Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations

• US 10,703,763 B2
• Filed: 03/04/2019
• Issued: 07/07/2020
• Est. Priority Date: 03/03/2005
• Status: Active Grant

• Current Assignee: Alfasigma S.p.A.
• Original Assignee: Alfasigma S.p.A.
• Inventors: Viscomi, Giuseppe Claudio, Campana, Manuela, Confortini, Donatella, Barbanti, Maria, Braga, Dario
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US16/291,900
• Publication Number:
  US 20200002350A1
• Time in Patent Office: 491 Days
• 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 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

Crystalline polymorphous forms of the rifaximin (INN) antibiotic named rifaximin δ and rifaximin ε useful in the production of medicinal preparations 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 determinate temperature and for a determinate period of time, followed by a drying carried out under controlled conditions until reaching a settled water content in the end product, are the object of the invention.

Claims

1. A method of treating bacterial activity in the gastrointestinal tract of a subject, the method comprising:

orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of rifaximin δ

together with a pharmaceutically acceptable excipient selected from the group consisting of diluting, binding, lubricating, disintegrating, colouring, flavouring and sweetening agents,

wherein rifaximin δ

has a powder X-ray diffractogram showing peaks at values of the diffraction angles 2θ

of about 5.7°

±

0.2, 6.7°

±

0.2, 7.1°

±

0.2, 8.0°

±

0.2, 8.7°

±

0.2, 10.4°

±

0.2, 10.8°

±

0.2, 11.3°

±

0.2, 12.1°

±

0.2, 17.0°

±

0.2, 17.3°

±

0.2, 17.5°

±

0.2, 18.5°

±

0.2, 18.8°

±

0.2, 19.1°

±

0.2, 21.0°

±

0.2, 21.5°

±

0.2.

2. The method of claim 1, wherein the pharmaceutical composition is in a formulation selected from the group consisting of coated or uncoated tablet, hard or soft gelatin capsule, sugar-coated pill, lozenge, wafer sheet, pellet, and powder in sealed packet.

5. The method of claim 1, wherein rifaximin δ

has a water content between 3.0% and 4.5%.

3. A method of treating bacterial activity in the gastrointestinal tract of a subject, the method comprising:

topically administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of rifaximin δ

,

wherein rifaximin δ

has a powder X-ray diffractogram showing peaks at values of the diffraction angles 2θ

of about 5.7°

±

0.2, 6.7°

±

0.2, 7.1°

±

0.2, 8.0°

±

0.2, 8.7°

±

0.2, 10.4°

±

0.2, 10.8°

±

0.2, 11.3°

±

0.2, 12.1°

±

0.2, 17.0°

±

0.2, 17.3°

±

0.2, 17.5°

±

0.2, 18.5°

±

0.2, 18.8°

±

0.2, 19.1°

±

0.2, 21.0°

±

0.2, 21.5°

±

0.2.

4. The method of claim 3, wherein the pharmaceutical composition is in a formulation selected from the group consisting of ointment, pomade, cream, gel and lotion.

6. A method of treating bacterial activity in the gastrointestinal tract of a subject, the method comprising:

orally administering to the subject by oral route a pharmaceutical composition comprising a therapeutically effective amount of rifaximin ε

together with a pharmaceutically acceptable excipient selected from the group consisting of diluting, binding, lubricating, disintegrating, colouring, flavouring and sweetening agents,

wherein rifaximin ε

has a powder X-ray diffractogram showing peaks at values of the diffraction angles 2θ

of 7.0°

±

0.2, 7.3°

±

0.2, 8.2°

±

0.2, 8.7°

±

0.2, 10.3°

±

0.2, 11.1°

±

0.2, 11.7°

±

0.2, 12.4°

±

0.2, 14.5°

±

0.2, 16.3°

±

0.2, 17.2°

±

0.2, 18.0°

±

0.2, 19.4°

±

0.2.

7. The method of claim 6, wherein the pharmaceutical composition is in a formulation selected from the group consisting of coated or uncoated tablet, hard or soft gelatin capsule, sugar-coated pill, lozenge, wafer sheet, pellet, and powder in sealed packet.

8. A method of treating bacterial activity in the gastrointestinal tract of a subject, the method comprising:

topically administering to the subject by oral route a pharmaceutical composition comprising a therapeutically effective amount of rifaximin ε

,

wherein rifaximin ε

has a powder X-ray diffractogram showing peaks at values of the diffraction angles 2θ

of 7.0°

±

0.2, 7.3°

±

0.2, 8.2°

±

0.2, 8.7°

±

0.2, 10.3°

±

0.2, 11.1°

±

0.2, 11.7°

±

0.2, 12.4°

±

0.2, 14.5°

±

0.2, 16.3°

±

0.2, 17.2°

±

0.2, 18.0°

±

0.2, 19.4°

±

0.2.

9. The method of claim 8, wherein the pharmaceutical composition is in a formulation selected from the group consisting of ointment, pomade, cream, gel and lotion.