U.S. patent application number 16/916421 was filed with the patent office on 2020-12-24 for formulations of rifaximin and uses thereof.
The applicant listed for this patent is Salix Pharmaceuticals, Inc.. Invention is credited to Pam Golden, Mohammed A. Kabir, Jon Selbo, Jing Teng.
Application Number | 20200397904 16/916421 |
Document ID | / |
Family ID | 1000005064713 |
Filed Date | 2020-12-24 |
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United States Patent
Application |
20200397904 |
Kind Code |
A1 |
Selbo; Jon ; et al. |
December 24, 2020 |
FORMULATIONS OF RIFAXIMIN AND USES THEREOF
Abstract
The present invention relates to new rifaximin forms comprising
solid dispersions of rifaximin, methods of making same and to their
use in medicinal preparations and therapeutic methods.
Inventors: |
Selbo; Jon; (West Lafayette,
IN) ; Teng; Jing; (West Lafayette, IN) ;
Kabir; Mohammed A.; (Cary, NC) ; Golden; Pam;
(Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Salix Pharmaceuticals, Inc. |
Bridgewater |
NJ |
US |
|
|
Family ID: |
1000005064713 |
Appl. No.: |
16/916421 |
Filed: |
June 30, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15615121 |
Jun 6, 2017 |
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16916421 |
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14250293 |
Apr 10, 2014 |
9737610 |
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15615121 |
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13181481 |
Jul 12, 2011 |
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14250293 |
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61419056 |
Dec 2, 2010 |
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61363609 |
Jul 12, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 9/4858 20130101; A61K 9/4866 20130101; A61K 9/146 20130101;
A61K 9/10 20130101; A61K 31/437 20130101; A61K 9/1641 20130101;
A61K 47/32 20130101; A61K 47/38 20130101; A61K 9/1652 20130101;
C07D 498/22 20130101; A61K 9/2054 20130101 |
International
Class: |
A61K 47/38 20060101
A61K047/38; C07D 498/22 20060101 C07D498/22; A61K 9/14 20060101
A61K009/14; A61K 9/16 20060101 A61K009/16; A61K 9/10 20060101
A61K009/10; A61K 9/48 20060101 A61K009/48; A61K 9/20 20060101
A61K009/20; A61K 31/437 20060101 A61K031/437; A61K 47/32 20060101
A61K047/32 |
Claims
1-12. (canceled)
13. A method of treating a bowel related disorder in a subject in
need thereof, comprising administering to the subject a solid
dispersion comprising rifaximin and a polymer, wherein the polymer
comprises from about 10% to about 60% by weight of the solid
dispersion and is selected from the group consisting of
polyvinylpyrrolidone (PVP) grade K-90, hydroxypropylmethyl
cellulose phthalate (HPMC-P) grade 55, hydroxypropyl
methylcellulose acetate succinate (HPMC-AS) grades HG and MG, and
polymethacrylate, and wherein said solid dispersion comprises a
non-crystalline fully miscible dispersion comprising said rifaximin
and said polymer.
14. The method of claim 13, wherein the bowel related disorder is
irritable bowel syndrome.
15. The method of claim 13, wherein the bowel related disorder is
hepatic encephalopathy.
16. The solid dispersion of claim 13, wherein said rifaximin and
said polymer are present in equal amounts, and each of said
rifaximin and said polymer comprises from about 10% to about 50% by
weight of said solid dispersion.
17. The solid dispersion of claim 14, wherein said rifaximin and
said polymer are present in equal amounts, and each of said
rifaximin and said polymer comprises from about 10% to about 50% by
weight of said solid dispersion.
18. The solid dispersion of claim 15, wherein said rifaximin and
said polymer are present in equal amounts, and each of said
rifaximin and said polymer comprises from about 10% to about 50% by
weight of said solid dispersion.
19. The solid dispersion of claim 13, wherein said polymer
comprises HPMC-AS grade MG or HPMC-AS grade HG.
20. The solid dispersion of claim 14, wherein said polymer
comprises HPMC-AS grade MG or HPMC-AS grade HG.
21. The solid dispersion of claim 15, wherein said polymer
comprises HPMC-AS grade MG or HPMC-AS grade HG.
22. The solid dispersion of claim 16, wherein said polymer
comprises HPMC-AS grade MG or HPMC-AS grade HG.
23. The solid dispersion of claim 17, wherein said polymer
comprises HPMC-AS grade MG or HPMC-AS grade HG.
24. The solid dispersion of claim 18, wherein said polymer
comprises HPMC-AS grade MG or HPMC-AS grade HG.
25. The solid dispersion of claim 13, wherein said non-crystalline
fully miscible dispersion further comprises a non-ionic
surfactant.
26. The solid dispersion of claim 14, wherein said non-crystalline
fully miscible dispersion further comprises a non-ionic
surfactant.
27. The solid dispersion of claim 15, wherein said non-crystalline
fully miscible dispersion further comprises a non-ionic
surfactant.
28. The solid dispersion of claim 16, wherein said non-crystalline
fully miscible dispersion further comprises a non-ionic
surfactant.
29. The solid dispersion of claim 19, wherein said non-crystalline
fully miscible dispersion further comprises a non-ionic surfactant.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/615,121, filed Jun. 6, 2017 which is a
continuation of U.S. patent application Ser. No. 14/250,293, filed
Apr. 10, 2014 which is a continuation of U.S. patent application
Ser. No. 13/181,481 filed 12 Jul. 2011 which claims the benefit of
U.S. Provisional Application No. 61/363,609 filed 12 Jul. 2010, and
U.S. Provisional Application No. 61/419,056, filed 2 Dec. 2010, the
entire contents of each of which are hereby incorporated herein by
reference.
BACKGROUND
[0002] 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)).
[0003] 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.
SUMMARY
[0004] Provided herein are solid dispersion forms of rifaximin with
a variety of polymers and polymer concentrations.
[0005] In one aspect, provided herein are forms solid dispersion of
rifaximin.
[0006] In one embodiment, 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.
[0007] In one embodiment, 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.
[0008] In one embodiment, the form has the appearance of a single
glass transition temperature (Tg).
[0009] In one embodiment, a Tg of a form increases with an
increased rifaximin concentration. In one embodiment, a form
stressed at 70.degree. C./75% RH for 1 week, solids are still x-ray
amorphous according to XRPD.
[0010] In one embodiment, a form stressed at 70.degree. C./75% RH
for 3 weeks, solids are still x-ray amorphous according to
XRPD.
[0011] In one embodiment, a form stressed at 70.degree. C./75% RH
for 6 weeks, solids are still x-ray amorphous according to
XRPD.
[0012] In one embodiment, a form stressed at 70.degree. C./75% RH
for 12 weeks, solids are still x-ray amorphous according to
XRPD.
[0013] In one aspect, provided herein are microgranules comprising
one or more of the solid dispersion forms of rifaximin described
herein.
[0014] In one embodiment, the microgranules further comprise a
polymer.
[0015] In one embodiment, 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.RTM. L100-55).
[0016] In specific embodiments, the microgranules comprises 25-75%
polymer, 40-60% polymer, or 40-50% polymer. In an exemplary
embodiment, the microgranules comprises 42-44% polymer.
[0017] In one embodiment, the microgranules comprise equal amounts
of rifaximin and polymer.
[0018] In another embodiment, the microgranules further comprising
an intragranular release controlling agent. In exemplary
embodiments, 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.
[0019] In one embodiment, 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.
[0020] In another embodiment, 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.
[0021] In another embodiment, the microgranules further comprise a
wetting agent or surfactant, e.g., a non-ionic surfactant.
[0022] In one embodiment, 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.
[0023] In one embodiment, the non-ionic surfactant comprises a
poloxamer, e.g., poloxamer 407 also known as Pluronic F-127.
[0024] In another embodiment, the microgranules further comprise an
antioxidant.
[0025] In exemplary embodiments, the antioxidant is butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or propyl
gallate (PG).
[0026] In another embodiment, 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.
[0027] In another aspect, provided herein are pharmaceutical
compositions comprising the microgranules described herein.
[0028] In one embodiment, the pharmaceutical compositions further
comprise one or more pharmaceutically acceptable excepients.
[0029] In one embodiment, the pharmaceutical compositions are
tablets or capsules.
[0030] In one embodiment, the pharmaceutical compositions comprises
a disintegrant.
[0031] In one embodiment, 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.RTM. L100-55).
[0032] In one aspect, provided herein are pharmaceutical solid
dispersion formulations comprising: rifaximin, HPMC-AS, at a
rifaximin to polymer ratio of 50:50, a non-ionic, surfactant polyol
and a intragranular release controlling agent.
[0033] In one embodiment, the intragranular release controlling
agent comprises about 10 wt % of the formulation.
[0034] In one aspect, provided herein are 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.
[0035] In one aspect, provided herein are 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.
[0036] In one embodiment, the intragranular release controlling
agent comprises croscarmellose sodium.
[0037] A process for producing form solid dispersion of rifaximin
comprising one or more of the methods listed in Tables 1-5.
[0038] In one embodiment, pharmaceutical compositions comprising SD
rifaximin, a polymer, a surfactant, and a release controlling agent
are provided. In one embodiment, provided are pharmaceutical
compositions comprising SD rifaximin, HPMC-AS, pluronic F127, and
croscarmellose Na (CS). In one embodiment, the pharmaceutical
compositions are tablets or pills.
[0039] In additional embodiments, the pharmaceutical compositions
further comprise fillers, glidants or lubricants.
[0040] In specific embodiments, the pharmaceutical compositions
comprise the ratios of components set forth in Table 37.
[0041] Other embodiment and aspects are disclosed infra.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1. Chemical structure of Rifaximin.
[0043] FIG. 2. Overlay of XRPD patterns for Rifaximin/PVP K-90
dispersions obtained from methanol by spray drying.
[0044] FIG. 3. mDSC thermogram for 25:75 (w/w) Rifaximin/PVP K-90
dispersion obtained from methanol by spray drying.
[0045] FIG. 4. mDSC thermogram for 50:50 (w/w) Rifaximin/PVP K-90
dispersion obtained from methanol by spray drying.
[0046] FIG. 5. mDSC thermogram for 75:25 (w/w) Rifaximin/PVP K-90
dispersion obtained from methanol by spray drying.
[0047] FIG. 6. Overlay of mDSC thermogram for Rifaximin/PVP K-90
dispersions obtained from methanol by spray drying.
[0048] FIG. 7. Overlay of XRPD patterns for Rifaximin/HPMC-P
dispersions obtained from methanol by spray drying.
[0049] FIG. 8. mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-P
dispersion obtained from methanol by spray drying.
[0050] FIG. 9. mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-P
dispersion obtained from methanol by spray drying.
[0051] FIG. 10. mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-P
dispersion obtained from methanol by spray drying.
[0052] FIG. 11. Overlay of mDSC thermogram for Rifaximin/HPMC-P
dispersions obtained from methanol by spray drying.
[0053] FIG. 12. Overlay of XRPD patterns for Rifaximin/HPMC-AS HG
dispersions obtained from methanol by spray drying.
[0054] FIG. 13. mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-AS
HG dispersion obtained from methanol by spray drying.
[0055] FIG. 14. mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-AS
HG dispersion obtained from methanol by spray drying.
[0056] FIG. 15. mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-AS
HG dispersion obtained from methanol by spray drying.
[0057] FIG. 16. Overlay of mDSC thermogram for Rifaximin/HPMC-AS HG
dispersions obtained from methanol by spray drying.
[0058] FIG. 17. Overlay of XRPD patterns for Rifaximin/HPMC-AS MG
dispersions obtained from methanol by spray drying.
[0059] FIG. 18. mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-AS
MG dispersion obtained from methanol by spray drying.
[0060] FIG. 19. mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-AS
MG dispersion obtained from methanol by spray drying.
[0061] FIG. 20. mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-AS
MG dispersion obtained from methanol by spray drying.
[0062] FIG. 21. Overlay of mDSC thermogram for Rifaximin/HPMC-AS MG
dispersions obtained from methanol by spray drying.
[0063] FIG. 22. Overlay of XRPD patterns for Rifaximin/Eudragit
L100-55 dispersions obtained from methanol by spray drying.
[0064] FIG. 23. mDSC thermogram for 25:75 (w/w) Rifaximin/Eudragit
L100-55 dispersion obtained from methanol by spray drying.
[0065] FIG. 24. mDSC thermogram for 50:50 (w/w) Rifaximin/Eudragit
L100-55 dispersion obtained from methanol by spray drying.
