only (50 or 100 mg of flibanserin) consecutively over a period of time.