WO2011061748A1 - Rifaximin premix - Google Patents

Rifaximin premix Download PDF

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Publication number
WO2011061748A1
WO2011061748A1 PCT/IN2009/000661 IN2009000661W WO2011061748A1 WO 2011061748 A1 WO2011061748 A1 WO 2011061748A1 IN 2009000661 W IN2009000661 W IN 2009000661W WO 2011061748 A1 WO2011061748 A1 WO 2011061748A1
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WO
WIPO (PCT)
Prior art keywords
rifaximin
premix
pharmaceutical compositions
agents
amorphous
Prior art date
Application number
PCT/IN2009/000661
Other languages
French (fr)
Inventor
Anil Kumar Ramachandrappa
Bidhubhusan Dash
Satya Srinivas Chetlapalli
Mailatur Sivaraman Mohan
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.)
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Publication date
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Priority to PCT/IN2009/000661 priority Critical patent/WO2011061748A1/en
Publication of WO2011061748A1 publication Critical patent/WO2011061748A1/en

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to Rifaximin premix comprising Rifaximin in an amorphous form and process for preparing said premix.
  • the present invention also relates to pharmaceutical compositions comprising said Rifaximin premix.
  • Rifaximin is a semi-synthetic, rifamycin-based non-systematic antibiotic. It is chemically termed as (2S,16Z,1SE,20S,21S,22R,23R,24R,25S,26 S,21S, 28E)-5,6,21,23,25- pentahydroxy-27-methoxy-2,4, 11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[ 1 , 1 1 , 13]trienimino)benzofuro[4,5-e]pyrido[l ,2-a]-benzimida-zole-l, 15(2H)-dione,25-acetate and structurally represented b following structure:
  • Rifaximin is primarily used for treatment of travelers' diarrhea caused by noninvasive strains of Escherichia coli.
  • Rifaximin is available in tablets, granules for oral suspension and ointment, marketed in Europe, in the U.S.A. and in many other countries.
  • Rifaximin was first disclosed in US4341785 which discloses a process for preparing Rifaximin and a method for crystallization of rifaximin using suitable solvents or mixture of solvents.
  • US7045620 (WO2005/044823) disclose crystalline polymorphic forms of rifaximin. These polymorphous forms are very important because they can change the intrinsic dissolution by approximately ten times and the bioavailability of Rifaximin by almost six hundred times. These changes have a strong effect on the efficacy and the safety of the product.
  • amorphous solids do not have lattice energy and hence they usually dissolve in a solvent more rapidly and consequently may provide enhanced bioavailability characteristics such as higher rate and extent of absorption of the compound from the gastrointestinal tract.
  • amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in the manufacturing process of solid dosage form such as compressibility. Consequently, a stable amorphous Rifaximin would be a significant contribution to the art.
  • Premixes are characterized by a variety of associated properties such as stability, flow, and solubility. Typical premixes represent a compromise of the above properties, as for example, an increase in stability and dissolution properties of the premix. Although there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit an improved mix of properties.
  • the instant invention provides a premix in which Rifaximin exists in stable amorphous form and process of manufacture of the premix and pharmaceutical compositions comprising said Rifaximin premix.
  • Figure 1 is an XRD of unprocessed Rifaximin API
  • Figure 2 is an XRD of premix of Rifaximin and HPMC as in example 1
  • Figure 3 is an XRD of premix of Rifaximin and PVP as in example 2
  • Figure 4 is an XRD of premix of Rifaximin and mannitol as in example 3.
  • Another object of the invention is to provide pharmaceutical compositions comprising the aforementioned Rifaximin premix.
  • the present invention provides Rifaximin premix having enhanced stability and dissolution properties and process for preparation thereof.
  • the invention provides for pharmaceutical compositions comprising said Rifaximin premix.
  • the present invention provides a premix of Rifaximin having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical compositions.
  • Rifaximin premix having enhanced stability and dissolution properties according to the invention, wherein Rifaximin is stabilized by combining with suitable polymers/agents. Further, Rifaximin is present in stable amorphous form in the premix of Rifaximin.
  • the ratio of Rifaximin to polymers/agents is in a range of 1:1 to 30: 1.
  • the premix of the present invention is prepared by combining Rifaximin with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties.
  • the polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Hypromellose, vinylpyrrolidone monomers but not limited to Polyvinylpyrrolidone and polyol but not limited to Mannitol.
  • the said polymers/agents are used to facilitate the presence of an amorphous Rifaximin.
  • the solvent system used in the process for manufacturing of the premix may be selected from a group of organic, aqueous, hydroalcoholic solvents either alone or in combinations thereof.
  • the said solvents are selected from water, methylene chloride, acetone, combination of Isopropyl alcohol and methylene chloride etc.
  • the present invention provides process for preparing the said Rifaximin premix which is prepared by spray drying and co precipitation method involving the interaction of Rifaximin with a suitable agent to generate an amorphous Rifaximin.
  • the process for preparing the Rifaximin premix comprises of dissolving Rifaximin in a solvent system selected from a group of organic solvents, aqueous solvents or hydro- alcoholic solvents alone or in combination.
  • the inlet temperature needs to be maintained at 50-200°c and more preferably 60 -100 °c.
  • Rifaximin API is characterized by the XRD.
  • the XRD of Rifaximin API is depicted in Fig 1.
  • the premix comprising Rifaximin and HPMC is depicted in Fig 2.
  • the premix comprising Rifaximin and Polyvinylpyrrolidone is depicted in Fig 3 and the premix comprising Rifaximin and Mannitol is depicted in Fig 4.
  • Rifaximin API is characterized by the distinct peaks as shown in Fig.l.
  • amorphous solids do not give a definitive X-Ray diffraction pattern (XRD). Hence, no distinct peaks can be seen of Rifaximin premixes.
  • the present invention provides a pharmaceutical composition containing said premix along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, lubricants and or anti-adherents.
  • the premix can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.
  • Example 1 Premix of Rifaximin with Hypromellose processed using combination of IPA and water
  • Example 2 Premix of Rifaximin with PVP processed using combination of IPA and water
  • Example 3 Premix of Rifaximin with mannitol processed using combination of IPA and water
  • the pharmaceutical composition as in example 4 can be processed to give tablets or for filling in capsules. It can be also processed to give granules or powder type formulations.