[0066] FIG. 25. mDSC thermogram for 75:25 (w/w) Rifaximin/Eudragit
L100-55 dispersion obtained from methanol by spray drying.
[0067] FIG. 26. Overlay of mDSC thermogram for Rifaximin/Eudragit
L100-55 dispersions obtained from methanol by spray drying.
[0068] FIG. 27. mDSC thergram for 25:75 (w/w) Rifaximin/HPMC-P
dispersion stressed at 40.degree. C./75% RH for 7 d.
[0069] FIG. 28. mDSC thergram for 75:25 (w/w) Rifaximin/HPMC-AS HG
dispersion stressed at 40.degree. C./75% RH for 7 d.
[0070] FIG. 29. mDSC thergram for 75:25 (w/w) Rifaximin/HPMC-AS MG
dispersion stressed at 40.degree. C./75% RH for 7 d.
[0071] FIG. 30. mDSC thergram for 25:75 (w/w) Rifaximin/Eudragit
L100-55 dispersion stressed at 40.degree. C./75% RH for 7 d.
[0072] FIG. 31. XRPD pattern for 50:50 (w/w) Rifaximin/HPMC-AS MG
dispersion.
[0073] FIG. 32. Modulate DSC thermograms for 50:50 (w/w)
Rifaximin/HPMC-AS MG dispersion.
[0074] FIG. 33. TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG
dispersion TGA data.
[0075] FIG. 34. TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG
dispersion Gram-Schmidt plot and waterfall plot.
[0076] FIG. 35. TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG
dispersion.
[0077] FIG. 36. XRPD pattern for 25:75 (w/w) Rifaximin/HPMC-P
dispersion.
[0078] FIG. 37. Modulate DSC thermograms for 25:75 (w/w)
Rifaximin/HPMC-P dispersion.
[0079] FIG. 38. TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P
dispersion--TGA data.
[0080] FIG. 39. TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P
dispersion--Gram-Schmidt plot and waterfall plot.
[0081] FIG. 40. TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P
dispersion.
[0082] FIG. 41. Overlay of pre-processed XRPD patterns in
multivariate mixture analysis.
[0083] FIG. 42. Estimated Concentrations of Rifaximin (blue) and
HPMC-AS MG (red) using Unscrambler MCR analysis.
[0084] FIG. 43. Estimated XRPD patterns of Rifaximin (blue) and
HPMC-AS MG (red) using Unscrambler MCR analysis.
[0085] FIG. 44. Overlay of estimated XRPD pattern of pure rifaximin
using MCR and measured XRPD pattern of 100% rifaximin.
[0086] FIG. 45. Overlay of estimated XRPD pattern of pure HPMC-AS
MG using MCR and measured XRPD pattern of 100% HPMC-AS MG.
[0087] FIG. 46. An exemplary XRPD pattern for combined solids of
Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
[0088] FIG. 47. A modulate DSC thermogram for combined solids of
Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
[0089] FIG. 48. A TG-IR analysis for combined solids of
Rifaximin/HPMC-AS MG/Pluronic ternary dispersion--TGA
thermogram.
[0090] FIG. 49. An exemplary TG-IR analysis for combined solids of
Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
[0091] FIG. 50. An exemplary overlay of IR spectra for X-ray
amorphous Rifaximin and combined solids of Rifaximin/HPMC-AS
MG/Pluronic ternary dispersion.
[0092] FIG. 51. An exemplary overlay of Ramam spectra for X-ray
amorphous Rifaximin and combined solids of Rifaximin/HPMC-AS
MG/Pluronic ternary dispersion.
[0093] FIG. 52. A particle size analysis report for combined solids
of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.
[0094] FIG. 53. An exemplary dynamic vapor sorption (DVS) analysis
for combined solids of Rifaximin/HPMC-AS MG/Pluronic ternary
dispersion.
[0095] FIG. 54. An exemplary overlay of XRPD patterns for
Rifaximin/HPMC-AS MG/Pluronic ternary dispersion post-DVS solids
and solids as-prepared.
[0096] FIG. 55. An exemplary overlay of XRPD patterns for Rifaximin
ternary dispersion post-stressed samples and as-prepared
sample.
[0097] FIG. 56. An exemplary mDSC thermgram for Rifaximin ternary
dispersion after 70.degree. C./75% RH 1 week.
[0098] FIG. 57. An exemplary mDSC thermgram for Rifaximin ternary
dispersion after 70.degree. C./75% RH 3 weeks.
[0099] FIG. 58. An exemplary mDSC thermgram for Rifaximin ternary
dispersion after 40.degree. C./75% RH 6 weeks.
[0100] FIG. 59. An exemplary mDSC thermgram for Rifaximin ternary
dispersion after 40.degree. C./75% RH 12 weeks.
[0101] FIG. 60. Pharmacokinetic data of solid dispersion in
dogs.
[0102] 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.
[0103] FIG. 62. Rifaximin SD capsules dissolution; acid phase: 2
hours; buffer phase: pH 6.8.
[0104] FIG. 63. Rifaximin capsule dissolution; phosphate buffer pH
6.8 with 0.45% SDS.
[0105] FIG. 64A-D. Rifaximin spray dried dispersion (SDD) capsule
dissolution. FIG. 64A acid phase 2 hours, buffer phase: P. Buffer,
pH. 7.4. FIG. 64B acid phase: 0.1N HCl with various exposure times,
buffer phase: P. buffer, pH 7.4 with 0.45% SDS. FIG. 64C shows the
general structure of hydroxypropyl methylcellulose (HMPC). FIG. 64D
represents the percent released at 30 min as a function of pH.
[0106] FIG. 65A-B. Rifamixin SDD with 10% CS formulation. FIG. 65A
kinetic solubility Rifamixin SD granules. 10% wt % CS sodium
FaSSIF, 10% wt % CS sodium FeSSIF. FIG. 65B dissolution profiles
SDD tablet 10% CS. 0.2% SLS, pH4.5; 0.2% SLS, pH5.5; 0.2% SLS, pH
7.4; FaSSIF.
[0107] FIG. 66A-B. Rifaximin SDD with 10% CS formulation. Rifaxamin
SDD capsules dissolution: FIG. 66A acid phase 2 hours, buffer
phase: P. Buffer, pH. 7.4. With 0.45% SDS; without SDS. FIG. 66B
acid phase: 0.1N HCl with variable exposure times, buffer phase: P.
buffer, pH 7.4 with 0.45% SDS.
[0108] FIG. 67A-B. Effects of media pH on dissolution. FIG. 67A
Rifaxamin SDD tablet dissolution. Acid phase: 2 hours, pH 2.0, FIG.
67B Dissolution profiles 0.2% SDS at pH 4.5, SDD tablet dissolution
at various levels of CS: 0%, 2.5%, 5%, and 10% CS.
[0109] FIG. 68A-B. Effects of media pH on dissolution. FIG. 68A
Rifaxamin SDD tablet dissolution at various levels of CS: 0%, 2.5%,
5%, and 10% CS, 0.2% SDS at pH 5.5. FIG. 68B Dissolution profiles
SDD tablet dissolution at various levels of CS: 0%, 2.5%, 5%, and
10% CS, 0.2% SDS at pH 7.4.
[0110] FIG. 69A-B. Effects of media pH on dissolution. FIG. 69A
Rifaxamin SDD tablet dissolution 2.5% CS, 0.2% SLS, pH4.5, 0.2%
SLS, pH 5.5, 0.2% SLS, pH 7.4. FIG. 69B Rifaxamin SDD tablet
dissolution 0% CS, 0.2% SLS, pH4.5, 0.2% SLS, pH 5.5, 0.2% SLS, pH
7.4.
[0111] FIG. 70A-B. Effects of media pH on dissolution. FIG. 70A
Rifaxamin SDD tablet dissolution 10% CS, 0.2% SLS, pH4.5, 0.2% SLS,
pH 5.5, 0.2% SLS, pH 7.4. FIG. 70B Rifaxamin SDD tablet dissolution
5% CS, 0.2% SLS, pH4.5, 0.2% SLS, pH 5.5, 0.2% SLS, pH 7.4.
[0112] FIG. 71A-B. CS release mechanism. FIG. 71A Kinetic
solubility in FaSSIF media, pH 6.5, FIG. 71B slope vs. time
point.
[0113] 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.
[0114] FIG. 73 depicts an mDSC thermogram of rifaximin quaternary
sample containing 0.063 wt % BHA.
[0115] FIG. 74 depicts an mDSC thermogram of rifaximin quaternary
sample containing 0.063 wt % BHT.
[0116] FIG. 75 depicts a mDSC thermogram of rifaximin quaternary
sample containing 0.094 wt % PG.
[0117] 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.
[0118] FIG. 77 depicts the pharmacokinetics of rifaximin following
administration of varying forms and formulations following a single
oral dose of 2200 mg in dogs.
[0119] FIG. 78 depicts Rifaximin SDD in dogs.
[0120] FIG. 79 depicts the quotient study design.
[0121] FIG. 80 summarizes the dose escalation/regional absorption
study, part A dose escalation/dose selection.
[0122] FIG. 81 depicts representative subject data from a dose
escalation study.
[0123] FIG. 82 depicts representative subject data from a dose
escalation study.
[0124] FIG. 83 depicts mean dose escalation data, on a linear
scale.
[0125] FIG. 84 depicts mean dose escalation data, on a log
scale.
[0126] FIG. 85 depicts a summary of Rifaximin SDD dose escalation
studies.
[0127] FIG. 86 is a Table of dose/dosage form comparison.
[0128] 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.
DETAILED DESCRIPTION
[0129] Embodiments described herein relate to the discovery of new
solid dispersion forms of rifaximin with a variety of polymers and
polymer concentrations. In one embodiment 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. For example, 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.
[0130] 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.
[0131] As used herein, the term "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.
[0132] In one embodiment, 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.
[0133] In another embodiment, the microgranule comprises a
surfactant, e.g., a non-ionic surfactant. In one embodiment, 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.
[0134] In another embodiment, the microgranule comprises an
antioxidant. In one embodiment, 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.
[0135] As used herein, the term "intragranular" refers to the
components that reside within the microgranule. As used herein, the
term "extragranular" refers to the components of the pharmaceutical
composition that are not contained within the microgranule.
[0136] As used herein, the term 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.
[0137] As used herein, 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-.theta..
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.sub.max, t.sub.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.
[0138] As used herein, "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.
[0139] 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.
[0140] Polymorphism, as used herein, 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.
Thus, 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. It is
desirable to investigate all solid state forms of a drug, including
all polymorphic forms, and to determine the stability, dissolution
and flow properties of each polymorphic form. Polymorphic forms of
a compound can be distinguished in a laboratory by X-ray
diffraction spectroscopy and by other methods such as, infrared
spectrometry. For a general review of 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.
[0141] As used herein, "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. The term
"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.
[0142] The language "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.
[0143] The language "therapeutically 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. In one
embodiment, the therapeutic benefit is wounding or killing a
bacterium, or in prolonging the survivability of a subject with
such a bowel or skin disorder. In another embodiment, 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.
[0144] 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)).
[0145] In respect to possible adverse events coupled to the
therapeutic use of rifaximin, the induction of bacterial resistance
to the antibiotics is of particular relevance.
[0146] From this point of view, 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 .mu.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)).
[0147] Forms, formulations and compositions of rifaximin have been
found to have differing in vivo bioavailability properties. Thus,
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.sub.max values from about 0.0 ng/ml to 5.0 .mu.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. For example, in the case of invasive bacteria, 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.
[0148] For XRPD analysis, accuracy and precision associated with
third party measurements on independently prepared samples on
different instruments may lead to variability which is greater than
.+-.0.1.degree. 2.theta.. For d-space listings, the wavelength used
to calculate d-spacings was 1.541874 .ANG., a weighted average of
the Cu-K.alpha.1 and Cu-K.alpha.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.
Methods of Treatment
[0149] Provided herein are methods of treating, preventing, or
alleviating bowel related disorders comprising administering to a
subject in need thereof an effective amount of one or more of the
solid dispersion compositions of rifaximin. 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.
[0150] 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.
[0151] The identification of those subjects who are in need of
prophylactic treatment for bowel disorder is well within the
ability and knowledge of one skilled in the art. Certain of the
methods for identification of subjects which are at risk of
developing a bowel disorder which can be treated by the subject
method are appreciated in the medical arts, such as family history,
travel history and expected travel plans, the presence of risk
factors associated with the development of that disease state in
the subject. A clinician skilled in the art can readily identify
such candidate subjects, by the use of, for example, clinical
tests, physical examination and medical/family/travel history.
