WO2016063289A2 - Compositions de comprimé pharmaceutique comprenant de la rifaximine - Google Patents

Compositions de comprimé pharmaceutique comprenant de la rifaximine Download PDF

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Publication number
WO2016063289A2
WO2016063289A2 PCT/IN2015/000312 IN2015000312W WO2016063289A2 WO 2016063289 A2 WO2016063289 A2 WO 2016063289A2 IN 2015000312 W IN2015000312 W IN 2015000312W WO 2016063289 A2 WO2016063289 A2 WO 2016063289A2
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WO
WIPO (PCT)
Prior art keywords
rifaximin
composition
prepared
powder diffraction
ray powder
Prior art date
Application number
PCT/IN2015/000312
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English (en)
Other versions
WO2016063289A3 (fr
Inventor
Kumar Mohan
Kumar Anil
Dash Bidhubhusan
Original Assignee
Strides Arcolab Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Strides Arcolab Limited filed Critical Strides Arcolab Limited
Publication of WO2016063289A2 publication Critical patent/WO2016063289A2/fr
Publication of WO2016063289A3 publication Critical patent/WO2016063289A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • This invention relates to pharmaceutical tablet compositions comprising Rifaximin and novel polymorph thereof. More particularly, the invention relates to pharmaceutical tablet compositions comprising novel polymorph of Rifaximin.
  • [1,1 1, 13]trienimino)benzofuro[4,5-e]pyrido[ 1 ,2-a]-benzimidazole- 1 , 15(2H)-dione, 25- acetate ⁇ represented by formula I, is a semisynthetic rifamycin-based non-systemic antibiotic, disclosed and claimed in IT 1 154655. It is marketed in the US as XifaxanTM by Salix Pharmaceuticals.
  • Rifaximin is useful for the treatment of travellers' diarrhoea in adults and in children 12- years or more of age caused by E. coli bacteria. Rifaximin has also been evaluated for the treatment of irritable bowel syndrome, diverticular disease, hepatic encephalopathy, pyogenic skin infections, and as an antibacterial prophylactic prior to colon surgery.
  • Rifaximin is a pyrido-imidazo derivative of 4-deoxy-4'- methylpyrido[r,2': l,2]imidazo[5,4-c]rifamycin SV (Rifamycin SV). Unlike other Rifamycin SV derivatives, rifaximin exerts broad spectrum activity and has a specific mode of action which results in low gastrointestinal absorption.
  • GB 2079270 discloses imidazo-rifamycin derivatives having antibacterial activity, prepared from 3-halorifamycin S.
  • U.S. Pat. No. 4,341 ,785 and EP 0161534 describe the processes for preparation of pyrido-imidazo rifamycin starting from rifamycin O.
  • solvent systems comprising methylene chloride, chloroform, methanol, ethanol, isopropanol and water as an anti-solvent without disclosing the polymorphic form of the obtained Rifaximin.
  • Rifaximin exhibits variety of polymorphism when subjected to differential conditions. It is very well established that the polymorphism in rifaximin is not only dependent on solvent, but also depends on other conditions such as moisture content, time and temperature at which both the crystallization and the drying are carried out.
  • EP1698630 reported two more polymorphic forms 6- and ⁇ -forms which are crystalline and there is a significant degree of overlap with the other reported forms.
  • U.S. Pat. No. 7,709,634 reported an amorphous form of rifaximin having two PXRD peaks at 2 ⁇ values 7.2° and 15.0°.
  • US8633234 describes another amorphous form and its preparation.
  • US8569326 and US 8067429 describes Rifaximin polymorph Form ⁇ (Zeta), Rifaximin polymorph Form ⁇ (Eta); Rifaximin polymorph Form I (Iota); Rifaximin mesylate form; Pharmaceutical compositions comprising the above forms in association with pharmaceutical excipients.
  • US8513275 describes polymorph Form kappa, a Rifaximin polymorph Form theta, a Rifaximi piperazine cocrystal 1 or a Rifaximi piperazine cocrystal 2.
  • US'275 further reports process for producing the polymorphic forms and pharmaceutical compositions comprising the polymorphic forms.
  • US8227482 reports Rifaximin polymorph Form Mu or a salt, or hydrate form thereof; polymorph Form Pi, or a salt, or hydrate form thereof; polymorph Form Omicron, or a salt, or hydrate form thereof.
  • US'482 further discloses a method of producing Rifaximin Form Eta and a method of treating a bowel related disorder using the above forms.
  • US2014/001 1828 discloses another amorphous form of Rifaximin that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ (+/-0.20 degree ⁇ ) at 7.3 (approximate halo maximum), 11.3-17.8 (amorphous halo range), and 15.8 (approximate halo maximum) degrees 2- ⁇ .
  • Rifaximin exhibits innumerable polymorphic forms under differential conditions that include solvent, moisture, temperature, time and drying conditions. It is also evident that Rifaximin exhibits polyamorphism as the molecule takes on several different amorphous modifications as reported in the literature.
  • Rifaximin is poorly water soluble and minimally absorbed drug. Formulation scientists always look for suitable polymorphic form which is more stable in formulation and bioavailable. Since Rifaximin is sensitive to external conditions and thus exhibits innumerable polymorphic forms under differential conditions, the bioavailability of the same also varies with polymorphic modification.
  • compositions comprising Rifaximin that is consistently stable during its shelf-life so as to minimize the fluctuation in bioavailability of the drug upon administration.
  • the object of the present invention is to provide Rifaximin compositions, wherein the polymorphic form is consistently stable during its shelf-life so as to minimize the fluctuation in bioavailability of the drug upon administration.