Abstract

Rifaximin premix characterized by amorphous Rifaximin in combination with suitable polymers/agents, useful for formulating different pharmaceutical compositions is disclosed herein.

Description

RIFAXIMIN PRE MIX
TECHNICAL FIELD OF THE INVENTION;
The present invention relates to Rifaximin premix comprising Rifaximin in an amorphous form and process for preparing said premix. The present invention also relates to pharmaceutical compositions comprising said Rifaximin premix.
BACKGROUND AND PRIOR ART:
Rifaximin is a semi-synthetic, rifamycin-based non-systematic antibiotic. It is chemically termed as (2S,16Z,1SE,20S,21S,22R,23R,24R,25S,26 S,21S, 28E)-5,6,21,23,25- pentahydroxy-27-methoxy-2,4, 11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[ 1 , 1 1 , 13]trienimino)benzofuro[4,5-e]pyrido[l ,2-a]-benzimida-zole-l, 15(2H)-dione,25-acetate and structurally represented b following structure:
Figure imgf000002_0001
Rifaximin is primarily used for treatment of travelers' diarrhea caused by noninvasive strains of Escherichia coli. Rifaximin is available in tablets, granules for oral suspension and ointment, marketed in Europe, in the U.S.A. and in many other countries.
Rifaximin was first disclosed in US4341785 which discloses a process for preparing Rifaximin and a method for crystallization of rifaximin using suitable solvents or mixture of solvents.
Further, US7045620 (WO2005/044823) disclose crystalline polymorphic forms of rifaximin. These polymorphous forms are very important because they can change the intrinsic dissolution by approximately ten times and the bioavailability of Rifaximin by almost six hundred times. These changes have a strong effect on the efficacy and the safety of the product.
Moreover it is known from US7045620 (2003) and EP1698630 (2005) that the Rifaximin polymorphous forms can easily convert into other forms depending on the possibility to acquire or to lose water. These transformations can occur also in the solid state, because of changes in humidity and temperature conditions.
The prior art discloses the importance of the production conditions of the medicinal products containing Rifaximin, wherein the Refaximin is reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. It is known in the prior art that amorphous solids do not have lattice energy and hence they usually dissolve in a solvent more rapidly and consequently may provide enhanced bioavailability characteristics such as higher rate and extent of absorption of the compound from the gastrointestinal tract. Also, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in the manufacturing process of solid dosage form such as compressibility. Consequently, a stable amorphous Rifaximin would be a significant contribution to the art.
Though amorphous Rifaximin and its process of manufacture has been described in Patent Applications WO2008/035109 and US2009/0082558 , Rifaximin in premix form, is a novel approach by the present inventors towards attaining a significantly more stable amorphous product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.
Premixes are characterized by a variety of associated properties such as stability, flow, and solubility. Typical premixes represent a compromise of the above properties, as for example, an increase in stability and dissolution properties of the premix. Although there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit an improved mix of properties. Thus, the instant invention provides a premix in which Rifaximin exists in stable amorphous form and process of manufacture of the premix and pharmaceutical compositions comprising said Rifaximin premix.
BRIEF DESCRIPTION OF FIGURES:
Figure 1 is an XRD of unprocessed Rifaximin API
Figure 2 is an XRD of premix of Rifaximin and HPMC as in example 1
Figure 3 is an XRD of premix of Rifaximin and PVP as in example 2
Figure 4 is an XRD of premix of Rifaximin and mannitol as in example 3
OBJECT OF THE INVENTION:
Therefore, it is an object of the invention to provide a premix of Rifaximin wherein the Rifaximin exists in a stable amorphous form and process for preparation of the said premix.