[0152] Topical skin infections and vaginal infections may also be
treated with the rifaximin compositions described herein. Thus,
described herein are methods of using 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. Provided herein are 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.
Pharmaceutical 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.
For example, 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.
These conditions may be caused by the Helicobacter pylori.
Pharmaceutical formulations known by those of skill in the art with
the benefit of this disclosure to be used for oral administration
of a drug may be used. Provided herein are methods of treating ear
infections with SD rifaximin compositions. Ear infections include
external ear infection, or a middle and inner ear infection. Also
provided herein are methods of using SD rifaximin compositions to
treat or prevent aspiration pneumonia and/or sepsis, including the
prevention of aspiration pneumonia and/or sepsis in patients
undergoing acid suppression or undergoing artificial enteral
feedings via a Gastrostomy/Jejunostomy or naso/oro gastric tubes;
prevention of aspiration pneumonia in patients with impairment of
mental status, for example, for any reason, for subjects undergoing
anesthesia or mechanical ventilation that are at high risk for
aspiration pneumonia. Provided herein are methods to treat or to
prevent periodontal conditions, including plaque, tooth decay and
gingivitis. Provided herein are methods of treating rosacea, which
is a chronic skin condition involving inflammation of the cheeks,
nose, chin, forehead, or eyelids.
Pharmaceutical Preparations
[0153] 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). In a further embodiment, 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.
[0154] For examples of the use of rifaximin to treat Travelers'
diarrhea, see Infante RM, Ericsson C D, Zhi-Dong J, Ke S, Steffen
R, Riopel L, Sack D A, DuPont, HL., Enteroaggregative Escherichia
coli Diarrhea in Travelers: Response to Rifaximin Therapy. Clinical
Gastroenterology and Hepatology. 2004; 2:135-138; and Steffen R, M.
D., Sack D A, M.D., Riopel L, PhD, Zhi-Dong J, Ph.D., Sturchler M,
M.D., Ericsson C D, M.D., Lowe B, M. Phil., Waiyaki P, Ph.D., White
M, Ph.D., DuPont H L, M. D. Therapy of Travelers' Diarrhea With
Rifaximin on Various Continents. The American Journal of
Gastroenterology. May 2003, Volume 98, Number 5, all of which are
incorporated herein by reference in their entirety. Examples of
treating hepatic encephalopathy with rifaximin see, for example, N.
Engl J Med. 2010_362_1071-1081.
[0155] 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. 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. For example, compositions may
be formulated for topical use, for example, ointments, pomades,
creams, gels and lotions.
[0156] In an embodiment, 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. The pharmaceutically-acceptable
formulations may contain microgranules comprising rifaximin as
described herein.
[0157] In certain embodiments, these pharmaceutical compositions
are suitable for topical or oral administration to a subject. In
other embodiments, as described in detail below, 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.
[0158] The phrase "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.
[0159] The phrase "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.
Some examples of 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 hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations.
[0160] Wetting agents, emulsifiers and lubricants, 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.
[0161] Examples of pharmaceutically-acceptable antioxidants
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.
[0162] 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. In
general, 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] Pharmaceutical 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. 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.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] Transdermal patches have the added advantage of providing
controlled delivery of a SD rifaximin composition(s) to the body.
Such 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.
[0173] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
the invention.
[0174] Pharmaceutical 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.
[0175] Examples of suitable aqueous and non-aqueous carriers which
may be employed in the pharmaceutical compositions 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. 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.
[0176] When the SD rifaximin composition(s) are 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.
[0177] Regardless of the route of administration selected, the SD
rifaximin composition(s) are formulated into
pharmaceutically-acceptable dosage forms by methods known to those
of skill in the art.
[0178] 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.
[0179] A preferred dose of the SD rifaximin composition disclosed
herein is the maximum that a subject can tolerate without
developing serious side effects. Preferably, 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.
[0180] In combination therapy treatment, 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. In one embodiment in which another therapeutic agent is
administered to an animal, the effective amount of the rifaximin SD
composition is less than its effective amount in case the other
therapeutic agent is not administered. In another embodiment, 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) will be apparent to those skilled in the
art.
[0181] In various embodiments, the therapies (e.g., prophylactic or
therapeutic agents) 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. In preferred embodiments, two or more therapies are
administered within the same subject's visit.
[0182] In certain embodiments, one or more compounds and one or
more other therapies (e.g., prophylactic or therapeutic agents) 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.
[0183] In certain embodiments, 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.
In other embodiments, 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.
[0184] Certain indications may require longer treatment times. For
example, 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.
Compositions and Formulations
[0185] Rifaximin solid dispersions, pharmaceutical compositions
comprising SD rifaximin or microgranules comprising rifaxmin 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.RTM. L100-55). 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). In addition to rifaximin and
polymer, solid dispersions may also comprise surfactants, for
example, non-ionic, surfactant polyols.
[0186] 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.
[0187] 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.
[0188] 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.
[0189] Exemplary Spray Drying Process Parameters, include for
example: [0190] Spray Dryer--e.g., PSD 1; [0191] Single or
multi-fluid nozzle: e.g., a two Fluid Niro Nozzle; [0192] Nozzle
orifice--0.1-10 mm; [0193] Inlet gas temperature--75-150.+-.5 deg
C.; [0194] Process gas flow (mmH2O)--20-70, preferred 44; [0195]
Atomizing gas pressure--0.7-1 bar; [0196] Feed rate--2-7 kg/Hr;
[0197] Outlet temperature--30-70.+-.3 deg C.; [0198] Solution
temperature--20-50 deg C.; and [0199] Post spray drying vacuum dry
at 20-60 deg C., for between about 2 and 72 hrs.
Article of Manufacture
[0200] 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.
[0201] 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.
[0202] Packaged 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.
[0203] 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.
[0204] 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.
[0205] The present invention is further illustrated by the
following examples, which should not be construed as further
limiting. The contents of all figures and all references, patents
and published patent applications cited throughout this
application, as well as the Figures, are expressly incorporated
herein by reference in their entirety.
EXAMPLES
[0206] The chemical structure of Rifaximin is shown below in FIG.
1.
Example 1. Solid Dispersions of Rifaximin
[0207] Various polymers were formulated with rifaximin into solids
prepared by methanol and spray drying at small scale (.about.1 g).
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.RTM. L100-55) were used.
Solids have compositions of 25:75, 50:50 and 75:25
(Rifaximin/polymer, by weight).
[0208] Samples generated were observed under polarized light
microscope after preparation and were characterized by XRPD. The
results are included in Table 1 through Table 5. Birefringence with
extinction (B/E) was not observed for any of the samples,
indicating solids without crystalline order were obtained. No sharp
peaks were evident by visual inspection of XRPD patterns of these
samples, consistent with non-crystalline materials, as shown in
FIG. 2 (with PVP K-90), FIG. 7 (with HPMC-P), FIG. 12 (with HMPC-AS
HG), FIG. 12 (with HMPC-AS MG), and FIG. 17 (with Eudragit
L100-55).
[0209] Materials were characterized by mDSC where the appearance of
a single glass transition temperature (Tg), provides support for a
non-crystalline fully miscible dispersion. All the dispersions
prepared with PVP K-90 display a single apparent Tg at
approximately 185.degree. C. (FIG. 3, 25:75 w/w), 193.degree. C.
(FIG. 4, 50:50 w/w), and 197.degree. C. (FIG. 5, 75:25)
respectively. The change in heat capacity (.DELTA.Cp) at Tg is
approximately 0.3 J/g.degree. C. for each dispersion. A
non-reversible endotherm, which is likely due to the residual
solvent in the materials, was observed in each of Rifaximin/PVP
K-90 dispersions centered at approximately 78.degree. C.,
59.degree. C. and 61.degree. C.
[0210] From FIG. 6, Tg of Rifaximin/PVP K-90 dispersions increases
with the increased Rifaximin concentration, which is due to the
higher Tg of Rifaximin (199.degree. C.) than PVP K-90 (174.degree.
C.). Evidence of a single Tg may suggest that the components of the
dispersion are intimately mixed, or miscible.
[0211] 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.degree. C. (FIG. 8, 25:75 w/w), 161.degree. C. (FIG. 9, 50:50
w/w) and 174.degree. C. (FIG. 10, 75:25 w/w) respectively, with
.DELTA.Cp at Tg approximately 0.4 J/g.degree. C.
[0212] With HPMC-AS HG, dispersions display Tg at 137.degree. C.
(FIG. 13, 25:75 w/w), 154.degree. C. (FIG. 14, 50:50 w/w) and
177.degree. C. (FIG. 15, 75:25 w/w) respectively; .DELTA.Cp at Tg
is approximately 0.4 or 0.3 J/g.degree. C.
[0213] With HPMC-AS MG, dispersions display Tg at 140.degree. C.
(FIG. 18, 25:75 w/w), 159.degree. C. (FIG. 19, 50:50 w/w) and
177.degree. C. (FIG. 10, 75:25 w/w) respectively; .DELTA.Cp at Tg
is approximately 0.4 or 0.3 J/g.degree. C.
[0214] Dispersions prepared with Eudragit L100-55 exhibit Tg at
141.degree. C. with .DELTA.Cp approximately 0.5 J/g.degree. C.
(FIG. 23, 25:75 w/w), 159.degree. C. with .DELTA.Cp approximately
0.3 J/g.degree. C. (FIG. 24, 50:50 w/w), and 176.degree. C. with
.DELTA.Cp at Tg approximately 0.2 J/g.degree. C. (FIG. 25, 75:25
w/w) respectively.
[0215] Similarly, as shown in FIG. 11 (with HPMC-P), FIG. 16 (with
HPMC-AS HG), FIG. 21 (with HPMC-AS MG, and FIG. 26 (with Eudragit
L100-55), Tg of material in each set of Rifaximin/polymer
dispersions increases with the increased Rifaximin concentration
due to the higher Tg of Rifaximin.
Physical Stability Assessment
[0216] An assessment of physical stability for rifaximin/polymer
dispersions was conducted under stress conditions of aqueous
solutions at different biologically relevant conditions, including
0.1N HCl solution at 37.degree. C. and pH 6.5 FASSIF buffer at
37.degree. C., elevated temperature/relative humidity (40.degree.
C./75% RH), and elevated temperature/dry (60.degree. C.). The x-ray
amorphous rifaximin--only sample prepared from methanol by spray
drying was also stressed under the same conditions for
comparison.
Stress in 0.1N HCl Solution at 37.degree. C.
[0217] For the assessment of physical stability for samples in a
0.1N HCl solution maintained at 37.degree. C., observations were
made and microscopy images were acquired using polarized light at
different time points including 0, 6 and 24 hrs, as summarized in
Table 6. Based on the absence of birefringent particles when
samples were observed by PLM, dispersions prepared with HPMC-AS HG
and HPMC-AS MG display the highest physical stability under this
particular stress condition. The results of this study for each of
samples are discussed below.
[0218] X-ray amorphous Rifaximin stressed in 0.1N HCl solution at
37.degree. C. at 0, 6, and 24 hrs showed evidence of
birefringence/extinctions was observed at 6 hrs, indicating the
occurrence of devitrification of the material.
[0219] Samples at compositions of 25:75 and 50:50 (w/w)
crystallized at 6 hrs; sample at 75:25 (w/w) composition
crystallized within 24 hrs while no evidence of crystallization was
observed at 6 hrs or earlier. The decreased stability of
Rifaximin/PVP K-90 dispersions in 0.1N HCl solution with increased
PVP K-90 concentration may due to the high solubility of PVP K-90
in the solution.
[0220] Irregular aggregates without birefringence/extinctions were
observed for dispersion prepared with HPMC-P at t=0 hr, the initial
time point when 0.1N HCl solution was just added into solids. After
24 hrs, samples at compositions of 25:75 and 50:50 (w/w) remained
as non-birefringent aggregates, indicating no occurrence of
devitrification under the conditions examined. Evidence of
crystallization was observed for sample of 75:25 (w/w) composition
at 6 hrs. No birefringence/extinctions were observed for all of
dispersions prepared with HPMC-AS HG and HPMC-AS MG after 24 hrs,
suggesting these samples are resistant to devitrification upon
exposure to 0.1N HCl solution for 24 hrs.
