US20120077835A1 - Formulations of rifaximin and uses thereof - Google Patents

Formulations of rifaximin and uses thereof Download PDF

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US20120077835A1
US20120077835A1 US13/181,481 US201113181481A US2012077835A1 US 20120077835 A1 US20120077835 A1 US 20120077835A1 US 201113181481 A US201113181481 A US 201113181481A US 2012077835 A1 US2012077835 A1 US 2012077835A1
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rifaximin
microgranule
hpmc
solids
dispersion
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Jon Selbo
Jing Teng
Mohammed A. Kabir
Pam Golden
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Salix Pharmaceuticals Ltd
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Salix Pharmaceuticals Ltd
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Assigned to SALIX PHARMACEUTICALS, LTD. reassignment SALIX PHARMACEUTICALS, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: APTUIT, INC.
Assigned to APTUIT, INC. reassignment APTUIT, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SELBO, JON, TENG, Jing
Publication of US20120077835A1 publication Critical patent/US20120077835A1/en
Assigned to SALIX PHARMACEUTICALS, LTD. reassignment SALIX PHARMACEUTICALS, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOLDEN, PAM, KABIR, Mohammed A.
Priority to US14/250,293 priority patent/US9737610B2/en
Assigned to BARCLAYS BANK PLC, AS COLLATERAL AGENT reassignment BARCLAYS BANK PLC, AS COLLATERAL AGENT SECURITY AGREEMENT Assignors: GLYCYX PHARMACEUTICALS, LTD., SALIX PHARMACEUTICALS, INC., SALIX PHARMACEUTICALS, LTD., SANTARUS, INC.
Priority to US15/281,543 priority patent/US20170087134A1/en
Priority to US15/615,121 priority patent/US20170333562A1/en
Priority to US16/916,421 priority patent/US20200397904A1/en
Abandoned legal-status Critical Current

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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
    • A61K31/4353—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/4858—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • 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 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 pancreatic insufficiency among other diseases. 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)).
  • Rifaximin is described in Italian Patent IT 1154655 and EP 0161534, both of which are incorporated herein by reference in their entirety for all purposes.
  • EP 0161534 discloses a process for rifaximin production using rifamycin O as the starting material (The Merck Index, XIII Ed., 8301).
  • U.S. Pat. No. 7,045,620 B1 and PCT Publication WO 2006/094662 A1 disclose polymorphic forms of rifaximin. There is a need in the art for formulations of rifaximin to better treat gastrointestinal and other diseases.
  • solid dispersion forms of rifaximin with a variety of polymers and polymer concentrations.
  • provided herein are forms solid dispersion of rifaximin.
  • the form solid dispersion of rifaximin is characterized by an XRPD substantially similar to one or more of the XRPDs of FIGS. 2 , 7 , 12 , 17 , 22 , 31 , and 36 .
  • the form solid dispersion of rifaximin is characterized by a Thermogram substantially similar to FIGS. 3-6 , 8 - 11 , 13 - 16 , 18 - 21 , 23 - 26 , 27 - 30 , and 32 .
  • the form has the appearance of a single glass transition temperature (Tg).
  • a Tg of a form increases with an increased rifaximin concentration
  • a form stressed at 70° C./75% RH for 1 week, solids are still x-ray amorphous according to XRPD.
  • a form stressed at 70° C./75% RH for 3 weeks, solids are still x-ray amorphous according to XRPD.
  • a form stressed at 70° C./75% RH for 6 weeks, solids are still x-ray amorphous according to XRPD.
  • a form stressed at 70° C./75% RH for 12 weeks, solids are still x-ray amorphous according to XRPD.
  • microgranules comprising one or more of the solid dispersion forms of rifaximin described herein.
  • the microgranules further comprise a polymer.
  • the polymer comprises one or more of polyvinylpyrrolidone (PVP) grade K-90, hydroxypropyl methylcellulose phthalate (HPMC-P) grade 55, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) grades HG and MG, or a polymethacrylate (Eudragit® L100-55).
  • PVP polyvinylpyrrolidone
  • HPMC-P hydroxypropyl methylcellulose phthalate
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • Eudragit® L100-55 polymethacrylate
  • the microgranules comprises 25-75% polymer, 40-60% polymer, or 40-50% polymer. In an exemplary embodiment, the microgranules comprises 42-44% polymer.
  • the microgranules comprise equal amounts of rifaximin and polymer.
  • the microgranules further comprising an intragranular release controlling agent.
  • the intragranular release controlling agent comprises a pharmaceutically acceptable excepient, disintegrant, crosprovidone, sodium starch glycolate, corn starch, microcrystalline cellulose, cellulosic derivatives, sodium bicarbonate, and sodium alginate.
  • the intragranular release controlling agent comprises between about 2 wt % to about 40 wt % of the microgranule, about 5 wt % to about 20 wt % of the microgranule, or about 10 wt % of the microgranule.
  • the intragranular release controlling agent comprises a pharmaceutically acceptable disintegrant, e.g., one selected from the group consisting of crosprovidone, sodium starch glycolate, corn starch, microcrystalline cellulose, cellulosic derivatives, sodium bicarbonate, and sodium alginate.
  • a pharmaceutically acceptable disintegrant e.g., one selected from the group consisting of crosprovidone, sodium starch glycolate, corn starch, microcrystalline cellulose, cellulosic derivatives, sodium bicarbonate, and sodium alginate.
  • the microgranules further comprise a wetting agent or surfactant, e.g., a non-ionic surfactant.
  • the non-ionic surfactant comprises between about 2 wt % to about 10 wt % of the microgranule, between about 4 wt % to about 8 wt % of the microgranule, or about 5.0 wt % of the microgranule.
  • the non-ionic surfactant comprises a poloxamer, e.g., poloxamer 407 also known as Pluronic F-127.
  • microgranules further comprise an antioxidant.
  • the antioxidant is butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or propyl gallate (PG).
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • PG propyl gallate
  • the antioxidant comprises between about 0.1 wt % to about 3 wt % of the microgranule or between about 0.5 wt % to about 1 wt % of the microgranule.
  • compositions comprising the microgranules described herein.
  • the pharmaceutical compositions further comprise one or more pharmaceutically acceptable excepients.
  • the pharmaceutical compositions are tablets or capsules.
  • the pharmaceutical compositions comprises a disintegrant.
  • the polymer comprises one or more of polyvinylpyrrolidone (PVP) grade K-90, hydroxypropyl methylcellulose phthalate (HPMC-P) grade 55, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) grades HG and MG, or a polymethacrylate (Eudragit® L100-55).
  • PVP polyvinylpyrrolidone
  • HPMC-P hydroxypropyl methylcellulose phthalate
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • Eudragit® L100-55 polymethacrylate
  • compositions comprising: rifaximin, HPMC-AS, at a rifaximin to polymer ratio of 50:50, a non-ionic, surfactant polyol and a intragranular release controlling agent.
  • the intragranular release controlling agent comprises about 10 wt % of the formulation.