Another object of the invention is to provide pharmaceutical compositions comprising the aforementioned Rifaximin premix.
SUMMARY OF THE INVENTION:
In accordance with the above objectives, the present invention provides Rifaximin premix having enhanced stability and dissolution properties and process for preparation thereof.
In another aspect, the invention provides for pharmaceutical compositions comprising said Rifaximin premix.
Other features and advantages will be apparent from the specification and claims which describe an embodiment of this invention. DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in details in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated.
In an embodiment, the present invention provides a premix of Rifaximin having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical compositions. Rifaximin premix having enhanced stability and dissolution properties, according to the invention, wherein Rifaximin is stabilized by combining with suitable polymers/agents. Further, Rifaximin is present in stable amorphous form in the premix of Rifaximin.
According to present invention, the ratio of Rifaximin to polymers/agents is in a range of 1:1 to 30: 1.
The premix of the present invention is prepared by combining Rifaximin with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties.
The polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Hypromellose, vinylpyrrolidone monomers but not limited to Polyvinylpyrrolidone and polyol but not limited to Mannitol. The said polymers/agents are used to facilitate the presence of an amorphous Rifaximin.
The solvent system used in the process for manufacturing of the premix may be selected from a group of organic, aqueous, hydroalcoholic solvents either alone or in combinations thereof. The said solvents are selected from water, methylene chloride, acetone, combination of Isopropyl alcohol and methylene chloride etc.
In another embodiment, the present invention provides process for preparing the said Rifaximin premix which is prepared by spray drying and co precipitation method involving the interaction of Rifaximin with a suitable agent to generate an amorphous Rifaximin.
The process for preparing the Rifaximin premix comprises of dissolving Rifaximin in a solvent system selected from a group of organic solvents, aqueous solvents or hydro- alcoholic solvents alone or in combination.
During the spray drying process the inlet temperature needs to be maintained at 50-200°c and more preferably 60 -100 °c.
The amorphous nature of Rifaximin in the premix has been characterized by XRD. The XRD of Rifaximin API is depicted in Fig 1. The premix comprising Rifaximin and HPMC is depicted in Fig 2. The premix comprising Rifaximin and Polyvinylpyrrolidone is depicted in Fig 3 and the premix comprising Rifaximin and Mannitol is depicted in Fig 4. Rifaximin API is characterized by the distinct peaks as shown in Fig.l. Generally amorphous solids do not give a definitive X-Ray diffraction pattern (XRD). Hence, no distinct peaks can be seen of Rifaximin premixes.
In a preferred embodiment, the present invention provides a pharmaceutical composition containing said premix along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, lubricants and or anti-adherents. The premix can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.
The instant invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes following examples and further can be modified and altered within the technical scope of the present invention. EXAMPLES:
RIFAXIMIN PREMIX:
Example 1: Premix of Rifaximin with Hypromellose processed using combination of IPA and water
Example 2: Premix of Rifaximin with PVP processed using combination of IPA and water
Example 3: Premix of Rifaximin with mannitol processed using combination of IPA and water
Example 4: Pharmaceutical composition:
Figure imgf000007_0001
The pharmaceutical composition as in example 4 can be processed to give tablets or for filling in capsules. It can be also processed to give granules or powder type formulations.