[0221] For dispersions prepared with Eudragit L100-55, upon
exposure to 0.1N HCl solution for 24 hrs, birefringent particles
with extinctions were observed only in the sample at 50:50 (w/w)
composition. Considered that no evidence of crystallization was
observed for dispersions of compositions at 25:75 and 75:25 (w/w),
it is unknown whether such birefringence was caused by some foreign
materials or by crystalline solids indicating the occurrence of
devitrification.
Stress in pH 6.5 FASSIF Buffer at 37.degree. C.
[0222] An assessment of physical stability of dispersions prepared
was also performed in pH 6.5 FASSIF buffer maintained at 37.degree.
C. X-ray amorphous Rifaximin material was also stressed under same
condition for comparison. PLM observations indicated that
dispersions prepared from HPMC-AS HG and HPMC-AS MG display the
highest physical stability under this stress condition. X-ray
amorphous rifaximin-only material crystallized within 6 hrs, so did
all rifaximin/PVP K-90 dispersions. For dispersions prepared with
HPMC-P, birefringent particles with extinctions were observed in
samples at 50:50 and 75:25 (w/w) compositions within 6 hrs,
indicating the occurrence of devitrification in materials. No
evidence of any birefringence/extinctions was observed in 25:75
(w/w) rifaximin/HPMC-P dispersion material after 24 hrs. No
birefringence/extinctions were observed for all of dispersions
prepared with HPMC-AS HG and HPMC-AS MG after 24 hrs, suggesting
these samples are resistant to devitrification upon exposure to pH
6.5 FASSIF buffer for 24 hrs. Rifaximin/Eudragit L100-55
dispersions at 50:50 and 75:25 (w/w) compositions crystallized with
6 hrs while no evidence of crystallization was observed in the
sample at 25:75 (w/w) composition after 24 hrs.
Stress at 40.degree. C./75% RH Condition
[0223] 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.degree. C./75% RH
condition for 7 days.
[0224] 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.degree. C./75% RH for 7 days. All
of samples display a single apparent Tg at approximately
148.degree. C. (FIG. 27, 25:75 (w/w) HPMC-P), 177.degree. C. (FIG.
28, 75:25 (w/w) HPMC-AS HG) 152.degree. C. (FIG. 29, 75:25 (w/w)
HPMC-AS MG) and 140.degree. C. (FIG. 30, 25:75 (w/w) Eudragit
L100-55) respectively, indicating the components of each dispersion
remained intimately miscible after stress. Although crimped with
manual pin-hole DSC pan was used, the release of moisture from
sample upon heating can still be observed from non-reversible heat
flow signals.
Stress at 60.degree. C./Dry Condition
[0225] All the dispersions and x-ray amorphous rifaximin-only
material were also stressed at 60.degree. C./dry condition for 7
days and 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 this condition for 7
days.
Rifaximin Solid Dispersions by Spray Drying
[0226] Based on the experimental results from screen, 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).
Characterization of 50:50 (w/w) Rifaximin/HPMC-AS MG Dispersion
[0227] Characterization and results for the 50% API loading HPMC-AS
MG are summarized in Table 10. The sample was x-ray amorphous based
on high resolution XRPD. A single Tg at approximately 154.degree.
C. was observed from the apparent step change in the reversing heat
flow signal in mDSC with the change of heat capacity 0.4 J/g
.degree. C. A non-reversible endotherm was observed at
approximately 39.degree. C. which is likely due to the residual
solvent in the materials (FIG. 32). TG-IR analysis was carried out
in order to determine volatile content on heating. TGA data for
this material is shown in FIG. 34. There was a 0.5% weight loss up
to .about.100.degree. C. A Gram-Schmidt plot corresponding to the
overall IR intensity associated with volatiles released by solids
upon heating at 20.degree. C./min is shown in FIG. 33. There was a
dramatic increase of intensity of released volatiles after .about.8
minutes, with a maximum at .about.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.
Characterization of 25:75 (w/w) Rifaximin/HPMC-P Dispersion
[0228] Characterization and results for the 25% API loading
dispersion of HPMC-P are summarized in Table 11. Solids were x-ray
amorphous based on high resolution XRPD (FIG. 36). By mDSC, there
is a single Tg at approximately 152.degree. C. from the apparent
step change in the reversing heat flow signal. The change of heat
capacity is 0.4 J/g .degree. C. (FIG. 37). A non-reversible
endotherm, which is likely due to the residual solvent in the
materials, was observed at approximately 46.degree. C. Volatiles
generated on heating were analyzed by TG-IR. The total weight loss
of sample was approximately 1.5 wt % to 100.degree. C. and the
dramatic change in the slope occurs at approximately 178.degree. C.
(FIG. 38). The Gram-Schmidt plot (FIG. 39) shows a small increase
of intensity upon heating after .about.2 minutes, followed by
negligible change of intensity until .about.9 minutes. Then
dramatic change of intensity can be observed with a maximum at
.about.11 minutes, followed by a final increase of intensity above
.about.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 .about.9 minutes.
Dispersions Miscibility Study by Multivariate Mixture Analysis
[0229] For Rifaximin/HPMC-AS MG dispersions prepared by spray
drying, a multivariate mixture analysis was performed using the
XRPD data to examine the physical state of the components and
inspect for evidence of miscibility. The analysis was done with
MATLAB (v7.6.0) and Unscrambler (v 9.8) and it was not performed
under cGMP guidelines. XRPD patterns of all the samples were
truncated with their baseline corrected, and unit area normalized
before analysis. The pre-possessed XRPD patterns are shown in FIG.
41.
[0230] In the analysis, Rifaximin and HPMC-AS MG were assumed to be
separated phases (no miscibility) and the compositions of Rifaximin
and HPMC-AS MG in each sample were estimated based on this
assumption. As shown in FIG. 42, the estimated ratios of Rifaximin
to HPMC-AS MG based on pure separated phases did not agree with
samples actual compositions, especially for the samples with high
compositions of HPMC-AS MG (low Rifaximin loading). Also, the
calculated XRPD patterns for Rifaximin and HMPC-AS MG based on the
assumption of separated phases (FIG. 43) compared to actual
experimental XRPD patterns for Rifaximin (FIG. 44) and HPMC-AS MG
(FIG. 45) were generated. Although the calculated Rifaximin pattern
is similar to its experimental pattern, the calculated HMPC-AS MG
pattern is quite different from its experimental pattern. Both
results suggest that Rifaximin and HPMC-AS MG are not separated
phases but miscible in the dispersions. The differences in the
estimated and actual compositions are likely due to the interaction
between Rifaximin and HPMC-AS MG.
TABLE-US-00001 TABLE 1 Solid Dispersion Attempts for Rifaximin/PVP
K-90 by Spray Drying Description (a, b) Habit/Description Analysis
Result (c) (25:75) solids orange; XRPD x-ray amorph. PVP K-90
aggregates, irregular, mDSC 185.degree. C. (T.sub.g, no B/E
midpoint); 0.3 J/g .degree. C. (.DELTA.C.sub.p) (50:50) solids
orange; XRPD x-ray amorph. PVP K-90 aggregates, irregular, mDSC
193.degree. C. (T.sub.g, no B/E midpoint); 0.3 J/g .degree. C.
(.DELTA.C.sub.p) (75:25) solids orange; XRPD x-ray amorph. PVP K-90
aggregates, irregular, mDSC 197.degree. C. (T.sub.g, no B/E
midpoint); 0.3 J/g .degree. C. (.DELTA.C.sub.p) (a): approximate
ratio of Rifaximin to polymer, by weight; (b): samples stored in
freezer over desiccant after prepared.
TABLE-US-00002 TABLE 2 Solid Dispersion Attempts for
Rifaximin/HPMC-P by Spray Drying Description (a, b)
Habit/Description Analysis Result (c) (25:75) solids light orange;
XRPD x-ray amorph. HPMC-P aggregates, irregular, mDSC 153.degree.
C. (T.sub.g, midpoint); no B/E 0.4 J/g .degree. C. (.DELTA.C.sub.p)
(50:50) solids orange; XRPD x-ray amorph. HPMC-P aggregates,
irregular, mDSC 161.degree. C. (T.sub.g, midpoint); no B/E 0.4 J/g
.degree. C. (.DELTA.C.sub.p) (75:25) solids orange; XRPD x-ray
amorph. HPMC-P aggregates, irregular, mDSC 174.degree. C. (T.sub.g,
midpoint); no B/E 0.4 J/g .degree. C. (.DELTA.C.sub.p) (a):
approximate ratio of Rifaximin to polymer, by weight; (b): samples
stored in freezer over desiccant after prepared.
TABLE-US-00003 TABLE 3 Solid Dispersion Attempts for
Rifaximin/HPMC-AS HG by Spray Drying Description (a, b)
Habit/Description Analysis Result (c) (25:75) solids light orange;
XRPD x-ray amorph. HPMC-AS HG aggregates, irregular, mDSC
137.degree. C. (T.sub.g, no B/E midpoint); 0.4 J/g .degree. C.
(.DELTA.C.sub.p) (50:50) solids orange; XRPD x-ray amorph. HPMC-AS
HG aggregates, irregular, mDSC 154.degree. C. (T.sub.g, no B/E
midpoint); 0.4 J/g .degree. C. (.DELTA.C.sub.p) (75:25) solids
orange; XRPD x-ray amorph. HPMC-AS HG aggregates, irregular, mDSC
177.degree. C. (T.sub.g, no B/E midpoint); 0.3 J/g .degree. C.
(.DELTA.C.sub.p) (a): approximate ratio of Rifaximin to polymer, by
weight; (b): samples stored in freezer over desiccant after
prepared.
TABLE-US-00004 TABLE 4 Solid Dispersion Attempts for
Rifaximin/HPMC-AS MG by Spray Drying Description (a, b)
Habit/Description Analysis Result (c) (25:75) solids light orange;
XRPD x-ray amorph. HPMC-AS MG aggregates, mDSC 140.degree. C.
(T.sub.g, midpoint); irregular, no B/E 0.4 J/g .degree. C.
(.DELTA.C.sub.p) (50:50) solids orange; XRPD x-ray amorph. HPMC-AS
MG aggregates, mDSC 159.degree. C. (T.sub.g, midpoint); irregular,
no B/E 0.4 J/g .degree. C. (.DELTA.C.sub.p) (75:25) solids orange;
XRPD x-ray amorph. HPMC-AS MG aggregates, mDSC 177.degree. C.
(T.sub.g, midpoint); irregular, no B/E 0.3 J/g .degree. C.
(.DELTA.C.sub.p) (a): approximate ratio of Rifaximin to polymer, by
weight; (b): samples stored in freezer over desiccant after
prepared.
TABLE-US-00005 TABLE 5 Solid Dispersion Attempts for
Rifaximin/Eudragit L100-55 by Spray Drying Description (a, b)
Habit/Description Analysis Result (c) (25:75) solids light orange,
XRPD x-ray amorph. Eudragit L100-55 aggregates, mDSC 141.degree. C.
(T.sub.g, irregular, no B/E midpoint); 0.5 J/g .degree. C.
(.DELTA.C.sub.p) (50:50) solids orange; XRPD x-ray amorph. Eudragit
L100-55 aggregates, mDSC 159.degree. C. (T.sub.g, irregular, no B/E
midpoint); 0.3 J/g .degree. C. (.DELTA.C.sub.p) (75:25) solids
orange; XRPD x-ray amorph. Eudragit L100-55 aggregates, mDSC
176.degree. C. (T.sub.g, irregular, no B/E midpoint); 0.2 J/g
.degree. C. (.DELTA.C.sub.p) (a): approximate ratio of Rifaximin to
polymer, by weight; (b): samples stored in freezer over desiccant
after prepared.