  • processes for producing a solid dispersion of rifaximin comprising: making a slurry of methanol, rifaximin, a polymer and a surfactant; spray drying the slurry; and blending the spray dried slurry with a intragranular release controlling agent.
  • processes for producing a solid dispersion of rifaximin comprising: making a slurry of methanol, rifaximin, HPMC-AS MG and Pluronic F-127; spray drying the slurry; and blending the spray dried slurry with a intragranular release controlling agent.
  • the intragranular release controlling agent comprises croscarmellose sodium.
  • a process for producing form solid dispersion of rifaximin comprising one or more of the methods listed in Tables 1-5.
  • compositions comprising SD rifaximin, a polymer, a surfactant, and a release controlling agent are provided.
  • pharmaceutical compositions comprising SD rifaximin, HPMC-AS, pluronic F127, and croscarmellose Na (CS).
  • the pharmaceutical compositions are tablets or pills.
  • compositions further comprise fillers, glidants or lubricants.
  • the pharmaceutical compositions comprise the ratios of components set forth in Table 37.
  • FIG. 1 Chemical structure of Rifaximin.
  • FIG. 2 Overlay of XRPD patterns for Rifaximin/PVP K-90 dispersions obtained from methanol by spray drying.
  • FIG. 3 mDSC thermogram for 25:75 (w/w) Rifaximin/PVP K-90 dispersion obtained from methanol by spray drying.
  • FIG. 4 mDSC thermogram for 50:50 (w/w) Rifaximin/PVP K-90 dispersion obtained from methanol by spray drying.
  • FIG. 5 mDSC thermogram for 75:25 (w/w) Rifaximin/PVP K-90 dispersion obtained from methanol by spray drying.
  • FIG. 6 Overlay of mDSC thermogram for Rifaximin/PVP K-90 dispersions obtained from methanol by spray drying.
  • FIG. 7 Overlay of XRPD patterns for Rifaximin/HPMC-P dispersions obtained from methanol by spray drying.
  • FIG. 8 mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-P dispersion obtained from methanol by spray drying.
  • FIG. 9 mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-P dispersion obtained from methanol by spray drying.
  • FIG. 10 mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-P dispersion obtained from methanol by spray drying.
  • FIG. 11 Overlay of mDSC thermogram for Rifaximin/HPMC-P dispersions obtained from methanol by spray drying.
  • FIG. 12 Overlay of XRPD patterns for Rifaximin/HPMC-AS HG dispersions obtained from methanol by spray drying.
  • FIG. 13 mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-AS HG dispersion obtained from methanol by spray drying.
  • FIG. 14 mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-AS HG dispersion obtained from methanol by spray drying.
  • FIG. 15 mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-AS HG dispersion obtained from methanol by spray drying.
  • FIG. 16 Overlay of mDSC thermogram for Rifaximin/HPMC-AS HG dispersions obtained from methanol by spray drying.
  • FIG. 17 Overlay of XRPD patterns for Rifaximin/HPMC-AS MG dispersions obtained from methanol by spray drying.
  • FIG. 18 mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-AS MG dispersion obtained from methanol by spray drying.
  • FIG. 19 mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion obtained from methanol by spray drying.
  • FIG. 20 mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-AS MG dispersion obtained from methanol by spray drying.
  • FIG. 21 Overlay of mDSC thermogram for Rifaximin/HPMC-AS MG dispersions obtained from methanol by spray drying.
  • FIG. 22 Overlay of XRPD patterns for Rifaximin/Eudragit L100-55 dispersions obtained from methanol by spray drying.
  • FIG. 23 mDSC thermogram for 25:75 (w/w) Rifaximin/Eudragit L100-55 dispersion obtained from methanol by spray drying.
  • FIG. 24 mDSC thermogram for 50:50 (w/w) Rifaximin/Eudragit L100-55 dispersion obtained from methanol by spray drying.
  • FIG. 25 mDSC thermogram for 75:25 (w/w) Rifaximin/Eudragit L100-55 dispersion obtained from methanol by spray drying.
  • FIG. 26 Overlay of mDSC thermogram for Rifaximin/Eudragit L100-55 dispersions obtained from methanol by spray drying.
  • FIG. 27 mDSC thergram for 25:75 (w/w) Rifaximin/HPMC-P dispersion stressed at 40° C./75% RH for 7 d.
  • FIG. 28 mDSC thergram for 75:25 (w/w) Rifaximin/HPMC-AS HG dispersion stressed at 40° C./75% RH for 7 d.
  • FIG. 29 mDSC thergram for 75:25 (w/w) Rifaximin/HPMC-AS MG dispersion stressed at 40° C./75% RH for 7 d.
  • FIG. 30 mDSC thergram for 25:75 (w/w) Rifaximin/Eudragit L100-55 dispersion stressed at 40° C./75% RH for 7 d.
  • FIG. 31 XRPD pattern for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion.
  • FIG. 32 Modulate DSC thermograms for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion.
  • FIG. 33 TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion-TGA data.
  • FIG. 34 TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion-Gram-Schmidt plot and waterfall plot.
  • FIG. 35 TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion.
  • FIG. 36 XRPD pattern for 25:75 (w/w) Rifaximin/HPMC-P dispersion.
  • FIG. 37 Modulate DSC thermograms for 25:75 (w/w) Rifaximin/HPMC-P dispersion.
  • FIG. 38 TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P dispersion-TGA data.
  • FIG. 39 TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P dispersion-Gram-Schmidt plot and waterfall plot.
  • FIG. 40 TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P dispersion.
  • FIG. 41 Overlay of pre-processed XRPD patterns in multivariate mixture analysis.
  • FIG. 42 Estimated Concentrations of Rifaximin (blue) and HPMC-AS MG (red) using Unscrambler MCR analysis.
  • FIG. 43 Estimated XRPD patterns of Rifaximin (blue) and HPMC-AS MG (red) using Unscrambler MCR analysis.
  • FIG. 44 Overlay of estimated XRPD pattern of pure rifaximin using MCR and measured XRPD pattern of 100% rifaximin.
  • FIG. 45 Overlay of estimated XRPD pattern of pure HPMC-AS MG using MCR and measured XRPD pattern of 100% HPMC-AS MG.
  • FIG. 46 An exemplary XRPD pattern for combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
  • FIG. 47 A modulate DSC thermogram for combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
  • FIG. 48 A TG-IR analysis for combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion-TGA thermogram.
  • FIG. 49 An exemplary TG-IR analysis for combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
  • FIG. 50 An exemplary overlay of IR spectra for X-ray amorphous Rifaximin and combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
  • FIG. 51 An exemplary overlay of Ramam spectra for X-ray amorphous Rifaximin and combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
  • FIG. 52 A particle size analysis report for combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
  • FIG. 53 An exemplary dynamic vapor sorption (DVS) analysis for combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
  • DVD dynamic vapor sorption
  • FIG. 54 An exemplary overlay of XRPD patterns for Rifaximin/HPMC-AS MG/Pluronic ternary dispersion post-DVS solids and solids as-prepared.
