Controlled release system and method for manufacturing the same

• US 20080069873A1
• Filed: 08/13/2007
• Published: 03/20/2008
• Est. Priority Date: 08/25/2006
• 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: Wagner, Karl, Friedl, Thomas, Pearnchob, Nantharat, Sommer, Florian
• Granted Patent: US 8,512,748 B2
• Time in Patent Office: Days
• US Class Current: 424/459
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

The invention is directed to a pharmaceutical controlled release system for administration, particularly oral administration, of active substances with pH-dependent solubilities, comprising a) a core material containing or consisting of one or more pharmaceutically acceptable pH modifiers; b) optionally an insulating layer, c) a first layer containing or consisting of one or more pharmaceutically acceptable water-insoluble polymers; d) a second layer containing or consisting of at least one active substance having a pH-dependent solubility; e) a third layer containing or consisting of one or more pharmaceutically acceptable polymers having anionic or no ionic groups; and f) optionally a fourth layer, preferably in form of an outer coating layer. It is provided a pH-independent release profile of active substances having pH-dependent solubilities in vitro and vivo.

Claims

1. A pharmaceutical controlled release system for administration of active substances with pH-dependent solubilities, comprising

a) a core material comprising one or more pharmaceutically acceptable pH modifiers;

b) optionally an insulating layer,

c) a first layer comprising one or more pharmaceutically acceptable water-insoluble polymers;

d) a second layer comprising at least one active substance having a pH-dependent solubility;

e) a third layer comprising one or more pharmaceutically acceptable polymers having anionic or no ionic groups; and

f) optionally a fourth layer.

2. The pharmaceutical controlled release system according to claim 1, wherein the system is for oral administration.

3. The pharmaceutical controlled release system according to claim 1, wherein the core material comprises one or more pH modifiers, one or more binders and optionally one or more other excipients.

4. The pharmaceutical controlled release system according to claim 1, wherein the pH modifier(s) is selected from the group consisting of one or more pharmaceutically acceptable organic acids, one or more pharmaceutically acceptable bases, one or more pharmaceutically acceptable buffers and mixtures thereof.

5. The pharmaceutical controlled release system according to claim 1, wherein the pH modifier(s) is in solid or liquid form.

6. The pharmaceutical controlled release system according claim 4, wherein the one or more pharmaceutically acceptable organic acids selected from the group consisting of acetic acid, ascorbic acid, tartaric acid, glutaric acid, malic acid, fumaric acid, citric acid, lactic acid, adipic acid and succinic acid or combinations thereof.

7. The pharmaceutical controlled release system according to claim 4, wherein the one or more pharmaceutically acceptable buffers are selected from the group consisting of McIlvaine buffers, ammonia solution, calcium carbonate, tribasic calcium phosphate, dibasic sodium or potassium phosphate, citric acid monohydrate, diethanolamine, malic acid, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, triethanolamine and derivatives and mixtures thereof.

8. The pharmaceutical controlled release system according to claim 1, wherein the core material has an average particle size of 0.4 to 1.5 mm.

9. The pharmaceutical controlled release system according to claim 1, wherein the first layer comprises one or more water-insoluble polymers, optionally one or more plastiziers and/or one or more separating agents and/or one or more pigments and/or other excipients.

10. The pharmaceutical controlled release system according to claim 1, wherein the water-insoluble polymer(s) contained in the first layer is (are) selected from acrylic and/or methacrylic (co-)polymer(s), alkylcelluloses, cellulose acetate, polyvinyl acetate and derivatives and mixtures thereof.

11. The pharmaceutical controlled release system according to claim 9, wherein at least one water-insoluble polymer in the first layer is an ethylcellulose.

12. The pharmaceutical controlled release system according to claim 1, wherein the third layer comprises one or more polymers having anionic or no ionic groups and one or more plastiziers and optionally one or more separating agents and/or other excipients.

13. The pharmaceutical controlled release system according to claim 12, wherein the polymer having anionic or no ionic groups contained in the third layer is selected from the group consisting of ethylcellulose, hydroxypropyl methylcellulose phthalate, and poly(methacrylic acid, ethylacrylate) 1:

1 (Eudragit®

L 100-55 or Eudragit®

L 30D-55); and

mixtures thereof.

14. The pharmaceutical controlled release system according to claim 1 wherein the third layer further comprises a pore former.