TABLE-US-00006 TABLE 6 Physical Stability Assessment in 0.1N HCl at
37.degree. C. for Rifaximin and Rifaximin Dispersions Prepared in
Methanol by Spray Drying Description Time (a) (b) Habit/Description
Analysis Results (100:0) 0 -- PLM agg., irr., no B/E Rifaximin-
agg., irr., no B/E only 6 hrs orange solids, no PLM agg., no B/E +
a liquid left few B/E particles clear view of B/E particles 24 hrs
orange solids, PLM agg., no B/E + a solution cloudy few B/E
particles (25:75) 0 -- PLM agg., irr., no B/E PVP K-90 agg., irr.,
no B/E 6 hrs orange solids, PLM agg., no B/E + solution slightly
B/E particles yellow clear view of B/E particles 24 hrs orange
solids, PLM agg., no B/E + solution slightly B/E particles yellow
(50:50) 0 -- PLM agg., irr., no B/E PVP K-90 agg., irr., no B/E 6
hrs orange solids, PLM agg., no B/E + a solution slightly few B/E
particles yellow clear view of B/E particles 24 hrs orange solids,
PLM majority agg., small amount of no B/E + liquid left a few B/E
particles clear view of B/E particles (75:25) 0 -- PLM agg., irr.,
no B/E PVP K-90 agg., irr., no B/E 6 hrs orange solids, PLM agg.,
no B/E solution slightly agg., no B/E yellow 24 hrs orange solids,
PLM agg., no B/E small amount of a few B/E particles liquid left in
view field (25:75) 0 -- PLM agg., irr., no B/E HPMC-P agg., irr.,
no B/E 6 hrs light orange solids, PLM agg., no B/E liquid turbid
agg., no B/E 24 hrs orange solids, PLM agg., no B/E liquid turbid
agg., no B/E (50:50) 0 -- PLM agg., irr., no B/E HPMC-P agg., irr.,
no B/E 6 hrs orange solids, PLM agg., no B/E liquid turbid agg., no
B/E 24 hrs orange solids, PLM agg., no B/E solution cloudy agg., no
B/E (75:25) 0 -- PLM agg., irr., no B/E HPMC-P agg., irr., no B/E 6
hrs orange solids, PLM agg., no liquid turbid B/E + some B/E
particles clear view of B/E particles 24 hrs orange solids, PLM B/E
particles small amount of observed liquid left clear view of B/E
particles (25:75) 0 -- PLM agg., irr., no B/E HPMC-AS agg., irr.,
no B/E HG 6 hrs light orange PLM no B/E observed solids in no B/E
observed cloudy liquid 24 hrs orange solids in PLM no B/E observed
cloudy solution no B/E observed (50:50) 0 -- PLM agg., irr., no B/E
HPMC-AS agg., irr., no B/E HG 6 hrs orange solids, PLM no B/E
observed liquid cloudy no B/E observed 24 hrs orange solids in PLM
no B/E observed cloudy solution (75:25) 0 -- PLM agg., irr., no B/E
HPMC-AS agg., irr., no B/E HG 6 hrs orange solids, PLM no B/E
observed liquid turbid no B/E observed 24 hrs orange solids + PLM
agg., no B/E cloudy solution agg., no B/E (25:75) 0 -- PLM agg.,
irr., no B/E HPMC-AS agg., irr., no B/E MG 6 hrs light orange PLM
no B/E observed solids in cloudy liquid 24 hrs orange solids in PLM
majority no B/E, a cloudy liquid few B/E particles B/E particles
seems fiber-like, may due to foreign materials (50:50) 0 -- PLM
agg., irr., no B/E HPMC-AS agg., irr., no B/E MG 6 hrs orange
solids, PLM agg., no B/E + liquid turbid a few B/E particles seems
due to foreign material clear view of B/E particles 24 hrs orange
solids in PLM no B/E observed cloudy solution no B/E observed
(75:25) 0 -- PLM agg., irr., no B/E HPMC-AS agg., irr., no B/E MG 6
hrs orange solids, PLM no B/E observed liquid turbid no B/E
observed 24 hrs orange solids in PLM no B/E observed cloudy liquid
agg., no B/E (25:75) 0 -- PLM agg., irr., no B/E Eudragit agg.,
irr., no B/E L100-55 6 hrs light orange PLM no B/E observed solids
in cloudy liquid 24 hrs orange solids in PLM no B/E observed cloudy
solution (50:50) 0 -- PLM agg., irr., no B/E Eudragit agg., irr.,
no B/E L100-55 6 hrs orange solids in PLM no B/E observed cloudy
liquid except 2 particles 24 hrs orange solids in PLM majority no
B/E, a cloudy solurion few B/E particles in center clear view of
B/E particles (75:25) 0 -- PLM agg., irr., no B/E Eudragit agg.,
irr., no B/E L100-55 6 hrs orange solids, PLM agg., no B/E liquid
turbid agg., no B/E 24 hrs orange solids in PLM agg., no B/E cloudy
liquid (a): approximate ratio of Rifaximin to polymer, by weight.
(b): time is cumulative and approximate; 100 .mu.L of 0.1N HCl
solution added into samples at t = 0. (c): 100 .mu.L of 0.1N HCl
solution added into the sample after PLM analysis at 6 hrs.
TABLE-US-00007 TABLE 7 Physical Stability Assessment at 40.degree.
C./75% RH/7 d Condition for Rifaximin and Rifaximin Dispersions
Prepared in Methanol by Spray Drying Description (a)
Habit/Description Analysis Results (100:0) orange solids, dry PLM
agg., irr., no B/E Rifaximin-only (25:75) dark yellow solids, PLM
agg., irr., no B/E PVP K-90 dry (50:50) orange solids, dry PLM
agg., irr., no B/E PVP K-90 (75:25) orange solids, dry PLM agg.,
irr., no B/E PVP K-90 (25:75) light orange solids, PLM agg., irr.,
no B/E HPMC-P dry mDSC 148.degree. C. (T.sub.g, midpoint); 0.3 J/g
.degree. C. (.DELTA.C.sub.p) (50:50) orange solids, dry PLM agg.,
irr., no B/E HPMC-P (75:25) orange solids, dry PLM agg., irr., no
B/E HPMC-P (25:75) light orange solids, PLM agg., irr., no B/E
HPMC-AS HG dry (50:50) orange solids, dry PLM agg., irr., no B/E
HPMC-AS HG (75:25) orange solids, dry PLM agg., irr., no B/E
HPMC-AS HG mDSC 177.degree. C. (T.sub.g, midpoint); 0.5 J/g
.degree. C. (.DELTA.C.sub.p) (25:75) light orange solids, PLM agg.,
irr., no B/E HPMC-AS MG dry (50:50) orange solids, dry PLM agg.,
irr., no B/E HPMC-AS MG (75:25) orange solids, dry PLM agg., irr.,
no B/E HPMC-AS MG mDSC 152.degree. C. (T.sub.g, midpoint) (25:75)
light orange solids, PLM agg., irr., no B/E Eudragit dry mDSC
140.degree. C. (T.sub.g, midpoint); L100-55 0.5 J/g .degree. C.
(.DELTA.C.sub.p) (50:50) orange solids, dry PLM agg., irr., no B/E
Eudragit L100-55 (75:25) orange solids, dry PLM agg., irr., no B/E
Eudragit L100-55 (a): approximate ratio of Rifaximin to polymer, by
weight. (b): analysis treated as non-cGMP.
TABLE-US-00008 TABLE 8 Physical Stability Assessment at 60.degree.
C./Dry/7 d Condition for Rifaximin and Rifaximin Dispersions
Prepared in Methanol by Spray Drying Description (a)
Habit/Description Analysis Results (100:0) orange solids PLM agg.,
irr., no B/E Rifaximin-only (25:75) orange solids PLM agg., irr.,
no B/E PVP K-90 (50:50) orange solids PLM agg., irr., no B/E PVP
K-90 (75:25) orange solids PLM agg., irr., no B/E PVP K-90 (25:75)
light orange solids PLM agg., irr., no B/E HPMC-P (50:50) orange
solids PLM agg., irr., no B/E HPMC-P (75:25) orange solids PLM
agg., irr., no B/E HPMC-P (25:75) light orange solids PLM agg.,
irr., no B/E HPMC-AS HG (50:50) orange solids PLM agg., irr., no
B/E HPMC-AS HG (75:25) orange solids PLM agg., irr., no B/E HPMC-AS
HG (25:75) light orange solids PLM agg., irr., no B/E HPMC-AS MG
(50:50) orange solids PLM agg., irr., no B/E HPMC-AS MG (75:25)
orange solids PLM agg., irr., no B/E HPMC-AS MG (25:75) light
orange solids PLM agg., irr., no B/E Eudragit L100-55 (50:50)
orange solids PLM agg., irr., no B/E Eudragit L100-55 (75:25)
orange solids PLM agg., irr., no B/E Eudragit L100-55 (a):
approximate ratio of Rifaximin to polymer, by weight.
TABLE-US-00009 TABLE 9 Parameters for Rifaximin Solid Dispersions
by Spray Drying Inlet temp. Aspirator Pump Inlet temp. Outlet temp.
Spray rate (b) Description (a) (set, .degree. C.) % % (measured,
.degree. C.) (measured, .degree. C.) mL/min (50:50) 120 95 40-30
120-119 60-45 9.6 HPMC-AS MG, ~10 g scale (25:75) 120 95 45-30
120-119 55-43 9.7 HPMC-P, ~10 g scale (a): approximate ratio of
Rifaximin to polymer, by weight. (b): flow rates are estimated at
30% pump.
TABLE-US-00010 TABLE 10 Characterizations of 50:50 (w/w)
Rifaximin/HPMC-AS MG Dispersion by Spray Drying Analysis Results
XRPD x-ray amorphous mDSC 154.degree. C. (midpoint, T.sub.g) 0.4
J/g .degree. C. (.DELTA.Cp) TG-IR 0.5 wt % (loss up to 100.degree.
C.) 199.degree. C. (onset, apparent decomp.) water, methanol and
unknown volatiles
TABLE-US-00011 TABLE 11 Characterizations of 25:75 (w/w)
Rifaximin/HPMC-P Dispersion by Spray Drying Analysis Results XRPD
x-ray amorphous mDSC 152.degree. C. (midpoint, T.sub.g) 0.4 J/g
.degree. C. (.DELTA.Cp) TG-IR 1.5 wt % (loss up to 100.degree. C.)
178.degree. C. (onset, apparent decomp.) water and methanol
TABLE-US-00012 TABLE 12 Sample Information of Rifaximin Dispersions
for Dissolution Test in pH 6.52 FASSIF Buffer at 37.degree. C.
Dissolution Solids Weight Volume of Description (a) Sample ID
Vessel No (mg) Buffer (mL) (50:50) 4042-97-01 1 122.1 300 HPMC-AS
MG 2 120.5 3 121.4 (25:75) 4103-01-01 4 242.5 300 HPMC-P 5 239.2 6
242.4 (a): approximate ratio of Rifaximin to polymer, by
weight.
TABLE-US-00013 TABLE 13 Rifaximin Concentrations of 50:50 (w/w)
Rifaximin/HPMC-AS MG Dispersion in pH 6.52 FASSIF Buffer at
37.degree. C. Dissolution Time Dilution Absorbance Concentration
Vessel No (mm.) (c) (d) (.mu.g/mL) 1 5 -- 0.0159 0.34 10 -- 0.0346
2.53 15 -- 0.0569 5.13 30 -- 0.09655 9.75 60 -- 0.1626 17.46 90 --
0.2216 24.35 120 -- 0.25625 28.39 1440 4 0.4093 184.99 2 5 2
0.02895 3.73 10 -- 0.0304 2.04 15 -- 0.04655 3.92 30 -- 0.104 10.62
60 -- 0.17755 19.21 90 -- 0.248 27.43 120 -- 0.3065 34.25 1440 4
0.3944 178.04 3 5 -- 0.0107 -0.26 10 -- 0.02555 1.47 15 -- 0.03975
3.13 30 -- 0.08735 8.68 60 -- 0.1766 19.10 90 -- 0.25815 28.61 120
-- 0.32055 35.89 1440 4 0.4202 190.08 (c): certain samples were
diluted before analyzed to avoid the possibility of falling outside
the linearity range of the instrument. (d): absorbance data less
than 0.05 is below instrument detection limit and therefore
concentration calculated from such absorbance is an approximate
value.
TABLE-US-00014 TABL 14 Rifaximin Concentrations of 25:75 (w/w)
Rifaximin/HPMC-P Dispersion in pH 6.52 FASSIF Buffer at 37.degree.
C. Dissolution Time Dilution Absorbance Concentration Vessel No
(mm.) (d) (e) (.mu.g/mL) 4 5 -- 0.01555 0.30 10 -- 0.03395 2.45 15
-- 0.0528 4.65 30 -- 0.12235 12.77 60 -- 0.2643 29.33 90 -- 0.37355
42.08 120 -- 0.455 51.58 1440 4 0.39465 178.16 5 5 -- 0.0329 2.33
10 -- 0.06805 6.43 15 -- 0.07905 7.71 30 -- 0.13745 14.53 60 --
0.242 26.73 90 -- 0.32595 36.52 120 -- 0.40555 45.81 1440 4 0.38525
173.77 6 5 -- 0.0155 0.30 10 -- 0.057 5.14 15 -- 0.09415 9.47 30 --
0.17145 18.49 60 -- 0.2724 30.27 90 -- 0.36815 41.45 120 -- 0.43155
48.84 1440 4 0.3838 173.09 (d): certain samples were diluted before
analyzed to avoid the possibility of falling outside the linearity
range of the instrument. (e): absorbance data less than 0.05 is
below instrument detection limit and therefore concentration
calculated from such absorbance is an approximate value.
