Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin

• US 7,906,542 B2
• Filed: 05/13/2008
• Issued: 03/15/2011
• Est. Priority Date: 11/04/2004
• Status: Active Grant

• Current Assignee: Alfasigma S.p.A.
• Original Assignee: ALFA Wassermann BV (Alfasigma S.p.A.)
• Inventors: Righi, Paolo, Braga, Dario, Confortini, Donatella, Viscomi, Giuseppe Claudio, Rosini, Goffredo, Cannata, Vincenzo, Campana, Manuela
• Primary Examiner(s): Kifle; Bruck
• Application Number:
  US12/119,622
• Publication Number:
  US 20080262012A1
• Time in Patent Office: 1,036 Days
• Field of Search: 514/393
• US Class Current: 514/393
• 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: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

Crystalline polymorphous forms of rifaximin (INN), referred to as rifaximin α and rifaximin β, and a poorly crystalline form referred to as rifaximin γ, useful in the production of medicaments containing rifaximin for oral and topical use and obtained by means of a crystallization process carried out by hot-dissolving the raw rifaximin in ethyl alcohol and by causing the crystallization of the product by addition of water at a fixed temperature and for a fixed period of time, followed by a drying under controlled conditions until reaching a precise water content in the end product, are the object of the invention.

Claims

1. A pharmaceutical composition comprising rifaximin in polymorphic Form α

and a pharmaceutically acceptable excipient or carrier, wherein the rifaximin Form α

has x-ray powder diffraction pattern peaks at about 7.4°

;

19.7°

;

21.0° and

22.1°

2-θ

, and wherein after administration to a patient, the observed plasma concentration of rifaxmin is no more than about 2.6 ng/ml.

2. The pharmaceutical composition of claim 1, wherein the polymorph Form α

has a water content of about 2% to about 3%.

3. The pharmaceutical composition of claim 1, wherein the excipient is selected from the group consisting of a diluting agent, a binding agent, a lubricating agent, a disintegrating agent, a coloring agent, a flavoring agent, and a sweetening agent.

4. The pharmaceutical composition of claim 1, wherein the composition is formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in a sealed packet.

5. The pharmaceutical composition of claim 1, wherein after administration to a patient, the t_max of the Form α

is about 9.5 hours.

6. The pharmaceutical composition of claim 1, wherein after administration to a patient, the AUC_{0-24 h} of the Form α

is about 13 ng·

h/ml.

7. The pharmaceutical composition of claim 2, wherein after administration to a patient, the t_max of the Form α

is about 9.5 hours.

8. The pharmaceutical composition of claim 2, wherein after administration to a patient, the AUC_{0-24 h} of the Form α

is about 13 ng·

h/ml.

9. A pharmaceutical composition comprising rifaximin in polymorphic Form β

and a pharmaceutically acceptable excipient or carrier, wherein the rifaximin Form β

has x-ray powder diffraction pattern peaks at about 5.4°

;

9.0°

; and

20.9°

2-θ

, and wherein after administration to a patient, the observed plasma concentration of rifaximin is no more than about 1.1 ng/ml.

10. The pharmaceutical composition of claim 9, wherein the polymorph Form β

has a water content of from between greater than about 4.5%.

11. The pharmaceutical composition of claim 9, wherein the excipient is selected from the group consisting of a diluting agent, a binding agent, a lubricating agent, a disintegrating agent, a coloring agent, a flavoring agent, and a sweetening agent.

12. The pharmaceutical composition of claim 9, wherein the composition is formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in a sealed packet.

13. The pharmaceutical composition of claim 9, wherein after administration to a patient, the t_max of the Form β

is about 4 hours.

14. The pharmaceutical composition of claim 9, wherein after administration to a patient, the AUC_{0-24 h} of the Form β

is about 11 ng·

h/ml.

15. The pharmaceutical composition of claim 10, wherein after administration to a patient, the t_max of the Form β

is about 4 hours.

16. The pharmaceutical composition of claim 10, wherein after administration to a patient, the AUC_{0-24 h} of the Form β

is about 11 ng·

h/ml.

17. The pharmaceutical composition of claim 10, wherein the intrinsic dissolution rate of the Form β

is about 0.014 mg/min/cm².

18. A pharmaceutical composition comprising rifaximin in polymorphic Form γ

and a pharmaceutically acceptable excipient or carrier, wherein the rifaximin Form γ

has x-ray powder diffraction pattern peaks at about 5.0°

, 7.1°

, and 8.4°

2-θ

, and wherein after administration to a patient, the observed plasma concentration of rifaximin is no more than about 668 ng/ml.

19. The pharmaceutical composition of claim 18, wherein the intrinsic dissolution rate of the Form γ

is about 0.14 mg/min/cm².

20. The pharmaceutical composition of claim 18, wherein the polymorph Form γ

has a water content of from between about 1% to about 2%.

21. The pharmaceutical composition of claim 18, wherein the excipient is selected from the group consisting of a diluting agent, a binding agent, a lubricating agent, a disintegrating agent, a coloring agent, a flavoring agent, and a sweetening agent.

22. The pharmaceutical composition of claim 18, wherein the composition is formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in a sealed packet.

23. The pharmaceutical composition of claim 18, wherein after administration to a patient, the t_max of the Form γ

is about 2.3 hours.

24. The pharmaceutical composition of claim 20, wherein after administration to a patient, the t_max of the Form γ

is about 2.3 hours.

25. The pharmaceutical composition of claim 18, wherein after administration to a patient, the AUC_{0-24 h} of the Form γ

is about 4000 ng·

h/ml.