WO2010044093A1 - Formulations containing rifaximin - Google Patents

Formulations containing rifaximin Download PDF

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Publication number
WO2010044093A1
WO2010044093A1 PCT/IN2009/000341 IN2009000341W WO2010044093A1 WO 2010044093 A1 WO2010044093 A1 WO 2010044093A1 IN 2009000341 W IN2009000341 W IN 2009000341W WO 2010044093 A1 WO2010044093 A1 WO 2010044093A1
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Prior art keywords
rifaximin
medicament composition
solid medicament
composition according
amount
Prior art date
Application number
PCT/IN2009/000341
Other languages
French (fr)
Inventor
Srinivas Chetiapalli Satya
Gowda Doddaveerappa Amruth
Vallabhbhai Goganbhai Pansuriya
Mailatur Sivaraman Mohan
Original Assignee
Strides Arcolab Limited
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Publication of WO2010044093A1 publication Critical patent/WO2010044093A1/en

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • 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
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the present invention relates to a stable orally administrable pharmaceutical formulation of a water insoluble drug Rifaximin encapsulated in soft gelatin capsule with higher bioavailability which contains the active ingredient is solubilized in solvent system of suitable vehicle, a solubilizer, an emulsifier and a viscosity-modifying agent.
  • Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin.
  • Rifaximin (Common International Denomination) which is the compound 4-desoxy-4'-methyl- pyrido[r2':l,2]imidazo[5,4-c]rifamycin, which is described in Italian Patent 1154655 having corresponding US Patent No 4341785.
  • Structural formula of Rifaximin is as follows:
  • US4341785 discloses process for preparation and method for crystallization of Rifaximin by using suitable solvents or mixture of solvents.
  • Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic, meaning that the drug will not pass the gastrointestinal wall into the circulation as is common for other types of orally administered antibiotics. It is used in the treatment of traveler's diarrhea and hepatic encephalopathy, for which it received orphan drug status from the U.S. Food and Drug Administration in 1998.
  • Rifaximin exerts its broad antibacterial activity, for example, in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, and/or pancreatic insufficiency. It has been reported that Rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe J J et al. Pharmacokinetic study of Rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994))
  • liquid, and especially concentrated liquid pharmaceutical compositions offer many advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, flexible capsule.
  • Encapsulation would also permit the accurate and uniform delivery of a unit dose of a pharmaceutical active, an advantage which becomes especially important when relatively small amounts of an active are to be delivered. Additionally, soft gelatin capsules are aesthetically appealed (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
  • Gelatin capsules especially soft gelatin capsules, have become increasingly important as a medical dosage form since it became feasible, in the 1930's, to manufacture them by making and filling the capsules in one operation.
  • Numerous drugs which, on account of their instability such as sensitivity to oxidation and to light, their thermal stability or their hygroscopicity, may not be easily processed into other medicinal forms can be encapsulated without impairment of their function.
  • the softgel is a one-piece, hermetically sealed soft gelatin shell containing a liquid, a suspension, or a semi-solid.
  • CN Pat. No. 1451386 describes the soft gelatin capsule formulation of Rifaximin which in the preparation has been micronized to ensure the high bioavailability. However this micronized form of the drug can not completely eliminate the requirement of dissolution of drug particles.
  • the novelty of the present invention is to provide a new preparation of Rifaximin, where in the Rifaximin solution is prepared and encased in capsule shell to make soft capsule.
  • the preparation is good for the oral administration and absorption of drug, thus achieves a higher bioavailability compared to available dosage forms with Rifaximin in solid form. Meanwhile, as described in the prior art it provides a new and better clinical choice of formulation.
  • the primary objective of the present invention is to provide a new solvent system for Rifaximin active.
  • Another objective of the present invention is to provide better bioavailability compared to formulations containing the same active in an oral non-solid medicament composition encased in a capsule.
  • the present invention relates to a stable oral non-solid medicament composition of a water insoluble drug Rifaximin encapsulated in soft gelatin capsule.
  • the active ingredient is solubilized in solvent system containing suitable vehicle, preferably polyethylene glycol or Diethylene glycol monoethyl ether base.
  • suitable vehicle preferably polyethylene glycol or Diethylene glycol monoethyl ether base.
  • the formulation optionally contains a solubilizer, an emulsifier and a viscosity-modifying agent like Povidone.
  • Rifaximin solutions encapsulated in soft gelatin formulations have different in vivo bioavailability properties and, therefore, are useful in the more efficient treatment of infections.
  • the present invention discloses an oral non solid medicament composition
  • the active ingredient i.e. water insoluble drug Rifaximin solubilized in solvent system comprising water insoluble oil or water miscible solvent or in the combinations of both.
  • the present invention comprises an oral non-solid medicament composition in a capsule such as soft gelatin capsule comprising Rifaximin as an active ingredient and a solvent system comprising water insoluble oil or water miscible solvent or in the combinations of both in the concentration wherein the average filling weight in a unit dosage form would be in the range of 400 to 850 mg.
  • non-solid medicament composition of the present invention comprises the water insoluble oil is selected from the group, but not limited to, Soyabean oil, Caprylocaproyl Macrogolglycerides and Diethylene glycol monoethyl ether base and oleic acid.
  • non-solid medicament composition of the present invention further comprises water miscible solvent selected from the group, but not limited to, polyethylene glycol, propylene glycol, Transcutol P, Glycerin and Ethanol.
  • non-solid medicament composition of the present invention further comprises the surfactant such as Tween 80, Labrasol or the other suitable surfactants known in the art.
  • non-solid medicament composition of the present invention comprises the active ingredient Rifaximin in the range of 100 mg to 500 mg, preferably 200mg.
  • the present invention also provides a solvent system for Rifaximin.
  • the solvent system is particularly useful to complete dissolution of Rifaximin and resulting products exhibit good bioavailability and is shelf-stable.
  • the various solvent systems identified for the Rifaximin formulation are described below:
  • the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg and Propylene glycol in an amount of 400 mg.
  • composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Propylene glycol in an amount of 30 mg and Polyethylene glycol 400 in an amount of 600mg.
  • the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Propylene glycol in an amount of 30 mg, Polyethylene glycol 400 in an amount of 400mg and Povidone K 30 in an amount of 10 mg.
  • the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Oleic acid in an amount of 400 mg and Tween 80 in an amount of 30 mg.
  • composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg and Soyabean oil in an amount of 400 mg.
  • composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Ethanol in an amount of 10 mg and Soyabean oil in an amount of 400 mg.
  • composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg and Soyabean oil in an amount of 350 mg along with glycerin in an amount of 20mg and Tween 80 in an amount of 30 mg.
  • composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg along with Labrasol or Transcutol P in an amount of 400 mg.