TABLE-US-00015 TABLE 15 Averaged Concentrations of 50:50 (w/w)
Rifaximin/HPMC-AS MG Dispersions in pH 6.52 FASSIF Buffer at
37.degree. C. Con- Average Description Dissolution Time centration
Con- Standard (a) Vessel No (min.) (.mu.g/mL) centration Deviation
(50:50) 1 5 0.34 1.27.sup.b 2.154 HPMC-AS 2 3.73 MG 3 -0.26 1 10
2.53 2.01.sup.b 0.5284 2 2.04 3 1.47 1 15 5.13 4.06.sup.b 1.008 2
3.92 3 3.13 1 30 9.75 9.69 0.970 2 10.62 3 8.68 1 60 17.46 18.59
0.977 2 19.21 3 19.10 1 90 24.35 26.80 2.202 2 27.43 3 28.61 1 120
28.39 32.85 3.945 2 34.25 3 35.89 1 1440 184.99 184.37 6.0455 2
178.04 3 190.08 .sup.aapproximate ratio of Rifaximin to polymer, by
weight. .sup.babsorbance data less than 0.05 is below instrument
detection limit and therefore concentration calculated from such
absorbance is an approximate value.
TABLE-US-00016 TABLE 16 Averaged Concentrations of 25:75 (w/w)
Rifaximin/HPMC-P Dispersions in pH 6.52 FASSIF Buffer at 37.degree.
C. Con- Average Description Dissolution Time centration Con-
Standard (a) Vessel No (min.) (.mu.g/mL) centration Deviation
(25:75) 4 5 0.30 0.98.sup.b 1.171 HPMC-P 5 2.33 6 0.30 4 10 2.45
4.67.sup.b 2.030 5 6.43 6 5.14 4 15 4.65 7.28 2.442 5 7.71 6 9.47 4
30 12.77 15.26 2.935 5 14.53 6 18.49 4 60 29.33 28.78 1.840 5 26.73
6 30.27 4 90 42.08 40.02 3.041 5 36.52 6 41.45 4 120 51.58 48.75
2.886 5 45.81 6 48.84 4 1440 178.16 175.01 2.749 5 173.77 6 173.09
.sup.aapproximate ratio of Rifaximin to polymer, by weight.
.sup.babsorbance data less than 0.05 is below instrument detection
limit and therefore concentration calculated from such absorbance
is an approximate value.
TABLE-US-00017 TABLe 17 Analysis of Rifaximin Dispersions after
Dissolution Test in pH 6.52 FASSIF Buffer at 37.degree. C.
Description Dissolution (a) Vessel No Analysis Results (50:50) 1
PLM no B/E observed HPMC-AS MG change view field, no B/E 2 PLM no
B/E observed change view field, no B/E 3 PLM no B/E observed
majority no B/E, only 1 B/E particle in view field (25:75) 4 PLM
B/E flakes and blades HPMC-P 5 PLM no B/E material + B/E flakes 6
PLM no B/E material + B/E flakes & blades (a): approximate
ratio of Rifaximin to polymer, by weight.
ABBREVIATIONS
TABLE-US-00018 [0231] Type Abbreviation Full Name/Description
INSTRU- XRPD x-ray powder diffractometry MENTAL mDSC modulated
differential scanning calorimetry TG-IR thermogravimetric infrared
PLM polarized light microscopy UV ultraviolet spectroscopy POLYMER
HPMC-AS hydroxypropylmethyl cellulose acetate succinate HPMC-P
hydroxypropylmethyl cellulose phthalate Eudragit L100 anionic
polymers with methacrylic acid as a functional group, dissolution
at pH > 6.0 PVP K-90 polyvinylpyrrolidone, grade K-90 RESULTS
T.sub.g glass transition temperature .DELTA.C.sub.p heat of
capacity change amorph. amorphous agg. aggregates irr. irregular
decomp. decomposition B birefringence E extinction
Example 2. Ternary Dispersion of 50:50 (w/w) Rifaximin:HPMC-AS
MG
[0232] 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.degree. C./75% RH for 1 week and 3 week, and post-stress sample
at 40.degree. C./75% RH for 6 weeks and 12 weeks.
Characterization of Rifaximin Ternary Dispersion
[0233] Characterizations of the spray dried Rifaximin ternary
dispersion (50:50 (w/w) rifaximin:HPMC-AS MG with 5.9 wt % Pluronic
F-127) are described in Table 18.
TABLE-US-00019 TABLE 18 Characterizations of Combined Rifaximin
Ternary Dispersion Solids-Spray Drying Sample ID Analysis Results
(b) 4103- XRPD x-ray amorphous 74-01a mDSC 136.degree. C.
(midpoint, T.sub.g) 0.4 J/g .degree. C. (.DELTA.Cp) TG-IR 0.7 wt %
(loss up to 100.degree. C.) 202.degree. C. (onset, volatilization
and apparent decomp.) methanol and possible acetic acid IR-ATR
consistent with structure Raman consistent with structure SEM
agglomerates of collapsed spheres PLM irregularly-shaped equant
particles PSA d10 (.mu.m): 3.627, d50 (.mu.m): 8.233, d90 (.mu.m):
17.530 DVS 0.13 wt % (loss at 5% RH) 11.14 wt % (gain, 5-95% RH)
10.80 wt % (loss, 95-5% RH) 4074-89-01 XRPD x-ray amorphous (c)
(b): temperatures are round to the nearest degree; .DELTA.Cp is
rounded to one decimal places and wt % is rounded to one decimal
place.
[0234] A high resolution XRPD pattern was acquired and material is
x-ray amorphous (FIG. 46). By mDSC (FIG. 47), a single apparent
T.sub.g is observed from the step change in the reversing heat flow
signal at approximately 136.degree. C. with a heat capacity change
at T.sub.g of approximately 0.4 J/g.degree. C.
[0235] Thermogravimetric analysis coupled with infra-red
spectroscopy (TG-IR) was performed to analyze volatiles generated
upon heating. The total weight loss of sample was approximately 0.7
wt % to 100.degree. C. and the dramatic change in the slope occurs
at approximately 202.degree. C. (FIG. 48). The Gram-Schmidt plot
corresponds to the overall IR intensity associated with volatiles
released by a sample upon heating at 20.degree. C./min. By
Gram-Schmidt, a negligible increase of intensity upon heating is
observed before .about.7 minutes followed by a dramatic increase of
intensity with the maximum at .about.11.8 min. The waterfall plot
(data not shown) of this sample indicates volatile are released
upon heating after .about.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.
[0236] 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
.mu.m.
[0237] 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 .mu.m in
length with some agglomerates 20-50 .mu.m in length. Particle size
analysis (FIG. 52) indicates that 50% of particles have size less
than 8.233 .mu.m and 90% of particles have size less than 17.530
.mu.m. Data was acquired in 2% (w/v) Lecithin in Isopar G.
[0238] 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).
[0239] Physical Stability Assessment on Rifaximin Ternary
Dispersion
[0240] An assessment of physical stability of this rifaximin
ternary dispersion is currently in progress by exposing solids to
varied elevated temperature/relative humidity conditions, including
25.degree. C./60% RH, 40.degree. C./75% RH and 70.degree. C./75% RH
for extended period of time. At designated time interval, such as
at 1 week, 3 week, 6 week, and 12 weeks, selected samples were
removed from stress conditions for characterization.
[0241] Table 19 summarized characterization results for the samples
that stressed at 70.degree. C./75% RH condition 1 week and 3 weeks,
and the sample that stressed at 40.degree. C./75% RH condition 6
weeks.
TABLE-US-00020 TABLE 19 Physical Stability Evaluation on Rifaximin
Ternary Dispersion Habit/ Condition Time Description Analysis
Results (a) 70.degree. C./75% RH 1 week orange solids, XRPD x-ray
amorphous aggregates, no mDSC 134.degree. C. (midpoint, T.sub.g)
B/E 0.4 J/g .degree. C. (.DELTA.Cp) SEM agglomerates of collapsed
spheres KF 3.80% 70.degree. C./75% RH 3 weeks dark orange XRPD
x-ray amorphous solids, mDSC 134.degree. C. (midpoint, T.sub.g)
aggregates, no 0.4 J/g .degree. C. (.DELTA.Cp) B/E SEM agglomerates
of collapsed spheres KF 3.19% 40.degree. C./75% RH 6 weeks orange
solids, XRPD x-ray amorphous aggregates, no mDSC 133.degree. C.
(midpoint, T.sub.g) B/E 0.4 J/g .degree. C. (.DELTA.Cp) SEM
agglomerates of collapsed spheres KF 4.05% 40.degree. C./75% RH 12
weeks orange solids, XRPD x-ray amorphous aggregates, no mDSC
132.degree. C. (midpoint, T.sub.g) B/E 0.5 J/g .degree. C.
(.DELTA.Cp) SEM agglomerates of collapsed spheres KF 3.37% (a):
temperatures are round to the nearest degree; .DELTA.Cp is rounded
to one decimal places.
[0242] For a sample that was stressed at 70.degree. C./75% RH for 1
week, solids are still x-ray amorphous according to XRPD (FIG. 55).
A single T.sub.g at approximately 134.degree. C. was observed from
the apparent step change in the reversing heat flow signal in mDSC
with the change of heat capacity 0.4 J/g .degree. C., indicating
the components of each dispersion remained intimately miscible
after stress (FIG. 56). A non-reversible endotherm was observed at
approximately 54.degree. C. which is likely due to the residual
solvent from spray drying and moisture that materials absorbed
during stress, which is confirmed by KF analysis that sample
contains 3.80 wt % of water (KF analysis for Rifaximin ternary
dispersion after 70.degree. C./75% RH 1 week; 1.2855 g--R1=3.72 and
0.988 g--R1=3.87%). 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.
[0243] For the sample that was stressed at 70.degree. C./75% RH for
3 weeks, although the color of the material appeared to be darker
than the 1-week sample, characterization results for 3-week sample
are similar to that for 1-week sample. Solids are also x-ray
amorphous by XRPD (FIG. 55) and display a single T.sub.g at
approximately 134.degree. C. by mDSC (FIG. 57). KF analysis
indicates it contains 3.19 wt % of water (KF analysis for rifaximin
ternary dispersion after 70.degree. C./75% RH 3 weeks; 1.2254
g--R1=3.45 and 1.1313 g--R1=2.93). By SEM (data not shown), the
material has morphology similar to the as-prepared dispersion and
1-week stress sample, which is composed of agglomerates of
collapsed spheres and particles sizes of spheres are not
uniform.
[0244] For the sample that was stressed at 40.degree. C./75% RH for
6 weeks, solids are still x-ray amorphous according to XRPD (FIG.
55). It has a single T.sub.g at approximately 133.degree. C. by
mDSC with the change of heat capacity 0.4 J/g .degree. C. (FIG.
58). It contains 4.05 wt % of water by KF (KF analysis for
rifaximin ternary dispersion after 40.degree. C./75% RH 6 weeks;
1.0947 g--R1=3.47 and 1.2030--R1=4.63). By SEM (data not shown),
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.
[0245] For the sample that was stressed at 40.degree. C./75% RH for
12 weeks, solids are x-ray amorphous (FIG. 55) and display a single
T.sub.g at approximately 132.degree. C. with the change of heat
capacity 0.5 J/g .degree. C. (FIG. 59). It contains 3.37 wt % of
water by KF (KF analysis for Rifaximin ternary dispersion after
40.degree. C./75% RH 12 weeks; 1.3687 g--R1=3.06 and 1.1630
g--R1=3.67). SEM analysis (data not shown) indicates that 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.
Example 3. Rifaximin Solid Dispersion Composition and
Procedures
Rifaximin Ternary Dispersion Ingredients:
[0246] 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:
TABLE-US-00021 TABLE 20 Components of Rifaximin Solid Dispersion
Component mg/g Purpose Rifaximin 472 active pharmaceutical
ingredient Hydroxypropylmethyl 472 stabilizing agent cellulose
acetate succinate (HPMC-AS), Type MG Pluronic F-127 56 wetting
agent Methanol -- volatile; removed during process
Spray Drying Procedures:
[0247] Rifaximin ternary dispersions were prepared by spray drying
in both small scale (.about.1 g API) and large scale (.gtoreq.34 g
API in a single batch).