  • FIG. 55 An exemplary overlay of XRPD patterns for Rifaximin ternary dispersion post-stressed samples and as-prepared sample.
  • FIG. 56 An exemplary mDSC thermgram for Rifaximin ternary dispersion after 70° C./75% RH 1 week.
  • FIG. 57 An exemplary mDSC thermgram for Rifaximin ternary dispersion after 70° C./75% RH 3 weeks.
  • FIG. 58 An exemplary mDSC thermgram for Rifaximin ternary dispersion after 40° C./75% RH 6 weeks.
  • FIG. 59 An exemplary mDSC thermgram for Rifaximin ternary dispersion after 40° C./75% RH 12 weeks.
  • FIG. 60 Pharmacokinetic data of solid dispersion in dogs.
  • FIG. 61 Rifaximin SD capsules dissolution; acid phase: 0.1 N HCl with variable exposure time. Buffer phase: pH 6.8 with 0.45% SDS.
  • FIG. 62 Rifaximin SD capsules dissolution; acid phase: 2 hours; buffer phase: pH 6.8.
  • FIG. 63 Rifaximin capsule dissolution; phosphate buffer pH 6.8 with 0.45% SDS.
  • FIG. 64 Rifaximin spray dried dispersion (SDD) capsule dissolution.
  • SDD spray dried dispersion
  • FIG. 65 Rifamixin SDD with 10% CS formulation.
  • FIG. 66 Rifaximin SDD with 10% CS formulation. Rifaxamin SDD capsules dissolution: (a) acid phase 2 hours, buffer phase: P. Buffer, pH. 7.4. With 0.45% SDS; without SDS. (b) acid phase: 0.1N HCl with variable exposure times, buffer phase: P. buffer, pH 7.4 with 0.45% SDS.
  • FIG. 67 Effects of media pH on dissolution.
  • FIG. 68 Effects of media pH on dissolution.
  • FIG. 69 Effects of media pH on dissolution.
  • FIG. 70 Effects of media pH on dissolution.
  • FIG. 71 CS release mechanism.
  • FIG. 72 depicts an overlay of XRPD patterns of rifaximin quaternary samples spray dried from methanol.
  • the top is a rifaximin quaternary sample containing 0.063 wt % BHA.
  • the second is rifaximin quaternary sample containing 0.063 wt % BHT.
  • the third: is rifaximin quaternary sample containing 0.094 wt % PG, and the bottom is a spray dried rifaximin ternary dispersion.
  • FIG. 73 depicts an mDSC thermogram of rifaximin quaternary sample containing 0.063 wt % BHA
  • FIG. 74 depicts an mDSC thermogram of rifaximin quaternary sample containing 0.063 wt % BHT.
  • FIG. 75 depicts a mDSC thermogram of rifaximin quaternary sample containing 0.094 wt % PG.
  • FIG. 76 depicts an XRPD pattern comparison of rifaximin solid dispersion powder 42.48% w/w with roller compacted material of rifaximin blend. Top: Rifaximin Solid Dispersion Powder 42.48% w/w; Bottom: roller compacted rifaximin blend.
  • FIG. 77 depicts the pharmacokinetics of rifaximin following administration of varying forms and formulations following a single oral dose of 2200 mg in dogs.
  • FIG. 78 depicts Rifaximin SDD in dogs.
  • FIG. 79 depicts the quotient study design.
  • FIG. 80 summarizes the dose escalation/regional absorption study, part A dose escalation/dose selection.
  • FIG. 81 depicts representative subject data from a dose escalation study.
  • FIG. 82 depicts representative subject data from a dose escalation study.
  • FIG. 83 depicts mean dose escalation data, on a linear scale.
  • FIG. 84 depicts mean dose escalation data, on a log scale.
  • FIG. 85 depicts a summary of Rifaximin SDD dose escalation studies.
  • FIG. 86 is a Table of dose/dosage form comparison.
  • FIG. 87 is a Table of dose/dosage form comparison. This table compares SDD at increasing doses to the current crystalline formulation in terms of systemic PK.
  • Embodiments described herein relate to the discovery of new solid dispersion forms of rifaximin with a variety of polymers and polymer concentrations.
  • the use of one or more of new solid dispersion forms of the antibiotic known as Rifaximin (INN) in the manufacture of medicinal preparations for the oral or topical route is contemplated.
  • the solid dispersion forms of rifaximin are used to create pharmaceutical compositions, e.g., tablets or capsules, or microgranules comprising solid dispersion forms of rifaximin.
  • Exemplary methods for producing rifaximin microgranules are set forth in the examples.
  • Rifaximin microgranules can be formulated into pharmaceutical compositions as described herein.
  • Embodiments described herein also relate to administration of such medicinal preparations to a subject in need of treatment with antibiotics.
  • Provided herein are solid dispersion forms of rifaximin with a variety of polymers and polymer concentrations.
  • intragranular release controlling agent include agents that cause a pharmaceutical composition, e.g., a microgranule, to breakdown thereby releasing the active ingredient, e.g., rifaximin.
  • exemplary intragranular release controlling agent include disintegrants such as crosprovidone, sodium starch glycolate, corn starch, microcrystalline cellulose, cellulosic derivatives, sodium bicarbonate, and sodium alginate.
  • the intragranular release controlling agent comprises between about 2 wt % to about 40 wt % of the microgranule, about 5 wt % to about 20 wt % of the microgranule, about 8-15 wt % or about 10 wt % of the microgranule.
  • the microgranule comprises a surfactant, e.g., a non-ionic surfactant.
  • the non-ionic surfactant comprises between about 2 wt % to about 10 wt % of the microgranule, between about 4 wt % to about 8 wt % of the microgranule, about 6 to about 7 wt % of the microgranule, or about 5.0 wt % of the microgranule.
  • the microgranule comprises an antioxidant.
  • the antioxidant comprises between about 0.1 wt % to about 3 wt % of the microgranule, between 0.3 wt % to about 2 wt % or between about 0.5 wt % to about 1 wt % of the microgranule.
  • the term “intragranular” refers to the components that reside within the microgranule.
  • extragranular refers to the components of the pharmaceutical composition that are not contained within the microgranule.
  • polymorph is occasionally used as a general term in reference to the forms of rifaximin and includes within the context, salt, hydrate, polymorph co-crystal and amorphous forms of rifaximin. This use depends on context and will be clear to one of skill in the art.
  • the term “about” when used in reference to x-ray powder diffraction pattern peak positions refers to the inherent variability of the peaks depending on, for example, the calibration of the equipment used, the process used to produce the polymorph, the age of the crystallized material and the like, depending on the instrumentation used. In this case the measure variability of the instrument was about ⁇ 0.2 degrees 2- ⁇ . A person skilled in the art, having the benefit of this disclosure, would understand the use of “about” in this context.