Abstract

The present invention relates to a stable oral non-solid medicament composition of water insoluble drug Rifaximin encapsulated in soft gelatin capsule with higher bioavailability which contains the active ingredient is solubilized in solvent system of suitable vehicle, a solubilizer, an emulsifier and a viscosity-modifying agent like Povidone.

Description

FORMULATIONS CONTAINING RIFAXIMIN
FIELD OF THE INVENTION:
The present invention relates to a stable orally administrable pharmaceutical formulation of a water insoluble drug Rifaximin encapsulated in soft gelatin capsule with higher bioavailability which contains the active ingredient is solubilized in solvent system of suitable vehicle, a solubilizer, an emulsifier and a viscosity-modifying agent.
BACKGROUND OF THE INVENTION:
Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin. Rifaximin (Common International Denomination) which is the compound 4-desoxy-4'-methyl- pyrido[r2':l,2]imidazo[5,4-c]rifamycin, which is described in Italian Patent 1154655 having corresponding US Patent No 4341785. Structural formula of Rifaximin is as follows:
Figure imgf000002_0001
US4341785 discloses process for preparation and method for crystallization of Rifaximin by using suitable solvents or mixture of solvents.
Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic, meaning that the drug will not pass the gastrointestinal wall into the circulation as is common for other types of orally administered antibiotics. It is used in the treatment of traveler's diarrhea and hepatic encephalopathy, for which it received orphan drug status from the U.S. Food and Drug Administration in 1998.
Further, Rifaximin exerts its broad antibacterial activity, for example, in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, and/or pancreatic insufficiency. It has been reported that Rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe J J et al. Pharmacokinetic study of Rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994))
However, since Rifaximin is usually used in a very small dose per single administration, it is difficult to give a predetermined exact amount per unit dose in case Rifaximin is formulated in the form of pill or tablet. Further it is well known in the art that liquid, and especially concentrated liquid pharmaceutical compositions offer many advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, flexible capsule. Encapsulation would also permit the accurate and uniform delivery of a unit dose of a pharmaceutical active, an advantage which becomes especially important when relatively small amounts of an active are to be delivered. Additionally, soft gelatin capsules are aesthetically appealed (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
Gelatin capsules, especially soft gelatin capsules, have become increasingly important as a medical dosage form since it became feasible, in the 1930's, to manufacture them by making and filling the capsules in one operation. Compared to other medical dosage forms they show many advantages such as being odorless and tasteless, they can be taken easily and, owing to their swelling capability and water solubility, the drugs are readily liberated in the stomach. Numerous drugs which, on account of their instability such as sensitivity to oxidation and to light, their thermal stability or their hygroscopicity, may not be easily processed into other medicinal forms can be encapsulated without impairment of their function.
The need for encapsulation of pharmaceutically active dosage forms such as liquids, semi-solids, and pastes within a gelatin shell in such a way as to prevent uncontrolled leakage has resulted in the development of a very fundamental pharmaceutical dosage form: the soft gelatin capsule. While a difficult and not particularly accurate process initially, current manufacturing processes for softgels are fully automated, with a high degree of precision.
The softgel is a one-piece, hermetically sealed soft gelatin shell containing a liquid, a suspension, or a semi-solid.
CN Pat. No. 1451386 describes the soft gelatin capsule formulation of Rifaximin which in the preparation has been micronized to ensure the high bioavailability. However this micronized form of the drug can not completely eliminate the requirement of dissolution of drug particles.
The novelty of the present invention is to provide a new preparation of Rifaximin, where in the Rifaximin solution is prepared and encased in capsule shell to make soft capsule. The preparation is good for the oral administration and absorption of drug, thus achieves a higher bioavailability compared to available dosage forms with Rifaximin in solid form. Meanwhile, as described in the prior art it provides a new and better clinical choice of formulation.
