Use of polymorphic forms of rifaximin for medical preparations

• US 7,915,275 B2
• Filed: 10/17/2007
• Issued: 03/29/2011
• Est. Priority Date: 11/07/2003
• Status: Active Grant

• Current Assignee: Alfasigma S.p.A.
• Original Assignee: ALFA Wassermann BV (Alfasigma S.p.A.)
• Inventors: Barbanti, Miriam, Calanni, Fiorella, Viscomi, Giuseppe C., Confortini, Donatella, Campana, Manuela
• Primary Examiner(s): Kifle; Bruck
• Application Number:
  US11/873,841
• Publication Number:
  US 20080132530A1
• Time in Patent Office: 1,259 Days
• Field of Search: 514/279
• US Class Current: 514/279
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

The present invention relates to Rifaximin polymorphic forms α, β and γ, to their use in medicinal preparations for the oral or topical route and to therapeutic methods using them.

Claims

1. A method of treating bacterial infection in a patient suffering from a bowel related disorder comprising administering to a patient in need thereof a solid pharmaceutical composition comprising a therapeutically effective amount of one or more of Form α

, Form β

, or Form γ

polymorph of rifaximin and a pharmaceutically acceptable excipient or carrier, wherein the amount of each of Form α

, Form β

, or Form γ

polymorph of rifaximin present in said pharmaceutical composition is an amount to control the amount of systemic absorption of said rifaximin,

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

,

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 the rifaximin Form γ

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

, 7.1°

, and 8.4°

2-θ

.

2. The method of claim 1, wherein bowel related disorder is selected from the group consisting of irritable bowel syndrome, traveler'"'"'s diarrhea, small intestinal bacterial overgrowth, Crohn'"'"'s disease, chronic pancreatitis, pancreatic insufficiency, and colitis.

3. The method of claim 1, wherein the pharmaceutical composition is administered orally.

4. The method of claim 1, wherein the pharmaceutical composition is administered topically.

5. The method of claim 1, wherein

the rifaximin Form α

has a water content of less than 4.5%;

the rifaximin Form β

has a water content of greater than or equal to 4.5%; and

the rifaximin Form γ

has a water content from about 0% to about 2%.

6. The method of claim 5, wherein the rifaximin Form β

has a water content of greater than or equal to 4.5%.

7. The method of claim 5, wherein the rifaximin Form γ

has a water content from about 0% to about 2%.

8. The method of claim 1, wherein after administering the polymorph Form α

to a patient, the bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 5.5 ng/ml.

9. The method of claim 8, wherein the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h.

10. The method of claim 8, wherein the bioavailable plasma AUC_0-24h is between about 0.0 and about 100 ng·

h/ml, and the bioavailable plasma AUC_0-inf is between about 0.0 and 110 ng·

h/ml.

11. The method of claim 1, wherein after administering the polymorph Form β

to a patient, the bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 3.7 ng/ml.

12. The method of claim 11, wherein the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h.

13. The method of claim 11, wherein the bioavailable plasma AUC_0-24h comprises between about 0.0 and about 40 ng·

h/ml and the bioavailable plasma AUC_0-inf comprises from about 0.0 to about 50 ng·

h/ml.

14. The method of claim 1, wherein the rifaximin Form β

has a dissolution rate of from about 0.001 to about 0.016 mg/min/cm².

15. The method of claim 1, wherein after administering the polymorph Form γ

to a patient, the bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 5000 ng/ml.

16. The method of claim 15, wherein the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h.

17. The method of claim 15, wherein the bioavailable plasma AUC_0-24h comprises between about 0.0 and about 22000 ng·

h/ml and the bioavailable plasma AUC_0-inf comprises from about 0.0 to about 22000 ng·

h/ml.

18. The method of claim 1, wherein the rifaximin Form γ

has a dissolution rate of from about 0.1 to about 0.16 mg/min/cm².

19. The method of claim 5, wherein the rifaximin Form α

has a water content of less than 4.5%.

20. The method of claim 5, wherein after administering the polymorph Form α

to a patient, the bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 5.5 ng/ml;

the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h; and

the bioavailable plasma AUC_0-24h is between about 0.0 and about 100 ng·

h/ml, and the bioavailable plasma AUC_0-inf is between about 0.0 and 110 ng·

h/ml.

21. The method of claim 5, wherein after administering the polymorph Form β

to a patient, the bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 3.7 ng/ml;

the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h; and

the bioavailable plasma AUC_0-24h comprises between about 0.0 and about 40 ngh/ml and the bioavailable plasma AUC_0-inf comprises from about 0.0 to about 50 ng·

h/ml.

22. The method of claim 5, wherein the rifaximin Form β

has a dissolution rate of from about 0.001 to about 0.016 mg/min/cm².

23. The method of claim 5, wherein after administering the polymorph Form γ

to a patient, the bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 5000 ng/ml;

the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h; and

the bioavailable plasma AUC_0-24h comprises between about 0.0 and about 22000 ng·

h/ml and the bioavailable plasma AUC_0-inf comprises from about 0.0 to about 22000 ng·

h/ml.

24. The method of claim 5, wherein the rifaximin Form γ

has a dissolution rate of from about 0.1 to about 0.16 mg/min/cm².

25. The method of claim 1,

wherein after administering the polymorph Form α

to a patient, bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 5.5 ng/ml;

the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h; and

the bioavailable plasma AUC_0-24h is between about 0.0 and about 100 ng·

h/ml, and the bioavailable plasma AUC_0-inf is between about 0.0 and 110 ng·

h/ml;

wherein after administering the polymorph Form β

to a patient, bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 3.7 ng/ml;

the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h; and

the bioavailable plasma AUC_0-24h comprises between about 0.0 and about 40 ng·

h/ml and the bioavailable plasma AUC_0-inf comprises from about 0.0 to about 50 ng·

h/ml; and

wherein after administering the polymorph Form γ

to a patient, bioavailable plasma concentration of the rifaximin reaches a maximum value (C_max) from about 0.0 ng/ml to about 5000 ng/ml;

the C_max is reached within a time (t_max) from about 1.0 h to about 6.0 h; and

the bioavailable plasma AUC_0-24h comprises between about 0.0 and about 22000 ng·

h/ml and the bioavailable plasma AUC_0-inf comprises from about 0.0 to about 22000 ng·

h/ml.

26. The method of claim 25, wherein the rifaximin Form α

has a water content of less than 4.5%.

27. The method of claim 25, wherein the rifaximin Form β

has a water content of greater than or equal to 4.5%.

28. The method of claim 25, wherein the rifaximin Form γ

has a water content from about 0% to about 2%.

29. The method of claim 25, wherein the rifaximin Form β

has a dissolution rate of from about 0.001 to about 0.016 mg/min/cm².

30. The method of claim 25, wherein the rifaximin Form γ

has a dissolution rate of from about 0.1 to about 0.16 mg/min/cm².