  • the term “about” in reference to other defined parameters, e.g., water content, C max , t max , AUC, intrinsic dissolution rates, temperature, and time indicates the inherent variability in, for example, measuring the parameter or achieving the parameter. A person skilled in the art, having the benefit of this disclosure, would understand the variability of a parameter as connoted by the use of the word about.
  • similar in reference to a form exhibiting characteristics similar to, for example, an XRPD, an IR, a Raman spectrum, a DSC, TGA, NMR, SSNMR, etc, indicates that the polymorph or cocrystal is identifiable by that method and could range from similar to substantially similar, so long as the material is identified by the method with variations expected by one of skill in the art according to the experimental variations, including, for example, instruments used, time of day, humidity, season, pressure, room temperature, etc.
  • rifaximin solid dispersion As used herein, “rifaximin solid dispersion,” “rifaximin ternary dispersion,” “solid dispersion of rifaximin,” “solid dispersion”, “solid dispersion forms of rifaximin”, “SD”, “SDD”, and “form solid dispersion of rifaximin” are intended to have equivalent meanings and include rifaximin polymer dispersion composition. These compositions are XRPD amorphous, but distinguishable from XRPD of amorphous rifaximin. As shown in the Examples and Figures, the rifaximin polymer dispersion compositions are physically chemically distinguishable from amorphous rifaximin, including different Tg, different XRPD profiles and different dissolution profiles.
  • Polymorphism refers to the occurrence of different crystalline forms of a single compound in distinct hydrate status, e.g., a property of some compounds and complexes.
  • polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, density, flowability, compactibility and/or x-ray diffraction peaks.
  • the solubility of each polymorph may vary, thus, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles.
  • polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
  • X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
  • polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.
  • subject includes organisms which are capable of suffering from a bowel disorder or other disorder treatable by rifaximin or who could otherwise benefit from the administration of rifaximin solid dispersion compositions as described herein, such as human and non-human animals.
  • non-human animals includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians, reptiles, etc.
  • Susceptible to a bowel disorder is meant to include subjects at risk of developing a bowel disorder infection, e.g., subjects suffering from one or more of an immune suppression, subjects that have been exposed to other subjects with a bacterial infection, physicians, nurses, subjects traveling to remote areas known to harbor bacteria that causes travelers' diarrhea, subjects who drink amounts of alcohol that damage the liver, subjects with a history of hepatic dysfunction, etc.
  • a prophylactically effective amount of a composition refers to an amount of a rifaximin solid dispersion formulation or otherwise described herein which is effective, upon single or multiple dose administration to the subject, in preventing or treating a bacterial infection.
  • terapéuticaally effective amount of a composition refers to an amount of a rifaximin solid dispersion effective, upon single or multiple dose administration to the subject to provide a therapeutic benefit to the subject.
  • the therapeutic benefit is wounding or killing a bacterium, or in prolonging the survivability of a subject with such a bowel or skin disorder.
  • the therapeutic benefit is inhibiting a bacterial infection or prolonging the survival of a subject with such a bacterial infection beyond that expected in the absence of such treatment.
  • Rifaximin exerts a broad antibacterial activity in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, including anaerobic strains. 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)).
  • any differences found in the systemic absorption of the forms of rifaximin disclosed herein may be significant, because at sub-inhibitory concentration of rifaximin, such as in the range from 0.1 to 1 ⁇ g/ml, selection of resistant mutants has been demonstrated to be possible (Marchese A. et al. In vitro activity of rifaximin, metronidazole and vancomycin against clostridium difficile and the rate of selection of spontaneously resistant mutants against representative anaerobic and aerobic bacteria, including ammonia-producing species. Chemotherapy, 46(4), 253-266, (2000)).
  • Forms, formulations and compositions of rifaximin have been found to have differing in vivo bioavailability properties.
  • the polymorphs disclosed herein would be useful in the preparation of pharmaceuticals with different characteristics for the treatment of infections. This would allow generation of rifaximin preparations that have significantly different levels of adsorption with C max values from about 0.0 ng/ml to 5.0 ⁇ g/ml. This leads to preparation of rifaximin compositions that are from negligibly to significantly adsorbed by subjects undergoing treatment.
  • One embodiment described herein is modulating the therapeutic action of rifaximin by selecting the proper form, formulation and/or composition, or mixture thereof, for treatment of a subject.
  • the most bioavailable form, formulation and/or composition can be selected from those disclosed herein, whereas in case of non-invasive pathogens less adsorbed forms, formulations and/or compositions of rifaximin can be selected, since they may be safer for the subject undergoing treatment.
  • a form, formulation and/or composition of rifaximin may determine solubility, which may also determine bioavailability.
  • d-space listings the wavelength used to calculate d-spacings was 1.541874 ⁇ , a weighted average of the Cu-K ⁇ 1 and Cu-K ⁇ 2 wavelengths. Variability associated with d-spacing estimates was calculated from the USP recommendation, at each d-spacing, and provided in the respective data tables and peak lists.
  • Bowel related disorders include one or more of irritable bowel syndrome, diarrhea, microbe associated diarrhea, Clostridium difficile associated diarrhea, travelers' diarrhea, small intestinal bacterial overgrowth, Crohn's disease, diverticular disease, chronic pancreatitis, pancreatic insufficiency, enteritis, colitis, hepatic encephalopathy, minimal hepatic encephalopathy or pouchitis.
  • the length of treatment for a particular bowel disorder will depend in part on the disorder. For example, travelers' diarrhea may only require treatment duration of 12 to about 72 hours, while Crohn's disease may require treatment durations from about 2 days to 3 months. Dosages of rifaximin will also vary depending on the diseases state. Proper dosage ranges are provided herein infra.
  • the polymorphs and cocrystals described herein may also be used to treat or prevent apathology in a subject suspected of being exposed to a biological warfare agent.
  • Topical skin infections and vaginal infections may also be treated with the rifaximin compositions described herein.
  • a solid dispersion composition of rifaximin (SD rifaximin compositions) to treat vaginal infections, ear infections, lung infections, periodontal conditions, rosacea, and other infections of the skin and/or other related conditions.
  • vaginal pharmaceutical compositions to treat vaginal infection, particularly bacterial vaginosis, to be administered topically including vaginal foams and creams, containing a therapeutically effective amount of SD rifaximin compositions, preferably between about 50 mg and 2500 mg.
  • compositions known to those of skill in the art for the treatment of vaginal pathological conditions by the topical route may be advantageously used with SD rifaximin compositions.
  • vaginal foams, ointments, creams, gels, ovules, capsules, tablets and effervescent tablets may be effectively used as pharmaceutical compositions containing SD rifaximin compositions, which may be administered topically for the treatment of vaginal infections, including bacterial vaginosis.
  • Also provided herein are method of using SD rifaximin compositions to treat gastric dyspepsia, including gastritis, gastroduodenitis, antral gastritis, antral erosions, erosive duodenitis and peptic ulcers.