Claims

We claim,
1. Rifaximin premix characterized by amorphous Rifaximin in combination with suitable polymers/agents, useful for formulating different pharmaceutical compositions.
2. Rifaximin premix characterized by amorphous Rifaximin in combination with suitable polymers/agents as claimed in claim 1, wherein the polymers/agents is selected from group of cellulose derivatives but not limited to Hypromellose, vinylpyrrolidone monomers but not limited to Polyvinylpyrrolidone and polypol but not limited to Mannitol.
3. The premix of Rifaximin according to claim 1 or 2, wherein ratio of Rifaximin to polymers/agents is in a range of 1 : 1 to 30: 1.
4. A process of manufacturing a Rifaximin premix, wherein said premix is prepared by spray drying involving interaction of Rifaximin with a suitable agent to generate amorphous Rifaximin.
5. A process of manufacture of Rifaximin as in claim 5, wherein the inlet temperature is between 50-200°c.
6. A process of manufacture of Rifaximin as in claim 5 and 6, wherein the inlet temperature is preferably between 60°c and 100°c.
7. A process of manufacturing a Rifaximin premix, wherein said premix is prepared by co precipitation method involving interaction of Rifaximin with a suitable agent to generate a stable amorphous Rifaximin.
8. A process of manufacturing a Rifaximin premix according to claims 1, 5 and 6, characterized by dissolution of Rifaximin in a solvent system selected from a group of organic solvents, aqueous solvents, hydroalcoholic solvents either alone or in combination.
9. The premix of Rifaximin according to claim 9, wherein solvents selected are water, methylene chloride, acetone, Isopropyl alcohol alone or in combination.
10. A pharmaceutical compositions comprising Rifaximin premix according to claim 1, along with pharmaceutically acceptable excipients.
11. A pharmaceutical compositions according to claims 11, wherein pharmaceutically acceptable excipients are selected from the group of diluents, chelating agents, disintegrant, glidant, lubricants and optionally anti adherents and coating material.
12. Pharmaceutical compositions according to claiml l, wherein the said composition is in the form of tablets, powder, granules, and capsules.
13. Pharmaceutical compositions according to claim 11, wherein tablet comprises of excipients but not restricted to Microcrystalline cellulose, Disodium edetate, Sodium starch Glycolate, colloidal silicon dioxide and Glycerol palmitostearate.
PCT/IN2009/000661 2009-11-19 2009-11-19 Rifaximin premix WO2011061748A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2593463A1 (en) * 2010-07-12 2013-05-22 Salix Pharmaceuticals, Ltd. Formulations of rifaximin and uses thereof
US9234872B2 (en) 2009-11-23 2016-01-12 California Institute Of Technology Chemical sensing and/or measuring devices and methods
US9271968B2 (en) 2005-03-03 2016-03-01 Alfa Wassermann S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US9452157B2 (en) 2012-07-06 2016-09-27 Alfa Wassermann S.P.A Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof
US9498442B2 (en) 2010-03-05 2016-11-22 Alfa Wassermann S.P.A. Rifaximin powder, process for preparing the same an controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect
CN107569692A (en) * 2017-09-01 2018-01-12 山东聊城阿华制药股份有限公司 A kind of microcrystalline cellulose carmethose pre-mixing agent preparation method
US9938298B2 (en) 2014-05-12 2018-04-10 Alfa Wassermann S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
US10874647B2 (en) 2016-09-30 2020-12-29 Salix Pharmaceuticals, Inc. Solid dispersion forms of rifaximin