15. The pharmaceutical controlled release system according to claim 14 wherein the pore former is selected from the group consisting of methylcellulose, hydroxypropyl methylcelluloses, hydroxypropyl cellulose, hydroxyethyl cellulose, povidone and Eudragit®

E (Poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) 1;

2;

1).

16. The pharmaceutical controlled release system according to claim 1, wherein the second layer comprises one or more active substances having pH-dependent solubility, one or more binders and optionally one or more other excipients.

17. The pharmaceutical controlled release system according to claim 1, wherein there is at least one insulating layer comprising one or more water-soluble polymers, optionally one or more plasticizers, and/or one or more separating agents and/or one or more pigments and/or other excipients.

18. The pharmaceutical controlled release system according to claim 1, wherein an insulating layer is provided on the core.

19. The pharmaceutical controlled release system according to claim 1, wherein an insulating layer is provided on the second layer.

20. The pharmaceutical controlled release system according to claim 1, wherein the controlled release system further comprises a fourth layer.

21. The pharmaceutical controlled release system according to claim 20, wherein the fourth layer comprises one or more polymers having anionic or no ionic groups and one or more plastiziers and optionally one or more separating agents and/or other excipients.

22. The pharmaceutical controlled release system according to claim 21, wherein the polymer contained in the fourth layer is selected from the group consisting of hydroxypropyl methylcellulose phthalate, and poly(methacrylic acid, ethylacrylate) 1:

1 (Eudragit®

L 100-55 or Eudragit®

L 30D-55); and

mixtures thereof.

23. The pharmaceutical controlled release system according to claim 1 wherein the fourth layer further comprises a pore former.

24. The pharmaceutical controlled release system according to claim 1, wherein the application quantities for the layers present, based on the specific surface area of the starting core, are as follows

optional (first) insulating layer:

in the range from 0.05 to 5 mg/cm²;

first layer;

in the range from 0.1 to 15 mg/cm²;

second layer;

in the range from 0.1 to 20 mg/cm²;

third layer;

in the range from 0.1 to 15 mg/cm², and

optional fourth layer;

in the range from 0.1 to 15 mg/cm².

25. The pharmaceutical controlled release system according to claim 1, wherein the active substance is flibanserin.

28. A method of treating a condition comprising the administration of a therapeutically effective amount of the pharmaceutical controlled release system according to claim 25 to the mammal wherein the condition is selected from the group comprising central nervous system disorders, affective disorders, anxiety, sleep and sexual disorders (Hyposexual Desire 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), premenstrual disorders like premenstrual dysphoria, premenstrual syndrome and premenstrual dysphoric disorder;

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.

29. The method according to claim 28, wherein flibanserin is administered in a dosis range between 0.1 to 400 mg per day.

26. A process for preparing a pharmaceutical controlled release system containing an active substance with pH-dependent solubility characteristics comprising the steps of:

step a) producing the core material from one or more pharmaceutically acceptable pH modifiers, optionally with the addition of one or more binders and/or other excipients, by pan methods, on pelleting plates or by extrusion/spheronisation;

step b) optionally applying an insulating layer comprising one or more water-soluble pharmaceutically acceptable polymers, optionally with the addition of one or more plasticizers, one or more separating agents and/or one or more pigments, and/or other excipients;

step c) applying a first layer comprising one or more water-insoluble pharmaceutically acceptable polymers, optionally with the addition of one or more plasticizers and/or one or more separating agents and/or one or more pigments and/or other excipients;

step d) applying a second layer comprising at least one active substance from a solution or dispersion optionally containing one or more binders and/or one or more separating agents and/or other excipients, and simultaneously or subsequently drying to eliminate the solvent or dispersing agent;

step e) optionally applying an insulating layer comprising one or more water-soluble pharmaceutically acceptable polymers, optionally with the addition of one or more plasticizers and/or one or more separating agents and/or one or more pigments and/or other excipients;

step f) applying a third layer comprising one or more pharmaceutically acceptable polymers having anionic or no ionic groups optionally with the addition of one or more plasticizers, one or more separating agents and/or one or more pigments and/or other excipients;

step g) optionally applying a fourth layer, optionally with addition of one or more plasticizers and/or one or more pigments and/or other excipients; and

step h) optionally packing the controlled release system containing active substance thus obtained into capsules.

27. The process for preparing a pharmaceutical controlled release system according to claim 26, wherein the active substance is flibanserin.