  • Ear infections include external ear infection, or a middle and inner ear infection.
  • methods of treating rosacea which is a chronic skin condition involving inflammation of the cheeks, nose, chin, forehead, or eyelids.
  • Embodiments also provide pharmaceutical compositions, comprising an effective amount of one or more SD rifaximin compositions, or microgranules comprising SD forms of rifaximin described herein (e.g., described herein and a pharmaceutically acceptable carrier).
  • the effective amount is effective to treat a bacterial infection, e.g., small intestinal bacterial overgrowth, Crohn's disease, hepatic encephalopathy, antibiotic associated colitis, and/or diverticular disease.
  • Embodiments also provide pharmaceutical compositions, comprising an effective amount of rifaximin SD compositions.
  • Embodiments also provide pharmaceutical compositions comprising rifaximin SD compositions and a pharmaceutically acceptable carrier.
  • Embodiments of the pharmaceutical composition further comprise excipients, for example, one or more of a diluting agent, binding agent, lubricating agent, intragranular release controlling agent, e.g., a disintegrating agent, coloring agent, flavoring agent or sweetening agent.
  • a diluting agent for example, one or more of a diluting agent, binding agent, lubricating agent, intragranular release controlling agent, e.g., a disintegrating agent, coloring agent, flavoring agent or sweetening agent.
  • One composition may be formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packet.
  • compositions may be formulated for topical use, for example, ointments, pomades, creams, gels and lotions.
  • the rifaximin SD composition is administered to the subject using a pharmaceutically-acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained or delayed delivery of the SD rifaximin composition to a subject for at least 2, 4, 6, 8, 10, 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • a pharmaceutically-acceptable formulation e.g., a pharmaceutically-acceptable formulation that provides sustained or delayed delivery of the SD rifaximin composition to a subject for at least 2, 4, 6, 8, 10, 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • the pharmaceutically-acceptable formulations may contain microgranules comprising rifaximin as described herein.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • the pharmaceutical compositions described herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • phrases “pharmaceutically acceptable” refers to those SD rifaximin compositions and cocrystals presented herein, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier includes pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier is preferably “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Methods of preparing these compositions include the step of bringing into association a SD rifaximin composition(s) or microgranules containing the SD rifaximin compositions with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a SD rifaximin composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a SD rifaximin composition(s) as an active ingredient.
  • a compound may also be administered as a bolus, electuary or paste.
  • the SD compositions of rifaximin disclosed herein can be advantageously used in the production of medicinal preparations having antibiotic activity, containing rifaximin, for both oral and topical use.
  • the medicinal preparations for oral use will contain an SD composition of rifaximin together with the usual excipients, for example diluting agents such as mannitol, lactose and sorbitol; binding agents such as starches, gelatines, sugars, cellulose derivatives, natural gums and polyvinylpyrrolidone; lubricating agents such as talc, stearates, hydrogenated vegetable oils, polyethylenglycol and colloidal silicon dioxide; disintegrating agents such as starches, celluloses, alginates, gums and reticulated polymers; coloring, flavoring, disintegrants, and sweetening agents.
  • diluting agents such as mannitol, lactose and sorbitol
  • binding agents such as starches, gelatines, sugars, cellulose derivatives,
  • Embodiments described herein include SD rifaximin composition administrable by the oral route, for instance coated and uncoated tablets, of soft and hard gelatin capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packets or other containers.
  • compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more SD rifaximin composition(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • Compositions which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a SD rifaximin composition(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active SD rifaximin composition(s) may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • Ointments, pastes, creams and gels may contain, in addition to SD rifaximin composition(s), excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a SD rifaximin composition(s), excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the SD rifaximin composition(s) can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • An aqueous aerosol is made, for example, by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically-acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a SD rifaximin composition(s) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of the invention.
  • compositions suitable for parenteral administration may comprise one or more SD rifaximin composition(s) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the SD rifaximin composition(s) When administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.
  • the SD rifaximin composition(s) are formulated into pharmaceutically-acceptable dosage forms by methods known to those of skill in the art.
  • Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • An exemplary dose range is from 25 to 3000 mg per day.
  • Other doses include, for example, 600 mg/day, 1100 mg/day and 1650 mg/day.
  • Other exemplary doses include, for example, 1000 mg/day, 1500 mg/day, from between 500 mg to about 1800 mg/day or any value in-between.
  • a preferred dose of the SD rifaximin composition disclosed herein is the maximum that a subject can tolerate without developing serious side effects.
  • the SD rifaximin composition is administered at a concentration of about 1 mg to about 200 mg per kilogram of body weight, about 10 to about 100 mg/kg or about 40 mg to about 80 mg/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part. For example, doses may range from 50 mg to about 2000 mg/day.
  • the other drug agent(s) are administered to mammals (e.g., humans, male or female) by conventional methods.
  • the agents may be administered in a single dosage form or in separate dosage forms.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range.
  • the effective amount of the rifaximin SD composition is less than its effective amount in case the other therapeutic agent is not administered.
  • the effective amount of the conventional agent is less than its effective amount in case the rifaximin SD composition is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized.
  • Other potential advantages including without limitation improved dosing regimens and/or reduced drug cost
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
  • two or more therapies are administered within the same subject's visit.
  • one or more compounds and one or more other therapies are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time, optionally, followed by the administration of a third therapy (e.g., prophylactic or therapeutic agent) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the therapies, to avoid or reduce the side effects of one of the therapies, and/or to improve the efficacy of the therapies.
  • a first therapy e.g., a first prophylactic or therapeutic agent
  • a second therapy e.g., a second prophylactic or therapeutic agent
  • a third therapy e.g., prophylactic or therapeutic agent
  • the administration of the same compounds may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
  • the administration of the same therapy (e.g., prophylactic or therapeutic agent) other than a SD rifaximin composition may be repeated and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months.
  • travelers' diarrhea treatment may only last from between about 12 hours to about 72 hours, while a treatment for Crohn's disease may be from between about 1 day to about 3 months.
  • a treatment for hepatic encephalopathy may be, for example, for the remainder of the subject's life span.
  • a treatment for IBS may be intermittent for weeks or months at a time or for the remainder of the subject's life.
  • Rifaximin solid dispersions can be made from, for example, polymers including polyvinylpyrrolidone (PVP) grade K-90, hydroxypropyl methylcellulose phthalate (HPMC-P) grade 55, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) grades HG and MG, and a polymethacrylate (Eudragit® L100-55).
  • PVP polyvinylpyrrolidone
  • HPMC-P hydroxypropyl methylcellulose phthalate
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • Eudragit® L100-55 polymethacrylate
  • Rifaximin solid dispersion compositions are comprised of, for example, 10:90, 15:85, 20:80, 25:75, 30:70, 40:60, 50:50 60:40, 70:30, 75:25, 80:20, 85:15, and 90:10 (Rifaximin/polymer, by weight).
  • Preferred solid dispersions are comprised of 25:75, 50:50 and 75:25 (Rifaximin/polymer, by weight).