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US20050031692A1 (en) * 2003-08-04 2005-02-10 Pfizer Inc Spray drying processes for forming solid amorphous dispersions of drugs and polymers
US20050272754A1 (en) * 2003-11-07 2005-12-08 Alfa Wassermann S.P.A. Polymorphic forms of rifaximin, processes for their production and uses thereof
US20090082558A1 (en) * 2007-09-20 2009-03-26 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation
US20090312357A1 (en) * 2006-09-22 2009-12-17 Cipla Limited Rifaximin
US20100137580A1 (en) * 2007-06-20 2010-06-03 Emilio Vecchio Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained
US20100174064A1 (en) * 2008-02-25 2010-07-08 Salix Pharmaceuticals, Ltd. Forms of rifaximin and uses thereof
US20100179207A1 (en) * 2009-01-14 2010-07-15 Novacta Biosystems Limited Compounds

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US20050031692A1 (en) * 2003-08-04 2005-02-10 Pfizer Inc Spray drying processes for forming solid amorphous dispersions of drugs and polymers
US20050272754A1 (en) * 2003-11-07 2005-12-08 Alfa Wassermann S.P.A. Polymorphic forms of rifaximin, processes for their production and uses thereof
US20090312357A1 (en) * 2006-09-22 2009-12-17 Cipla Limited Rifaximin
US20100137580A1 (en) * 2007-06-20 2010-06-03 Emilio Vecchio Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained
US20090082558A1 (en) * 2007-09-20 2009-03-26 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation
US20100174064A1 (en) * 2008-02-25 2010-07-08 Salix Pharmaceuticals, Ltd. Forms of rifaximin and uses thereof
US20100179207A1 (en) * 2009-01-14 2010-07-15 Novacta Biosystems Limited Compounds

Cited By (19)

* 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
US9271968B2 (en) 2005-03-03 2016-03-01 Alfa Wassermann S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US9234872B2 (en) 2009-11-23 2016-01-12 California Institute Of Technology Chemical sensing and/or measuring devices and methods
US9498442B2 (en) 2010-03-05 2016-11-22 Alfa Wassermann S.P.A. Rifaximin powder, process for preparing the same an controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect
AU2011279261B2 (en) * 2010-07-12 2016-03-31 Salix Pharmaceuticals, Ltd. Formulations of rifaximin and uses thereof
EP3750526A1 (en) * 2010-07-12 2020-12-16 Salix Pharmaceuticals, Inc. Formulations of rifaximin and uses thereof
EP2593463A1 (en) * 2010-07-12 2013-05-22 Salix Pharmaceuticals, Ltd. Formulations of rifaximin and uses thereof
US9737610B2 (en) 2010-07-12 2017-08-22 Salix Pharmaceuticals, Ltd Formulations of rifaximin and uses thereof
US20170333562A1 (en) * 2010-07-12 2017-11-23 Salix Pharmaceuticals, Ltd Formulations of rifaximin and uses thereof
EP2593463A4 (en) * 2010-07-12 2014-04-23 Salix Pharmaceuticals Ltd Formulations of rifaximin and uses thereof
US9452157B2 (en) 2012-07-06 2016-09-27 Alfa Wassermann S.P.A Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof
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
US10874647B2 (en) 2016-09-30 2020-12-29 Salix Pharmaceuticals, Inc. Solid dispersion forms of rifaximin
US11129817B2 (en) 2016-09-30 2021-09-28 Salix Pharmaceuticals, Inc. Solid dispersion forms of rifaximin
US11311521B2 (en) 2016-09-30 2022-04-26 Salix Pharmaceuticals, Inc. Solid dispersion forms of rifaximin
US11660292B2 (en) 2016-09-30 2023-05-30 Salix Pharmaceuticals, Inc. Solid dispersion forms of rifaximin
CN107569692A (en) * 2017-09-01 2018-01-12 山东聊城阿华制药股份有限公司 A kind of microcrystalline cellulose carmethose pre-mixing agent preparation method
CN107569692B (en) * 2017-09-01 2020-10-02 山东聊城阿华制药股份有限公司 Preparation method of microcrystalline cellulose-carboxymethylcellulose sodium premix

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