  • the present invention provides pharmaceutical tablet compositions comprising Rifaximin, wherein, the Rifaximin polymorphic form in the composition is characterized by X-ray powder diffraction having peaks, in terms of 2 ⁇ , at least two or more of about 8.80; about 9.38; about 9.44; about 14.85; about 15.14; about 15.16; about 15.66; about 15.76; about 15.93; about 16.06; about 20.55; about 21.21 ; about 21.
  • composition is prepared by using amorphous Rifaximin characterized by X-ray powder diffraction comprising a sharp peak at angle 2 ⁇ 7.2°.
  • novel polymorphic form characterized as above remains stable in the formulation during its shelf-life.
  • the present invention provides pharmaceutical tablet compositions comprising Rifaximin, wherein, the Rifaximin polymorphic form in the composition is characterized by X-ray powder diffraction having peaks, in terms of 2 ⁇ , at least two or more of about 9.38; about 9.44; about 15.16; about 15.66; about 15.93; about 21. 94; about 25.18; about 25.22; about 25.25; about 25.33; about 28.55; about 28.59; about 28.67; about 34.35; about 34.45 and about 34.58 ⁇ 0.2 and wherein, the composition is prepared by using amorphous Rifaximin characterized by X-ray powder diffraction comprising a sharp peak at angle 2 ⁇ 7.2°.
  • the novel polymorphic form characterized as above remains stable in the formulation during its shelf-life.
  • compositions provided according to the invention are prepared by the methods known in the art viz., dry granulation and wet granulation.
  • the invention provides dissolution profile of the compositions according to the invention that matches with the profile of marketed drug.
  • Fig 1 depicts the XRD of the formulation 1 containing Rifaximin 200mg (after 3 months) prepared by wet granulation
  • Fig 2 depicts the XRD of the formulation 3 containing Rifaximin 550mg (after 3months) prepared by wet granulation
  • Fig 3 depicts the XRD of the formulation 4 containing Rifaximin 550mg (after 3months) prepared by wet granulation
  • any of the words “including,” “includes,” “comprising,” and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
  • the term "about” when used with regard to x-ray powder diffraction pattern peak positions that invariably denotes to the inherent variability of the peaks of Rifaximin in the composition depending on various factors, for example, the process used to produce such formulation such as wet and dry granulation methods, compression forces, the age of the amorphous Rifaximin that has been used in the composition and the calibration of the equipment used.
  • the variability of the instrument in measuring the peaks may be considered about ⁇ 0.2 degrees 2- ⁇ .
  • the variability as disclosed herein is in consistent with the USP definition for peak position error. Therefore, a skilled person in the pertinent art would understand as such the use of "about” in the context of the disclosure and appreciate the same.
  • the invention provides pharmaceutical tablet compositions comprising Rifaximin, wherein, the Rifaximin polymorphic form in the formulation is characterized by X-ray powder diffraction having peaks, in terms of 2 ⁇ , at least two or more of about 8.80; about 9.38; about 9.44; about 14.85; about 15.16; about 15.66; about 15.93; about 16.06; about 20.55; about 21.21 ; about 21.
  • composition is prepared by using amorphous Rifaximin characterized by X-ray powder diffraction comprising a sharp peak at angle 2 ⁇ 7.2°,
  • the present invention provides pharmaceutical tablet compositions comprising Rifaximin, wherein, the Rifaximin polymorphic form in the composition is characterized by X-ray powder diffraction having peaks, in terms of 2 ⁇ , at least two or more of about 9.33; about 9.44; about 15.16; about 15.66; about 15.93; about 21. 94; about 25.18; about 25.22; about 25.25; about 25.33; about 28.55; about 28.59; about 28.67; about 34.35; about 34.45 and about 34.58 ⁇ 0.2 and wherein, the composition is prepared by using amorphous Rifaximin characterized by X-ray powder diffraction comprising a sharp peak at angle 2 ⁇ 7.2°.
  • the novel polymorphic form characterized as above remains stable in the formulation during its shelf-life.
  • the original amorphous form incorporated into the formulation according to the invention is converted into another polymorphic form, which remains stable in the formulation during its shelf-life, as per the XRD data provided.
  • the tablet compositions according to the invention are subjected to accelerated degradation studies (40°C/75% RH) before subjecting to X-ray powder diffraction.
  • the compositions provided according to the invention is prepared by the methods known in the art viz., dry granulation and wet granulation.
  • the invention provides dissolution profile of the compositions according to the invention that matches with the profile of marketed drug.
  • step (a) Granulating the mixture of step (a) with the solution of step (b) in RMG; Drying at 60 P C in rapid drier & Sizing through 20mesh;
  • step (c) Passing Extragranular material like sodium starch glycolate, colloidal silicon dioxide , Purified talc through # 40mesh and blending with step (c); and e) Lubricating the blend with Glycerol palmito sterate (40mesh) and compressed with tablet presser.
  • step (b) Blending the mixture of step (a) with Colloidal silicon dioxide and Glycerol palmito sterate passed through 40mesh;
  • step (c) lubricating the blend of step (c) with Glycerol palmito sterate, Purified Talc through # 40mesh followed by compressed with tablet presser.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne une composition de comprimé pharmaceutique comprenant de la rifaximine et un procédé de préparation de celle-ci.
PCT/IN2015/000312 2014-10-22 2015-08-04 Compositions de comprimé pharmaceutique comprenant de la rifaximine WO2016063289A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3379/MUM/2014 2014-10-22
IN3379MU2014 2014-10-22