  • solid dispersions may also comprise surfactants, for example, non-ionic, surfactant polyols.
  • An example of a formulation comprises about 50:50 (w/w) Rifaximin:HPMC-AS MG with from between about 2 wt % to about 10 wt % of a non-ionic, surfactant polyol, for example, Pluronic F-127.
  • One example of a formulation comprises 50:50 (w/w) Rifaximin:HPMC-AS MG with about 5.9 wt %) of a non-ionic, surfactant polyol, for example, Pluronic F-127.
  • Spray dried rifaximin ternary dispersion (50:50 (w/w) rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127) was blended with 10 wt % croscarmellose sodium and then filled into gelatin capsules.
  • Each capsule contains 275 mg of rifaximin and the blend formulation is 85:5:10 of 50:50 (w/w) Rifaximin:HPMC-AS MG:Pluronic:croscarmellose sodium (calculated in total solids).
  • Other examples of microgranules and pharmaceutical compositions comprising SD rifaximin are described in the examples.
  • rifaximin solid dispersion To form the rifaximin solid dispersion, the components, e.g., rifaximin, polymer and methanol are mixed and then spray dried. Exemplary conditions are summarized in Table 9 and the procedure outlined below and in Examples 3 and 4.
  • Exemplary Spray Drying Process Parameters include for example:
  • Another embodiment includes articles of manufacture that comprise, for example, a container holding a rifaximin SD pharmaceutical composition suitable for oral or topical administration of rifaximin in combination with printed labeling instructions providing a discussion of when a particular dosage form should be administered with food and when it should be taken on an empty stomach. Exemplary dosage forms and administration protocols are described infra.
  • the composition will be contained in any suitable container capable of holding and dispensing the dosage form and which will not significantly interact with the composition and will further be in physical relation with the appropriate labeling.
  • the labeling instructions will be consistent with the methods of treatment as described hereinbefore.
  • the labeling may be associated with the container by any means that maintain a physical proximity of the two, by way of non-limiting example, they may both be contained in a packaging material such as a box or plastic shrink wrap or may be associated with the instructions being bonded to the container such as with glue that does not obscure the labeling instructions or other bonding or holding means.
  • Another aspect is an article of manufacture that comprises a container containing a pharmaceutical composition comprising SD rifaximin composition or formulation wherein the container holds preferably rifaximin composition in unit dosage form and is associated with printed labeling instructions advising of the differing absorption when the pharmaceutical composition is taken with and without food.
  • compositions are also provided, and may comprise a therapeutically effective amount of rifaximin.
  • Rifaximin SD composition and a pharmaceutically acceptable carrier or diluent wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.
  • Kits are also provided herein, for example, kits for treating a bowel disorder in a subject.
  • the kits may contain, for example, one or more of the solid dispersion forms of rifaximin and instructions for use.
  • the instructions for use may contain proscribing information, dosage information, storage information, and the like.
  • Packaged compositions are also provided, and may comprise a therapeutically effective amount of an SD rifaximin composition and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.
  • Rifaximin The chemical structure of Rifaximin is shown below in FIG. 1 .
  • Tg of Rifaximin/PVP K-90 dispersions increases with the increased Rifaximin concentration, which is due to the higher Tg of Rifaximin (199° C.) than PVP K-90 (174° C.).
  • Evidence of a single Tg may suggest that the components of the dispersion are intimately mixed, or miscible.
  • Dispersions prepared with other polymers also display a single apparent Tg, as a step change in the reversing heat flow signal by mDSC.
  • Dispersions prepared with HPMC-P exhibit Tg at 153° C. ( FIG. 8 , 25:75 w/w), 161° C. ( FIG. 9 , 50:50 w/w) and 174° C. ( FIG. 10 , 75:25 w/w) respectively, with ⁇ Cp at Tg approximately 0.4 J/g ⁇ ° C.
  • dispersions display Tg at 137° C. ( FIG. 13 , 25:75 w/w), 154° C. ( FIG. 14 , 50:50 w/w) and 177° C. ( FIG. 15 , 75:25 w/w) respectively; ⁇ Cp at Tg is approximately 0.4 or 0.3 J/g ⁇ ° C.
  • dispersions display Tg at 140° C. ( FIG. 18 , 25:75 w/w), 159° C. ( FIG. 19 , 50:50 w/w) and 177° C. ( FIG. 10 , 75:25 w/w) respectively; ⁇ Cp at Tg is approximately 0.4 or 0.3 J/g ⁇ ° C.
  • Dispersions prepared with Eudragit L100-55 exhibit Tg at 141° C. with ⁇ Cp approximately 0.5 J/g ⁇ ° C. ( FIG. 23 , 25:75 w/w), 159° C. with ⁇ Cp approximately 0.3 J/g ⁇ ° C. ( FIG. 24 , 50:50 w/w), and 176° C. with ⁇ Cp at Tg approximately 0.2 J/g ⁇ ° C. ( FIG. 25 , 75:25 w/w) respectively.
  • Tg of material in each set of Rifaximin/polymer dispersions increases with the increased Rifaximin concentration due to the higher Tg of Rifaximin.
  • the samples including all the dispersions and x-ray amorphous rifaximin-only material were assessed for evidence of crystallization based on observations by microscopy using polarized light. Each of the samples remained as irregular aggregates without birefringence/extinctions after stressed at 40° C./75% RH condition for 7 days.
  • Modulated DSC analyses were carried out on selected samples including 25:75 (w/w) rifaximin/HPMC-P, 75:25 (w/w) rifaximin/HPMC-AS HG, 75:25 (w/w) rifaximin/HPMC-AS MG, and 25:75 (w/w) Rifaximin/Eudragit L100-55 to inspect for evidence of phase separation after exposure to 40° C./75% RH for 7 days. All of samples display a single apparent Tg at approximately 148° C. ( FIG. 27 , 25:75 (w/w) HPMC-P), 177° C. ( FIG. 28 , 75:25 (w/w) HPMC-AS HG) 152° C. ( FIG.
  • HPMC-AS MG and HPMC-P were used to prepare additional quantities of solid dispersions at gram-scale by spray drying.
  • the operating parameters used for processing are presented in Table 9. Based on visual inspection, both dispersions were x-ray amorphous by XRPD ( FIG. 31 and FIG. 36 ).
  • FIG. 33 A Gram-Schmidt plot corresponding to the overall IR intensity associated with volatiles released by solids upon heating at 20° C./min is shown in FIG. 33 . There was a dramatic increase of intensity of released volatiles after ⁇ 8 minutes, with a maximum at ⁇ 11.5 minutes.
  • the waterfall plot ( FIG. 34 ) and the linked IR spectrum ( FIG. 35 ) are indicative of the loss of water loss up to ⁇ 8 minutes then methanol and some unknown volatiles thereafter. This is consistent with the dramatic change in the slope in the TGA and may indicate decomposition of material.
