Flouxetine pharmaceutical formulations

• US 5,747,068 A
• Filed: 07/18/1995
• Issued: 05/05/1998
• Est. Priority Date: 07/20/1994
• Status: Expired due to Term

• Current Assignee: Lilly Sa
• Original Assignee: Lilly S. A.
• Inventors: Mendizabal, Flavia Arce
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US08/503,570
• Time in Patent Office: 1,022 Days
• Field of Search: 424/44, 424/465
• US Class Current: 424/465
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• 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 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine

Abstract

Pharmaceutical formulations of fluoxetine or an acid addition salt thereof, suitable for manufacturing dispersible tablets by direct compression and comprising, in addition to the active ingredient, the appropriate excipients and coadjuvants, selected from among disintegrants, diluents, lubricants, anti-adherents, sweeteners, flavorings and, optionally, colorants.

Said formulations are suitable for manufacturing dispersible tablets which disintegrate in less than three minutes in water at 19° C.-21° C., and are appropriate for treatment of depression.

Claims

1. A pharmaceutical formulation suitable for the manufacture of dispersible tablets by direct compression, said tablets dispersible in water at 19°

-21°

C. in less than three minutes, consisting of fluoxetine or an addition salt thereof, as active ingredient, in a quantity between 4% and 7.5% by weight in relation to the total formulation weight, along with;

a) a disintegrant selected from the group consisting of sodium starch glycollate, polymeric derivatives of acrylic acid, and crospovidone;

b) a diluent selected from the group consisting of microcrystalline cellulose, lactose, hydroxypropyl cellulose (HPC), pregelatinized starch, dry flowing starch, and combinations and mixtures thereof;

c) a lubricant selected from the group consisting of talcum and stearyl sodium fumarate unless the diluent is pregelatinized starch, where the formulation is lubricant free;

d) colloidal silicon dioxide as an anti-adherent;

e) artificial or natural sweeteners selected from the group consisting of sodium saccharin, aspartame, mannitol, sorbitol, and ammonium glyciricinate, or mixtures thereof;

f) a flavoring selected from the group consisting of mint aroma, peppermint aromas, orange flavoring, peach aroma, apricot aroma, raspberry aroma, lemon aroma, coconut aroma, pineapple aroma, strawberry aroma, aniseed, and mixtures thereof; and

optionally

g) titanium dioxide as a colorant.

2. A formulation as set forth in claim 1, containing a quantity of sodium starch glycolate between 9.5% and 17% by weight in relation to the total weight of the formulation.

3. A formulation as set forth in claim 1, containing a quantity of acrylic acid derivatives of between 10% and 21% by weight in relation to the total weight of the formulation.

4. A formulation as set forth in claim 1, containing a quantity of crospovidone of between 9% and 13% by weight in relation to the total weight of the formulation.

5. A formulation as set forth in claim 1, containing a quantity of hydroxypropyl cellulose, preferably L-HPC, of between 5% and 25% by weight in relation to the total weight of the formulation.

6. A formulation as set forth in claim 1, comprising a combination of pregelatinized starch, and hydroxypropyl cellulose, preferably L-HPC, containing a quantity of pregelatinized starch of between 60% and 70% by weight in relation to the total weight of the formulation, and a quantity of HPC of approximately 5% by weight in relation to the total weight of the formulation.

7. A formulation as set forth in claim 1, containing a quantity of microcrystalline cellulose of between 62% and 76% by weight in relation to the total weight of the formulation.

8. A formulation as set forth in claim 7, wherein said microcrystalline cellulose has a mean particle size of between 50 and 90 microns.

9. A formulation as set forth in claim 1, comprising a combination of microcrystalline cellulose and dry flowing starch, with a quantity of dry flowing starch of between 15% and 27% by weight in relation to the total weight of the formulation, and a quantity of microcrystalline cellulose of between 46% and 58% by weight in relation to the total weight of the formulation.

10. A formulation as set forth in claim 1, containing a quantity of stearyl sodium fumarate as lubricant of between 1% and 2.5% by weight in relation to the total weight of the formulation.

11. A formulation as set forth in claim 1, containing as anti-adherent a quantity of colloidal silicone dioxide of between 1% and 2% by weight in relation to the total weight of the formulation.

12. A formulation as set forth in claim 1, containing a quantity of sodium saccharin as artificial sweetener of between 0.4% and 5% by weight in relation to the total weight of the formulation, or a quantity of aspartame of approximately 1.6% by weight in relation to the total weight of the formulation.

13. A formulation as set forth in claim 1, containing a quantity of mannitol of between 2.5% and 5% by weight in relation to the total weight of the formulation.

14. A formulation as set forth in claim 1, containing a quantity of sorbitol of between 1.5% and 4% by weight in relation to the total weight of the formulation.

15. A formulation as set forth in claim 1, containing a quantity of ammonium glyciricinate of between 0.5% and 1% by weight in relation to the total weight of the formulation.

16. A formulation as set forth in claim 1, comprising a mixture of sodium saccharin and mannitol containing a quantity of sodium saccharin of between 0.5% and 4.5% by weight in relation to the total weight of the formulation, and a quantity of mannitol of between 2.5% and 5% by weight in relation to the total weight of the formulation.

17. A formulation as set forth in claim 1 comprising, as flavorings, mint aroma, peppermint aromas, orange flavoring, peach aroma, apricot aroma, raspberry aroma, lemon aroma, coconut aroma and pineapple aroma, or their mixtures, in quantities of between 1.4% and 12.5% by weight in relation to the total weight of the formulation.

18. A formulation as set forth in claim 1, containing a quantity of mannitol and sorbitol as sweetener, and a flavoring comprising strawberry aroma, of between 10% and 12% by weight in relation to the weight of the formulation;

or a quantity of aniseed of between 0.6% and 0.7% by weight in relation to the weight of the formulation;

or a quantity of peppermint of approximately 0.3% by weight of the formulation;

or combinations of the last two.

19. A formulation as set forth in claim 1, wherein the acid addition salt of fluoxetine is the hydrochloride.

20. A dispersible tablet containing fluoxetine or an acid addition salt thereof, obtainable by direct compression of a pharmaceutical formulation of claim 1.