Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations

• US 10,745,415 B2
• Filed: 09/11/2019
• Issued: 08/18/2020
• Est. Priority Date: 03/31/2014
• Status: Active Grant

• Current Assignee: Curia IP Holdings LLC
• Original Assignee: AMRI, Italy S.r.l.
• Inventors: Grisenti, Paride, Argese, Maria, Pengo, Daniele, Grilli, Maria Donata, Fumagalli, Emanuela, Motta, Giuseppe
• Primary Examiner(s): Kassa, Tigabu
• Application Number:
  US16/567,852
• Publication Number:
  US 20200002356A1
• Time in Patent Office: 342 Days
• Field of Search: None
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• 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: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/2893 Tablet coating processes mechanical aspects A61J3/06
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

A Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3 and a process for its preparation. The polymorphic mixture of Rifaximin is for use as a medicament, in particular in the treatment of traveler'"'"'s diarrhea and hepatic encephalopathy. A pharmaceutical composition comprises the polymorphic mixture of Rifaximin as active ingredient, in particular, a solid formulation, more in particular, a film coated tablet. A polymorphic form of crude wet rifaximin and of purified wet rifaximin their use are used as intermediates in a process for the preparation of Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15±3.

Claims

1. A method of treating a subject suffering from traveler'"'"'s diarrhea comprising:

selecting a subject in need of treatment of traveler'"'"'s diarrhea;

administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of Rifaximin in an α

/β

polymorphic mixture of 85/15±

3 in an amount sufficient to treat the traveler'"'"'s diarrhea, wherein the Rifaximin α

/β

polymorphic mixture is characterized by an X-Ray spectrum with characteristic 2theta values at;

5.32, 5.78, 6.50, 7.24, 7.82, 8.80, 10.50, 11.02, 11.58, 13.08, 14.42, 17.32, 17.68, 18.58, 19.52, 21.04, 21.60, and 21.92.

2. The method of claim 1, wherein the pharmaceutical composition is a solid pharmaceutical composition.

3. The method of claim 2, wherein the pharmaceutical composition is a film coated tablet.

4. The method of claim 1, wherein the pharmaceutical composition comprises 550 mg of Rifaximin α

/β

polymorphic mixture of 85/15±

3.

5. The method of claim 1, wherein the pharmaceutical composition further comprises excipients.

6. The method of claim 5, wherein the excipients comprise cellulose microcrystalline, sodium starch glycolate, glyceryl palmitostearate, hydrated silicon dioxide, and talc.

7. The method of claim 6, wherein the pharmaceutical composition further comprises polyvinyl alcohol, polyethylene glycol, titanium dioxide, and red iron oxide.

8. The method of claim 7, wherein the pharmaceutical composition has a hardness of 18.49±

1.30 Kp, a thickness of about 5.48±

0.06 mm, a friability of about 0.058%, and a disintegration in purified water at 37°

C. of about 1′

20″

.

9. A method of treating a subject suffering from hepatic encephalopathy comprising:

selecting a subject in need of treatment of hepatic encephalopathy;

administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of Rifaximin in an α

/β

polymorphic mixture of 85/15±

3 in an amount sufficient to treat the hepatic encephalopathy, wherein the Rifaximin α

/β

polymorphic mixture is characterized by an X-Ray spectrum with characteristic 2theta values at;

5.32, 5.78, 6.50, 7.24, 7.82, 8.80, 10.50, 11.02, 11.58, 13.08, 14.42, 17.32, 17.68, 18.58, 19.52, 21.04, 21.60, and 21.92.

10. The method of claim 9, wherein the pharmaceutical composition is a solid pharmaceutical composition.

11. The method of claim 10, wherein the pharmaceutical composition is a film coated tablet.

12. The method of claim 9, wherein the pharmaceutical composition comprises 550 mg of Rifaximin α

/β

polymorphic mixture of 85/15±

3.

13. The method of claim 9, wherein the pharmaceutical composition further comprises excipients.

14. The method of claim 13, wherein the excipients comprise cellulose microcrystalline, sodium starch glycolate, glyceryl palmitostearate, hydrated silicon dioxide, and talc.

15. The method of claim 14, wherein the pharmaceutical composition further comprises polyvinyl alcohol, polyethylene glycol, titanium dioxide, and red iron oxide.

16. The method of claim 15, wherein the pharmaceutical composition has a hardness of 18.49±

1.30 Kp, a thickness of about 5.48±

0.06 mm, a friability of about 0.058%, and a disintegration in purified water at 37°

C. of about 1′

20″

.