OBJECTIVES OF THE INVENTION:
The primary objective of the present invention is to provide a new solvent system for Rifaximin active.
Another objective of the present invention is to provide better bioavailability compared to formulations containing the same active in an oral non-solid medicament composition encased in a capsule. SUMMARY OF THE INVENTION:
The present invention relates to a stable oral non-solid medicament composition of a water insoluble drug Rifaximin encapsulated in soft gelatin capsule. The active ingredient is solubilized in solvent system containing suitable vehicle, preferably polyethylene glycol or Diethylene glycol monoethyl ether base. The formulation optionally contains a solubilizer, an emulsifier and a viscosity-modifying agent like Povidone.
DESCRIPTION OF THE INVENTION:
In accordance with the above aspects, the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
It has now been unexpectedly found that Rifaximin solutions encapsulated in soft gelatin formulations have different in vivo bioavailability properties and, therefore, are useful in the more efficient treatment of infections.
In a preferred embodiment the present invention discloses an oral non solid medicament composition comprising the active ingredient i.e. water insoluble drug Rifaximin solubilized in solvent system comprising water insoluble oil or water miscible solvent or in the combinations of both.
Accordingly the present invention comprises an oral non-solid medicament composition in a capsule such as soft gelatin capsule comprising Rifaximin as an active ingredient and a solvent system comprising water insoluble oil or water miscible solvent or in the combinations of both in the concentration wherein the average filling weight in a unit dosage form would be in the range of 400 to 850 mg.
Further, the non-solid medicament composition of the present invention comprises the water insoluble oil is selected from the group, but not limited to, Soyabean oil, Caprylocaproyl Macrogolglycerides and Diethylene glycol monoethyl ether base and oleic acid.
Accordingly, the non-solid medicament composition of the present invention further comprises water miscible solvent selected from the group, but not limited to, polyethylene glycol, propylene glycol, Transcutol P, Glycerin and Ethanol.
Further, the non-solid medicament composition of the present invention further comprises the surfactant such as Tween 80, Labrasol or the other suitable surfactants known in the art.
Moreover, the non-solid medicament composition of the present invention comprises the active ingredient Rifaximin in the range of 100 mg to 500 mg, preferably 200mg.
In another embodiment the present invention also provides a solvent system for Rifaximin. The solvent system is particularly useful to complete dissolution of Rifaximin and resulting products exhibit good bioavailability and is shelf-stable. The various solvent systems identified for the Rifaximin formulation are described below:
In one of the preferred embodiment, the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg and Propylene glycol in an amount of 400 mg.
In another embodiment, the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Propylene glycol in an amount of 30 mg and Polyethylene glycol 400 in an amount of 600mg.
Alternatively, the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Propylene glycol in an amount of 30 mg, Polyethylene glycol 400 in an amount of 400mg and Povidone K 30 in an amount of 10 mg. In another embodiment, the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Oleic acid in an amount of 400 mg and Tween 80 in an amount of 30 mg.
In yet another embodiment, the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg and Soyabean oil in an amount of 400 mg.
Alternatively, the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg, Ethanol in an amount of 10 mg and Soyabean oil in an amount of 400 mg.
Alternatively, the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg and Soyabean oil in an amount of 350 mg along with glycerin in an amount of 20mg and Tween 80 in an amount of 30 mg.
In further embodiment the composition of the present invention in a unit dosage form comprises Rifaximin in an amount of 200 mg along with Labrasol or Transcutol P in an amount of 400 mg.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example 1
Figure imgf000007_0001
Example 2
Ingredient Mg/unit
Rifaximin 200
Soyabean oil 400
Avg. fill weight (mg) 600
Example 3
Ingredient Mg/unit
Rifaximin 200
Soyabean oil 350
Glycerin 20
Tween 80 30
Avg. fill weight (mg) 600
Example 4
Figure imgf000008_0001
Example 5
Figure imgf000008_0002
Example 6
Example 7
Example 8
Example 9
Example 10
Figure imgf000009_0001