[0248] For the small-scale sample, rifaximin and then the methanol
were added to a flask. The mixture was stirred at ambient
temperature for .about.5 min to give a clear solution. HPMC-AS MG
and Pluronic F-127 were added in succession and the sample was
stirred for .about.1 hr. An orange solution was obtained.
[0249] For large-scale samples, a solution was prepared at
.about.40.degree. C. Rifaximin and then methanol were added to a
flask and the mixture was stirred at .about.40.degree. C. for
.about.5 min until clear. HPMC-AS MG, and then Pluronic F-127 were
added into the rifaximin solution under stirring at
.about.40.degree. C. The sample continued to stir for .about.1.5 hr
to 2 hr at this temperature. A dark red solution was obtained. The
sample was removed from the hot plate and left at ambient to
cool.
[0250] Experimental conditions to prepare Rifaximin ternary
solutions are summarized in Table 21 below:
TABLE-US-00022 TABLE 21 Experimental Conditions to Prepare
Rifaximin Ternary Solutions weight Concen- (API/HPMC AS tration
Solvent MG/Pluronic F127, g) Temperature (g/L) methanol, 100 mL
1.0535/1.0529/0.1249 ambient 22.3 methanol, 1000 mL
34.07/34.07/4.02 ~40.degree. C. 72.2 methanol, 1250 mL
50.34/50.32/5.94 ~40.degree. C. 85.3 methanol, 1250 mL
50.16/50.14/5.92 ~40.degree. C. 85 methanol, 1250 mL
50.05/50.06/5.91 ~40.degree. C. 85
[0251] During the spray drying process, both the small and large
scale rifaximin ternary solutions were kept at ambient temperature.
The pump % was decreased during the process in an attempt to
control outlet temperature above 40.degree. C. The operating
parameters used for processing are presented in Table 22 below.
TABLE-US-00023 TABLE 22 Operating Parameters Used For Processing
Rifaximin SD Inlet Spray rate temp. Aspirator Pump Inlet temp.
Outlet temp. (b) Description (a) (set, .degree. C.) % % (measured,
.degree. C.) (measured, .degree. C.) mL/min 50:50 120 95 35 120
60-55 10.4 Rifaximin:HPM 120 95 65-30 120-119 61-42 23 C-AS MG 120
95 50-30 120-119 67-43 16 5.9 wt % 120 95 50-30 120-119 65-43 16
Pluronic F-127 120 95 50-30 120-119 67-43 16 (a): 50:50 is
approximate ratio of Rifaximin to polymer, by weight; 5.9 wt %
Pluronic is weight fraction to 50:50 rifaximin:HPMC-AS MG
dispersion. (b): Flow rates are estimated. Flow rate for 4103-41-01
was measured at pump 35%; for 4103-56-01 was measured at pump 65%,
while for others were measured at pump 50%.
[0252] Solids recovered after spray drying were dried at 40.degree.
C. under vacuum for 24 hours and then stored at sub-ambient
temperatures over desiccant.
Spray Drying Process Parameters:
[0253] Spray Dryer--PSD 1 [0254] Two Fluid Niro Nozzle [0255]
Nozzle orifice--1 mm [0256] Inlet gas temperature--125.+-.5 deg C.
[0257] Process gas flow (mmH2O)--44 [0258] Atomizing gas
pressure--0.7-1 bar [0259] Feed rate--4.7 kg/Hr [0260] Outlet
temperature--55.+-.3 deg C. [0261] Solution temperature--36 deg C.
[0262] Post spray drying vacuum dry at 40 deg C. for 48 hrs
Example 4
[0263] Exemplary formulations for micronized, API, amorphous, solid
dispersion and micronized capsules are below in Table 23. These
capsules were used in the dog study of Example 5.
TABLE-US-00024 TABLE 23 Capsule Formulation composition (Solid
Dispersion (SD) Capsules) Micronized Amorphous Micronized Capsules
API Capsules Capsules SD Capsules Tablets Ingredients % g/dose %
g/dose % g/dose % g/dose % g/dose Rifaximin 95.5 2.2 47.2 2.2 51.7
2.2 42.47 2.2 50 2.2 Ac-di-sol 4.5 0.1 5 0.23 5 0.21 10.02 0.52 7.5
0.33 Mannitol 160C 47.8 2.23 43.3 1.84 Pluronic 188 5.04 0.26 HPMC
AS 42.47 2.2 Avicel 113 26 1.14 Avicel 112 15 0.66 Magnesium 1 0.04
Stearate Cab-o-sil 0.5 0.02 Avicel CL-611 Mannitol 160C Total 100
2.3 100 4.66 100 4.26 100 5.18 100 4.4
TABLE-US-00025 TABLE 24 Manufacture of rifaximin/HPMC-AS/Pluronic
275 mg Capsules % mg/ Theo. Actual Component Formula caps Qty (g)
Qty (g) Rifaximin 42.47 275 113.7 113.7 HPMC-AS 42.47 275 113.7
113.7 (type MG) Pluronic F-127 5.04 32.63 13.49 13.49 Sodium 10.02
64.87 26.82 26.82 Croscarmellose Hard Gelatin 1 N/A 300 300 Capsule
(size 000) Clear Total 100 647.5 267.7 g
Blending/Encapsulation Procedure:
[0264] To form the capsules 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.
[0265] 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).
[0266] 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. As shown in the FIGS. 61-63
rifaximin SD near 100% dissolution is achieved in 0.45% SDS and the
SD formulation dissolves more slowly than the amorphous
rifaximin.
Example 5. Pharmacokinetic (PK) Studies of Solid Dispersion in
Capsules
[0267] Presented herein are dog pharmacokinetics (PK) studies
comparing various forms of rifaximin. PK following administration
of rifaximin API in capsule, micronized API in capsule, nanocrystal
API in capsule (containing surfactant), amorphous in capsule, and
solid dispersion (SD) in capsule were tested.
[0268] In the SD dosage form, 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).
[0269] A brief study design: male beagle dogs (N=6, approximately
10 kg) received rifaximin 2200 mg in the dosage forms described
above as a single dose (capsules, 275 mg, 8 capsules administered
in rapid succession), in a cross-over design with one week washout
between phases. Blood was collected at timed intervals for 24 h
after dosage administration, and plasma was harvested for LC-MS/MS
analysis. The mean concentrations are shown in FIG. 60.
[0270] 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.
TABLE-US-00026 TABLE 25 PK Parameters of API, Amorphous and Solid
Dispersion to Dogs Half-life* Tmax Cmax AUClast AUCINF_obs AUC_0-24
ID h h ng/mL h*ng/mL h*ng/mL h*ng/mL 901_API 16.76 0.5 65.5 101 118
101 902_API 9.41 1 3.83 25 29 25 903_API 10.03 1 197 344 360 344
904_API 3.56 1 1.21 5 6 6 905_API 2.94 1 1.53 5 6 6 906_API 24 0.52
7 7 mean 6.98 1 44.93 81 104 82 SD [0.5-24] 78.75 134 150 134
901_amorph 5.38 1 536 1407 1421 1407 902_amorph 5.93 2 4100 12258
12762 12258 903_amorph 6.25 2 1050 3375 3523 3375 904_amorph 4.77 2
763 2291 2306 2291 905_amorph 7.72 1 1200 2041 2059 2041 906_amorph
5.63 2 704 2076 2090 2076 mean 5.88 2 1392.17 3908 4027 3908 SD
[1-2] 1348.24 4141 4334 4141 901_SD amorph 6.66 2 491 1354 1394
1354 902_SD amorph 2.04 2 6550 25140 25149 25140 903_SD amorph 2.8
4 2410 10490 10508 10490 904_SD amorph 2.24 1 1410 6343 6350 6343
905_SD amorph 3.97 2 2860 7885 7895 7885 906_SD amorph 4.89 2 1900
4532 4558 4532 mean 3.01 2 3026 10878 10892 10878 SD [1-4] 2043.58
8267 8264 8267 *geometric mean **median and range
[0271] API exposures were low, in keeping with what has been
previously observed for rifaximin. In contrast, mean exposures
(AUCinf) following amorphous and SD rifaximin administration were
substantially higher, with .about.40- and .about.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.
Example 6. Human Clinical Studies
[0272] Rifaximin SDD with 10% CS formulation was used in human
clinical studies. FIG. 65A-B show 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. As shown in FIG. 65A-B, rifaximin SDD 100%, or
near 100%, dissolution is achieved in 0.2% SLS, pH 4.5, 5.5 and
7.4. FIG. 66A-B show that release can be delayed up to two hours
and extended up to three hours.
Example 7. Effects of Media pH on Dissolution
[0273] FIG. 67A-B, FIG. 68A-B, FIG. 69A-B, and FIG. 70A-B 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. FIG. 67A-B and
FIG. 68A-B 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. FIG. 69A-B and FIG. 70A-B 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.
71A-B show CS release mechanism.
Example 8
[0274] 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).
Sample preparation and Characterization
[0275] Three rifaximin quaternary samples were prepared by spray
drying from methanol. Spray drying parameters are summarized in
Table 26. Table 2 Parameters for Samples Prepared by Spray
Drying
TABLE-US-00027 TABLE 26 Inlet Outlet Spray temp. Inlet temp. temp.
rate (set, Aspirator Pump (measured, (measured, (a) Sample ID
.degree. C.) % % .degree. C.) .degree. C.) mL/min 0.063 wt % 120 95
45-35 120-124 61-49 19 of BHA in the dispersion 0.063 wt % 120 95
45-35 120-121 60-50 20 of BHT in the dispersion 0.094 wt % 120 95
45-35 119-120 60-48 20 of propyl gallate in the dispersion (a):
flow rates are estimated based on initial pump % of 45%.
TABLE-US-00028 TABLE 27 Characterization of Rifaximin Quaternary
Samples Habit/Description Analysis Results (b) orange solids, XRPD
x-ray amorphous irregular mDSC 133.degree. C. (midpoint, T.sub.g)
aggregates, no B/E 0.3 J/g .degree. C. (.DELTA.Cp) orange solids,
XRPD x-ray amorphous irregular mDSC 133.degree. C. (midpoint,
T.sub.g) aggregates, no B/E 0.4 J/g .degree. C. (.DELTA.Cp) orange
solids, XRPD x-ray amorphous irregular mDSC 134.degree. C.
(midpoint, T.sub.g) aggregates, no B/E 0.4 J/g .degree. C.
(.DELTA.Cp)
[0276] A small sub-lot from each of spray dried materials was
visually inspected by PLM and then characterized by XRPD and mDSC.
Characterization results are summarized in Table 27. The prepared
materials are x-ray amorphous, as shown in FIG. 72 the overlay of
XRPD patterns, which agree with their PLM observations.
[0277] In the mDSC, each of material displays a single apparent
T.sub.g in the reversing heat flow signal at approximately
133.degree. C. (FIG. 73, with 0.063 wt % BHA), 133.degree. C. (FIG.
74, with 0.063 wt % BHT), and 134.degree. C. (FIG. 75, with 0.094
wt % PG), which is consistent with the T.sub.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.degree. C.).
Example 9: Rifaximin Solid Dispersions
[0278] This example sets forth exemplary microgranules of rifaximin
and pharmaceutical compositions comprising the same.
[0279] Spray dry dispersion (SDD), solid dispersion, amorphous
solid dispersion are used interchangabley herein to refer to the
rifaximin formulations.
