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

• US 8,853,231 B2
• Filed: 11/16/2012
• Issued: 10/07/2014
• 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: Viscomi, Giuseppe Claudio, Campana, Manuela, Braga, Dario, Confortini, Donatella, Cannata, Vincenzo, Righi, Paolo, Rosini, Goffredo
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/679,602
• Publication Number:
  US 20130289269A1
• Time in Patent Office: 690 Days
• Field of Search: 514/279
• US Class Current: 514/279
• 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 a polymorphic form of rifaximin together with a pharmaceutically acceptable carrier, wherein the polymorphic form is form α

, having x-ray powder diffraction pattern peaks at about;

7.4°

, 7.9°

, and 11.8°

;

or

7.4°

, 8.8°

, and 11.8°

;

or

7.4°

, 10.5°

, and 11.8°

;

or

7.4°

, 11.1°

, and 11.8°

;

or

7.4°

, 11.8° and

12.9°

;

or

7.4°

, 11.8° and

17.6°

;

or

7.4°

, 11.8° and

19.7°

;

or

7.4°

, 11.8° and

21.4°

;

or

7.4°

, 11.8° and

22.1°

, or

7.4°

,11.1°

, and 12.9°

;

or

7.4°

, 11.1°

, and 19.7°

;

or

7.4°

, 12.9°

, and 19.7°

;

or

11.1°

, 11.8°

, and 19.7°

;

or

11.1°

, 19.7°

, and 21.4°

;

or

11.1°

, 19.7°

, and 22.1°

, or

11.8°

, 12.9°

, and 19.7°

;

or

11.8°

, 19.9°

, and 22.1°

, 2θ

.

2. The pharmaceutical composition of claim 1, wherein after administration of the pharmaceutical composition to a patient, an observed plasma concentration of rifaximin in the patient is negligible.

3. The pharmaceutical composition of claim 1, wherein the composition further comprises an excipient.

4. The pharmaceutical composition of claim 2, 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.

5. The pharmaceutical composition of claim 2, wherein the composition is for oral use and is in a form selected from the group consisting of coated or uncoated tablets, hard or soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets, and powders in sealed packet.

6. The pharmaceutical composition of claim 2, wherein the composition comprises one or more of colloidal silicon dioxide, hydroxypropyl methylcellulose, cellulose, microcrystalline cellulose, propylene glycol, sodium starch glycolate.

7. A pharmaceutical composition comprising a polymorphic form of rifaximin together with a pharmaceutically acceptable carrier, wherein the polymorphic form is form β

, having x-ray powder diffraction pattern peaks at about;

5.4°

, 6.4°

, and 7.0°

, or

5.4°

, 6.4°

, and 7.8°

;

or

5.4°

, 6.4°

, and 9.0°

;

or

5.4°

, 6.4°

, and 10.4°

;

or

5.4°

, 6.4°

, and 13.1°

, or

5.4° and

7.0°

, and 14.4°

;

or

5.4°

, 10.4°

, and 18.3°

;

or

5.4°

, 10.4°

, and 20.9°

;

or

5.4°

, 10.4°

, and 17.1°

, or

6.4°

, 7.0°

, and 10.4°

;

or

6.4°

, 7.8° and

10.4°

;

or

6.4°

, 9.0° and

10.4°

;

or

6.4°

, 10.4°

, and 14.4°

;

or

10.4°

, 13.1°

, and 14.4°

;

or

10.4°

, 17.1°

, and 17.9°

;

or

10.4°

, 17.9°

, and 18.3°

;

or

10.4°

, 17.9°

, and 20.9°

;

or

10.4°

, 18.3°

, and 20.9°

;

or

14.4°

, 17.1°

, and 18.3°

;

or

17.1°

, 18.3°

, and 20.9°

;

or

14.4°

, 17.1°

, and 20.9°

, 2θ

.

8. The pharmaceutical composition of claim 7, wherein after administration of the pharmaceutical composition to a patient, an observed plasma concentration of rifaximin in the patient is negligible.

9. The pharmaceutical composition of claim 7, further comprising an excipient.

10. 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.

11. The pharmaceutical composition of claim 7, wherein the composition is for oral use and is in a form selected from the group consisting of coated or uncoated tablets, hard or soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets, and powders in sealed packet.

12. The pharmaceutical composition of claim 10, wherein the composition comprises one or more of colloidal silicon dioxide, hydroxypropyl methylcellulose, cellulose, microcrystalline cellulose, propylene glycol, sodium starch glycolate.

13. A pharmaceutical composition comprising a polymorphic form of rifaximin together with a pharmaceutically acceptable carrier, wherein the polymorphic form is form γ

, having x-ray powder diffraction pattern peaks at about 5.0°

, 7.1°

, and 8.4°

2θ and

an intrinsic dissolution rate of about 0.14 mg/min/cm².

14. The pharmaceutical composition of claim 13, wherein after administration of the pharmaceutical composition to a patient, an observed plasma concentration of rifaximin is of about 670 ng/ml.

15. The pharmaceutical composition of claim 14, wherein the composition further comprises an excipient.

16. The pharmaceutical composition of claim 15, 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.

17. The pharmaceutical composition of claim 14, wherein the composition is for oral use and is in a form selected from the group consisting of coated or uncoated tablets, hard or soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets, and powders in sealed packet.

18. The pharmaceutical composition of claim 16, wherein the composition comprises one or more of colloidal silicon dioxide, hydroxypropyl methylcellulose, cellulose, microcrystalline cellulose, propylene glycol, sodium starch glycolate.