Publications (2)

Publication Number Publication Date
WO2016063289A2 true WO2016063289A2 (fr) 2016-04-28
WO2016063289A3 WO2016063289A3 (fr) 2016-07-14

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9938298B2 (en) 2014-05-12 2018-04-10 Alfa Wassermann S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
KR20190062458A (ko) * 2016-09-30 2019-06-05 샐릭스 파마슈티컬스 인코포레이티드 리팍시민의 고체 분산물 형태
WO2020128583A1 (fr) * 2018-12-19 2020-06-25 Friulchem S.P.A. Procédé de fabrication d'un comprimé de rifaximine et comprimé de rifaximine
US10703763B2 (en) 2005-03-03 2020-07-07 Alfasigma S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2069363B1 (fr) * 2006-09-22 2013-03-20 Cipla Ltd. Rifaximine sous une forme amorphe
IT1398550B1 (it) * 2010-03-05 2013-03-01 Alfa Wassermann Spa Formulazioni comprendenti rifaximina utili per ottenere un effetto prolungato nel tempo
US8759513B2 (en) * 2010-09-13 2014-06-24 Sequent Scientific Limited Polymorphic form of rifaximin and process for its preparation
IT1403847B1 (it) * 2010-09-22 2013-11-08 Alfa Wassermann Spa Composizioni farmaceutiche comprendenti rifaximina e loro uso.

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10703763B2 (en) 2005-03-03 2020-07-07 Alfasigma S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US9938298B2 (en) 2014-05-12 2018-04-10 Alfa Wassermann S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
KR20190062458A (ko) * 2016-09-30 2019-06-05 샐릭스 파마슈티컬스 인코포레이티드 리팍시민의 고체 분산물 형태
KR102494049B1 (ko) 2016-09-30 2023-01-31 샐릭스 파마슈티컬스 인코포레이티드 리팍시민의 고체 분산물 형태
US11660292B2 (en) 2016-09-30 2023-05-30 Salix Pharmaceuticals, Inc. Solid dispersion forms of rifaximin
WO2020128583A1 (fr) * 2018-12-19 2020-06-25 Friulchem S.P.A. Procédé de fabrication d'un comprimé de rifaximine et comprimé de rifaximine

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