Claims

We Claim,
1. An oral non-solid medicament composition in a capsule comprising: Rifaximin as an active ingredient and a solvent system.
2. A non-solid medicament composition according to claim 1, wherein the capsule is a soft gelatin or a hard gelatin capsule.
3. A non-solid medicament composition according to claim 1 , wherein the solvent system comprises either water insoluble oil or water miscible solvent or the combinations of both.
4. The non-solid medicament composition according to claim 3, where in the water insoluble oil is selected from the group, but not limited to, Soyabean oil, Caprylocaproyl Macrogolglycerides and Diethylene glycol monoethyl ether and Oleic acid.
5. The non-solid medicament composition according to claim 3, wherein the water miscible solvent is selected from the group, but not limited to, Polyethylene glycol, Propylene glycol, Glycerin and Ethanol.
6. The non-solid medicament composition according to claim 3, wherein the surfactant is, but not limited to, Tween 80.
7. A non-solid medicament composition according to claim 1, wherein the active ingredient Rifaximin is used in the range of 100 mg to 500 mg, preferably 200mg.
PCT/IN2009/000341 2008-10-16 2009-06-12 Formulations containing rifaximin WO2010044093A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2540/CHE/2008 2008-10-16
IN2540CH2008 2008-10-16

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN106074433A (en) * 2016-06-30 2016-11-09 浙江安宝药业有限公司 rifaximin soft capsule medicine and preparation method 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
US10258610B2 (en) 2011-07-29 2019-04-16 Alfasigma S.P.A. Pharmaceutical compositions comprising rifaximin, processes for their preparation and their use in the treatment of vaginal infections
US10285944B2 (en) 2005-03-07 2019-05-14 Alfasigma S.P.A. Gastroresistant pharmaceutical formulations containing rifaximin
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352679A (en) * 1993-03-23 1994-10-04 Alfa Wassermann S.P.A. Use of rifaximin and pharmaceutical formulations containing it in the treatment of gastric dyspepsia caused by helicobacter pylori
US20070298099A1 (en) * 2004-11-24 2007-12-27 Peresypkin Andrey V Liquid and Semi-Solid Pharmaceutical Formulations for Oral Administration of a Substituted Amide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352679A (en) * 1993-03-23 1994-10-04 Alfa Wassermann S.P.A. Use of rifaximin and pharmaceutical formulations containing it in the treatment of gastric dyspepsia caused by helicobacter pylori
US20070298099A1 (en) * 2004-11-24 2007-12-27 Peresypkin Andrey V Liquid and Semi-Solid Pharmaceutical Formulations for Oral Administration of a Substituted Amide

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
US10285944B2 (en) 2005-03-07 2019-05-14 Alfasigma S.P.A. Gastroresistant pharmaceutical formulations containing rifaximin
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
US10258610B2 (en) 2011-07-29 2019-04-16 Alfasigma S.P.A. Pharmaceutical compositions comprising rifaximin, processes for their preparation and their use in the treatment of vaginal infections
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
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
CN106074433A (en) * 2016-06-30 2016-11-09 浙江安宝药业有限公司 rifaximin soft capsule medicine and preparation method thereof

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