[0280] The complete statement of the components and quantitative
composition of Rifaximin Solid Dispersion Formulation
(Intermediate) is given in Table 28
TABLE-US-00029 TABLE 28 Composition of Rifaximin Solid Dispersion
Formulation Component Quantity (%) Function Rifaximin Drug 42.48
Active Ingredient Substance Hypromellose Acetate 42.48 Solubility
Enhancer Succinate (HPMC-AS) Poloxamer 407 5.04 Surfactant
Croscarmellose 10.00 Dissolution Enhancer Sodium
Composition of Rifaximin Solid Dispersion IR Capsule
TABLE-US-00030 [0281] TABLE 29 Composition of Rifaximin solid
dispersion IR capsule Component Quantity Function Rifaximin solid
dispersion 75 mg-275 mg* Active ingredient (amorphous) Hard Gelatin
capsules 1 unit Capsule Coni-Snap, Size 000, Transparent *Rifaximin
dose equivalent
Description of Manufacturing Process and Process Controls
Manufacturing Process for Rifaximin Solid Dispersion
Formulation
Table 30 Sets Forth the Manufacture of Rifaximin Solid Dispersion
Microgranules
TABLE-US-00031 [0282] TABLE 30 Component Process Methanol Rifaximin
HPMC-AS Poloxamer 407 ##STR00001## Feed Solution ##STR00002##
Croscarmellose Sodium ##STR00003##
Manufacturing Process for Rifaximin Solid Dispersion IR
Capsules
[0283] The manufacturing process the Rifaximin solid dispersion IR
capsules is given in Table 31.
TABLE-US-00032 TABLE 31 Manufacture of Rifaximin solid dispersion
microgranules in IR capsules Component Process Rifaximin solid
dispersion Formulation ##STR00004##
Exemplary spray drying processes are set forth in Table 32.
TABLE-US-00033 TABLE 32 Spray Drying Process: Spray Dryer--PSD 1
Two Fluid Niro Nozzle Nozzle orifice--1 mm Inlet gas
temperature--125 .+-. 3 deg C. Process gas flow (mmH2O)--44
Atomizing gas pressure--1 bar Feed rate--4.7 kg/Hr Outlet
temperature--55 .+-. 3 deg C. Solution temperature--36 deg C. Post
spray drying vacuum dry at 40 deg C. for 48 hrs Micronized
Amorphous Amorphous Micronized Caps API Caps Caps SD caps Tab
Ingredients % g/dose % g/dose % g/dose % g/dose % g/dose Rifaximin
95.5 2.2 47.2 2.2 51.7 2.2 42.47 2.2 50 2.2 Ac-di-sol 4.5 0.1 5
0.23 5 0.21 10.02 0.52 7.5 0.33 Mannitol 47.8 2.23 43.3 1.84 160C
Pluronic 5.04 0.26 188 HPMC AS 42.47 2.2 Avicel 113 26 1.14 Avicel
112 15 0.66 Magnesium 1 0.04 Stearate Cab-o-sil 0.5 0.02 Avicel CL-
611 Mannitol 160C Total 100 2.3 100 4.66 100 4.26 100 5.18 100
4.4
Example 10: Characterization of Drug Product Samples Containing
Rifaximin Solid Dispersion
[0284] 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.
[0285] Three roller compacted material of Amorphous Solid
Dispersion Rifaximin with varying levels (0, 2.5%, 5%) of
croscarmellose sodium were dissolution tested. Results are compared
to dissolution of the rifaximin granules with 10% croscarmellose
sodium.
Dissolution Studies with USP Paddle Method
[0286] 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.degree. C. for 24 hrs.
[0287] At designated time points of 5, 10, 20, 30, 60, 90, 120, 240
and 1440 minutes, aliquots were removed from each of the samples.
Analysis of the date indicates that an increase in rifaximin
concentration is apparent with the rising croscarmellose sodium
level in materials, particularly in the early stage of the
dissolution. After 24 hrs, the rifaximin concentration from
granules containing 5 wt % croscarmellose sodium is similar to
granules with 10 wt % croscarmellose sodium.
Example 11: Characterization of Rifaximin Solid Dispersion Powder
42.48% w/w
[0288] Described herein is the characterization of Rifaximin Solid
Dispersion Powder 42.48% w/w. Dissolution testing was also
performed on the material at pH 6.5 in FaSSIF at 37.degree. C.
[0289] A sample of rifaximin ternary dispersion was characterized
by XRPD, mDSC, TG-IR, SEM and KF.
[0290] X-ray powder diffraction (XRPD) analysis using a method for
Rifaximin Solid Dispersion Powder 42.48% w/w was conducted. The
XRPD pattern by visual inspection is x-ray amorphous with no sharp
peaks (FIG. 76). By mDSC a single apparent T.sub.g is observed from
the step change in the reversing heat flow signal at approximately
134.degree. C. with a heat capacity change at T.sub.g of
approximately 0.36 J/g.degree. C.
[0291] Thermogravimetric analysis coupled with infra-red
spectroscopy (TG-IR) was performed to analyze volatiles generated
upon heating. The total weight loss of sample was approximately 0.4
wt % to 100.degree. C., and a dramatic change in the slope occurs
at approximately 190.degree. 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.degree. C./min. Gram-Schmidt indicates that volatiles
are released upon heating after .about.8 min, and volatiles were
identified as residual methanol from the processing solvent in
spray drying and possible acetic acid from HPMC-AS MG.
[0292] KF analysis indicates that the material contains 1.07 wt %
water [(1.00+1.13)/2=1.07%].
Example 12: Methods for Spray Drying Rifaximin Ternary Dispersion
(50:50 w/w Rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127)
[0293] Provided herein are procedures to spray dry Rifaximin
ternary dispersion (50:50 w/w Rifaximin:HPMC-AS MG with 5.9 wt %
Pluronic F-127).
[0294] Rifaximin ternary dispersions (50:50 w/w Rifaximin:HPMC-AS
MG with 5.9 wt % Pluronic F-127) were prepared from methanol using
Buchi B-290 Mini Spray Dryer in closed mode suitable for processing
organic solvents. Ingredients are listed in Table 33 below:
TABLE-US-00034 TABLE 33 No. Component mg/g Purpose 1 Rifaximin 472
active pharmaceutical ingredient 2 Hydroxypropylmethyl cellulose
472 stabilizing agent acetate succinate (HPMC-AS), Type MG 3
Pluronic F-127 56 wetting agent 4 Methanol -- volatile; removed
during process
[0295] Rifaximin ternary dispersions were prepared by spray drying
in both small scale (.about.1 g API) and large scale (.gtoreq.34 g
API in a single batch).
[0296] For a small-scale sample, rifaximin and then the methanol
were added into a clean flask. The mixture was stirred at ambient
for .about.5 min to give a clear solution. HPMC-AS MG and Pluronic
F-127 were added in succession and the sample was stirred for
.about.1 hr. An orange solution was obtained.
[0297] For a large-scale sample, a solution was prepared at
.about.40.degree. C. Rifaximin and then methanol were added to a
clean flask and the mixture was stirred at .about.40.degree. C. for
.about.5 min until clear. HPMC-AS MG, and then Pluronic F-127 were
added into the rifaximin solution under stirring at
.about.40.degree. C. The sample continued to stir for .about.1.5 hr
to 2 hr at this temperature. A dark red solution was obtained. The
sample was removed from the hot plate and left at ambient to
cool.
[0298] Experimental conditions to prepare Rifaximin ternary
solutions are summarized in Table 34 below:
TABLE-US-00035 TABLE 34 weight Concen- (API/HPMC AS MG/ tration
Solvent Pluronic F127, g) Temperature (g/L) methanol, 100 mL
1.0535/1.0529/0.1249 ambient 22.3 methanol, 1000 mL
34.07/34.07/4.02 ~40.degree. C. 72.2 methanol, 1250 mL
50.34/50.32/5.94 ~40.degree. C. 85.3 methanol, 1250 mL
50.16/50.14/5.92 ~40.degree. C. 85.0 methanol, 1250 mL
50.05/50.06/5.91 ~40.degree. C. 85.0
[0299] During spray drying process, both the small and large scale
rifaximin ternary solutions were kept at ambient temperature. The
Pump % was decreased during process in attempt to control outlet
temperature above 40.degree. C. The operating parameters used for
processing are presented in Table 35 below.
TABLE-US-00036 TABLE 35 Inlet temp. Aspirator Pump Inlet temp.
Outlet temp. Spray rate (b) Description (a) (set, .degree. C.) % %
(measured, .degree. C.) (measured, .degree. C.) mL/min 50:50 120 95
35 120 60-55 10.4 Rifaximin:HPMC-AS 120 95 65-30 120-119 61-42 23
MG 120 95 50-30 120-119 67-43 16 5.9 wt % Pluronic F-127 120 95
50-30 120-119 65-43 16 120 95 50-30 120-119 67-43 16 (a): 50:50 is
approximate ratio of Rifaximin to polymer, by weight; 5.9 wt %
Pluronic is weight fraction to 50:50 Rifaximin:HPMC-AS MG
dispersion. (b): flow rates are estimated. Flow rate for 4103-41-01
was measured at pump 35%; for 4103-56-01 was measured at pump 65%,
while for others were measured at pump 50%.
[0300] Solids recovered after spray drying were dried at 40.degree.
C. under vacuum for 24 hours and then stored at sub-ambient
(freezer) over desiccant.
Example 13. Non-Clinical Data-Form/Formulation Comparison and Dose
Ranging in Dogs
[0301] Described herein is non-clinical data, form/formulation
comparison in dogs and SDD dose ranging in dogs. 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). In order of
decreasing exposure among forms dosed in gelatin capsule
formulation,
SDD>amorphous>iota>micronzed>eta>current crystalline
API. Lower in systemic exposure than all of those are the
micronized suspension formulation (reconstituted powder for oral
suspension) and the current 550 mg Xifaxan tablet. Table 36, below,
shows Pk parameters for dog forms.
TABLE-US-00037 TABLE 36 Tmax Cmax AUCall AUCINF_obs HL_Lambda_z h h
ng/mL h*ng/mL h*ng/mL Eta 9.70 1.5 162.28 434.14 608.14 Iota 6.56 2
276.50 718.23 739.94 Amorphous 5.82 2 1392.17 3907.84 4026.86 API
capsules 5.64 1 44.93 81.20 103.83 SDD 3.16 2 2603.50 9290.71
9308.83 Micronized capsules 8.10 1 473.43 894.65 905.97 Micronized
suspension 5.22 3 0.68 5.11 8.41 Micronized tablets 4.77 5 0.83
6.81 10.20 Nanocrystal capsules 5.01 5 0.99 9.05 8.70
[0302] 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.
Example 14. Human Studies
[0303] Described herein are clinical studies carried in ten male
human subjects. 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. To summarize, there are roughly dose proportional
increases in exposure (C.sub.max and AUC) with increases in dose,
as shown by C.sub.max multiple and AUC multiple columns. T.sub.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. Taken together, 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.
[0304] 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. As noted in FIG.
87, as compared to the PK of rifaximin from the current
formulation, the SDD formulation at the same dose shows an
approximate 6.4-fold increase in C.sub.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.
Example 15. Exemplary Tablet Formulations
[0305] According to certain exemplary embodiments, microgranules,
blends and tablets are formulated as set forth in Table 37,
below
TABLE-US-00038 Rifaximin 5DD Granules % w/w % w/w % w/w % w/w
Component Function (0% CS) (2.5% CS) (5% CS) (10% CSf Rifaximin
Drug 47.2 46.02 44.84 42.48 HPMC-AS Polymer 47.2 46.02 44.84 42.48
Pluronic F-127 Wetting agent 5.6 5.46 5.32 5.04 Croscarmellose Rate
0 2.5 5 10 Na (CS) controlling Total 100 100 100 100
TABLE-US-00039 Granule Blend mg/Tab mg/Tab mg/Tab mg/Tab Roller
Compacted Granules 635.59 652.34 669.05 706.21 Granules Avicel
PH102 Filler 166 149.18 132.52 95.38 Croscarmellose Na Disintegrant
42.5 42.5 42.5 42.5 (Extra-granuler) Cab-O-Sil Glidant 1.7 1.7 1.7
1.7 Magnesium Stearate Lubricant 4.25 4.25 4.25 4.25 Total 850.04
849.97 850.02 850.04
TABLE-US-00040 Overall Rifaximin Tablet Composition % w/w % w/w %
w/w % w/w Component Function (0% CS) (2.5% CS) (5% CS) (10% CS)
Rifaximin Drug 35.29 35.32 35.29 35.29 HPMC-AS Polymer 35.29 35.32
35.29 35.29 Pluronic F-127 Wetting agent 4.19 4.19 4.19 4.19
Croscarmellose Rate 0.00 1.92 3.94 8.31 Na (intra- controlling
granuler} Avicel PH102 Filler 19.53 17.55 15.59 11.22
Croscarmellose Disintegrant 5.00 5.00 5.00 5.00 Na (Extra-
granuler) Cab-O-Sil Glidant 0.20 0.20 0.20 0.20 Magnesium Lubricant
0.50 0.50 0.50 0.50 Stearate Total 100 100 100 100
* * * * *