  • the Gram-Schmidt plot ( FIG. 39 ) shows a small increase of intensity upon heating after ⁇ 2 minutes, followed by negligible change of intensity until ⁇ 9 minutes. Then dramatic change of intensity can be observed with a maximum at ⁇ 11 minutes, followed by a final increase of intensity above ⁇ 12 minutes. As seen in the waterfall plot ( FIG. 39 ), some volatiles were released during entire heating period (data is shown in FIG. 40 using the linked IR spectrum at different time points as an example). The sample released water during entire heating period and methanol after ⁇ 9 minutes.
  • a ternary dispersion of 50:50 (w/w) Rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127 was prepared in large quantity (containing approximately 110 g of Rifaximin) by spray drying. Disclosed herein are the analytical characterizations for Rifaximin ternary dispersion as-prepared and post-stress samples at 70° C./75% RH for 1 week and 3 week, and post-stress sample at 40° C./75% RH for 6 weeks and 12 weeks.
  • FIG. 46 A high resolution XRPD pattern was acquired and material is x-ray amorphous ( FIG. 46 ).
  • mDSC FIG. 47
  • T g a single apparent T g is observed from the step change in the reversing heat flow signal at approximately 136° C. with a heat capacity change at T g of approximately 0.4 J/g ⁇ ° C.
  • Thermogravimetric analysis coupled with infra-red spectroscopy was performed to analyze volatiles generated upon heating.
  • the total weight loss of sample was approximately 0.7 wt % to 100° C. and the dramatic change in the slope occurs at approximately 202° C. ( FIG. 48 ).
  • the Gram-Schmidt plot corresponds to the overall IR intensity associated with volatiles released by a sample upon heating at 20° C./min.
  • Gram-Schmidt a negligible increase of intensity upon heating is observed before ⁇ 7 minutes followed by a dramatic increase of intensity with the maximum at ⁇ 11.8 min.
  • the waterfall plot (data not shown) of this sample indicates volatile are released upon heating after ⁇ 7 min (data is shown in FIG. 49 using the linked IR spectrum at different time points as an example) and volatiles were identified as residual methanol from the processing solvent in spray drying and possible acetic acid from HPMC-AS MG.
  • Vibrational spectroscopy techniques including IR and Raman were employed to further characterize this ternary dispersion.
  • the overlay of IR spectra for the dispersion and X-ray amorphous Rifaximin is shown in FIG. 50 . Based on visual inspection, two spectra are very similar. Similar observations can be drawn from the comparison of Raman analysis ( FIG. 51 ).
  • the sample is composed of agglomerates of collapsed spheres. Particles sizes of spheres are not uniform, ranging from slightly larger to much less than 10 ⁇ m.
  • PLM images (data not shown) of solids dispersed in mineral oil were collected, which indicate sample primarily is composed of irregularly-shaped equant particles approximately 5-15 ⁇ m in length with some agglomerates 20-50 ⁇ m in length.
  • Particle size analysis ( FIG. 52 ) indicates that 50% of particles have size less than 8.233 ⁇ m and 90% of particles have size less than 17.530 ⁇ m. Data was acquired in 2% (w/v) Lecithin in Isopar G.
  • the DVS isotherm of solids is shown in FIG. 53 .
  • the material exhibits a 0.13 wt % loss upon equilibration at 5% RH. Solids then gain 11.14 wt % between 5% and 95% RH and exhibits some hysteresis with 10.80 wt % loss upon desorption from 95% to 5% RH.
  • XRPD analysis of the solids recovered after completion of the desorption step showed no evidence of sharp peaks indicative of a crystalline solid ( FIG. 54 ).
  • Table 19 summarized characterization results for the samples that stressed at 70° C./75% RH condition 1 week and 3 weeks, and the sample that stressed at 40° C./75% RH condition 6 weeks.
  • the sample is composed of agglomerates of collapsed spheres and particles sizes of spheres are not uniform, which is similar to the as-prepared material.
  • Rifaximin ternary dispersions 50:50 w/w Rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127 were prepared from methanol using spray drying in closed mode suitable for processing organic solvents. Ingredients are listed as below in Table 20:
  • Rifaximin ternary dispersions were prepared by spray drying in both small scale ( ⁇ 1 g API) and large scale ( ⁇ 34 g API in a single batch).
  • Solids recovered after spray drying were dried at 40° C. under vacuum for 24 hours and then stored at sub-ambient temperatures over desiccant.
  • micronized, API, amorphous, solid dispersion and micronized capsules are below in Table 23. These capsules were used in the dog study of Example 5.
  • sodium croscarmellose was added to the bag of SD rifaximin dispersion and bag blend for 1 minute, and then the material was added to the V-blender and blended for 10 minutes at 24 rpm.
  • the material was then discharged into a stainless steel pan and record the height of material in the pan. Empty capsules were tared using an analytical balance, then the capsules were filled by depressing into the bed of material. The weight is adjusted within + or ⁇ 5% of target fill weight of 647.5 mg (acceptable fill range 615.13-679.88 mg).
  • FIGS. 61-63 show the rifaximin solid dispersion (SD) capsules in various buffers; with and without SDS; and compared to amorphous rifaximin.
  • FIG. 61 shows results of dissolution studies of rifaximin SD capsules in acid phase: 0.1 N HCl with variable exposure times in a buffer containing 0.45% SDS at pH 6.8.
  • FIG. 62 shows results of dissolution studies of rifaximin SD capsules in acid phase for 2 hours buffered at pH 6.8 with and without SDS.
  • FIG. 63 shows results of dissolution studies of rifaximin SD capsules in acid phase in a phosphate buffer at pH 6.8 with 0.45% SDS compared to amorphous rifaximin.
  • rifaximin SD near 100% dissolution is achieved in 0.45% SDS and the SD formulation dissolves more slowly than the amorphous rifaximin.
  • PK pharmacokinetics
  • the polymer used was HPMC-AS at a drug to polymer ratio of 50:50.
  • the formulation also comprised pluronic F127 and crosscarmellose sodium (see Example 4).
  • Table 25 shows the PK parameters. From the table it can be seen that systemic exposure of the solid dispersion formulation is greater than that of amorphous or crystalline form (API) of rifaximin.
  • API amorphous or crystalline form
  • API exposures were low, in keeping with what has been previously observed for rifaximin.
  • mean exposures (AUCinf) following amorphous and SD rifaximin administration were substantially higher, with ⁇ 40- and ⁇ 100-fold greater exposure, respectively, as compared with API.
  • Variability was high in all three dose groups. In general, the shapes of all three profiles were similar, suggesting effects of the dosage forms on bioavailability without effects on clearance or volume of distribution.
  • FIG. 65 shows the kinetic solubility of rifaximin SD granules 10% wt CS FaSSIF or 10% wt CS FeSSIF (a) and the dissolution profiles of SDD tablet 10% CS in 0.2% SLS at pH 4.5, 5.5 and 7.4.
  • rifaximin SDD 100%, or near 100%, dissolution is achieved in 0.2% SLS, pH 4.5, 5.5 and 7.4.
  • FIG. 66 shows that release can be delayed up to two hours and extended up to three hours.
  • FIGS. 67-70 show the effects of media pH on Rifaximin SDD tablet SDD tablet dissolution at various levels of CS: 0%, 2.5%, 5%, and 10% CS.
  • FIGS. 67 and 68 show dissolution profiles of SDD tablet with 0%, 2.5%, 5% or 10% CS in 0.2% SDS at 2 hours pH 2.0, pH 4.5, 0.2% SDS pH 5.5, or 0.2% SDS, pH 7.4.
  • FIGS. 69 and 70 show the dissolution profiles of SDD tablet 2.5% CS, 0% CS, 10% CS and 5% CS in 0.2% SLS, pH4.5, 0.2% SLS, pH 5.5 and 0.2% SLS, pH 7.4.
  • FIG. 71 shows CS release mechanism.
  • Described herein are the preparation and characterization of rifaximin quaternary dispersions with antioxidants.
  • Antioxidants used were butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate (PG).
  • the prepared materials are x-ray amorphous, as shown in FIG. 72 the overlay of XRPD patterns, which agree with their PLM observations.
  • each of material displays a single apparent T g in the reversing heat flow signal at approximately 133° C. ( FIG. 73 , with 0.063 wt % BHA), 133° C. ( FIG. 74 , with 0.063 wt % BHT), and 134° C. ( FIG. 75 , with 0.094 wt % PG), which is consistent with the T g of the spray dried rifaximin ternary dispersion of 47.2:47.2:5.6 w/w/w/rifaximin/HPMC-AS MG/Pluronic F-127 (135 or 136° C.).
  • This example sets forth exemplary microgranules of rifaximin and pharmaceutical compositions comprising the same.
  • Spray dry dispersion (SDD), solid dispersion, amorphous solid dispersion are used interchangabley herein to refer to the rifaximin formulations.
  • Table 30 sets forth the manufacture of Rifaximin solid dispersion microgranules
  • Exemplary Spray Drying Processes are Set Forth in Table 32.
  • Disclosed herein is dissolution data for roller compacted materials of Solid Dispersion Rifaximin with varying levels (0, 2.5%, 5%, and 10%) of croscarmellose sodium.
  • Dissolution tests were performed on as received roller compacted materials of Solid Dispersion Rifaximin with 0, 2.5 wt %, and 5 wt % croscarmellose sodium. Powders of solids were directly added into pH 6.5 FaSSIF buffer with gentle agitation of the media (50 rpm paddle stirrer) at 37° C. for 24 hrs.
  • a sample of rifaximin ternary dispersion was characterized by XRPD, mDSC, TG-IR, SEM and KF.
  • the XRPD pattern by visual inspection is x-ray amorphous with no sharp peaks ( FIG. 76 ).
  • T g X-ray powder diffraction
  • Thermogravimetric analysis coupled with infra-red spectroscopy was performed to analyze volatiles generated upon heating.
  • the total weight loss of sample was approximately 0.4 wt % to 100° C., and a dramatic change in the slope occurs at approximately 190° C. which is likely due to decomposition.
  • the Gram-Schmidt plot corresponds to the overall IR intensity associated with volatiles released by a sample upon heating at 20° C./min Gram-Schmidt indicates that volatiles are released upon heating after ⁇ 8 min, and volatiles were identified as residual methanol from the processing solvent in spray drying and possible acetic acid from HPMC-AS MG.
  • Rifaximin ternary dispersions 50:50 w/w Rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127 were prepared from methanol using Büchi B-290 Mini Spray Dryer in closed mode suitable for processing organic solvents. Ingredients are listed in Table 33 below:
  • Rifaximin ternary dispersions were prepared by spray drying in both small scale ( ⁇ 1 g API) and large scale ( ⁇ 34 g API in a single batch).
  • Solids recovered after spray drying were dried at 40° C. under vacuum for 24 hours and then stored at sub-ambient (freezer) over desiccant.
  • FIG. 77 indicates the results of two studies conducted to characterize the pharmacokinetics of rifaximin following administration of varying forms and formulations following a single oral dose. Blood samples were collected at timed intervals over the 24 h after single dose administration (2200 mg total dose in each case) and processed to plasma for analysis of rifaximin concentrations. PK parameters were estimated by noncompartmental methods. The results are shown in FIG. 77 . Of the forms/formulations shown, the spray-dried dispersion showed that the highest exposure, and therefore the highest bioavailability, resulted from administration of the SDD formulation (dosed as SDD powder in gelatin capsules).
  • FIG. 78 shows the results of the dog dose escalation, in which dogs received single doses of the SDD formulation in capsules, at doses from 150 mg to 2200 mg.
  • the results indicate an essentially linear dose escalation (increases in exposure that are approximately proportional to increase in dose) up to 550 mg, followed by a greater-than-proportional increase at 1100 mg and 2200 mg.
  • This is quite unusual in the linear range in that the current crystalline form of rifaxmin does not dose escalate, generally, exposure does not increase substantially on increasing dose.
  • the greater than dose proportional increase on increasing dose is also remarkable and suggests that, at the higher doses, rifaximin is saturating intestinal P-glycoprotein transport that would otherwise limit systemic absorption, thereby allowing increased absorption.
  • FIG. 79 sets out the quotient study design for rifaximin SDD dose escalation.
  • FIG. 80 outlines the dose escalation/regional absorption study, dose escalation/dose selection.
  • FIGS. 81 and 82 show representative subject data from an exemplary dose escalation study. Mean data (linear scale and log scale) is shown in FIGS. 83 and 84 , respectively. Mean profiles, log scale. Terminal phases are parallel, in clearance mechanisms.
  • a summary of rifaximin SDD dose escalation is shown indicating that it is likely that there is not saturation of any metabolic or other systemic FIG. 85 .
  • C max and AUC dose proportional increases in exposure
  • T max is not delayed by dose increases, further indicating an early absorption window (corroborated by regional absorption data).
  • the percent of dose in urine is remarkable in that it stays low, approximately 0.2% or less of the dose excreted over 24 h. This result is surprising in that this is quite low in spite of the significant increases in systemic exposure as compared with the crystalline formulation.
  • the results indicate a considerably increased solubility that presumably leads to increased local/lumenal soluble rifaximin, with accompanying increases in systemic exposure, but without significant increases in urinary excretion that are reflective of percent of rifaximin dose absorbed.
  • FIGS. 86 and 87 Dose/dosage form comparisons are shown in FIGS. 86 and 87 .
  • the tables compare SDD at increasing doses to the current crystalline formulation in terms of systemic PK.
  • the SDD formulation at the same dose shows an approximate 6.4-fold increase in C max and an approximate 8.9-fold increase in AUC. Nonetheless, these exposures are less than those observed in any hepatic impaired subject with the current tablet formulation.
  • microgranules, blends and tablets are formulated as set forth in Table 37, below

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